2003 Book IntegratedNeuroscience PDF

INTEGRATED NEUROSCIENCE
A Clinical Problem Solving Approach

INTEGRATED NEUROSCIENCE
A Clinical Problem Solving Approach
by
Elliott M. Marcus, M.D.

Professor Emeritus of Neurology, University of
Massachusetts School of Medicine; Lecturer in Neurology,
Tufts University School of Medicine; Chairman Emeritus,
Dept. of Neurology, St. Vincent Hospital and Fallon Clinic
and
Stanley Jacobson, Ph.D.

Professor of Anatomy & Cellular Biology
Tufts University Health Science Campus, Boston, M A
With Contributions by Brian Curtis, Ph.D.

University of Illinois School of Medicine at Peoria
Illustrations by Mary Gauthier Delaplane

Boston University School of Medicine
SPRINGER SCIENCE+BUSDSfESS MEDIA, L L C

Library of Congress Cataloging-in-Publication Data
Marcus, Elliott M , 1932-

Integrated neuroscience : a clinical problem solving approach / by Elliott M . Marcus
and Stanley Jacobson ; with contributions by Brian Curtis ; illustrations by Mary
Gauthier Delaplane.
p.; cm.
Includes bibliographical references and index.
Additional material to this book can be downloaded from http://extras.springer.com
ISBN 978-1-4613-5383-6 I S B N 978-1-4615-1077-2 (eBook)
D O I 10.1007/978-1-4615-1077-2
1. Neurosciences. 2. Nervous system—Diseases. I. Jacobson, Stanley, 1937-11. Title.
[DNLM: 1. Nervous System Diseases—diagnosis. 2. Nervous System
Diseases—therapy. 3. Nervous System—anatomy & histology. 4. Nervous System
Physiology. W L 140 M322i 2002]
RC341 .M29 2002
612.8—<lc21 2002073000
Copyright © 2003 by Springer Science+Business M e d i a N e w Y o r k

Originally published by Kluwer Academic Publishers i n 2003
Softcover reprint o f the hardcover 1st edition 2003
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Printed on acid-free paper.

TABLE OF CONTENTS
Preface
Dedication
SECTION I:INTRODUCTION TO BASIC NEUROBIOLOGY
1. Overview of the nervous system 1-21
The neuron 1-1
The central nervous system 1-3
Spinal Cord 1-3
Brain Stem 1-4
Diencephalon 1-6
Cerebrum 1-8
CNS pathways 1-14
Glands associated with the brain 1-17
Blood supply 1-17
Meninges 1-18
Ventricular system 1-19
2. Overview of localization of function and neurological diagnosis 1-28
Where is the disease located? What is the nature of the pathology? 2-1
The neurological history and examination 2-8
Diagnostic studies in Neurology 2- 11
3. Neurocytology 1-31
Neurons, 3-1
Myelin 3-8
Axoplasmic flow 3-10
Synapse 3-14
Supporting Cells ofthe Central Nervous System 3-20
Response of Nervous system to Injury 3-24
Degeneration 3-24
Regeneration 3-26
4. Neuroembryology 1-23
Introduction 4-1
Histogenesis 4-2
Neuronal Necrosis and apoptosis 4-4
Differentiation of CNS areas
Ventricular System 4-5
Spinal Cord 4-5
Brain 4-7
Cranial Nerves 4-10
Cerebral cortex 4-13
Abnormal development 4-16
5.Basic Physiology 1-28
I. Cell physiology 5-1
Cell Membrane 5-1
Channels 5-2
Potassium Channels 5-5
VI
II. Nerve Physiology 5-11

Action Potential 5-10
Sodium Channels 5-11
Saltatory Conduction 5-15
Calcium channels 5-17
SECTION II: REGIONAL APPROACH TO NEUROANATOMY AND LOCALIZATION
6. Skeletal Muscle and Nerve-Muscle Junction 1-25
Gross Structure and function 6-1
Molecular Architecture of Contraction 6-5
Nerve Muscle Junction 6-9
Disease of Muscle 6-12
Muscular Dystrophies 6-12
Myotonic Dystrophy
Congenital Myopathies 6-16
Acquired Disorders of Muscle 6-18
Disease of the Neuromuscular Junction 6-19
7. Spinal Cord: Structure and Physiology 1-27
Anatomy 7-1
Segmental functions 7-4
Reflexes 7-6
Membrane basis of integration 7-9
Stretch receptors 7-12
Lamination in spinal cord gray matter 7-17
Nociception and pain 7-19
Tracts 7-22
descending 7-23
Ascending 7-23
8. Disease of Peripheral Nerve and Nerve Root 1-25
Introduction 8-1
Mononeuropathies 8-4
Polyneuropathies 8-15
Radiculopathies 8-19
9. Clinical Considerations of the Spinal Cord 1-29
Spinal cord compression and transection syndromes 9-1
Extrinsic disorders 9-3
Intrinsic diseases:
Segmental 9-10
System 9-17
Multifocal 9-17
10. Case History Problem Solving Part I: Spinal Cord, Nerve Root 1-9
Lesion Diagrams 10-1
Case Histories 10-2
11. Functional Anatomy of the Brain Stem 1-33
Introduction 11-1
Functional Localization in Coronal Sections of the brain stem 11-2
Vll
Functional Centers in the Brain Stem 11-20

Localization of Disease Processed in the Brain Stem 11-25
Brain Stem and Eye Movements 11-30
12. Cranial Nerves 1-25

Components 12-1
Function of each cranial nerve 12- 23
Effects of Extrinsic Lesions on Cranial Nerves 12-23
Voluntary Control of the Cranial Nerves 12-23
13. Brain Stem: Clinical Considerations 1-21
Differentiation of extrinsic and intrinsic lesions
Extrinsic disorders 13-2
Intrinsic disorders 13-8
Vascular 13-8
Neoplastic 13-19
Multiple Sclerosis 13-19
14. Case History Problem Solving Part II: Brain Stem and Cranial Nerves 1-9
Lesion Diagrams 14-1
Case Histories 14-2
15. Diencephlaon 1-21
introduction 15-1
Nuclei of the thalamus 15-2
Functional organization of Thalamus 15-3
White Matter of the diencephalon 15-7
Relationship between the thalamus and the cerebral cortex 15-8
Subthalamus 15-9
Major Sensory Pathways of the CNS 15-12
SECTION ill: MAJOR SYSTEMS
16. Hypothalamus, Neuroendocrine and Autonomic systems 1-16
Introduction 16-1
Hypothalamus 16-2
Neuroendocrine systems, 16-5
Hormnes produced in by hypothalamus 16-7
Hormones produced by Adenohypophysis 16-7
Hypothalamus and the Autonomic system 16- 10
Hypothalamus and Emotions 16-11
Autonomic Nervous system 16-12
17. Cerebral cortex, Cytoarchitecture, Functional localization 1-28
Anatomy 17-1
Functional localization 17-8
Subcortical white matter 17-16
Neurophysiology and Seizure Correlations 17-24
18. Motor System I: Reflex Activity and Cortical Motor Function 1-26
Reflexes and central pattern generators 18-1
Motor functions of cerebral cortex 18-8
Vlll
Primary Motor Cortex 18-10
Premotor Cortex 18-16
Pyramidal Tract 18-17
Cortical control of eye movements 18- 19
Prefrontal cortex 18-23
Gait disorders in the elderly 18-25
19. Motor System III: Basal Ganglia and Movement Disorders 1-24
Structure, connections, transmitters 19-1
Parkinson's disease 19-7
Choreiform disorders 19-15
Other dyskinesias 19-21
20. Motor System III: Cerebellum and Movement 1-22
Anatomy 20-1
Syndromes of the lobes 20-6
Vascular Syndromes 20-14
Spinocerebellar Degenerations 20-16
Overview of Tremor 20-21
21. Somatosensory Function and the Parietal Lobe 1-10
PostCentral gyrus and Syndromes 21-1
Parietal lobules: Dominant Hemisphere syndromes 21-7
Non-Dominant Hemisphere Syndromes 21-8
22. Limbic System 1-27
Anatomy 22-1
Emotions 22-6
Hippocampus 22-8
Temporal lobe and Seizures 22-14
Prefrontal Cortex and Emotions 22-20
23. Visual system 1-20
The eye 23-1
The retina 23-3
Pathways, Lesions and Syndromes 23-7
Occipital Cortex and Syndromes 23-12
24. Speech, Language, Cerebral Dominance and the Aphasias 1-18
Language dominance and development 24-1
Aphasia:
nnonfluent 24-6
nonfluent 24-9
Visual Agnosia 24-15
Aparaxia 24-17
Nondominant functions 24-17
25. Case History Problem Solving III: Cortical Localization 1-9
Case Histories 25-1
26. Disease of the Cerebral Hemispheres: I: Vascular SYndromes 1-31
Ischemic occlusive 26-1
Embolic disease
IX
Carotid 26-4
Middle Cerebral Artery 26-11
Anterior Cerebral Artery 26-16
Posterior Cerebral Artery 26-18
Emboism 26-19
Intracerebral hemorrhage 26-22
Subarachnoid hemorrhage 26-24
27. Disease of the Cerebral Hemispheres: II. Non Vascular 1-34
Trauma 27-1
Neoplasms 27-7
Infections 27-18
(Non bacterial on CD ROM)
System disorders (CD ROM)
Disorders of myelin (CD ROM)
28. Case History Problem Solving IV: Cerebral Hemispheres 1-11
Lesion diagrams
Case Histories
SECTION IV: COMPLEX FUNCTIONS
29. Alterations in Consciousness: Seizures, Coma, and Sleep 1-28
Basic definitions 29-1
Seizures and Epilepsy 29-3
Focal Epilepsy 29-3
General Epilepsy 29-6
Sleep 29-23
Coma 29-28
30. Learning, Memory, Amnesia, Dementias 1-20
Definitions 30-1
Stages of Human Memory 30-2
Disorders of Recent Memory 30-5
Wernicke'Korsakoff 30-5
Diencephalic Mechanisms 30-6
Hippocampal Lesion 30-7
Progressive Dementia 30-11
31. Case History Problem Solving: V: Part I General Case Histories 1-11
Case Histories 31-1
31 A. Case History Problem Solving V: Part II General Case Histories 1-13
Imaging Correlations Lesion Diagrams 31A-l
Case Histories 31A-7
TABLE OF CONTENTS - CD
ATLAS PDF Format
Brain Stem Myelin Stain Still Born Levels -medulla, pons
Gross Brain Labeled Levels

x
Coronal
Horizontal
MRI from similar levels
Myelin Stained & Labeled Sections
Coronal
Horizontal
Sagittal
Descriptive Atlas of Brain
Spinal Cord Levels; Cervical, Thoracic, Lumbar, Sacral
Brain Stem: Medulla Levels - Junction with spinal cord, Narrow, and Wide,
Pons Levels - Facial Colliculus and Trigeminal Nerve Rootlet
Midbrain Levels - Inferior Colliculus, Superior Colliculus
Thalamus: Levels - Anterior tubercle, Mid-thalamic, Posterior thalamus
Blood Supply Overview
Localization in Cerebrum
Skull
CASES IN LONG FORMAT - PDF Format

Part I Spinal Cord PNS, Embryology 1-35
Part II Brain Stem 1-36
Part III Cerebral Hemispheres: Motor system, Cerebellum Basal Ganglia 72-110
Part IV Cerebrum: Vision, Disease Memory 109 -157
CRANIAL NERVE Illustrations in PDF Format

Illustrations of all the Cranial Nerves from chapter 12 in Color
SPECIAL SENSES
Vestibular & Cochlear Nerves
Visual System - Chapter 23
PATHWAYS IN THE CNS PDF Format
SUPPLEMENTAL
Psychiatric Overview
Survey of Pathology
Preface
INTEGRATED NEUROSCIENCES
This textbook takes as a premise that, in order to make intelligent diagnosis and provide a
rational treatment in disorders of the nervous system, it is necessary to develop the capacity to
answer the basic questions of clinical neurology: (1) Where is the disease process located? (2)
What is the nature of the disease process?
The purpose of this textbook is to enable the medical student to acquire the basic information
of the neurosciences and neurology and most importantly the ability to apply that information to
the solution of clinical problems. The authors also suggest that hospital trips be a part of any
Clinical Neurosciences Course so that the student can put into actual practice what he has learned
in the classroom.
We believe that this textbook will be of value to the student throughout the four years of the
medical school curriculum.
Medical, psychiatry and neurology residents may also find this text of value as an introduction
or review.
It is more true in neurology than in any other system of medicine that a firm knowledge of
basic science material, that is, the anatomy, physiology and pathology of the nervous system,
enables the student and physician to readily arrive at the diagnosis of where the disease process is
located and the nature of the most likely pathology. Subsequently that knowledge may be applied
to problem solving in clinical situations.
The two authors have a long experience in teaching neuroscience courses at the first or second
year medical student level in which clinical information and clinical problem solving are integral
to the course. In addition the first author has developed a case history problem solving seminar in
which all medical students at the University of Massachusetts participate during their clinical
neurology clerkship rotation. This provides the students an opportunity to refresh their problem
solving skills and to review and update that basic science material essential for clinical neurology.
The second author has had extensive experience in utilizing sections of this text in neuroscience
courses for advanced undergraduate college students and ancillary health profession students.
At these several levels, we have observed that this approach reinforces the subject matter
learned by markedly increasing the interest of the students in both basic and clinical science
material.
This text is an updated version of an earlier integrated textbook originally developed by the
authors along with Dr Brian Curtis and published by W. B. Saunders in 1972 as "An Introduction
to the Neurosciences".
The present text provides an updated approach to lesion localization in neurology, utilizing the
techniques of computerized axial tomography (CT scanning), magnetic resonance imaging (MRI)
and magnetic resonance angiography (MRA) that were not available in 1972. In addition, the
other modem clinical techniques of evoked potentials, positron emission tomography (PET),
single photon emission computerized tomography (SPECT) and functional MRI neuroimaging
are discussed and illustrated. Multiple illustrations demonstrating the value of these techniques in
clinical neurology and neuroanatomical localization have been provided. The clinical case
illustrations have been utilized both in the body of the text and in special problem solving
chapters.
An anatomical atlas including MRI images is provided on the accompanying CD.
Neuropathology illustrations in color will also be found on the CD ROM
There are specific review and problem solving chapters with a strong emphasis on clinical case
history problem solving. These clinical problem solving exercises are found as specific chapters
with part I (chapter 10) covering diseases of spinal cord, nerve root, peripheral nerve and muscle,
part II (chapter 14) covering disorders of the brain stem and cranial nerves, part III (chapter 25)
XII
covering cortical localization and part IV (chapter 28) covering diseases of the cerebral
hemispheres with an emphasis on cerebral vascular disease. Finally part V (chapter31) provides
case history problem solving that encompasses all regions of the brain. This final part V, also
provides an appendix in which various clinical neuro images are provided for identification of
location of lesion and of the type pathology. A series of clinical cases is then provided in which
the advanced student is requested to select the appropriate study that was utilized for the
particular cases. Review questions for many of the chapters will be found on the CD ROM.
The case history problem solving exercises are designed to be utilized in weekly case history
problem solving discussion groups, with an instructor, usually a neurologist, neurosurgeon,
neurology or neurosurgical resident. Some medical school courses may provide a physical
diagnosis session devoted to the neurological history and examination.
In Chapter 2 we have included an outline of a complete and abbreviated neurological history
and an overview of the diagnostic studies to be utilized at each level of the neural axis.
The emphasis through out the text however is on clinical diagnosis. What is the diagnosis
before the laboratory and imaging studies were selected. Thus for each of the illustrative case
histories, a provisional clinical diagnostic impression is provided before the results of the
ancillary studies are presented. This should instill in the student the concept that the history and
neurological examination must first be completed, subjected to analysis and a clinical diagnosis
or differential impression established before the ancillary studies are selected. Even in this era of
modem imaging this is the most efficient and effective approach. It has been said that 75% of
neurological diagnosis is dependent on the history. The student should be aware that this stated
clinical diagnostic impression does not always correspond to the final diagnosis. The case
histories, in all instances, present actual patients. It is our impression that such cases are more
instructive and more interesting to students than manufactured, stereotype case histories. Because
these are cases based on clinical reality, at times there are minor deviations from the classic
picture, or multiple disorders are present.
Many of the case history examples have been abbreviated in the text. More complete versions
of these case histories with a commentary providing an analysis of the case will be found on the
CD ROM Bibliographies for the various chapters are provided on the CD-ROM
In general for the problem solving exercises, the cases have been arranged in an increasing
order of difficulty. In a number of instances within the text or within the case history problem
solving exercises, we have chosen to retain case histories from the earlier version of this text. In
some instances, the history and/or findings presented were of a "classical" nature with an
opportunity to study the full natural evolution of disease. In most cases, the location of disease
process was clearly confirmed by surgery and/or by autopsy. This was more likely to be the case
before the development of modem neuro imaging It will also be evident that some cases were
retained because those patients continued to have neurological follow-up allowing an overview of
the long-term course of particular diseases.
A number of the topics are sometimes covered in other courses and this material has therefore
been placed in PDF files on the CD- ROM which accompanies this book. The section of chapter
27 which covers in detail, diffuse disorders of the cerebral hemispheres such as aseptic
meningitis, encephalitis, AIDS ,nutritional and toxic disorders is found in a separate file on the
CD ROM. Summary information, tables and illustrations for these topics will be found in the
textbook. Many of these topics are covered in internal medicine courses.
Supplementary material will also be found for chapter 13. Additional discussion of psychiatric
disorders and of complex partial seizures will be found in a PDF file for chapter 22 on the limbic
system. Additional discussion of the pathophysiology of the epilepsies will be found in a PDF file
for chapter 29 on disorders of consciousness.
It is planned that a web page will be established by the publisher. This will provide a means for
sending additional material to the reader. In addition, information regarding the solution of the
clinical case history problem solving exercises will be provided.
Xlll
Most of the case histories utilized in the chapters and in the problem solving exercises, have
been drawn from the files of Dr. Marcus. For a number of the cases, our associates at the New
England Medical Center, St Vincent Hospital, Fallon Clinic and the University of Massachusetts
School of Medicine either requested our opinion or brought the case to our attention, and
provided information from their case files. These individual neurologists and neurosurgeons are
identified in the specific case histories. Weare also indebted to the many referring physicians of
those institutions. Some of the cases were presented to Dr. Marcus during morning report by
medical house officers at St Vincent Hospital.
In particular, our thanks are due to our associates in Worcester: Drs. Bernard Stone, Alex
Danylevich, Robin Davidson, Harold Wilkinson and Gerry McGillicuddy. Drs. Sandra Horowitz,
Tom Mullins, Steve Donhowe, Martha Fehr, Lawrence Recht, Paula Raven and Carl Rosenberg,
provided additional or followup clinical information from their files for some of the case
histories. Our associates at the New England Medical Center: Drs. John Sullivan, Sam Brendler,
Peter Carney, John Hills, Huntington Porter, Bertram Selverstone, Thomas Twitchell, C W
Watson and Robert Yuan and Thomas Sabin likewise provided access to some of the clinical
material for the earlier version of this text.
Dr Milton Weiner at St Vincent Hospital was particularly helpful in providing many of the
modem neuroradiological images. Dr. Sam Wolpert and Dr Bertram Selverstone provided this
material for the earlier version of the text. The normal MRJ's were provided by Dr Val Runge
from the University of Kentucky Imaging Center. Dr. Anja Bergman (left handed) had the
patience to be our normal case and the images from her brain form the normal MRJ's in the basic
science chapters and atlas.
Dr. Tom Smith and his associates in pathology provided much of the recent neuropathological
material, particularly for the chapters on muscle, peripheral nervous system and dementia. Drs
John Hills and Jose Segarra provided access to neuropathological material for the earlier version
of the text. Critical review of particular chapters was provided by Dr. Sandra Horowitz, and Dr.
David Chad.
Dr Brian Curtis contributed material for inclusion in chapters 5 (cell and nerve physiology), 6
(muscle physiology) 7 (spinal cord physiology) and 23 (the physiology of the visual system). In
addition in the section on special senses found on the CD ROM, Dr Curtis has contributed
material included in the auditory system.
Many of the new anatomical drawings were provided by Mary Gauthier Delaplane now a
medical student at Boston University School of Medicine. Dr Marc Bard provided drawings for
the earlier version of this text while a student at Tufts University School of Medicine. Ms Mary
Gauthier Delaplane and Mr Seymour Levy provided graphic services and assisted in the layout of
text and illustrations. Ms Jane Griesbach and her associates at St. Vincent Hospital provided
photographic prints of many of the neuro images which we had selected. Ms Helen Johnson
provided typographic assistance in the formative stages of this project.
We have continued to utilize or have modified some of the illustrations which were borrowed
with permission from other published sources for the earlier version of this text. We have
attempted to contact these original sources for continued permissions. We will acknowledge
subsequently any sources which have been inadvertently over looked.
In many of the clinical chapters, various medications are discussed . Before utilizing these
medications, the reader should check dosage and indications with other sources and modify as
necessary for the individual patient.
It is with great pleasure we extend our thanks to our publishers and particularly our editor Ms
Joanne Tracy" she kept our noses to the grindstone". Any faults or errors are those of the authors
and we would therefore appreciate any suggestions or comments from our colleagues.
Elliott M. Marcus
Stanley Jacobson
DEDICATION
To our wives andfamilies who demonstrated infinite patience and support.

To our teachers and students.
CHAPTER 1
An Overview of the Central Nervous System
Introduction UNIPOLAR PSEUDOUNIPOLAR BIPOLAR

Human beings come into this world naked
yet equipped with a nervous system that, with
experience, is ready to function in almost any
environment. One word summarizes the func-
tion of the nervous system: response. The central
nervous system (brain and spinal cord) monitors
and controls the entire body by its peripheral
divisions, which are distributed to all the muscles,
organs, and tissues. The brain has an advanta-
geous site in the head and above the neck, which
MULTIPOLAR
1C«I!CUl Q:I1 I'
can move in about a 140-degree arc. Close to the
brain are all of the specialized sense organs,
which permit us to see, smell, taste, and hear our
world.
The central nervous system is protected by
fluid-filled membranes, the meninges, and sur-
rounded by the bony skull and vertebrae. The
blood supply to the brain originates from the first
major arterial branches from the heart insuring Figure 1-1. Types of Neurons and Blia
that over 20% of the entire supply of oxygenated
neurons:
blood flows directly into the brain.
1) Receptors, the ganglia of the spinal dorsal
The Neuron roots and of the cranial nerves,
The basic conducting element in the nervous 2) Effectors, the ventral horn cells, motor
system is the nerve cell, or neuron (Fig. 1-1). A cranial nerve nuclei, and motor division of the
neuron has a cell body, dendrite, and axon. The autonomic nervous system
cell body contains many of the organelles vital to 3) Interneurons, the vast majority of the
maintain the cells structure and function, includ- neurons in the brain.
ing the nucleus and nucleolus, and is considered The cells in the nervous system are classified
the trophic center of the nerve cell. The den- based on their shapes: unipolar, bipolar, and mul-
drites extend from the cell body and increase the tipolar (Table 1-1).
receptive surface of the neuron. The axon leaves The areas in the central nervous system that
the cell body and connects to other cells. Axons contain high numbers of neuronal cell bodies are
are covered by a lipoproteinaceous membrane called gray matter, while the regions that contain
called myelin that insulates the axons from the primarily myelinated axons are called white mat-
fluids in the central nervous system. The site of ter. In the cerebral cortex and cerebellar cortex
contact between the axon of one nerve cell and the gray matter is on the surface and the white
the dendrites and cell body of another neuron is matter inside. In the basal nuclei of the cere-
the synapse (see Chapter 3). brum, diencephalon, and brain stem, the gray
In the central nervous system the nerve cells and white matters are intermingled. In the spinal
are supported by glia and blood vessels; in the cord gray matter is encircled by white matter
peripheral nervous system they are supported by (Fig. 1-2).
satellite cells, fibroblasts, Schwann cells, and Neurons are organized into lamina, nuclei,
blood vessels. There are three basic categories of
1-2 CHAPTER 1
TABLE 1-1. TYPES OF NEURONS IN ganglia in autonomic chains or associated with

THE NERVOUS SYSTEM visceral organs.
The Senses
Cell % of Location in Body Aristotle distinguished five senses: hearing,
Type Nerve Cells sight, smell, taste, and touch. Modern neuro-
Unipolar 0.05 - Dorsal root ganglia of science, however, includes the five special senses
spinal cord (balance, vision, hearing, taste, and smell) and
- Cranial nerve ganglia the four general senses (pain, temperature, touch,
of brain stem and pressure). Humans have evolved a series of
- Mesencephalic nucleus
specialized receptors for each of these different
of CN V in midbrain
sensory functions (Table 1-2).
Bipolar 0.05 - Retina, inner ear, The special sensory apparatuses are found in
and taste buds the head: the eye and its protective coverings and
muscles, the membranous labyrinth in the tem-
Multipolar
- Autonomic ganglia
poral bone for hearing and balance, the nose
-peripheral 0.1
-central 99.S - Brain and spinal cord with olfactory receptors, and the tongue with
taste buds.
The receptors for general sensation (mechani-
coreceptors, nociceptors, and thermoreceptors)
White Matter Grey Matter
are located primarily in the bodies largest organ,
the skin. Certain areas, e.g., the lips, fingers, feet,
and genitalia have a proliferation of the tactile
mechanicoreceptors. Everywhere except on the
soles and palms we have hair, which is an impor-
tant tactile receptor but is continually being
depleted by our concern for grooming. The pain
receptors, or free nerve endings in the skin, are
located throughout the body, but probably more
receptors are in the skin over the face, lips, hands,
and feet then over the rest of the body. As you
review the receptors in Table 1-2, sense on your
own body how the soles are especially good for
feeling pressure and placing the body safely in
light or darkness and the fingers and face are sen-
Figure 1-2. A cross section of the spinal cord showing sitive to touch and temperature.
the gray and while matter. Remember that we have only discussed the
skin receptors so far, which respond to external
and ganglia. Neurons on the cortex of the cere- stimuli. However, there are also similar receptors
brum, cerebellum, and superior coliiculus consist within the respiratory, cardiovascular, endocrine,
of lamina, highly organized layers and columns gastrointestinal, and urogenital systems that
of multipolar neurons with axons that enter and monitor our internal environment.
exit the cortex primarily vertically from the inner
surfaces. Nuclei are found in the brain and spinal Muscles
cord and consist of groupings of neuronal cell Muscles form the bulk of the body and con-
bodies with a common function, e.g., cranial sist of three different functional and histological
nerve nuclei. Axons enter and leave in all direc- entities: skeleta~ smooth, and cardiac. Skeletal
tions. Ganglia are an aggregation of neurons muscles are found in the head, neck, arms, legs,
found in the peripheral nervous system. They and trunk and permit us to undertake voluntary
include unipolar sensory ganglia of the spinal movements. Smooth, or unstriated, muscles are
cord and brain stem and multipolar autonomic found in the viscera, blood vessels, and hair folii-
AN OVERVIEW OF THE CENTRAL NERVOUS SYSTEM 1-3
TABLE 1-2. SENSORY RECEPTORS
Class of Receptor Function Location See Chapter

Chemoreceptor TasteSmell Taste buds on tongueOHactory mucosa In nose 11 22
Mechanlcoreceptor Balance Inner ear (semicircular ducts and vestibule) Vestibular System
Sound Inner ear (cochlea)Skln, muscles, on CD 5
Tactile discrimInation Tendons, joints
and pressure
NOCiceptor Pain Free nerve endings in skin and organs 5
Photoreceptor Vision and color Retina 22
ThermoreceptorTemperatureSkin, tissues, and organs 5
cles. Cardiac muscles form the heart. Each mus- cells whose cell bodies reside in the dorsal root,
cle group has a specialized nerve ending that per- cranial nerve, and visceral ganglia associated with
mits the impulse carried down the motor nerve the spinal cord and brain stem or from the ven-
to contract the muscle through release of a spe- tral horn cells in the spinal cord and the nuclei of
cific chemical. cranial nerves with motor functions in the brain
The general and special sensory receptors in stem.
the skin provide the afferent nerves that carry The peripheral nervous system is divided into
sensory information to the spinal cord and brain. a somatic and a visceral division. The somatic
Often the brain analyzes the sensory input before division innervates the skin and skeletal muscles
the muscles, which are controlled by the efferent in the body. The visceral, or autonomic, division
nerves carrying information from the brain or innervates the cardiac muscles of the heart and
spinal cord, make a response. These integrative the smooth muscles and receptors in the blood
functions of the central nervous system form the vessels and gastrointestinal, respiratory, urogeni-
bulk of this book. tal, and endocrine organs.
The Nervous System The peripheral nervous system is usually
The nervous system consists of the peripher- taught as part of Gross Anatomy, so the student
al and central nervous system. The central ner- may want to review an anatomy text. Chapter 8
vous system (brain and spinal cord) is surround- provides a general introduction to the peripheral
ed by fluid-filled membranes (meninges) and nervous system. The autonomic nervous system
housed in either the skull or vertebrae. In con- is more easily understood if divided into a cran-
trast, the peripheral nervous system does not iosacral (parasympathetic) and thoracolumbar
have a bony covering. Peripheral nerves, mus- (sympathetic) system (see Chapter 16).
cles, and ganglia have axons that connect all tis- CENTRAL NERVOUS SYSTEM
sues and organs in the body.
The sensory information reaches the central Spinal Cord
nervous system through the sensory divisions of The spinal cord gray matter lies in the verte-
the peripheral nerves; movement of the three bral canal from the upper border of the atlas (first
muscle groups in response to sensory informa- cervical vertebrae) to the lower border of the first
tion travels from the central nervous system via lumbar vertebrae in the adult (or third lumbar
motor peripheral nerves. vertebrae in the neonate). The spinal cord has 32
segments divided into five regions based on the
PERIPHERAL NERVOUS SYSTEM area innervated by those segments (Table 1-3).
Peripheral nerves are found everywhere in Each segment has ganglia on the dorsal, or
the body: skin, muscles, organs, and glands. The afferent (sensory), rootlets and a series of ventral,
neuronal processes originate either from nerve or efferent (motor), rootlets (Fig. 1-3). The
1-4 CHAPTERl
Me e!'s
Discs
11'1
canal.
Figure 1-3. Sensory receptors and effectors in the skin.
Although the spinal cord may look some-
largest segments of the spinal cord are seen thing like a continuation of the peripheral ner-
where the segments of the spinal cord innervate vous system, there are more nerve cells and dif-
the upper limb (C5 to Tl) and lower limb (Tl2 ferent supporting cells in the spinal cord than in
to 52). The thoracic levels are narrower. In the the peripheral nervous system. In the spinal cord
center of the spinal cord is the nearly atrophic the gray matter, which is covered by the white
ventricular system of the spinal cord, the spinal mater, is divided into a dorsal sensory horn, ven-
tral motor horn, intermediate zone, and com-
TABLE 1-3. SPINAL CORD FUNCTIONAL COMPONENTS missural region. The largest neuronal cell bodies
are found in the ventral horn (ventral horn cells),
Spinal Cord Functions 01 Segments whose ax:ons form the efferent division of the
Regions peripheral nervous system and innervate the
8 cervical Nerves to the head, neck, skeletal muscles (Fig 1-4).
and upper extremities. The white matter of the spinal cord is divid-
ed into three columns: anterior, posterior, and
12 thoracic Nerves to the thorax, abdomen, lateral. The pathways interconnecting the spinal
and autonomics to these regions. cord and brain are found in these columns.
5 Lumbar Nerves to the skin; upper buttocks; Brain Stem
anterior, medial, and lateral aspect 01 the The brain stem (Figs. 1-5) consists of three
Ihigh and leg; and medial aspect 01 the regions from inferior to superior: medulla, pons,
1001. L1 and L2 lorm sympathetic 10
pelvic plexus. and midbrain. The brain stem is often the hard-
est region of the central nervous system for the
5 Sacral Nerves to the skin and bullocks, posterior student to learn because of the presence of the
surface 01 the thigh and leg, lateral aspect many cranial nerves and associated nuclei. You
01 the loot and to the genitalia via the may initially feel overwhelmed by its intricacy but
pudendal plexus.
be patient. Approach neuroanatomy as you
2 coccygeal Nerves to the skin and muscles would a foreign language: first master the vocab-
01 coccygeal region. ulary and grammar before becoming fluent in
conversation.
Midbrain
Cervical
Pons
---
Thoracic
--- Medu Ia
Lumbar
Sacral
Figure 1-5. The brain stem (posterior view).
Dorsal gray horn Dorsal root
~and ganglion
In order to understand the functions of the
brain stem the student should first appreciate the
extensive distribution of the 12 cranial nerves in
the head, trunk, and abdomen. Cranial nerves
III to XII are located in the brain stem. The key
to identifYing function and dysfunction in the
brain stem is to know what cranial nerve nucleus
lies at each level. Table 1-4 lists the location of
Figure 1-4. Cross sections of the spinal cord with one the cranial nerve nuclei in the appropriate brain
showing the afferent and efferent pathways. stem level. Chapter 11 discusses the nuclei and
tracts of the brain stem in greater detail and
The distinct gray and white matter in the
includes many examples of the consequences of
spinal cord undergoes a slow transition from the
disease in the brain stem.
upper cervical region to the medulla oblongata
until they are completely intermingled. In the TABLE 1·4. LOCATION OF CRANIAL NERVES (CN) IN THE
center of the brain stem, the ventricular system BRAIN STEM TEGMENTUM
enlarges. The region of the brain stem anterior to
the ventricular system is called the tegmentum Medulla eN VIII 10 XII and descending nucleus of eN v
(ventricle floor), and the posterior region is called
the tectum (ventricle roof). The zone that lies on Pons eN vto VII (motor) and chief sensory
nucleus of eN V
the most anterior surface of the medullary
tegmentum is called the basilar zone. Midbrain eN III and IV and mesencephalic nucleus
The relatively new technology of magnetic of eN V
resonance imaging (Fig. 1-21) provides high res-
olution of the nerve tissue and readily differenti-
Since the tegmentum of the brain stem is an
ates gray from white matter. It can demonstrate
especially important region for the student to
many significant cortical and nuclear areas in the
master, we have divided this region bilaterally
normal brain and spinal cord and is ideally suited
into five zones like an apple with the core, the
for diagnosing most neurologic disorders.
center, being the reticular formation and the
1-6 CHAPTER 1
pulp being the surrounding four zones (Table 1- TABLE 1-6. PHYLOGENETIC REGIONS OF
5). CEREBELLAR CORTEX
TABLE 1-5. CONTENTS OF THE ZONES IN THE BRAIN
STEM TEGMENTUM Region Cerebellar Lobes
Archicerebellum Floccular, nodular, and uvula.

Ventricular Motor and sensory cranial nuclei on the floor
(first and Also called vestibulo-cerebellum
of the fourth ventricle or aqueduct.
smallest part) because it receives direct input
Medial Fiber tracts. from CN VIII.
Lateral Ascending and descending fiber tracts Paleocerebellum Vermis and adjacent hemisphere.
and trigeminal nuclei. (old part) Also called spinocerebellum as it
receives spino- and cuneocerebellar
Central Reticular formation with associated fibers.
nuclei and tracts.
Neocerebellum Includes cerebellar hemispheres.
Basilar Descending pathways, from the cerebrum (new and Also called corticocerebellum because
to brain stem (corticobulbar), cerebellum largest part) it receives the bulk of its informafion
(corticopontine), and spinal cord from the cerebral cortex via
(corticospinal). the pontine gray.
ing the functional divisions. Chapter 20 will dis-

Cerebellum (Figs. 1-6) cuss the cerebellum and movement from an inte-
The cerebellum, like the cerebrum, consists grated structural and functional approach.
of gray matter on the surface and white matter In the white matter of the cerebellum are
inside. It attaches to the tegmentum of the found four deep cerebellar nuclei: fastigium, den-
medulla and pons. The cerebellum is divided tatus, emboliformus, and globosus. The cerebel-
into two lateral hemispheres and the midline ver- lar cortex projects onto these nuclei, and then
mis. From the phylogenetic (evolutionary devel- these nuclei project to other areas of brain stem
opment) standpoint there are three regions: or diencephalon.
archicerebellum, paleocerebellum, and neocere- Three major cerebellar peduncles (Table 1-7)
bellum. The cerebellum functions at an uncon- contain the fiber projections to and from the
scious level to permit voluntary motor functions cerebellum. They can be best visualized when the
to occur smoothly and accurately. Alcohol con- cerebellum is separated from the medulla and
sumption and many drugs affect this region and pons by a horizontal section.
temporarily impair, for example, gait and coordi-
Diencephalon
nation. Table 1-6 lists the three phylogenetic
This region, identifiable in the gross brain
regions of the cerebellum useful in understand-
afrer a sagittal section separates the cerebral
TABLE 1-7. CEREBELLAR PEDUNCLES
Floccular-
Nodular
lobe
Peduncle Connections
Inferior Interconnects vermis and flocculonuodular
peduncle with nuclei in medulla and spinal cord
including CN V and VIII.
Middle Receives input from all cerebral cortical

peduncle areas that project onto the pontine gray
and then decussates and enters
cerebellar hemispheres.
Superior Originates from dentate nucleus;

peduncle projects to the midbrain and thalamus.
Figure 1-6. The Cerebellum_
/ypoth
Diencephalon Thai
Spinal
Medulla Cord
Figure 1-7. The diencephalon (insert cross section is at level of dashed line)
hemispheres, lies in the center of the cerebral begin to interpret this data according to the per-
hemispheres. The third ventricle separates the ceptions of the emotional areas in the brain. A
right and left diencephalic masses. Their lateral detailed discussion of the thalamus is found in
margin is the posterior limb of the internal cap- Chapter 15.
sule, and their superior surface is the body of the The epithalamus is a small zone on the
lateral ventricle and the corpus callosum. mediodorsal portion of the diencephalon con-
The diencephalon (Figure 1-7) stands as the sisting of habenular nuclei, with its associative
great way station between the brain stem and pathway, the stria medullaris, and the pineal
cerebral cortex. All the ascending pathways ter- gland; its functions are similar to the hypothala-
minate in the diencephalon before they are pro- mus.
jected onto their respective region of the cerebral The hypothalamus is the smallest subdivision
cortex. The functional organization in the dien- of the diencephalon and is found inferiorly in the
cephalon is the basis for much of the function third ventricle. However, by its controlling the
seen in the cerebrum and also contains the mul- pituitary gland and functioning as the "head gan-
timodal associations that make the cerebrum of glion" in the autonomic nervous system, it may
the human such a potent analyzer (Table 1-8). well be the most important portion and emo-
The dorsal thalamus, sometimes called the tional center of the diencephalon. The hypothal-
thalamus, is the largest subdivision of the dien- amus and the autonomic nervous system are dis-
cephalon, and is divided into three major divi- cussed in Chapter 16.
sions: the anterior, medial, and lateral nuclear The metathalamus in the posterior dien-
masses, each of which has many subdivisions cephalon includes the lateral and medial genicu-
(nuclei). The functions of this region are to inte- late nuclei, which are the thalamic relay nuclei for
grate sensory and motor information and to vision (from cranial nerve II) and audition (from
1-8 CHAPTERl
TABLE 1-8. DIVISIONS OF THE DIENCEPHALON
Division Subnuclei Functions
Dorsal Thalamus Anterior, medial,and lateral Termination of most ascending sensory and motor pathways and
projects onto sensory, motor and associational areas In cerebral cortex
Epithalamus Habenula, stria medullaris, Similar to hypothalamus

and pineal
Hypothalamus Anterior, medial,posterior, Highest subcortical center for emotions as controls autonomies,
and periventricular pineal and pituitary glands
Metathalamus Lateral geniculate and Subcortical centers for sight and sound
medial geniculate
Subthalamus Subthalamus and Subcortical unconscious center for movement

zona incerta
cranial nerve VIII), respectively. in the cerebral hemispheres and surprised by its
The subthalamus, found below the thalamus, weight (about 1500 gm). If you have a series of
consists of the subthalamic nucleus and the zona brains to observe, note that there is a great vari-
incerta with its fiber pathways. It is an important ation in size. Remember that the size of the brain
subcortical motor coordination center between is related to the size of the skeleton, muscles, and
the corpus striatum and the diencephalon. viscera (but not adipose tissue), so a person of
Cerebrum small stature has a proportionally smaller brain.
Since women tend to be smaller than men, a
The cerebrum, forming the bulk of the brain
woman's brain is usually smaller, although this in
and thus of the central nervous system, consists
no way reflects intelligence or abilities.
of a left and a right hemisphere containing the
One of the first clues about the different
cortical gray matter, white matter, and basal
functions in the two cerebral hemispheres was
nuclei (Table 1-9).
observed in stroke victims. Since the left cerebral
The cerebral cortex consists of a corrugated
hemisphere is dominant for language in right-
surface, the gyri, separated by narrow spaces or
handed people (93% of the population), strokes
grooves, the sulci (Figs. 1-8 through 1-17). The
in that hemisphere usually affect speech. Besides
10 to 12 billion cortical neurons are found in the
language, dominance includes functions as
gray cortical mantle.
diverse as initiation of movement and artistic
Students handling a preserved brain are often
abilities.
initially struck by the number of the gyri and sulci
Note that the left hemisphere controls the
right side of the body. This is because the motor
pathway from the left cerebral cortex crosses over
in the transition between the spinal cord and
medulla to the right side of the nervous system (the
fibers from the left cerebral hemisphere cross into
the right side of the spinal cord while fibers from
the right cerebral hemisphere cross into the left
spinal cord). Also the sensory fibers from the
muscles and skin of the right side of the body
cross over to the left side of the nervous system
so the same sides of the body are represented in
the cerebrum. (Dominant hemispheric function
is discussed in Chapter. 21)
Figure 1-8. Major surface topography of the cerebrum.
TABLE 1-9. COMPONENTS OF THE CEREBRUM
Region Components
Cerebral cOrlex Divided into lobes based on the
consists of gray relationship to overlying cranial
matter on the surface bones: frontal, parietal, occipital,
of each hemisphere. temporal, insular, and cingular gyri.
White maller, found Associational bundles

internal to gray (see Table 1-11). Commissural--
maller, forms corpus callosum and anterior
connections within a commissure
hemisphere Subcortical--afferents
(associational) to (corlicopetal) and efferents
the other hemisphere (corlicofugal). Figure 1-9. Lobes of the brain.
(commissural) or
subcortically areas are involved with multimodal integration,
(projectional). which combines sensory and motor with an
Basal nuclei are Corpus striatum (caudate, emotional content to determine how to respond
found deep inside putamen, globus pallidus), in any situation. These emotional or limbic areas
cerebral hemispheres. amygdala, claustrum) occupy much of the temporal and frontal lobes.
(The limbic region denotes the cortical and sub-
CEREBRAL HEMISPHERES cortical brain areas with tracts primarily involved
with emotions, including the cingulate gyrus,
General Features hippocampal formation, parahippocampal gyrus,
The cerebral cortex is divided on its lateral and nuclei in the diencephalon; see Chapter 22).
(convexity), medial, and inferior surface into four Human beings also use language extensively and
lobes, named for the overlying cranial bones: the much of the frontal-parietal-occipital-temporal
frontal, parietal, occipital, and temporal lobes regions that abut the lateral sulcus in the domi-
(Fig. 1-9). Two other important regions in the nant (left) hemisphere undertake these functions.
cerebrum are the insula deep within the lateral Similar areas of the right hemisphere are devoted
sulcus and the cingulate gyrus on the medial sur- to visual-spatial integration
face. Three of the lobes also have poles: the You might wonder just how we have such
frontal, temporal, and occipital pole. detailed information on the organization and
The frontal lobe is separated from the parietal functions of the human nervous system. Much of
lobe by the central sulcus and from the temporal it comes from research on primates or from
lobe by the lateral sulcus. The other lobes can be defects observed in patients after strokes, trauma,
identified (Fig. 1-9) by first drawing a line from tumors, or neurologic diseases like Alzheimer's.l.
the parieto-occipital sulcus on the medial surface Frontal Lobe
of the hemisphere to the preoccipital notch on
Surface Anatomy. On the lateral surface of
the inferior lateral surface of the hemisphere. A
the cerebral hemisphere, Figure 1-10 identifies
line is then extended posteriorly from the lateral
the vertically oriented gyrus; the precentral or
sulcus until it intersects the first line. The parietal
motor strip Then note the three anterior-posteri-
lobe lies above the lateral sulcus and behind the
or oriented gyri, the superior, middle, and inferi-
central sulcus, anterior to the occipital lobe. The
or frontal gyri, which are separated from the pre-
temporal lobe lies below the lateral sulcus anteri-
central gyrus by the precentral sulcus and from
or to the occipital lobe. The occipital lobe is most
each other by the superior and inferior frontal
posteriorly placed.
sulci. The inferior frontal gyrus is further subdi-
FWlctional Localization vided into orbital, triangular, and opercular por-
The cerebral cortex includes motor, sensory, tions. The inferior or orbital surface of the frontal
auditory, and visual regions. In addition, broad lobe is divided into medial and lateral orbital gyri
1-10 CHAPTERl
ry-motor information with emotional responses

and forming judgments.
Parietal Lobe
Surface Anatomy. The parietal lobe Figure
1-11 lies posterior to the frontal lobe and is sep-
arated from it by the central sulcus. In Figure I-
II identifY the superiorly and inferiorly oriented
gyrus of the postcentral gyrus or sensory strip.
Remember that functionally the pre- and post-
central gyrus should be considered a unit, the
sensorimotor strip. The remainder of the parietal
lobe is divided into a superior and inferior pari-
etallobule by the intraparietal sulcus. IdentifY in
Figure 1-11 the postcentral sulcus that separates
Figure 1-10. Frontal lobe of the cerebral cortex.
the postcentral gyrus from the inferior and supe-
and the medially placed gyri rectus. The superior rior parietal lobules. The inferior parietal lobule is
frontal gyrus and precentral gyrus also are found further divided into a supramarginal and angular
on the medial surface of the hemisphere (Fig. 1- gyrus. Can you see these subdivisions that are
13). significant in language functions? The portion of
Functional Localization. IdentifY in Figure the parietal lobe above the lateral sulcus is the
1-10 the motor cortex, precentral gyrus, premo- parietal operculum. The postcentral gyrus and
tor cortex, and the posterior portions of the superior parietal lobule extend onto the medial
superior, middle, and inferior frontal gyri. The surface of the hemisphere.
precentral gyrus, or motor strip, is best consid- Functional Localization. The postcentral
ered as a unit with the postcentral gyrus forming gyrus of the parietal lobe is the sensory cortex
the sensorimotor strip. and postcentral gyri are a functional entity: the
Since humans have superb control of their sensory-motor strip the postcentral gyrus is func-
hands and face, these regions in the cerebral cor- tionally organized like the precentral gyrus,
tex are very highly developed. The somatotopic except it is primarily sensory. The superior pari-
organization places the musculature in the head etallobule is sensory associational. In the hemi-
on the lower third of the motor strip (just above sphere dominant for language the supramarginal
the lateral sulcus); the region controlling the gyrus is the sensory language area concerned
hand, fingers, and distal arm constitutes the mid- with reading and related functions (lesions here
dle third of the motor strip, and the musculature produce aphasia). Deep in the upper bank of the
of the proximal arm, abdomen, and thorax is lateral fissure is the taste region.
controlled by the upper third of the motor strip. Temporal Lobe
The musculature of the lower extremity below Surface Anatomy. The temporal lobe
the knee is controlled by the portion of the (Figure 1-12) is found on the lateral and inferior
motor strip on the medial surface of the hemi- surface of the brain; it lies below the lateral sul-
sphere. cus anterior to the occipital lobe. Deep in the lat-
The corticospinal and corticonuclear path- eral sulcus are seen the transverse gyri ofHeschl.
ways, which control the motor cranial and spinal The fibers from cranial nerve VIII end here. The
nerves, arise primarily from this region. The infe- temporal lobe is divided into six anteroposterior-
rior frontal gyrus pars opercularis and triangu- ly placed gyri: the superior, middle, and inferior
laris, in the hemisphere dominant for language, is temporal gyri on the lateral surface and the
Broca's motor speech area (lesions here produce occipitotemporal, parahippocampal and hip-
nonfluent motor aphasia). The remainder of the pocampal formation on the inferior surface. The
frontal lobe (prefrontal region) is reserved for the hippocampal formation is the most medial and
most complex functions, e.g., integrating senso- inferior cortical structure in the temporal lobe
Postcentral Gyrus (Sensory Stnp)
Supenor Parietal Lobule

Intraparietal Sulcus
:;r.J;::~- Infer or Par eta I Lobule
Angular Gyrus
Supramarginal Gyrus
Figure 1-11. Parietal lobe of the Cerebral Cortex.

and is found adjacent to the inferior hom of the occipital lobe is separated from the parietal lobe
lateral ventricle. by the parieto-occipital sulcus (Fig. 1-13), and
Functional Localization. The. temporal the prominent calcarine sulcus extends from the
lobe is divided into lateral and inferior regions parieto-occipital sulcus to the occipital pole. The
with distinct functions. On the lateral surface in collateral sulcus is identified parallel to and below
the lateral sulcus is the auditory cortex, the trans- the calcarine sulcus. The visual cortex forms the
verse temporal gyri of HescW and adjacent to it upper and lower bank of the calcarine sulcus.
are other language areas related to understanding Functional Localization. The prime func-
speech. The planum temporale, a center for lan- tion of this region is vision. The calcarine, or pri-
guage is revealed when the frontal and parietal mary visual, cortex consists of the cuneus gyrus
operculum are opened in the dominant hemi- above the calcarine sulcus and the lingual gyrus
sphere. This region contains the auditory associ- below the calcarine sulcus. Information from the
ation cortex. The inferior surface of the temporal optic nerve reaches the visual cortex after an ini-
lobe is divided into: (1) associative cortex for tial synapse in the lateral geniculate of the dien-
emotions (especially temporal pole and uncus), cephalon. The remainder of the occipital lobe
(2) new memory (hippocampus), and (3) visual relates to visual association, including identifica-
integration (posterior temporal). tion of visual images (the mental equivalent of a
Occipital Lobe Rolodex), which is vital in language, whether
Surface Anatomy. The occipital lobe is the spoken, written, or read.Cingulate Gyrus
most posteriorly placed lobe (Figure 1-12). On Surface Anatomy. After the cerebral hemi-
its lateral surface the lateral occipital gyri are spheres are separated by sectioning the major
found. If the cerebral hemispheres are separated, white commissure of the cerebrum the corpus
the medial and inferior surface of the occipital callosum, the medial surface of the hemisphere is
lobe can be seen. On the medial surface the seen and the cingulate lobe and the cingulate sul-
1-12 CHAPTERl
Supenor Tempora Gyrus

Middle Temporal Gyrus
Inferior Temporal Gyrus
Figure 1-12, Temporal and occipital lobes of the cerebral cortex.

cus are noted above the corpus callosum. If you temporal lobe.
look carefully you will also note the cingulate Functional Localization. This associative area
lobe is continuous around the back of the corpus in the limbic brain is especially important due to
callosum with the parahippocampal gyrus of the its relationship to the hypothalamus, thalamus,
Figure 1-13. Medial surface of the cerebral hemispheres.

and frontal association cortex. TABLE 1-10. OVERVIEW OF CEREBRAL FUNCTIONS
Insular Gyri
Part Function
This region is found when the lateral sulcus is
opened (Figure 1-14) and is 'seen to contain this Frontal lobe Volitional movement of the muscles
deeply placed island of cerebral cortex. The func- of the body including limbs, face
tions of this region are probably related to the and voice. Judgmental center.
emotional brain.
Parietal lobe Tactile discrimination from !he body,
Cerebral Functions body image, taste, and speech.
Besides all the functions already mentioned,
Occipital lobe Vision (Sight and interpretation).
the cerebral hemispheres also have the memory
stores, which are the foundation for most con- Temporal lobe Emotions and new memories, hearing,
scious and unconscious thought, cultural activity, language, o~aclion, and visual
sexual behavior and all of the other positive or recognnion.
negative traits which make the human being so
Cingulate gyrus Emotions.
distinctive. Each cortical region has a memory
store that permits the function of that region
(Table 1-10). cerebrum. These nuclei are motor associative in
function. They carry on at a subconscious level
Basal Nuclei
until a dysfunction, such as in Parkinson's disease
In a coronal section through a midpoint of or Huntington's chorea occurs. The caudate
the cerebral hemispheres we can identifY laterally nucleus and putamen are more laterally placed
the cerebral cortex, cortical white matter, and surrounding the white matter, which connects
basal nuclei (Figure 1-15). Three important the cortex with the subcortical areas, the internal
nuclear groups deep within the hemispheres are capsule. The caudate nucleus lies medial and dor-
the corpus striatum, claustrum, and amygdala. sal to the thalamus. The functions of these nuclei
This section focuses on the corpus striatum: the will be discussed in further detail in Chapter 20).
caudate nucleus, putamen, and globus pallidus.
They are separated from the cerebral cortex by Cortical White Matter
white matter but are functionally linked to the The axons entering or leaving the cerebral
Central
Sulcus
Insula
Auditory C
Figure 1-14. The insulargyri.
1-14 CHAPTERl
hemispheres form three distinctive groups of of the temporal lobe and the olfactory cortex of
fibers: associational, commissural, and subcorti- the uncus are interconnected by the anterior
cal (Table 1-11). commissure. The hippocampus, an important
area for memory, is also connected by a commis-
TABLE 1-11. WHITE MATTER OF THE sure associated with the fornix.
CEREBRAL HEMISPHERES
Subcortical Fibers. This category of fibers
includes fiber bundles reaching the cortex from
Fiber Category Functional Significance subcortical areas, corticopetal (toward the cor-
Short u Associational fibers form the bulk of tex), and axons leaving the cortex and connect-
(e.g., arcuate) the white mailer in each hemisphere ing to subcortical nuclei, corticofugal (away from
or long and interconnect diverse areas in a the cortex).
associational hemisphere providing the multimodal Corticopetal fibetS are the subcortical affer-
(e.g., uncinate associations essential for cortical ents to each cerebral hemisphere and are primar-
and cingulum) functions. ily from the thalamus. The fibers that enter the
fibers
cerebral cortex arise in functionally diverse sub-
Commissural Commissural fibers interconnect the cortical regions (see Chapter 15, Fig BA&B).
(e.g., corpus left and right cerebral hemispheres Corticofugal fibers from the cerebral hemi-
callosum and and permit the learning and memory sphere project onto subcortical structures includ-
anterior in one hemisphere to be shared ing the basal nuclei, diencephalon, brain stem,
commissure) with the other.
cerebellum, and spinal cord. The major subcorti-
fibers
cal fiber tracts leaving the cerebrum are the cor-
Subcortical Corticofugal fibers provide connections ticospinal, corticonuclear, corticopontine, corti-
(e.g., corticofugal from cortex to diencephalon, brain comesencephalic, and the fornix.
and corticopetal) stem, cerebellum and spinal cord; The internal capsule contains the major
fibers corticopetal fibers provide afferents grouping of corticofugal and corticopetal fibers
to cerebrum from diencephalon.
of the cerebral cortex and consists of an anterior
limb, genu, and posterior limb (Figs. 1-15 and
Associational Fibers. These two types of 15-6). The anterior limb provides fibers to and
fibers (short U and long associational) provide from the frontal lobe. The genu provides fibers
the integrative circuitry for movement, language, to and from the lower part of the frontal and
memory, and emotions. parietal lobes (corticonuclear). The posterior
Commissural Fibers. The bulk of the limb is the largest portion of the internal capsule
frontal, parietal, occipital and temporal lobes are and includes the auditory radiations (auditory
interconnected by the corpus callosum, best seen fibers to the auditory cortex), visual radiations as
in the medial surface of the hemisphere. The cor- well as projections from the sensorimotor cortex
pus callosum consists of a rostrum, genu, body, to the spinal cord, and brain stem (corticospinal,
and splenium (Fig. 1-16). The most rostral part corticonuclear, and corticopontine fibers).
Central Nervous System Pathways
Up to this point, the diverse functional gray
units in the brain and spinal cord have been iden-
tified. In order for the nervous system to work,
an extensive circuitry has been established to
interconnect areas throughout the central ner-
vous system. We have just described the intrinsic
white matter circuitry within the cerebrum: the
associational, commissural, and subcortical
fibers. The subcortical fibers consist of a multi-
tude of axonal pathways that provide afferents to
the cerebrum and efferents from the cerebrum.
Figure 1-15. The basal nuclei (coronal section).
Many names are used for pathways within the functionally significant major circuit in the brain
central nervous system, including fasciculus that provides volitional motor control to the
(bundle), lemniscus (ribbon), peduncle (stalk), hand muscles.
and tract (trail). Many of the pathways also ha~e Motor Control of the Hand
a name that indicates its function (e.g., the OptIC
In order to perform a skilled motor task one
tract connects the eyes and visual regions, the
is dependent on precise sensory input, so we will
corticospinal (Fig 15-13) tract runs from the
first describe the sensory portion of this circuit.
cortex to the spinal cord, and the corticonuclear
Sensory Infonnation from the Hand to
(Fig 15-14) tract connects the cerebral cortex to
the Sensorimotor Cortex. In the sensory sys-
the cranial nerve nuclei). Unfortunately, other
tem three different neuronal groupings are tra-
pathways have more obscure n~es that ~ve. no
versed before the sensory information reaches
clue to function (e.g., the medial longitudinal
the cerebral cortex from the periphery: the pri-
fasciculus, lateral lemniscus, and cerebral pedun-
mary, secondary, and tertiary neurons. The sen-
cle). The major tracts and their role in the central
sory information of importance for preci~e
nervous system are discussed in Chapter 11. For
movement originates from stretch receptors ill
each pathway the student needs to learn the fol-
the muscles, tendons, and joints of the hand and
lowing:
is encoded as electrical impulses that detail the
1. Cells of origin
contraction status of the muscles, tendons, and
2. Location of the tract in the brain
joints. The cells of origin, the primary cell bod-
3. Site of termination of pathway
ies, are in the sensory ganglia attached to the
4. Function.
lowest cervical segments of the spinal cord. The
We are now going to use as an example of
information is carried in by the dendrite of the
circuitry within the central nervous system a
primary sensory cell and its axon enters the cen-
Central Sulcus
Parietooccipital
______ S._UICU~
Anterior Cerebral
Artery
Figure 1-16. Medial surface of a cerebral hemisphere.

1-16 CHAPTER 1
tral nervous system, ascends uncrossed and ipsi- cord ventral horn cells produces lower motor
laterally in the posterior column of the cord until neuron paralysis and atrophy of the muscle and
the medullospinal junction. In the medullospinal decreased reflex tone (Table 1-12).
junction second-order nerve cells appear in the In summary, it takes three orders of sensory
posterior column, the cuneate nucleus. The neurons to provide the information to the cere-
axons from the primary neurons synapse on this bral cortex and two levels of motor neurons to
nucleus. The axons of the second-order axons produce a hand movement in response to the
cross the midline and ascend contralaterally in sensory information. Note that the sensory infor-
one of the major ascending white matter path- mation ascends and crosses over. While the
ways, the medial lemniscus, into the thalamus of motor information descends and crosses back so
the diencephalon where they synapse on the that the same side is represented in the cerebral
third-order neurons in the ventral posterior lateral cortex. Of course, the hand movement also
nucleus, which then send fibers ipsilaterally onto needs a conscious decision to be made, which is
the hand region of the postcentral gyrus. what the cerebral cortex working as a unit does.
Motor Control of the Hand from the The following Case History illustrates
Motor-Sensory Cortex. In the motor system the effects of a lesion in the motor strip on
two distinct neuronal groups are necessary for a movement.
movement: one in the motor cortex of the cere-
TABLE 1-12 EFFECTS OF LESIONS IN THE VOLUNTARY
brum (the upper motor neuron) and the other in UPPER AND LOWER MOTOR PATHWAYS
the spinal cord or brain stem (the lower motor
neuron). Location of Lesion Changes in Reflexes and
Motor control to the hand is carried cen- Muscle Tone
trifugally by the corticospinal pathway. The corti-
cospinal pathway to the hand originates in the 1.Upper Motor Neuron Reflexes Increase +3, +4,
motor cortex of the precentral gyrus and to a Lesion (In cortex or muscles spastic, Sign of
corticospinal pathway) Babinski (extensor planlar
lesser degree in the postcentral gyrus. The fibers
response)
before exiting the gray matter are covered with
myelin and descend on the same side through 2.Lower Molar Neuron Reflexes decrease 10 absenl
the internal capsule, cerebral peduncle, pons, and Lesion (venlral horn cells, 0, + 1, muscles flaccid and
medullary pyramid. The corticospinal fibers cross ventral rools, molar cranial atrophied.
(decussate) to the other side of the brain in the nerve nuclei and rools)
medullospinal junction and enter the lateral col-
umn of the spinal cord. Fibers to the musculature Chapter One, Case History One.
of the hand descend to lower cervical levels and
This 45 year old right handed, married, white
synapse in either the intermediate region of the
female, mother of four children and an artist in
gray matter of the spinal cord or directly on the
sculpture and calligraphy was referred for evalu-
ventral horn cells. The axons from the ventral
ation of progressive weakness of the right lower
horn cell leave the central nervous system and
extremity of two years duration. This weakness
synapse on the motor endplates of the muscles,
was primarily in the foot so that she would stub
which produce the contraction. The actual initi-
the toes and stumble. Because she had experi-
ation of the movement is from the prefrontal and
enced some minor non-specific back pain for a
premotor region of the frontal lobe (see Chapter
number of years, the question of a ruptured lum-
20). Volitional motor control to the muscles
bar disc had been raised as a possible etiology.
controlled by the cranial nerves descend in the
The patient labeled her back pain as "sciatica"
corticonuclear and corticomesencephalic path-
but denied any radiation of the back pain into the
ways; these fibers originate in the lower third of
leg. She had no sensory symptoms, and no blad-
the motor-sensory strip (see Chapter 11).
der symptoms. Six months before the consulta-
Interruption of the corticospinal pathway
tion, the patient had transient mild weakness of
produces upper motor neuron paralysis with
the right leg that lasted a week. The patient
increased reflex tone while injury to the spinal
attributed her symptoms to "menopause" and an MRI of the patient's head was obtained and
depression, and her depression had improved the MRI con-firmed the clinical impression
with replacement estrogen. (Figure 1-17). Meningioma in the right cerebral
Neurological examination revealed the hemisphere,). This tumor was successfully
patient's mental status was normal and the cra- removed by the neurosurgeon with an essential-
nial nerves were all intact. There was a minimal ly complete restoring of function.
drift down of the outstretched right arm, and
there was significant weakness in the right lower
ex-tremity with ankle dorsiflexion and plantar
flexion was less than 30o/00f normal. Inversion at
the ankle was only 10-20% of normal. Toe exten-
sion was 50% of normal. and there was minor
weakness present in the flexors and extensors at
the knee. In walking, the patient had a foot drop
gait and had to over lift the foot to clear the floor.
Examination of the shoes showed greater wear at
the toes of the right shoe with evidence of scuff-
ing of the toe.
The patient's deep tendon stretch reflexes
were increased at the patellar and achilles ten-
dons on the right. In addition reflexes in the
right arm at the biceps, triceps and radial
periosteal were also slightly increased. The plan-
tar response on the right was extensor (sign of
Babinski), and the left was equivocal. All sensory Figure 1-17. Meningioma in the left cerebral
modalities were intact. Scoliosis was present with hemisphere.
local ten-derness over the lumbar, thoracic and
cervical vertebrae, but no tenderness was present Glands Associated with the Brain
over the sciatic and femoral nerves. The brain has two glands, the pituitary and
Comments the pineal, both of which are attached to the
The diagnosis in this case was not certain. It diencephalon. The pituitary (Atlas Figure 4) or
was clear that the symptoms and signs were not hypophysis cerebri is attached to the base of the
related to compression of the lumbar nerve roots hypothalamus. Its functions are related to the
by a ruptured disc. Such a compression (lumbar hypothalamus. The other gland, the pineal
radiculopathy) would have produced a lower (Gross Figure 16), or epiphysis cerebri, is found
motor neuron lesion, a depression of deep ten- in the epithalamus. By its location its functions in
don stretch reflexes, lumbar radicular pain in the relationship to light levels and diurnal cycles
distribution of the sciatic nerve and tenderness would not be apparent.
over the sciatic nerve, and no increase in reflexes Blood Supply to the Brain
in the upper or lower extremities, and no sign of
The central nervous system is dependent on
Babinski.
a continuous supply of enriched, oxygenated
The fact that reflexes were more active in
arterial blood. This has been accomplished by
both upper and lower extremities on the right,
prioritizing blood supply to the brain as regards
with the sign of Babinski on the right, suggested
the initial branches of the major artery that leaves
a pro-cess involving the corticospinal tract. The
the heart, the aorta. Its first major branch is the
fact that the weakness was greatest in the foot
common carotid, which supplies the neck, head,
suggested a meningioma involving the parasagit-
and brain. Its continuation, the subclavian artery,
tal motor cortex where the foot area is repre- also supplies the same three areas (figure 1-18).
sented. With these clinical considerations in mind
Blood flow to the brain is divided into the
1-18 CHAPTERl
of the cerebral hemispheres. The posterior circu-

lation (subclavian, vertebral, basilar, posterior
communicating, and posterior cerebral arteries)
supplies the upper cervical spinal cord, cerebel-
lum, brain stem, most of the diencephalon, and
inferior and posterior surfaces of the temporal
and occipital lobes of the cerebral hemispheres.
At the base of the brain is a set of arteries
called the circle of Willis (Fig. 1-19) that inter-
connects the main portions of the anterior and
posterior circulation by the formation of anterior
and posterior communicating vessels.
Meninges
The brain is enclosed by three membranes,
the dura mater, arachnoid, and pia mater (Fig. 1-
20) (see Chapter 19). These protective fluid-
filled membranes are formed by connective tissue
with embedded nerves, especially in the dura.
The dura mater is the most external membrane,
followed by the arachnoid and finally the pia
Figure 1-18. The blood supply to the brain. mater, which adheres to the central nervous
system.
anterior and posterior circulation. The anterior
circulation (internal carotid, middle cerebral, Dura Mater
anterior communicating, and anterior cerebral The externally located dura mater (figure 1-
arteries) supplies the basal ganglia, anterior dien- 20) consists of a tough fibrous connective tissue.
cephalon, and the lateral surface of the cerebral In the cranial vault the dura forms the perios-
hemispheres, anterior two-thirds of the medial teum on many of the adjacent bones and also
surfaces of the cerebral hemisphere including the forms an inner, or meningeal, portion that com-
corpus callosum and the orbital froOntal surfaces partmentalizes the brain:
Middle Cerebral Artery

Anterior Cerebral Artery
Internal Carotid Artenes
Postenor Communicating Artery
Postenor Cerebral Artery ~.:--.!---"111111
Superior Cerebellar Artery
BaSilar Artery - - - - - - - - - -
Anterior Infenor Cerebellar Artery
Vertebral Artenes --=========~~
Figure 1-19. Arterial circle of Willis.

• Falx cerebri (between the cerebral in the ventricular system into the lower pressure
hemispheres ) of the venous sinuses.
• Tentorium cerebelli (between the Pia Mater
cerebellum and cerebrum) The pia adheres to the entire central nervous
• Falx cerebelli (between the cerebellar system (figure 1-20) and is continuous with the
hemispheres) . perineurium of cranial and spinal nerves. It
The spinal dura forms a sac surrounding the attaches to the blood vessels entering and leaving
spinal cord. The vertebrae have their own perios- the central nervous system and fuses with the
teum. The dural sac attaches at the margin of the dura. The cranial pia actually invests the cere-
foramen magnum to the occipital bone and to brum and cerebellum and extends into the sulci
the inner surface of the second and third cervical and fissures. It also forms the non-neural roof of
vertebrae. It is also continuous with the per- the third ventricle, lateral ventricle, and fourth
ineurium on the spinal nerves and covers the ventricle. The pia forms the denticulate ligaments
filum terminale and becomes continuous with that anchor the spinal cord to the dura between
the periosteum on the coccyx as the coccygeal the exiting spinal nerve rootlets.
ligaments.
Ventricular System (Fig. 1-21)
Arachnoid
As already mentioned, the central nervous
This thin membrane (figure 1-20) is located system is surrounded by cerebrospinal fluid
between the dura and pia. The space between the (CSF). Externally, the meninges, especially the
pia and arachnoid, the subarachnoid, is filled subarachnoid space, contain CSF. Internally, the
with the cerebrospinal fluid (CSF). The arach- ventricular system and cisterns contain CSF, and
noid bridges the cerebral sulci and extends from a specialized structure, the choroid plexus,
the posterior surface of the medulla to the cere- excretes CSF. CSF also is found in the extracellu-
bellum (cisterna magna) and below the neural lar space in the brain.
ending of the spinal cord (lumbar cistern). All of The ventricular system consists of the lateral
these spaces contain CSF. The arachnoid is usu- ventricles, third ventricle, cerebral aqueduct,
ally separated from the dura by the subdural fourth ventricle, and spinal canal.
space. The arachnoid membranes form arach- The lateral ventricles are found within the
noid granulations (Pacchionian bodies) that per- cerebral hemispheres and consist of the body and
mit passage of the CSF from the higher pressure the anterior, posterior, and inferior horns. A hor-
izontal section of the brain shows the relation-
ship between the ventricles and the central ner-
vous system.
The third ventricle lies in the midline
between the left and right diencephalon and is
continuous superiorly with the frontal horn of
the lateral ventricles and inferiorly with the cere-
bral aqueduct. Several recesses associated with
the third ventricle are important radiologic land-
marks: the optic recess, hypophyseal recess, and
pineal recess.
The cerebral aqueduct is the narrow ventricu-
lar space in the center of the midbrain connect-
ing the third and fourth ventricles.
The fourth ventricle forms that portion of
the ventricle seen in pontine and medullary lev-
els. The fourth ventricle is continuous laterally
(foramina of Luschka) and medially (foramen
Magendie) with the subarachnoid space. The
Figure 1-20. The meninges.
1-20 CHAPTERl
Body of Lateral Posterior

Ventri
Ventricle
Intraventricular Foramen
Figure 1-21. The 'Ventricular system.
fourth ventricle is continuous inferiorly with the The narrow spinal canal is seen in the center
narrow central canal of the spinal cord. of the gray commissure of the spinal cord.
Cerebrospinal Fluid. The ventricular system
TABLE 1-12. COMPONENTS OF PLASMA AND is lined by ependymal cells (see Fig. 3-27).
CEREBROSPINAL FLUID Mostly the choroid plexus in the lateral ventri-
cles, third ventricle, and fourth ventricle, which
Plasma (mgldl) C5F (mgldl) are supplied by the choroidal arteries, forms CSF.
Na+ 330 310 It is a clear, colorless, and basic fluid that resem-
bles protein-free plasma but with many signifi-
HC03- 1200 1310 cant differences (Table 1-12). The total volume
ofCSF is usually between 100 and 150 ml. The
CA++ 10-11 5.3
rate of formation is 20 mljhr, or about 500
K+ 17 12 mllday. Excess fluid is readily absorbed into the
venous sinuses through the arachnoid granula-
HP04- 3 1.8 tions because the pressure in the CSF is higher.
0.6
Cerebrospinal Fluid Circulation. CSF
504- 1.9
flows from the lateral ventricles through the
Glucose 100 70 foramen of Monro into the third ventricle and
then throughout the cerebral aqueduct into the
Proleln 8000 45 fourth ventricle. In the fourth ventricle it is con-
tinuous with the subarachnoid space at the fora-
mens of Luschka (lateral) and Magendie
(medial). In the subarachnoid space the fluid
passes into the venous sinuses through the arach-
noid granulations. An excess in CSF produces
hydrocephalus, which is frequendy a consequence
of meningitis or hemorrhage (communicating
hydrocephalus) or a blockage in the ventricular
system (noncommunicating hydrocephalus)
caused by hemorrhage, tumors, or trauma.
CHAPTER 2
An Overview of Localization of Function,
and Neurological Diagnosis
In considering the patient with neurologi- 4. Disturbance of motor control and coordina-
cal disease, accurate diagnosis is required for a tion reflecting -
determination of appropriate therapy and for a) Disease of motor cortex and corticospinal
the establishment of prognosis. Diagnosis in tracts: loss of speed and accuracy.
neurology seeks to answer two essential ques- b) Disease of the premotor and supplemen-
tions. tary motor cortex / motor association cortex
1. Where is the disease (lesion) located? resulting in defects in patterns of movement,
a) Central nervous system versus defects in the visual and tactile control of
b) Peripheral nervous system versus movement. Apraxia occurs and the release of
c) Neuromuscular junction or muscle. automatisms may occur.
2. What is the nature of the pathology? c) Disease of cerebellum - resulting in
defects in coordination of limb and axial move-
PART I: LOCATION ments and of "balance"
AND PATHOLOGY d) Disease of basal ganglia resulting in
A LOCATION OF DISEASE PROCESS: 1) Slowness of movement (akinesia and
SYMPTOMS AND SIGNS bradykinesia)
And/or 2) resting tremor
Patients with neurological disease come to
And/or 3) other dyskinesias
medical attention because of certain symptoms
And/or 4) loss of righting reflexes and
or complaints elicited in the history and certain
"balance"
signs elicited on examination. These symp-
And/or 5) alterations in tone
toms and signs fall into several categories:
5. Disturbance of sensation:
1. Disturbance of mental status (cognitive
a) Primary modalities (pain, touch, vibra-
function) and language function related to
tion) due to disease of peripheral nerve,nerve
disease of cerebral cortex.
root, spinal cord or brain stem or thalamus
2. Disturbance of cranial nerVe function due to
b) Discriminative modalities (position,
direct involvement of cranial nerves or of
sense, graphesthesia, stereognosis, tactile local-
brain stem.
ization, awareness of double simultaneous
3. Disturbance of motor strength reflecting -
stimulation) due to disease of posterior column
a) Disease of the lower motor neuron and
system or cerebral cortex.
the motor unit at the level of the anterior horn
6. Pain including headache - the localiza-
cell, or the nerve root or the peripheral nerve
tion of pain may reflect disease of peripheral or
or the neuromuscular junction or muscle pro-
cranial nerve, nerve root, spinal cord, brain
ducing atrophy of the muscle, flaccid weakness
stem, thalamus, or cortex.
and a variable loss of reflex activity or
b) Severe upper neuron disease due to Meninges and blood vessels about the head
involvement of motor cerebral cortex, or due (intra and extracranial) or increased intracranial
to the involvement of corticospinal tracts at the pressure, or the sinuses or orbits, or dental sys-
level of internal capsule cerebral peduncles, tem, may provide the origin of headache.
basilar pons, medullary pyramids or lateral B. PRELIMINARY
columns of spinal cord producing spastic paral- DIFFERENTIATIONS OF
ysis, increased deep tendon reflexes and a LESION LOCATION:
release of the sign of Babinski.
1. Disease of muscle
2-2 CHAPTER 2
a) Patients manifest lower motor neuron dis- Or 4) generalized type- polyneuropathy.

ease affecting limbs, trunks and in some cases, This is the most common variety.
cranial nerves. In early cases, however, deep c) When motor function is involved the pat-
tendon reflexes are preserved tern is that of a lower motor neuron type lesion
b) Involvement is more often proximal with atrophy, flaccid weakness and loss of reflex
than distal. function.
c) No sensory symptoms or signs are d) When sensory involvement is present;
present. some or all modalities may be involved. In the
d) No long tract motor or sensory involve- generalized type, the sensory pattern may be a
ment is present. glove and stocking type
e) Cognitive function - mental status is nor- e) Cranial nerves may be involved but with-
mal but may be affected in certain hereditary out direct brain stem involvement.
types. £) Long tract finding are not present
£) The major disorders are of two types g) Cognitive function is intact.
1) Hereditary (muscular dystrophy or h) If compression (entrapment) is present,
congenital myopathies) localized pain may be a prominent feature.
2) Acquired (polymyositis or dermato- 4. Nerve root or spinal nerve disease
myositis).
a) Motor and/or sensory function may be
2. Disease of neuromuscular junction involved.
a) Patients manifest intermittent dysfunction b) Pain is often a prominent feature.
of lower motor neuron. c) The symptoms and signs (pain, sensory,
b) Involvement of cranial nerve, motor func- motor and reflex) follow a segmental (der-
tion is prominent, (extraocular muscles and matomal) distribution. Refer to Tables 2-1,
bulbar motor neurons). 2-2,2-3,2-4.
c) If limbs are involved - proximal weakness d) When motor function is involved; the
is often greater than distal weakness. pattern is that of a lower motor neuron type
d) Deep tendon stretch reflexes are lesion as above.
preserved. e) Some or all sensory modalities are
e) No sensory symptoms are present. involved, in a dermatomal pattern. Fig. 2-1.
£) No long tract findings are present. £) Cranial nerves are not involved.
g) Cognitive function is not involved. g) There are no long tract findings - unless,
h) The major disorder is myasthenia gravis, spinal cord is also involved.
an autoimmune disorder in which antibodies h) Cognitive function is not involved.
are produced which block and damage the
acetylcholine receptor. Dermatomal-Radicular Patterns
3. Disease of peripheral nerve Fig 2-2 compares dermatomal and periph-
a) Motor and/or sensory and/or autonom- eral nerve patterns.
ic function are involved. 5. Spinal Cord:
b) The pattern of involvement indicates dis- a) Lesions are either
ease of: 1) Transverse (segmental)
1) A specific peripheral nerve 2) System involving a system of neurons or
(mononeuropathy), e.g., median, ulnar, radial, fibers over many segments
femoral, sciatic, peroneal. 3) Multifocal producing spotty lesions over
Or 2) a plexus, such as brachial, lumbar multiple levels of the CNS
sacral (mononeuropathy)
Transverse lesions
Or 3) multiple peripheral nerves
a) Transverse lesions are usually extrinsic
(mononeuropathy multiplex)
with the implication of compressive mass and
LOCALIZATION OF FUNCTION, AND NEUROLOGICAL DIAGNOSIS 2-3
possible surgical therapy. shoulders and arms "cape like".
b) Four exceptions are intrinsic lesions, f) Transverse lesions producing damage to
which involve multiple adjacent segments: the anterior horn cell or anterior root will pro-
syringomyelia intrinsic spinal cord tumors duce signs of a lower motor neuron lesion at
(astrocytomas and ependymomas), infarcts due the segmental level of involvement.
to occlusion of the inferior spinal artery and Fasciculations, twitching of muscle, will be
transverse myelitis. noted in the Segment involved. Fasciculations
c) Generally both motor and sensory fimc- are indicative of disease of anterior horn cells.
tion are involved. g) Transverse lesions producing damage to
d) When the motor long fiber systems are the posterior root will produce a local segmen-
involved, the signs of an upper motor neuron tal defect at the level of involvement.
lesion are produced: spastic weakness or paral- h) Cranial nerves are not involved.
ysis, increased deep tendon reflexes and the i) Mental status, cognitive fimction, is not
sign of Babinski. involved.
e) Involvement of the long fiber sensory sys-
tems may produce involvement of all modali- Concept of Level of Lesion at
ties below the lesion in a transverse lesion or the Spinal Cord Level
selective involvement of specific sensory In transverse lesions it is then evident that
modalities, e.g., position and vibratory sensa- several determinants of level are considered.
tion when the posterior columns are involved 1. Local anterior root or anterior horn level
and pain and temperature when the lateral indicated by segmental atrophy and segmental
spinothalamic tract is involved. Syringomyelia flaccid weakness.
involves the decussating pain and temperature 2. Local segmental sensory level indicated
fibers in the anterior white commissure of the by segmental (radicular) loss of all modalities of
cervical area producing a selective dissociated sensation.
pain and temperature sensory loss over the 3. Local segmental losses or depression of
TABLE 2-1: SEGMENTAL SENSORY PAmRNS deep tendon reflexes due to loss of the afferent
(FIG. 2-1 AND 2-2. SEE ALSO 8-18 FOR THE or efferent component of the monosynaptic
UPPER EXTREMITY DETAILS) stretch reflex.
4. Segmental long motor tract level with
The following radicular patterns should be compared 10 presence of spastic weakness, increased deep
peripheral nerve panerns tendon reflexes and release of the sign of
Babinski below this level.
C2 posterior scalp versus trigeminal
5. Segmental long sensory tract levels indi-
C6, C7, C8 the hand
cated by posterior column (uncrossed) and lat-
a. C6 thumb and index finger eral spinothalamic (crossed) deficits below this
b. C7 middle finger level.
c. C8 ring and IInle (5th) finger TABLE 2-2: MOTOR - RADICULAR MUSCLE INNERVATIONS
Tl axilla 1. Shoulder muscles, C4, C5, C6
T5, T6 xiphoid process 2. Biceps C5,C6
TlO umbilicus 3. Triceps C6,C7,C8
Tl2 above inguinailigamenl 4. Intrinsic hand muscles C7, C8, Tl
L4 medial calf, palella and laleralthigh 5. Hip nexors, iliopsoas L2, L3, L4
L5 lateral calf and medial fool 6. Quadriceps L2, L3, L4
51 posterior calf and laleral fool 7. Gastrocnemius L5, L5, 51, 52
52 posterior Ihigh 8. Dorsinexors of fool (peroneal) L4, L5, SI
53, 4, 5- perianal areas. * Bold indicales major innervations
2-4 CHAPTER 2
Figure 2-1 JJmnatome clmrts of the human body determined by the pattern of hypalgesitl following rupture of lin
intervertebrlll disk. From Keeglln, IJ., lind Gllrrett, RD.: Anllt. Re&., 102-411, lind 1948 (Wiley)
TABLE 2-3: DEEP TENDON STRETCH REFLEXES 6. Brain Stem

1. Jaw cranial nerve V- pons a) Cranial nerves findings are present with
2. Biceps C5,C6 the specific lower motor neuron or sensory
3. Triceps C6, e7, C8 deficits dependent on the level of in v 0 I v e -
ment.
4. Brachioradlalis C5, C6, C7
(Radial periosteal) 1) CN 12, 11, 10, 9 due to medullary
5. Fingers- C7, C8, Tl
lesions
2) CN 8, 7 and 6 due to pontomedullary
6. Patellar- L2, L3, L4
involvement
7. Achilles L4, L5, Sl, S2
3) Trigeminal - 5 midpontine
* Bold Indicates major innervations
4) CN 3 and 4- midbrain
TABLE 2-4: SUPERFICIAL REFLEXES
1. Upper abdomen - T7, T8, T9, Tl 0 b) Selective involvement of pain in the
trigeminal distribution may be present due to
2. Lower abdomen - T10, Tll, Tl2
involvement of the descending spinal tract and
3. Plantar Sl, S2 nucleus of the 5th nerve.
c) Long tract motor findings may be present
6. Segmental autonomic level deficits in which are unilateral or more often bilateral.
autonomic function below this level.
PERIPHERAL NERVES SPINAL (RADICULAR)

DERMATOMES
TAIGEMINAL -f 0PHTHALIoIIC
MAXILLARY 8R.
MANDIBULAR
CERVICAL CUTANEOUS
AXILLARY
INTERCOSTOBRACHiAl
MEDIAL BRACHIAL CUT._-...,.......;+1\
POST. BRACH IAL CUT.
LAT. THORACIC RAMI
1oIfD. AHTEIlRACHIAL WI .. -t--~
LUWeOINGUI
IoIEOIAN----.L.j,HiIJ
LATERAL FEMORAL CU1.---.......-
08TURATOA.---~~~
ANTE RlOR FE IIOIIAL CU1~ --""""I\t'"'""
COIrlIrlON PERONEAL
SAPHENOUS
SUPERFICIAL PE"ON"AL--.,-
Figure 2-2 Comparison of radieular (dermatome or segmental) and peripheral nerve innervation.
A.) anterior
2-6 CHAPTER 2
~ (RADICULAR) PERIPHERAL NERVES

CEAW.TOMES
LATERAL THORACIC RMII
ILIOHYPCMIAITRIC
\-1-o+-i--1IED. AHttIllUCHlAi. CUT.
POST. AHttllRACMlAl CU't
tlR. OF "AO... '
SCULOGUlMEOUS
(lAT. ANTEBRACHIAL CUT.)
1+-i~-JI-O'TUItATOR
-+-COIoIIIDIN I'EIIONEAL N.
FiDuf'e 2-2 Comparison of radicular (dermtltome or segmentfll) find peripheml nerJle innerJlflnon.
B.)posterWrl1iew
d) Long tract sensory findings may be pre- the speech areas.
sent which may be selective, that is dissociated d) Cranial nerve involvement of a lower
e.g., pain and temperature only when unilater- motor neuron type does not occur.
al or bilateral and nonselective. Mediallemnis- Corticobulbar involvement may produce
cus or lateral spinothalamic may be involved. supranuclear weakness of the lower half of the
e) Cerebellar pathways may be involved pro- face. Bilateral corticobulbar damage may pro-
ducing alteration in balance, stance, gait and duce a pseudobulbar state involving cranial
appendicular coordination. nerves 5; 7, 9,10, 11and 12.This is manifested
f) In general, mental status, cognitive func- by a hyperactive jaw jerk, spastic speech and
tion is well preserved although level of con- emotional lability.
sciousness may be depressed. e) Changes in personality and behavior are
g) Particular combinations of cranial nerve indicative of disease involving the cerebral cor-
finding ± long tract findings are diagnostic. tex particularly the frontal and temporal lobes.
1) The jugular foramen syndrome (cranial f) Changes in immediate (working) memo-
nerve 9,10,11). ry often reflect neocortical pathology particu-
2) The cerebellar pontine angle syndrome: larly involving the prefrontal areas. Changes in
(cranial nerves 7 (facial) 8 (auditory and the ability to consolidate new learning may
vestibular) and cerebellum plus or minus CN reflect limbic pathology (medial temporal and
5,9, 10, 11. medial thalamus).
3) The lateral medullary syndrome (lateral
8. Basal Ganglia
medullary tegmentum) "Wallenberg's syn-
drome", or syndrome of the posterior inferior a) There is no direct involvement of the
cerebellar artery. lower motor neuron.
4) Ipsilateral peripheral facial weakness and b) Major upper motor neuron descending
contralateral hemiplegia. motor pathways such as the pyramidal tract are
5) Weber's syndrome: Ipsilateral third not affected.
nerve and contralateral hemiplegia. c) A modulating circuit is dysfunctional.
h) Vestibular + cochlear symptoms are This dysfunction is manifested by alterations in
indicative of cranial nerve 8 disease at the level motor function characterized by the following
of the labyrinth or of the cranial nerve 8. If findings:
other symptoms are present, brain stem may be 1) A lack of movement, akinesia or slow-
involved. ness of movement, bradykinesia
2) Excessive movement: tremor or
7. Cerebral Cortex
dyskinesia
a) Focal (partial) seizures are always indica-
3) Increased resistance to passive motor:
tive of disease involving the cerebral cortex.
rigidity
The specific clinical phenomena of the seizure
4) Alteration in righting reflexes affecting
will depend on the location of the lesion.
gait and balance
Rapid secondary generalization of the seizure
d) No sensory symptoms are present
discharge may obscure the origin.
e) No direct involvement of cranial nerve
b) Lateralized deficits in terms of upper
function is present but the motor effects
motor neuron findings and cortical sensory
described above may alter cranial nerve
deficits (somatosensory or visual) may occur
function
based on the location of the lesion.
f) Cognitive function is usually not directly
c) Aphasia is always indicative of involve-
involved although, many diseases that affect
ment of the dominant (usually left) hemi-
the basal ganglia also affect cerebral cortex or
sphere, in particular involvement of the speech
frontal basal ganglia connections and thus are
areas or of the fiber systems inter-connecting
2-8 CHAPTER 2
associated with changes in mental status. b. At the levd of the neuromuscular junc-
tion, the most common disorder is myasthenia
9. The Cerebellum gravis, an autoimmune disorder in which an
a) Lower motor neuron function is not antibody to the acetylcholine receptor blocks
affected. and damages the postsynaptic receptor. Other
b) Upper motor neuron function in terms of disorders, involve a paraneoplastic related anti-
long tracts is not affected. body to calcium channels, which alters the
c) A modulating circuit is dysfunctional. The release of acetylcholine from the pre synaptic
clinical effects of this dysfunction depend on sites. Botulinum toxin produced by an anaero-
the area of cerebellum involved. bic bacterium also alters transmission at the
l) Lateral cerebellar hemisphere relates to neuromuscular junction.
the ipsilateral arm and leg. Deficits produce c. At the levd of peripheral nerve, the
dysmetria of the arms and legs: intention most common causes of a mononeuropathy
tremor, finger-to-nose and heel-to-shin deficits are direct trauma and the entrapment
and an incoordination of movements. syndromes in which compression of a nerve
2) Midline cerebellum relates to the axis of occurs. Vascular disease may also produce a
the body. Deficits produce ataxia of trunk. mononeuropathy. As regards polyneuro-
3) Floccular nodular (archicerebellum) pathies, the most common causes are diabetes
relates to the vestibular system. Deficits pro- mellitus, and B vitamin nutritional deficiencies,
duce a loss of balance in sitting and standing followed by toxic and hereditary disorders. In
d) Sensory function of a conscious nature is parts of the world the infectious disorder lep-
intact. rosy is the most common cause of a multiple
e) Cranial nerve function is generally intact, mononeuropathy or of a poly neuropathy.
although speech and eye movement are altered d. At the levd of the nerve root, the most
by cerebellar dysfunction. At times vestibular common disorder is compression due to rup-
function may be altered tured disks or to the osteophytes of the degen-
f) Certain aspects of cognitive function and erative disk disorder cervical spondylosis.
motor learning are altered. Tumors (Schwannomas) may also arise from
nerve roots and peripheral nerve and in the
C. THE NATURE OF process compress the nerves.
THE PATHOLOGY: e. At the levd of the spinal cord extrinsic
1. The Concept Of Extrinsic Versus disorders are the more common disorders. The
Intrinsic: Extrinsic diseases are usually focal mass may be a ruptured disc, a tumor in the
mass lesions compressing the spinal cord or epidural or intradural space, collapsed verte-
brain. Intrinsic disorders arise within the sub- brae due to metastatic disease, trauma or infec-
stance of the nervous system. Disorders of tion, or an infectious process such as an epidur-
muscle, and neuromuscular junction are usual- al empyema. Intrinsic processes may be focal,
ly not due to compressive disorders. system disorders or multifocal disorders.
2. The common pathological processes Examples of focal intrinsic processes are infarcts
related to the site of lesion. due to anterior spinal artery occlusion, intrinsic
a. At the levd of muscle, the common tumors such as gliomas, or a focal enlarging
processes are (l) degenerative disorders on a cyst as in syringomyelia or transverse myelitis.
genetic basis: the dystrophies primarily occur- Examples of system disorders are amyotrophic
ring in children (2) genetic congenital lateral sclerosis due to the degeneration of the
myopathies, (3) the metabolic myopathies, motor neuron in the anterior horn or posterior
often with a genetic basis, (4) the acquired lateral column disease of vitamin Bl2 deficien-
inflammatory myopathies related to auto cy. An example of a multifocal disorder is mul-
immune disorders. tiple sclerosis, which is the most frequent of the
intrinsic disorders. adult, intrinsic tumors of the glial series are a
f. At the level of the brain stem, most dis- major consideration. In the older patient,
orders are intrinsic. The most frequent disor- ischemic-occlusive vascular disease is a major
der is vascular disease. The major type is neuropathologic process. In the elderly patient,
ischemic occlusive involving the vertebral- the degenerative disorder, Alzheimer's disease
basilar arteries producing infarcts. Other intrin- afflicts a significant proportion of the popula-
sic disorders include tumors, hemorrhage, and tion. In all disorders involving the cerebral cor-
demyelinating disease. However the brain tex, recurrent seizures (epilepsy) are major
stem may be affected by extrinsic processes considerations at all ages. Extrinsic disorders
arising in cerebellum (tumors and hemor- include the previously mentioned head trauma
rhages) or by tumors arising from the Schwann and the extrinsic tumor, the meningioma.
cells in cranial nerves (primarily the vestibular
nerve). Part IT - Neurological History and
g. At the level of the cerebellwn most dis- Examination will be found on
orders are intrinsic. Infarcts secondary to CD-ROM.
occlusive disease are the most common. Other
Part ill - Diagnostic Studies in
disorders are due to hemorrhage, neoplasms,
Neurology will be found on
degenerative disease and multiple sclerosis. In
CD-ROM.
infunts and children, tumors are the most com-
mon disorder.
PART 2: THE NEUROLOGICAL
h. At the level of the diencephalon, most
HISTORY AND EXAMINATION
disorders are intrinsic with the exception of
The neurological examination provides a
twnors arising from the pituitary and sec-
means for the systematic analysis of symptoms
ondarily compressing the hypothalamus. The
and signs.
most common intrinsic disorder is vascular dis-
ease (infarcts and hemorrhage). Other disor- I. AN OUTLINE OF THE COMPLETE
ders are gliomas, and nutritional (Wernicke's NEUROLOGICAL HISTORY &
encephalopathy due to thiamine deficiency). In EXAMINATION
children neoplasms are the most common dis- [Note - that for each patient the total his-
order. tory and examination may be tailored so that
i. At the level of the basal ganglia, all dis- for some cases abbreviated evaluations may be
orders to be considered are intrinsic with carried out in a particular area.]
degenerations being the most common HISTORY: The importance of the
(Parkinson's and Huntington's disease). detailed history cannot be overemphasized,
However, the basal ganglia are also the most 75% of neurological diagnosis is dependent on
frequent site of intracerebral hemorrhage relat- the history.
ed to the penetrating branches of the middle 1. Demographic Data: Age, sex, marital
cerebral artery. These lenticulostriate branches status, handedness, occupation, level of educa-
are also subject to occlusion producing infarct tion.
involving the internal capsule and basal ganglia. 2. Chief Complaint.
j. At the level of cerebral cortex and sub-
3. Present Illness.
cortical white matter, the common patho-
logical processes are intrinsic and relate to 4. Review of Symptoms Relevant to the
the age of the patient. In infant's hydro- Neurological System:
cephalus or congenital malformations or a. Mental Status: Orientation, memory, per-
migration disorders may affect cortical func- sonality changes, mood changes, delusions,
tion. In children, adolescents and young hallucinations, (see below regarding witnesses)
adults, trauma is a major consideration. In the b. Language function.
2-10 CHAPTER 2
c. Loss of consciousness: Syncope, Seizures: d. Memory:

Details as to the onset, course, duration, con- 1. Immediate recall (working memory):
fusion or other neurological symptom before, digit span and repetition of words.
during and after. If relevant may need to obtain 2. New learning - at times, referred to as
information from wimesses and/or relatives, short term or test of labile phase of remote
friends, etc. memory: delayed recall 5 out of 5 in 5 minutes
d. Alterations in alermess and sleep patterns. or 3 out of 3 in three minutes.
e. Cranial Nerves: 3. Remote recall: date of birth, marriage,
I - Anosmia names and ages of children, siblings, parents,
II - Blurring or loss of or distortion of etc.
vision e. Insight as regards illness, etc.
III, IV, VI - Double vision £ Abstract reasoning -
V - Numbness or pain in the face 1. Similarities: concrete versus abstract
VII - Weakness of the face, alterations in 2. Proverb interpretation: concrete or
taste abstract
VIII - Decrease, loss of or distortion of g. Calculations: simple additions, subtrac-
hearing, Tinnitus, vertigo, dizziness + nausea tions, problems and serial 7s subtractions.
& vomiting h. Language and Related Functions:
IX, X: Dysarthria: (change in voice, 1. Fluency
hoarseness); dysphagia (Difficulty in swallow- 2. Naming of objects
ing). 3. Repetitions
XII - Alterations in tongue movements 4. Ability to follow spoken and written
£ Motor system: Weakness, incoordination, commands
clumsiness, unsteadiness - in sitting, standing, 5. Reading
walking 6. Writing
g. Alterations in sensation: paresthesias, 7. Arithmetic
dysesthesias, tingling, and numbness 8. Drawing: constructions
h. Strokes 9. Apraxia testing
i. Headaches 10. Left right orientation
j. Trauma to head, neck, back or extremities. 11. Recognition of objects, pictures
k. Bladder and bowel function: inconti- i. Mood, affect, how appropriate, level of
nence, frequency, and spasticity. anxiety
5. General Medical History j. Observed hallucinations and perceptual
a. System Review distortions
b. Hospital admissions 2. Observed seizure activity describe in detail
c. Surgical history 3. Cranial Nerves:
6. Family History a. I: Sense of smell
7. Social History b. II: Fundi, visual fields, blind spot, acuity
c. III, IV, VI:
EXAMINATION: 1. Pupillary responses: light, accommoda-
General Physical Examination to include tion direct and consensual
vital signs 2. Extraocular movements
Neurological Examination 3. Nystagmus: spontaneous, induced by
1. Mental Status eye movement, caloric stimulation, Hallpike
a. Level of consciousness: alertness maneuvers
b. Orientation: time, place and person d.V:
c. Information: presidents, capitals, historical 1. Sensation: Touch and pain
or local or sports or political information. 2. Jaw movement
3. Jaw jerk b. Superficial
e.Vll: 1. Abdominal
1. Facial movements: upper and lower face 2. Plantar: Sign of Babinski and associated
2. Labial sounds - dysarthria reflexes
3. Taste c. Frontal release signs: Grasp, suck,
£ VIII: Auditory tested. Vestibular ifindicat- palmomental
ed as in coma, test calorks. 6. Sensation:
1. Hearing: Whisper perception; a. Primary: pain, touch vibration
watch tick b. Cortical modalities: position, double
2. Weber, Rinne simultaneous stimulation, tactile
g.IX,X: localization, stereognosis, graphesthesia.
1. Movement of palate 7. Meningeal Irritation Signs:
2. Sensation of pharynx Kernig's and Brudzinski
3. Gag reflex 8. Vascular:
4. Guttural sounds dysarthria a. Carotid and temporal artery pulses and
h. XI: Sternocleidomastoids, trapezii: auscultation
strength against resistance b. Subclavian pulses and auscultation
i. XII: Tongue c. Radial pulses and lower extremities (per-
1. protrusion, lateral movements, oneal, and posterior tibials)
fasciculations and fibrillations d. Bruits over head, orbits, vessels
2.Iingual sounds - dysarthria 9. Cervical Spine:
4. Motor System: a. Range of motion: flexion, extension, rota-
a. Atrophy and fasciculations tion, and lateral displacements.
b. Motor power: Grade 0-5: Note pattern of b. Local tenderness
weakness: hemiparesis, paraparesis, distal, c. Supraclavicular tenderness
proximal 10. Thoracic Spine: Local tenderness
c. Tone: Flaccid, spastic, and rigid ll. Lumbar Spine:
d. Posture: sitting, standing with eyes open a. Local tenderness
and closed (Romberg test) b. Mobility for flexion and lateral motion
e. Gait: c. Sciatic and femoral tenderness
1. Standard d. Straight-leg-raising and reverse straight-
2. Heel to toe, tandem gait leg-raising
3. Accessory movements 12. Peripheral Nerves: Palpation + tap
£ Coordination: a. Occipital at occipital notch
1. Finger to finger to nose b. Dlnar at olecranon groove
2. Heel to shin c. Median at carpal tunnel
3. Rapid alternating hand movement d. Sciatic at sciatic notch
4. Foot tapping e. Femoral at femoral canal
g. Spontaneous movements: f. Peroneal at fibular head
1. Fasciculations g. Post tibial behind medial malleolus
2. Tremor - at rest; maintained posture, or Note - tenderness, enlargement, Tinel's sign
on movement (tingling on palpation)
3. Chorea, athetosis, myoclonus 13. Examination of head, face, tongue, and
4. Dystonia mouth for bruises, lacerations, hematomas of
5. Reflexes: the scalp.
a. Deep tendon stretch: Grade 0-4 at biceps, 14. Examination of the limbs and body for
triceps, brachioradialis, patella and Achilles. bruises and malformations: Cafe au lait spots,
vascular nevi, etc.
2-12 CHAPTER 2
Clinical Impression: points

Anatomical location of lesion 1. What is today's date? Month_
Differential Diagnosis as regards pathology Date_ Year_
Laboratory Data already available: if relevant Day of week?_ Season_ _(5)
Conclusion and plan of diagnostic and ther-
2. Where are we? City:_ County:_
apeutic management
State_ Hospital_ Floor_ _ (5)
II: ABBREVIATED NEUROLOGICAL 3. Repeat after me: ball - flag - tree
EXAMINATION Record the number recited initially _ (3)
A Mental Status and Language Function: Repeat them up to six times
1. Alertness for registration
2. Orientation 4. Subtract 7 from 100: 93 - 86 -
3. Delayed recall (5/5 objects in 5 minutes) 79 - 72 - 65
4. Naming of 5 objects Spell WORLD forward and
5. Repetitions: "No US, ands or buts" backward: D - L- R- 0 - W
B. Cranial Nerves II - XII: Fundi, pupils, (Write the greater of these
EOM's, facial movement and sensation, tongue two scores to the right) _(5)
move and gag, shoulder shrug and and SCM 5. Repeat the three words:
on head rotation ball - flag - tree _(3)
C. Motor System:
1. Resistance against force at shoulder abduc- 6. Read and obey ("close your eyes")
(1)
tors, biceps, triceps, wrist extensors, hand grip
and finger abductors; hip flexors, quadriceps, 7. Name these items (pen and watch)
hamstrings, ankle and toe dorsiflexors (2)
2. Walk. a routine gait; walk. a tandem gait; 8. Repeat after me
walk. on toes and heels ("no us and or buts") _(1)
3. Stand on narrow base, eyes open, eyes
9. Take the piece of paper in your
closed
right hand, fold it in half, and
4. Other cerebellar - finger to nose, alternat-
put it on the floor. _ (3)
ing hand motions
5. Any atrophy or fasciculations 10. Write a sentence:
6.Any tremor or other extra movements _(1)
noted 11. Copy this design:
D. Reflexes:
1. Deep tendon reflexes at biceps, triceps,
brachioradialis, patella and Achilles
2. Plantar responses
E. Sensation:
1. Pain and touch sensation - extremities, _(1)
shoulders, body Total Score:
2. Vibration and position at toes _(30)
ill: Mini-Mental State Examination PART 3: DIAGNOSTIC STUDIES
(MMSE) IN NEUROLOGY
(After FOlstein, M.S., Folstein, S.B., and Specific laboratory studies are appropriate
McHugh, P.R. "Mini-Mental State". A in providing information about disease affect-
Practical Method for Grading the Cognitive ing particular levels of the nervous system or
State of Patients for the Clinician. about particular types of pathology.
J.Psychiatr.Res, 12:189-198, 1975)
A. Muscle and Nerve (fig 2-3): involvement of vertebrae, fractures of vertebral
1. EMG: Small needles are inserted into elements and osteophyte (spur) formation.
muscle to record the electrical activity of motor Neurofibromas may widen the neural forami-
units. Under normal circumstances, at rest, no na. Intrinsic tumors and syringomyelia may
activity is recorded. With voluntary contrac- produce an increase in the diameter of the ver-
tion, a significant number of units are record- tebral canal.
ed. These units have a range of amplitude and 2. Computerized axial tomography
duration. In disease of muscle, voluntary con- scanning (CT scan) is now the most fre-
traction results in motor units of small ampli- quently employed technique in neurology but
tude and altered duration. In contrast when is less frequently utilized for spinal cord.
the anterior horn cell or peripheral nerve has A computer is utilized to determine the dif-
been damaged resulting in denervation, spon- ferential attenuation of X-rays by the various
taneous activity is present at rest. This consists tissues such as gray vs. white matter vs. blood
of small amplitude fibrillations (the contraction vs CSF vs bone based on the differential con-
of single muscle fibers) and fasciculations cor- tent of water. An X-ray beam is passed through
responding to the contraction of all the fibers the tissues from multiple sites along a specific
in a motor unit innervated by a single anterior plane of section. The computer generates a
horn cell. series of slices usually in the horizontal plane.
2. Nerve Conduction Velocity: Contrast enhancement is the technique of
Stimulation of nerves at two points along the administering radio-opaque dyes intravenous-
nerve will allow the calculation of speed of con- ly of the types employed in intravenous pyelo-
duction over specific segments. A specific site grams. These dyes do not usually cross the
of block may be determined with normal con- blood brain barrier. When this barrier is dam-
duction above and delayed conduction below aged as in tumors, brain abscesses, arteriove-
that site, e.g. median nerve at carpal tunnel or nous malformation, increased density will
ulnar nerve at olecranon groove of the elbow. occur around or within the lesion. The barrier
Alternatively a general modification in conduc- is also damaged in meningitis and around
tion may be found in generalized peripheral infarcts.
neuropathies. Those peripheral neuropathies For the spinal cord; the most frequent use
which involve primarily myelin produce a is in the lumbar area to image the nerve roots
decrease in speed of conduction. Neuropathies of the cauda equina.
that are predominantly axonal do not alter 3. Magnetic Resonance Imaging (MRI
speed of conduction but may alter amplitude scanning) (fig. 2-5, 2-6) also utilizes comput-
of the action potential. Repetitive nerve stimu- er-generated images. MRI is now the study of
lation recording from appropriate muscle with choice for imaging spinal cord and nerve root.
measurement of the amplitude of muscle Instead of utilizing X-rays, a strong magnetic
action potential may be utilized to study disor- field and radio frequency waves are employed.
der of the neuromuscular junction. A progres- Placement of the patient's body in a magnetic
sive decrement occurs with myasthesia gravis field directionally orients the protons of that
and a progressive increment with Eaton- body. Passage of a brief radiofrequency current
Lambert Syndrome. alters this directional orientation. When the
radiofrequency current ceases the protons
B. Spinal Cord and Nerve Root: realign in the magnetic field. This realignment
1. Simple radiological studies: (fig 2-4) results in a signal. The signal as in CT scans,
Cervical spine, thoracic spine and lumbar sacral depends on the tissue density that is the differ-
spine X-rays provide information about ential water content of the specific tissue. Bone
collapse of vertebrae, narrowing of spaces, has little water content; gray matter and white
narrowing of the neural foramina, metastatic matter have differential water content.
2-14 CHAPTER 2
.1 PER()EAL m.L 12:04:31

1~:tUt IRate:Non-ReaJrreI1t
10 !TIS I : 1 IA : 0If
6,1,0
452""
1 RecordiIg Site : 8JB
SIiruIus Sie
A A1:riIe 12.1 0.6
2 2rrW /Q.1at.1TB1~ nerve
A3: IluIar heai 19.9 0.5
M:knee 22.4 0.5
A 35.1""
3 SOOuV
EOO-anIde
A 39
EfB.Iat nmUacc. neIVe
4 SOOuV a.fbJIar hea:I 41
anIde-knee 41
Figure 2-3 Motor nerJIe conduction velociPy (normal). Various points along the course of the peroneal nerJIe were
stimulated, with recordings from extensor digitorum breflis. The diffirences in latencies are calculated and then
divided by the distance to yield a conduction velocitJy of 41 meters per second. (Courtesy Neurodiagnostic Laboratory
UniversitJy ofMassachusetts Hospital)
Edematous and acutely necrotic tissue, as in Images obtained with a short relaxation time
infarcts and malignant tumors, usually has rela- are labeled as Tl and emphasize the normal
tively high water content. In contrast to CT gray-white anatomical features with the CSF
scan, images are obtained in the horizontal appearing as black. Images produced after
coronal and sagittal planes. longer relaxation times, labeled as T2, produce
As in CT scans, contrast enhancement may increased white appearance of CSF and other
be utilized. Gadolinium DTPA that normally water content. Demyelinating lesions in multi-
does not cross the blood brain barrier is the ple sclerosis are often prominent in T2 (MRI).
agent employed. 4. Other Radiographic Techniques
The MRI procedure may be modified to Utilized in the Pre CT and MRI Era
vary the appearance of cerebrospinal fluid and Myelography: In this technique a radio-
of tissue water content. Altering the relaxation contrast dye is introduced into the subarach-
time (the interval after the application of the noid space via a lumbar puncture. The spinal
radiofrequency wave) will achieve this effect: cord and nerve roots are then visualized by tilt-
allowed to enter the 4th ventricle or the cis-
terns around the brainstem.
5. Electrophysiological Techniques for
Studying Spinal Cord Function:
a. H. reflex: submaximal stimulation of a
mixed sensory-motor nerve at a voltage inten-
sity which is insufficient to produce a direct
orthodromic motor response (the M wave) will
produce a muscle contraction after a long
latency. This long latency response - the H.
wave, involves the activation of the afferent
fibers involved in the monosynaptic stretch
reflex with activation of the anterior hom cell,
anterior root motor fibers to the muscle.
b. The F response: Supramaximal stimulation
of a motor sensory nerve produces an even
longer latency response in the muscles. This
depends on antidromic activation of motor
neurons, which then induces, the longer laten-
cy discharge, activating the muscle fibers.
c. Evoked Potentials: There are computer-
averaged signals associated with peripheral and
central conduction following stimulation of
specific sensory systems. The specific technique
relevant to spinal cord is the somatosensory
evoked potential. (fig.2-8) . Stimulation of
median nerve in the upper extremity or of the
posterior tibial or peroneal nerves in the lower
extremities produces a series of waves. These
waves are related to specific points in the con-
duction pathway. In the case of median nerve
Figure 2-4. CerPictU spine x mys. MRrked
Enlargement of the neurRl forRmen hIlS occurred on stimulation the waves relate to brachial plexus,
the left Rt C5-6 e.xtetuling into C6-7 ronsistent with R cervical spinal cord and thalamocortical system.
neurojibrtnna/&hwRnnoma Rt this /erJel. This 26- These studies are useful in detecting whether
yeRT-Olti fomRle rollege mlJintenRn&e worker tie-PeWped abnormalities are present in the posterior col-
numbness in the left Rrm e.xtetuling from the elbow to umn/mediallemniscal system in multiple scle-
Rll of the fingers Rnd pRin in the neck Rnd left SUprR-
rosis or in spinal cord compression.
clavicular RreR. She hIul Rhsent deep tendon reflexes Rt
left biceps Rnd triceps. A} R.ight neurRl forRminR on C. Brain Stem, Posterior Fossa
oblique view. B} Left neurRl forRminR on oblique and Skull Base
view. (Courtesy ofRRdiology DepRrtment BtJy Smte 1. Radiological studies and other
MedicRl Center). See figure 2-5.
imaging studies:
ing the body. Previously, oil soluble dyes
a) Skull X -rays have in large part been
(Pantopaque) were employed and had to be
replaced by CT scan and MRI scan but are still
removed at the end of the procedure. Now
useful in providing information about skull
water-soluble dyes are employed and these are
fractures, enlargement of the pituitary, invagi-
absorbed. At times, CT scan is combined with
nation of the odontoid and intracranial calcifi-
myelography (fig. 2-7). At times, the dye was cations (Fig.2- 9).
b) CT scan discussed previously may provide
2-16 CHAPTER 2
Figure 2-6 Cervieal spine. MRJ. Same ease as figure

2-4. The eause of the enlargement of the neural foram-
ina is now apparent .A large dumbbell tumor is pre-
sent in the intra spinal bony canal and extends
through the foramen to the exeraspinal spaee.
A) Sagittal view B) axial/transverse view. (Courtesy
Radiology Department Bay State Medical Center)
information regarding tumors, infarcts and

hemorrhages affecting. the cerebellum and
brain stem (Fig 2-10).
c) MRI in general has become the standard
Figure 2-5. Magnetie Resonanee Imaging (MRJ) of technique for imaging the brain stem and cere-
the eervieal and upper thoraeie spine and spinal eord. bellum (Fig 2-11).
A) Tl weighted B) 12 weighted from another patient: 2. Physiological Techniques
sagittal seaion dose to midline. In both eases although a) Brain stem auditory evoked potentials
degenerative dise disease is demonstrated, the spinal (fig. 2-12): A sequence of waves occurs which
cord remains normal.
have been associated with specific points in the
Figure 2-8: Short latency somatosensory e1loked poten-

tials (SER) median nerve stimulation at wrist.
Recordings from supraclavicular area (FZ- ERB),
cervical spine-VII (FZ-Cervical VII), cervical spine-
II (FZ-Cervical II) and somatosensory cortical projec-
tion area and scalp (F2-C3). The specific wave forms-
originate as follows: NIO-Brachial plexus at ErhJs
Figure 2-7 cr Computerized .Axial Tomography point, Nl2-lower cervical spine-root entry area, NI4-
(CT) after metrizamide myelography: normal spinal dorsal columns and dorsal column nuclei-lower
cord. A) Reference film for Inel of cross sections in medulla. N20-thalamocortical fibers and cortex. P23-
this patient. B) Scans 3,4, 6, 7- sections through CS- Somatosensory cortex. (From Marcus, E.M. and Stone,
C6lrPels. B. In Evoked Potentials II, Ed. R.N. Nodar and C.
auditory conduction system: Barber: Butterworth Publishers, Boston, 1984).
Wave I; is associated with electrical activity waves I and III in patients with acoustic neu-
generated in the cochlea at the origin of the romas (vestibular Schwannomas).
auditory nerve. Somatosensory Evoked Potentials also pro-
Wave II; is associated with the entry of vide possible information about conduction
impulses from the auditory nerve into the delays in the medial lemniscus.
cochlear nucleus at the medullary pontine b) Special test of auditory and vestibular
junction. function: audiograms, caloric testing an
Wave III; relates to signals generated at the electronystagmograms.
level of the superior olivary nucleus in the 3) Radiological Techniques No Longer
lower pons. Employed
Wave IV; relates to the nerve impulses gen-
a). Pneumoencephalography (PEG) (Fig. 2-
erated in the lateral lemniscus.
Wave V; relates nerve impulses generated 13): Air was injected into the subarachnoid
at the level of the inferior colliculus in the lower space via a lumber puncture. With the patient
in the sitting position, the air would rise into
midbrain.
Delays are noted after wave I or between the cisterns and ventricular system allowing
2-18 CHAPTER 2
Figure 2-9: Skull X -ray Suprasellar Tumor:

Craniopharyngioma. Enlarged sella turcica, and
suprasellar calcification with changes in the anterior
and posterior bony components (clinoids). This 23-
year-old female had a six-year history of intermittent
headaches and amenorrhea and recent diplopia. She
had bilateral papilledema and an elevated serum
prolactin level. Refer to figure 2- 13 (A) for a nor-
mal comparison (see also figure 27-14 for a CT scan
of this case).
Figure 2-11. MRI: A) T1 sagittal section in a 29-

year-old woman with multiple symptoms including
headaches and depression but with no neurological
findings. MRI/MRA was obtained because sister had
an aneurysm and subarachnoid hemorrhage. This
study reveals an apparently benign lesion of the
pineal. B) MRI B) T1 horizontal/axial section in a
young man with multiple sclerosis. No definite
demyelinating lesions are demonstrated but the rela-
tionship of the mesial temporal areas to the mid brain
is well demonstrated.
Figure 2-10 Computerized tomographic (eI') scan of visualization of structures such as the fourth
the posterior fossa with contrast enhancement (C+). ventricle and aqueduct of Sylvius, as well as the
Cerebellar pontine angle tumor in a 65 year old lateral and third ventricle.
female with a 17 year history of deafness in the left ear b. Ventriculography: In patients with
and a minor reduction of hearing in the right ear who increased intracranial pressure, or with tumors
had had additional findings of mild left peripheral mass lesions in temporal lobe or cerebellum,
facial weakness, ataxia ofgait and dysmetria of left
the PEG was dangerous with the possible
hand. The broad base along the left parous bone sug-
gested a meningioma. Courtesy ofDr. Tom Mullins. complication of herniation. Instead, a needle
was introduced into the frontal horn and air or
D. Cerebral Hemispheres
1. Imaging Techniques:
a) CT scans are usually employed in cases of
A
acute trauma, intracerebral hemorrhage, sub-
arachnoid hemorrhage, acute infarcts and
acute brain abscess. In the case presented at the
end of this chapter, an acute hemorrhage was
J
demonstrated involving the leg and proximal
arm areas. (fig 2-29). (Refer to fig 1- for loca-
.,
][
O.' tion of these areas on lateral surface of the cere-

B
bral hemisphere.
I mttc b) MRI - Has become the preferred tech-
nique for imaging patients with brain tumors,
9 '10 mate malformations, seizure disorders, inflammato-
Figure 2-12 Brain Stem audirory evoked potentials ry and demyelinating disorders (fig. 2-14). In
(BARR). This 49 year old.female had a progressipe patients with ischemia and infarctions special
decrease in hearing in the left ear, decreased sensation diffusion weighted and perfusion studies are of
on the left side offace for 2 years and additional find- value and are discussed in chapters 26.
ings of a left peripheral fa&ial weakness and decrease Functional MRI - may allow correlation of
pain sensation wer the face. Imaging studies were metabolic activities and normal or disordered
normal but a delay was present in the II-III interval
function (fig 2-15) .
on the left suggesting a lesion between the cochlear
nmleus and the superior olipe. of unknown etiology. c) As discussed above, pneumoencephalo-
A) Normal right ear stimulation, B) abnormal left grams and ventriculograms are no longer
ear stimulation. employed.
d) Radioisotope Techniques have a limited
radio-opaque dye was introduced outlining the
value in selected cases.
ventricular system and cisterns.
1. Radioactive Brain Scans are no longer
Figure 2-13. Pneumoemephalogram: A large pituimry adenoma has ballooned out the sella turcua on the X-ray.
With the injection of air, via a lumbar puncture the extrasellar extension may be seen. A. Norma~ B. Abnormal.
(Courtesy of Dr. Samuel Wolpert, New England Center Hospimls)
2-20 CHAPTER 2
performed. Prior to the development of CT nucleotides combined with computer imaging

and MRI this technique was of value in detect- of the emission to assess metabolic changes in
ing lesions in which damage to the blood brain specific areas of the brain. Resolution does yet
barrier or increased metabolic activity was pre- reach the level of MRI or current high level CT
sent. Metastatic tumors, meningiomas, scanning but now approaches that of early CT
glioblastomas, abscess and acute infarcts were scans. Cost is high and availability limited since
demonstrated but anatomical detail was poor. a cyclotron is required to produce the short life
Several examples will be provided in the text radioisotopes required. The major clinical use
2. Radioisotope flow studies are still occa- is in relation to focal (partial) epilepsy (Fig. 2-
sionally utilized to visualize the passage of a 17). During seizure activity metabolic activity
radioisotope injected into the lumbar sub- at the focus is increased. Between seizures the
arachnoid space into the ventricles, out into the metabolic activity at the focus is decreased.
cisterns and through the subarachnoid space The investigational use of PET scanning has
over the convexity to be absorbed into the provided valuable information about localiza-
venous sinuses. Normally, the isotope is no tion of function during the increased metabol-
longer present in the ventricles at 48 and 72 ic activity of normal cognitive activities, such as
hours. In the presence of communicating reading, motor activities, etc. In addition,
hydrocephalus (primarily normal pressure information has been provided about the local-
hydrocephalus), the isotope is still present in ization of altered metabolic activity in patients
the cerebral ventricles at 48 and 72 hours with schizophrenia, depression and various dis-
(chapter 18 for an example). orders of the basal ganglia. Functional MRI
3. Single photon emission computed tomograph may provide a more effective technique for
(SPECT) scanning remains, as a modified form such metabolic correlations. Since positron
of the radionucleotide brain scan. Unlike the emission tomography (PET scan) has not been
positron emission tomography scan a cyclotron previously considered in detail we will briefly
is not necessary. Therefore cost is less, and review the technique at this point. This
availability is greater but resolution is poor (fig method combines CT with the use of positron
2-16). emitting radioisotopes, which have been
4. Positron emission tomography (PET) bound to compounds, which have significant
scan employs positron emitting radio biological function as metabolites or transmit-
Figure 2-14. MRI. Multiple sclerosis. This 47-year-old female farm owner and manager had a 2-month episode of
numbness ({(nuvocaine type sensation") over the entire rigltt trigeminal distribution. Five years previously she had
intermittent unsteadiness Her examination demonstrated only a selective decrease in touch sensation over the
entire rigltt trigeminal distribution. The MRI studies confirmed a rigltt mid pontine tegmental lesion but also
indicated multiple areas of demyelination in the white matter of the cerebral hemispheres particularly involving
the corpus callosum. A) Tl sagittal, (B) 12 horizontal views, (C) 12 axial of brain stem.
Figure 2-16. SPEer: Areas of increased perfusion

during seizure activity are indicated in this scan. A)
ictal uptake in areas of riglJt temporal parietal and
frontal lobes B) interictal. This 3-year-old child ini-
tially had infantile spasms with an EEG pattern con-
sistent with the disorder hypsarrhythmia. Subsequently
the EEG abnormalities were riglJt anterior quadrant
or parietal. Courtesy ofDr. Paul Marshall Pediatric
Neurology University of Massachusetts.
the activity of the neurons. Thus, areas of cere-
bral cortex undergoing active seizure discharge
will show increased activity and increased
uptake. In normal individuals with activity of
the visual system, e.g., opening the eyes to scan
a scene, activity and uptake will increase in the
visual projection area of the occipital lobe.
With auditory stimulation, on the other hand,
Figure 2-15. Functional MRI. This 33-year-old
woman had a 2-year history offocal seizures involving activity and uptake will increase in the auditory
the riglJt foot and arm. A large area of the left premo- projection area of Heschl' s transverse gyrus of
tor and motor cortex is involved by a grade 2 astrocy- the temporal lobe. Areas of damage will show
toma A) The relation of the areas activated by riglJt decreased uptake.
hand or foot movements to the intrinsic brain tumor 2. Physiological Techniques: NOTE
are indicated. B) Comparison of normal hemisphere THAT SEVERAL ILLUSTRATIONS OF
to abnormal hemisphere. Note the displacement of the
arm and leg areas by the tumor. Courtesy ofDrs.
EEG RECORDS WILL BE FOUND IN
B.R.Buchbinder, H. Jiang, G.R. Cosgrove A Cole, D. AN EEG ATLAS SECTION OF THE CD
Hoch and R. Hill at the Massachusetts General ROM
Hospital Epilepsy Center. a. Electroencephalography: This technique
ters. In contrast to standard CT scanning provides information about the electrical activ-
(where the source of radiation is the X-ray ity of the cerebral cortex. This activity repre-
tube), in PET the positron-emitting isotope sents primarily the summated activity of post-
taken up by the tissue is the source of radiation. synaptic potentials generated in the cerebral
2-Desoxyglucose is often employed since it is cortex. The electroencephalogram in the nor-
taken up by the neurons, and is phosphorylat- mal awake adult resting with eyes closed is
ed as is glucose but is not further metabolized. characterized by the alpha rhythm (Fig. 2-18).
The isotope oftluorine (18F) is bonded to the This rhythm is composed of a sequence of
desoxy glucose. The uptake of glucose or of sinusoidal waves of 8-13 Hz (cps), which is
desoxy glucose into neurons is proportional to maximal over the parietal-occipital recording
2-22 CHAPTER 2
Figure 2-17. PET scans. The most prOminent feature is

the increased activity in visual cortex most likely
reflecting visual activity during the study. MRI
demonstrated mesial temporal sclerosis on the right
and this study did demonstrate a possible decrease in
activity right temporal area. This 22-year-old female
had romplex partial seizures since puberty. She had
prolonged stntus epilepticus as an infant related to
fever. A) Horizontlll, B) sagittili. Courtesy ofDr.
Cathy Phillips Neurology University ofMassachusetts
area. Activity faster than alpha rhythm is dural or intra cerebral hemorrhage) or with
referred to as beta activity and may be present total destruction of tissue. (Fig 2-23.)
over frontal areas. Increase amounts of beta 2.Generalized abnormalities:
activity occur as an effect of various drugs such a. Generalized dischat;ges of spike or poly-
as barbiturates and benzodiazepines. spike - slow wave complexes are associated with
Alterations occur in this normal background various types of generalized epilepsy. These will
activity related to the following factors: (1) eye be discussed in chapter 29.
opening producing reduction of amplitude 1) Generalized bursts of 3/second spike wave
(Fig2-18C): (2) age: slower activity with infan- complexes are associated with absence seizures
cy and childhood (delta 0.5- 3 Hz, theta 4-7 previously labeled petit mal epilepsy.
Hz), (Fig.2-19-CD ATIAS). (3) Sleep, (Fig.2- 2) Generalized bursts of polyspike and slow
20- CD ATIAS), (4) drugs and anesthesia: wave complexes are associated with myoclonic
faster and then slower activity (Fig.2-21-CD seizures.
ATIAS) 3) Generalized polyspike dischat;ges may be
Abnormalities may be (1) focal or found in the tonic phase of the generalized
(2) generalized. tonic clonic seizures.
1. Focal abnormalities may be catego- b. Generalized slow waves are associated
rized as: with diffuse disorders: infectious, ischemic,
A. Focal spikes implying focal excessive toxic or metabolic encephalopathies (Fig. 2-24,
neuronal discharge involving the cerebral cor- 25).
tex and associated with partial (focal) epilepsy. c. Generalized periods ofsuppression imply a
(See chapter 29). more serious type of diffuse dysfunction, as in
b. Focal slow wave activity, which implies anoxia or a deep stage of anesthesia. Figure 17-
focal cortical damage, as in infarcts, brain 16 provides an example of a burst suppression
tumors and brain abscess. (Fig. 2-22). pattern.
c. Focal suppression of activity implies non- d. Total suppression ofactivity may be found
active electrical tissue under the electrodes - when neocortical death has occurred - as in
this may be seen with a fluid collection (sub-
18A
c-O
F-T
c ............""'..~~
R""_.... ~,~.",...-~
T-O
L ~M\i~,'ttfN\\\'f#.ot\~!N':N, ~'N~ ~\\','~.ftl~ 'tll~~r(\~~\'/M~
R h\lwMf'w!\tI(,';~\\YlyJIHi,,'rjI«('·I,~,W'~ ~\Wi;~'N,',"'iii1'-4IM'&/i'I!Vovl(,\"1
, !JO>N
'I.e
l8C
ErE OPENING ErE CLOSURE
c-o L t~WNI(~""''''lh~.,\wtW,~f~W'-~JNW/
R ~~II\W~~~W~~"""!{:fi·""'rNN"""~l;~ifti..~
T-O
L fr-,WI""I~""\~~~U,~~
R ~""\~~~M'MW.
I ~"V
lue.
Figure 2-18. A) The International Fetkrlltion Ten-Twenty Ele&trode Pltuement System. Frontal superior lind pos-
terior views; lind II single plllne projection of the hetld tIemonstrR.ting the standllrd positions lind the rolllndic lind
sylvian fissures. The mom ten-twenty is blUed on the pltuement ofelectrodes lit ptlrticulllr percentages of the distanu
between nIIsion lind inion. From JIUj1er, RH.: Electroeneepb. Clin. NeuroPlrPsiol.10: 374, 1958 (Elsnier).
B) The not"mlll tldult e/earoencepbtdogmm. The ptltient is IIWllke but in II resting state, recumbent with eyes closed.
F =fronta~ T =tempor~ C =centrlllllnd 0 .. occipital. (Bipolllr recordings) These abbrePilltions will be utilized
in subseiJ.uent ill14Strlltlons. C) EjfraJ of Eye Opening lind Closure. Opening is lISSOCillteil with II blocking or sup-
pression of the alpbll rhythm of 10 cps lind with the IIppellrllnu of II low voltage fost-lUtivity of20 cps (beta rhythm).
With eye closure, there is II return of the alpbll rhythm.
severe anoxic encephalopathy or the vegetative
state. This total suppression of activity accom-
panied by an absence of brain stem reflex activ-
ANT. t - MID. "[
ity and an absence of spontaneous respiration
occurs in brain death. Similar findings of total R_
Moo. t-l'OStt
suppression of activity both electrical and reflex
may also occur under condition of deep anes-
thesia. PAR. - OCC.
b. Specialized Techniques Employing

Electroencephalography:
1. Sphenoidal electrodes - these are small
needle electrodes placed in the sphenoidal Figure 2-22. Foc1I12-3 Hz slow wllve IUtivity in the
sinus area to record from the medial aspects of e/ectroeneepblllogrllm: /eft tempomlilrell indiclJting
the temporal lobe. foclll tiamllge in this llrell. Brllin abscess, /eft temporal
lobe in II 14-yellr-oltl fomaIe secondary to lin acute S
2. Video EEG monitoring: The recording of
lIureus mastoiditis extending into the petrous ridge.
EEG and behavior onto single videotape allows Electroeneepblllogrilm. Bipolllr recording. (LAT. F. -
correlation of electrical activity and of clinical IIIteral frontal; ANT- T- .. IInterior temporal; MID. T.
seizure activity. This is usually a prerequisite .. mid- temporll~ POST. T- =posterior temporll~ PAR.
study prior to epilepsy surgery and is also uti- .. Pllrieta~ occ. .. occipital). (Listed in text lind CD
ROM as Figure 27-22).
2-24 CHAPTER 2
L~"fIr~ F - C
.~_,,~
POS"t f - PAR.
L ",\"'/.I~'frfrt¥'AJt~~~~4r(
.~~
C - 0
PAR. -OCC.
50"N1~~ _______________________
, 68Il.
Figure 2-25. Generalized theta 5 Hz slow wave activ-

ity. This 67-year-old female had a metabolic
encephalopathy due to impaired hepatic Junction sec-
ondary to cirrhosis and at this point was semicomatose
~
I .... in a stuporous state. When the patient was more deeply
comatose, the awake activity was even slower at 4 Hz.
Figure 2-23. Focal suppression of EEG activity right
When the patient was alert during intervening peri-
temporal area and focal slow wave activity right
ods of recovery, the dominant activity was in alpha
frontal. Total right middle cerebral artery occlusion
range.
in a 61-year-old female with hypertension. Case 26-4.
ANT.F. = Anterior frontal parasagittal; POST.F. = e. Electrocorticography: recording directly
Posterior frontal (parasagittal); PAR. = parietal; from the pial surface may be utilized during
OCc. = occipital; ANT.T. = anterior temporal; epilepsy surgery.
MID.T. =mid temporal; POST.T. =Posterior tempo-
f Polysomnography(PSG): this technique is
ral. (Listed in text and CD ROM as Figure 26-14).
utilized in the evaluation of sleep disorders
such as narcolepsy and sleep apnea. EEG activ-
c
ity from the parietal occipital or vertex areas of
the scalp is correlated with
(I) Cardiac activity (EKG) rate and
rhythm
(2) Respiratory activity rate and rhythm
(3) Oxygen (02) saturation
(4) Extraocular movements
(5) EMG activity chins and or limb
The use of the PSG and the multiple sleep
5OmVI- AGE 4 yr. EEG N040998
latency study will be discussed in chapter 29
I ... 3-SO-69 c. Evoked Potentials:
Figure 2-24 Generalized delta 1-2 Hz slow wave ( I) Visual (VER or pattern reversal visual
activity that persisted despite attempts at arousal this evoked potential: PVER): The time of conduc-
4-year-old male had acute viral encephalitis. tion over the entire visual pathway - to cerebral
lized in the analysis of pseudoseizures or other cortex is measured. Pattern reversal generates
unresolved "spells". a prominent very stable wave at approximately
c. Depth electrode recording: from medial lOOms, the PIOO wave (Fig.2-26).
temporal and other structures may be per- (2) Somatosensory evoked potentials: As dis-
formed prior to epilepsy surgery often in com- cussed above, these studies may provide infor-
bination with video monitoring. mation regarding delays in conduction in the
d. Subdural surface grids of electrodes: may thalamocortical system.
be placed on the cortical surface for better cor- 3. Neuropsychological tests: A variety of tests
relation of seizure discharges arising in the have been developed, These include the
frontal or other neocortical areas, Wechsler Adult Intelligent Score (WAIS) for-
merly termed the Wechsler Bellevue Test of 26A
Adult Intelligence. This has a series of separate
subtests covering multiple areas of verbal and
performance functions. A total, verbal and per-
formance intelligence quotients are derived. A
series of tests have been developed to study
aphasia and frontal lobe function and are dis-
cussed in those chapters. The Wisconsin Card
Sorting Test is utilized to study cognitive per-
severation. The Wechsler Memory Score pro-
vides a quantitative measure of memory func-
tion. The Minnesota Multiphasic Personality
index, provides information regarding person- '''"l.~ tHin VI,UAL POlitO IIUIIONIU 26B
ANALYStS P21"OO, AT CMECK SIlt:" I, ... HI.. 102" "'*' (CIACL.IE)
ality, affect, depression etc. Projection tests LATE:NcY {WSI!C) AS fUNCTION Of' CH[CJ(. SIZE TOTAL. eMECICS PlA MONITOR
SCREEN (VISUAl AHGLG OF ARC rOAI EACH CHlCK AT I M£lERI
have also been developed to study personality S~ CoNI"Oi'.H . .. 2 l.,- 417- , HI ,as', 10;1011:10'1 "*
•.
114~·J "fZ~· ' i l~' 1
U'" 'I ...... CYHA'lOfJ
function the Rorshark and the Thematic
Apperception Test. The answers to the pictures ......
.....,... 'SO 1oth9
......
.,. .
IQI!, '11 101 I !'I l006.! 6
,..
9thlS
,'.'09
1D'3',!o
... '
13·llo. fl ·"" .s·I11
u...,. ·lSOIP .." Il" IUJ ,.;,r 11.,

provided unless very bizarre may be difficult to wK( YIID.
score and the results are open to several inter-

.. ..
.... ,,' I SD "C." I !4 LU Z'1l1 ahllJ lh1' ':WI
...... 0-" ..... ...' .... ...,

pretations. ,. n.
C>-I
Ilk,a ... ' 3501P T 01)31 ,.1 n.

3. Techniques for the study of the cere-
bral circulation
a. Magnetic Resonance Angiography
(MRA) - Normally in MRI scans, rapidly mov-
ing blood is not clearly imaged. However with
special software programs, a non-invasive visu-
alization of flow through vessels can be
achieved. (Fig 2-27, 2-28). At present, resolu-
tion in the range of 2-3 mm can be achieved,
allowing visualization of significant aneurysms.
This procedure allows imaging of the carotid rJ'1:1- ' ... 'l - .. /1.. +. +... .... .. ...... " "11'\: . I"
and other arteries prior to carotid .. •. ,... '. ......•....•... . ; ..... ···1··· ~G I 9,
.. .........:.. ~ ... "f-l-- ~ :I':" ....... . , .............. : .. '5' "
endarterectomy* . ... '" .. !"'\o:\ilill +· .. ·-f···· ....... '.. ~' . ~.
b. In contrast, cerebral angiography (or ~ :~: ... :~::;~ ~ I · ~;~ :·::~:"::.· "·:.:·iJ: ~+';.:(~.; ' ~
arteriography) is invasive. A catheter must be ...... +....... f-V' ~ .......,......~ ro'"' . ~ ~;.. !i
placed in the femoral artery and advanced into : ... '_ ~ 'J ~'ff9Z ~:. : :..". . .: :::: r ... ,... .'
the aorta and then into the carotid or vertebral , ",::. ,·1 .
",-iJ" '" ~
i'\.rI.J.<. . ' ......... ~ ~i
arteries. Radiopaque dye is then injected to I <i-+-f-"'-
-,tf'....,.H\Hf-~·I- : "-,:-
···+-'··+ ' '-/'" _.... _,.. '+-'......
"1 -+--+----1
directly image the cerebral vessels. This is the .. ,J " '''1' "; ". _ ~"';:"" ....L
best technique when detailed study of the cere-
bral vascular is required, e.g., prior to Figure 2-26. Visual evoked potentials. A) Normal. Each
aneurysm surgery. With the increase resolu- tracing represents the summation of 256 trials at diffir-
tion of MRA and of CT scan angiography, entcheck sizes. Note the stability of the PlOO response. B)
direct arteriography may be replaced by Normal and abnormal values are obtained by statistical
these non-invasive techniques. analysis with abnormal defined as >mean + 3 standard
deJJiations. C) A patient with multiple sclerosis who had
Under special circumstances, spinal angiog-
experienced several episodes of optic neuritis involving
raphy employing selective catheterization of first one eye and then the other eye. Note the bilateral pro-
longation of the PlOO responses.
2-26 CHAPTER 2
radicular arteries may be performed to visualize pressure when the patient is relaxed, but posi-
spinal cord arteriovenous malformations. tioned on one side, will be usually less than 150
c. Duplex scans of the extracranial carotid mm of CSF. Values in the relaxed state greater
and vertebral arteries: this technique combines than 200 mm are considered abnormal.
Doppler and ultrasound techniques to image Respiration, abdominal pressure, flexion of
blood flow in the major extra-cranial arteries. head on chest or thighs and knees onto
d. Transcranial Doppler - may provide abdomen will all increase the pressure.
gross information regarding flow in the major Normally no significant red blood cells
intracranial vessels. (rbe's) should be present. When the puncture
CEREBROSPINAL FLUID is traumatic the first tube collected will contain
(CSF) EXAMINATION red cells but these should significantly decrease
CSF fluid is usually obtained by a lumbar by the time that the fourth tube is collected.
puncture. The lower end of the spinal cord, Normally, less than 7 white blood cells
the conus medullaris, does not extend below (wbc's) should be present and all should be
the L2 vertebra. Therefore, introduction of a mononuclears. Any polymorphonuclears are
needle into the subarachnoid space between abnormal and should raise the question of
the L2-L3, or L3-IA, or IA-L5 spinous infection or inflammatory reaction. Spinal
processes will not damage the spinal cord. CSF fluid glucose should be no less than 50% of the
Figure 2-27. Magnetic resonance angiography (MRA).

A) Aortic arch and major arteries in the neck.
Bl & 2) Intracranial circulation coronal submental
view demonstrated in two patients 27-B2labels only
the dijfrrences from 27-Bl C) Intracranial
circulation (lateral view).
AGA= Anterior Cerebral A.
ACOM= Anterior Communications A.
CGA= Commono carotid.
EGA= External carotid A.
lGA= Internal carotid A.
MGA= Middle cerebral artery. SGA= Superior cerebral artery.
PCA= Posterior cerebral artery. VA= Vertebral amy.
PCOM= Posterior communications
Total CSF protein is usually less than 45
mgOAl. It is increased in a nonspecific manner in
many processes affecting the nervous system.
a. Acute inflammation (meningitis and
encephalitis ).
b . Acute necrosis: infarcts, abscess and
tumors
c. Blocks in the CSF - peripheral nerve bar-
rier as in Guillain Barre syndrome. In the lat-
ter case no cells are present. This is referred to
as albumin- cytologic dissociation and may also
be present in patients with diabetes mellitus or
myxedema.
d. Blockage of the CSF pathway at a spinal
cord level. In patients with blocks in the lower
thoracic or lumbar area, the protein level may
be very high, with several grams present .The
thick yellow fluid may clot in the test tube
(Froin's syndrome)
The gamma globulin (IgG) percentage of the
total protein may be increased under the fol-
lowing circumstances
1. Production of IgG in the serum is
increased.
2. IgG is selectively produced within eNS
by plasma cells - as in multiple sclerosis or neu-
rosyphilis. Oligoclonal bands will also be pre-
sent within the gamma globulin band.
ILLUSTRATIVE CASE mSTORY.
This patient should be compared to the
patient of chapter 1. Both began with
symptoms of weakness in the leg. However,
the time course for evolution of symptoms
differed significantly resulting in different
diagnoses.
Case 2-1 This 90 year old right handed white
male with a past history of hypertension awoke
Figure 2-28.Magnetic resonance angiography. Basilar on the morning of admission with weakness of
vertebral (posterior) circulation. A) AP view.
the left side, which was most marked in the leg.
B) Lateral view. The vertebral, basilar, posterior cere-
bra~ and all of the circumferential cerebellar branch-
The initial admission examination indicated no
es aYe evident. motor function of the left leg, severe weakness
blood glucose obtained at the time of the of the left arm and minimal weakness of the left
puncture or within two hours prior to the lum- side of the face.
bar puncture. In acute bacterial meningitis - Past history indicated a previous minor
the CSF glucose is low due to the interference "stroke" involving the left side of the body,
with the transport system and/or the increased from which he had made a full functional
metabolic activities. recovery with only minimal left sided weakness.
During year prior to admission, occasional
2-28 CHAPTER 2
periods of confusion had been present and pro- In the present episode, the sudden develop-
gressive problems in memory had developed. ment of symptoms would suggest an addition-
Neurological Examination: Mental Status: al vascular event. Compare this case to Case I-
The patient was disoriented for time and place. I in which the patient had a gradual develop-
He was however cooperative and able to follow ment of weakness in the leg secondary to a
all commands. He was fluent with no distur- meningioma.
bance of language function. His remote mem- As regards the localization, the marked
ory was excellent. He could repeat the name of involvement ofleg and proximal arm with rel-
the examiner and of his primary physician but ative sparing of hand and face might suggest a
could recall neither name after five minutes. process involving the upper half of the motor
Cranial Nerves: A minor left central facial cortex (refer to fig 18-12).
weakness was present. Motor System: He had no
movement of the left leg. There was little func-
tion of the left shoulder and elbow. However
handgrip was strong and independent finger
movements were present the patient was
recumbent in bed with external rotation of the
left leg into a hemiplegic posture. Reflexes:
Deep tendon stretch reflexes were absent in the
lower extremities and the left upper extremity.
The plantar responses were extensor bilaterally
(bilateral sign of Babinski. Sensory System: No
definite abnormalities within limits of testing.
Clinical diagnosis: 1. Cerebrovascular acci-
dent involving the superior parasagittal precen-
tral gyrus either due to an anterior cerebral
artery occlusion or a cerebral hemorrhage sec-
ondary to amyloid angiopathy. 2. Alzheimer's
disease.
Laboratory data: A CT scan of the head
demonstrated an acute hemorrhage in the Figure 2-29 .CT scan. Cerebral hemorrhage in a 90-
superior parasagittal Rolandic area consistent year-old man with left sided weakness primarily
involving the right leg and shoulder. See case 2-1 at
with amyloid angiopathy. (Fig. 2-29).
end of this chapter.
Comment: This patient presents many of the
neurological problems, which occur in the
elderly. The patient had a one-year history of
progressive memory problems, which primari-
ly involved the formation of new memories. At
age 90 such memory problems occur in more
than 50% of the population. Usually, this rep-
resents the development of those degenerative
changes in the neurons of the cerebral cortex
seen in the process defined as Alzheimer's
senile dementia.
The patient had elevated blood pressure for
many years and had already experienced one
"stroke" affecting the left side 10-15 years pre-
viously
CHAPTER 3
Neurocytology
This chapter focuses on the two major cell

types that form the nervous system: supporting
cells and conducting cells. The supporting cells
consist of the glia, epedenymal cells lining cells
the ventricles, the meningeal coverings of the
brain, the circulating blood cells, and the
endothelial lining cells of the blood vessels. The
conducting cells, or neurons, form the circuitry
within the brain and spinal cord and their axons
can be as short as a few microns or as long as one
meter. The supporting cells are constantly being
Figure 3-1. Golgi type II cells in the motor cortex of
replaced, but the majority of conducting the rat. (Golgi-Cox stain, <16450.)
cells/neurons, once formed, remain throughout
our lives. reveal details of the neuron=s internal structure.
Any investigation of the structure of the ner- However, the most pronounced organelle in the
vous system is complicated by the fact that no soma, the rough endoplasmic reticulum, or Nissl
single stain demonstrates all details of a neuron substance, is demonstrable with basophilic dyes.
or of the glia. Instead, many techniques are used The Neuron
for microscopic examination of the nervous sys-
The basic functional unit of the nervous sys-
tem. But before nerve tissues can be examined,
tem is the neuron. The neuron doctrine (postu-
they must be preserved (fixed). Neutral-buffered
lated by Waldeyer in 1891, described the neuron
formalin is the most commonly used fixative in
as having one axon, which is efferent, and one or
light microscopy.
more dendrites, which are afferent. It was also
Golgi Neuronal Method (Figs. 3-1 and 3-2) noted that nerve cells are contiguous, not con-
The shapes of neurons and glia can best be tinuous, and all other elements of the nervous
seen by means of the Golgi neuronal method. system are there to feed, protect, and support the
Brain slices 3 to 5 mm thick (either fixed or neurons.
unfixed, normal or abnormal, from vertebrates Although muscle cells can also conduct elec-
or invertebrates) are encrusted with heavy metals tric impulses, only neurons, when arranged in
(usually dichromate or mercury) and then networks and provided with adequate informa-
immersed in silver nitrate. With the Golgi tional input, can respond in many ways to a stim-
method, only about 1 in every 70 cells stains ulus. Probably the neuron's most important
completely and reveals the axon, soma, den- feature is that each is unique. If one is damaged
drites, and dendritic spines in full detail. With or destroyed, no other nerve cell can provide a
either a camera lucida or the modern technique precise or complete replacement. Fortunately,
of image analysis, one is able to fully reconstruct though, the nervous system was designed with
the cell and determine the morphology of nor- considerable redundancy, so it takes a significant
mal or diseased cells. injury to incapacitate the individual (as in
With the Golgi neuronal method some of the Alzheimer's disease).
most elegant cells have been identified, including Neuronal parts and their functions are shown
the Purkinje cell of the cerebellum, the pyramidal in Figure 3-2 and Table 3-1.
cell of the cerebrum (Fig 3-1), the stellate cells of Neurons in the adult nervous system are
the cerebrum (Fig 3-3) and the mitral cell of the either pseuodunipolar, bipolar, or multipolar.
olfactory bulb. A disadvantage is that it does not
3 -2 CHAPTER 3
Figure 3-2. Golgi type I cells in the motor cortex of a rat. A, shows entire cell--soma, axon, and dendrite (Golgi
rapid stain, <.x>100). B demonstrates dendritic spines (Golgi rapid stain, <.}(>350). C and D are electron micro-
graphs of dendritic spines (<.X>30,000).
True unipolar cells are found in the invertebrate as a single process acts as the axon and the den-
nervous system (Fig 1-1). In the mammalian cen- drite. Bipolarneurons(fig 1-1), which are senso-
tral nervous system pseudounipolar cells (fig 1-1) ry in function, are found in the rods and cones of
are found in the sensory ganglia of the spinal the retina, in the olfactory neuroepithelial celis,
cord (dorsal root ganglia) and cranial nerves and in the olfactory mucosa at the upper end of the
in the mesencephalic nucleus of cranial nerve V, nasal passages, and in the vestibular and auditory
NEUROCYTOLOGY 3-3
TABLE 3-1. PARTS OF ANEURON neuron varies greatly in form and size. Unipolar
cells have circular cell bodies; bipolar cells have
Soma The neuron=s trophic center, containing the ovoid cell bodies; multipolar cells have polygonal
nucleus, nucleolus, and many organelles. cell bodies.
The majority of inhibitory synapses are Golgi Type I and IT Neurons
found on ils surface.
Neurons can also be grouped by axon length:
Dendrites Continuation of the soma; has many those with long axons are called Golgi type I (or
neurolubules and majority of synapses pyramidal) cells; those with short axons are called
on ils surface; type I neurons have Golgi type II (or stellate) cells (Gray, 1959).
dendritic spines
Golgi type I axons are projectional (Fig. 3-2).
Axon Conducts action potentials to other neurons They form the tracts and commissures in the
via the synapse. Ranges from a few central nervous system, as well as the axons of the
millimeters to a meter in length; peripheral nervous system. In Figure 3-6 #1, a
In CNS covered by myelin, an insulator. cerebral pyramidal cell (Golgi type I) with a long
axon is compared in figure 3-6 #2, with a stellate
Synapse The site where an axon connecls to the
dendrites, soma or axon of another neuron. (Golgi type II) cell with a short axon.
Consists of a presynaptic parf containing The Golgi type I cell (Fig 3-1) has an apical
neurotransmillers and postsynaptic portion and basal dendrite, each of which has secondary,
with membrane receptors separated tertiary, and quaternary branches, with smaller
by a narrow clen. branches arising from each of these branches that
extend into all planes. Spines are absent from the
receptors of the inner ear. Multipolar initial segment of the apical and basal dendrite of
neurons(Fig 1-1) are found throughout the cen- pyramidal neurons, but they become numerous
tral nervous system and in the sympathetic gan- farther along the dendritic branches. The axons
glia of the peripheral nervous system. They con- of pyramidal neurons run long distances within
vey both sensory and motor impulses. the cortex, but they may also exit from the cor-
Multipolar neurons vary greatly in size and in the
complexity of their axonal and dendritic fields.
Dendrites
The dendritic zone receives input from many
different sources. The action potential originates
at the site of origin of the axon and is transmit-
ted down the axon in an all-or-nothing fashion
to the synapse, where the impulse is transmitted
to the dendritic zone of the next neuron on the
chain.
Dendrites have numerous processes that
increase the neuron=s receptive area. The major-
ity of synapses on a nerve cell are located on the
dendrite surface. With the electron microscope
the largest dendrites can be identified by the
presence of parallel rows of neurotubules, which
may help in the passive transport of the action Figure 3-3. Demonstration ofaxoplasmu .flow with
potential (Fig. 3-5) 3-12). The dendrites in many the horseradish peroxidase method. A, Pyramidal cells
neurons are also studded with small membrane in the sensory cortex after injection in the opposite
extensions, the dendritic spines. hemisphere. B, Pyramidal cell in motor cortex labeled
after injection into gyrate hemisphere. (Dark field,
Soma <X>350.)
The soma (perikaryon, or cell body) of the
3-4 CHAPTER 3
tex and distribute to the subcortical nuclei. method or fluorescent markers, appears dis-
The Golgi type II cell has a small axonal field persed (heterochromatic) in mature neurons.
and dendrites (fig 3-3). The axon usually extends (These cells are very active in metabolizing pro-
only a short distance within the cerebral cortex tein; consequently, the DNA is dispersed.)
(0.3 to 5 mm). Golgi type II cells have fewer In females, the nucleus also contains a perin-
dendritic spines than type I cells. Spines, which uclear accessory body, called the Barr body
are common to many neurons, are small knob- (Fig.3-9). The Barr body is an example of the
shaped structures approximately 1 to 3 microns inactivation and condensation of one of the two
in diameter (Fig. 3-1). Their importance stems female sex, or X, chromosomes (Barr and
from the fact that they greatly expand the den- Bertram, 1949). The process of inactivation of
drite=s receptive synaptic surface. one of the X chromosomes is often called
Neuronal Cytoplasmic Organelles lyonization, after the cytogenetist who discov-
Organelles found in the cytoplasm allow each ered it, Mary Lyons.
neuron to function (Fig. 3-9) In these eukary- Recently much progress has been made in
otic cells the organelles tend to be compartmen- the localization of genes associated with neuro-
talized and include the nucleus, polytibosomes, logic processes, e.g., Huntington's Chorea,
rough endoplasmic reticulum, smooth endoplas- Down=s syndrome.
mic reticulum, mitochondria, and inclusions Endoplasmic Reticuhun. The largest mem-
(Fig. 3-10). Most neuronal cytoplasm is formed brane in the eukaryotic nerve cell is the endo-
in the organelles of the soma and flows into the plasmic reticulum (ER). It consists of a rough
other processes. Newly synthesized macromole- endoplasmic reticulum, which is the site of ribo-
cules are transported to other parts of the nerve some and protein synthesis, and the smooth
cell, either in membrane-bound vesicles or as endoplasmic reticulum, which is the site of the
protein particles. As long as the somas with a synthesis and metabolism of fatty acids and phos-
majority of its organelles are intact, the nerve cell pholipids.
can live. Thus it is the trophic center of the neu- Rough Endoplasmic Reticulum (Figs. 3-
ron. Separation of a process from the soma 10, 3-11 and 3-12). The rough endoplasmic
produces death of that process. reticulum, or Nissl substance, is the chromidial
Nucleus. The large ovoid nucleus is found substance found in the cell body. It can be
in the center of the cell body (Figs. 3-7,3-8 and demonstrated by using a light microscope and
3-9. Within the nucleus there is usually only a basic dyes, such as methylene blue, cresyl violet,
single spherical nucleolus, which stains strongly and toluidine blue. The appearance and amount
for RNA. The DNA, which can be demonstrat- vary from cell to cell. With electron microscopy,
ed by staining the neuron by the Feulgen cisterns containing parallel rows of interconnect-
ing rough endoplasmic reticulum are revealed
(Fig. 3-11). Ribosomes (clusters of ribosomal
RNA) are attached to the outer surfaces of the
membranes and consist of a large and a small
RNA-protein subunit. Protein synthesis begins
when there is a combination of initiation factors,
messenger RNA (mRNA) and transfer RNA
(tRNA) with the small subunit. This is then fol-
lowed by the presence of an elongation factor,
which then starts the peptide chain to grow.
The Nissl substance is most concentrated in
Figure 3-4. Wallerian Ikgeneration. Medullary the soma and adjacent parts of the dendrite (Fig.
pyramids in a human some months after an infarct 3-12A). It is, however, also found throughout
in the motor-sensory strip. Left silk is norma~ note the dendrite (Fig. 3-12B). Before the electron
the absence of myelin on right silk. (Weigert myelin microscope it was always presumed that the axon
sheath stain, <.}680.) hillock was devoid of Nissl substance, but it has
NEUROCYTOLOGY 3-5
now been shown that there are polyribosomes in apparatus consists of stacks of flattened smooth-
this region. surface membranes called saccules.
Smooth Endoplasmic Reticulwn (Fig. 3- The protein secretion from the Nissl sub-
10). All nerve cells have some smooth endo- stance is transferred to the Golgi apparatus where
plasmic reticulum, but in neurosecretory cells in a carbohydrate component is added to the
the hypothalamus, the smooth endoplasmic protein. The product is released in a secretory
reticulum is greatly enlarged. The smooth endo- vesicle.
plasmic reticulum consists of GERL--Golgi Lysosomes (Figs. 3-10, and 3-11).
apparatus, endoplasmic reticulum, and lyso- Lysosomes are common in the cell body, appear
somes--which work together to synthesize, mod- as dense bodies, and function as centers of degra-
ifY, or even degrade secretory proteins. The dation. They are membrane-bound, vary in size
Golgi apparatus is found in all cells and is visible from 0.35 to 3.0 microns in diameter, and com-
by a light microscope with osmium and silver monly contain small granules. Lysosomes con-
stains as an irregular network in a perinuclear tain acidic hydrolytic enzymes (4.8 pH) that are
location. In electron micrographs, the Golgi capable of breaking down proteins, DNA, RNA,
Figure 3-5. Electron micrograph (<1(>6000) of the cerebral cortex showing the principal cell types in the nervotU
system: neuron, astrocyte (astro), oligodendrocyte (oligo), and a blood vessel (BV)
3-6 CHAPTER 3
formed by many reactions .

• Mitochondria (Figs. 3-10, 3-11, and 3-
12). Mitochondria are the principal site of
adenosine triphosphate (ATP) production in the
cell. These organelles, found throughout the
neuron, are the third largest organelles after the
nucleus and endoplasmic reticulum. They are
rod-shaped and vary from 0.35 to 10 microns in
.... • length and 0.35 to 0.5 microns in diameter.
Mitochondria can be demonstrated in light
microscopy, but details of their structure are best
seen in electron micrographs.
The wall of a mitochondrion consists of two
layers--an outer and inner membrane. The outer
membrane contains pores that render the mem-
brane soluble to proteins with molecular weights
of up to 10,000. The inner membrane is less
permeable and has folds called cristae that project
into the center of the mitochondrial matrix. The
interior of the mitochondrion is filled with a fluid
denser than cytoplasm. Cations and mitochon-
drial DNA have been demonstrated in the mito-
chondrial matrix. Mitochondrial DNA is derived
from the mother. An intriguing study links this
Figure 3-6 Motor cortex of the chimpanzee, demon- mitochondrial DNA to a common human female
strating a pyramidal neuron. 1, Golgi Pype I cells ancestor, Lucy, who lived in Africa over 300,000
(neurons with long axons). 2, Golgi Pype II cells (with years ago.
short axons). (Nissl stain, <X> 1500.)
On the inner membrane are found enzymes
and certain carbohydrates. The lysosomes help that provide much of the energy required for the
digest macromolecular polymers into subunits nerve cell. These respiratory enzymes (flavopro-
(de Duve and Wattiaux, 1966). They are neces- teins and cytochromes) catalyze the addition of a
sary for the degradation of older portions of phosphate group to adenosine diphosphate
membranes as newer ones are formed and also (ADP), forming ATP. ATP is broken down in
help in the elimination of deleterious toxins from
the nerve cells.
Tay-Sachs disease illustrates the importance
of the lysosome in the normal function of the
nerve cells. When a specific lysosomal hydrolase
is missing, B- N-hexosaminidase A, the degrada-
tion of the ganglioside GM3 is stopped, and Tay-
Sachs results. Other instances oflysosomal enzy-
matic defects can also result in lysosomal storage
diseases in the brain and spinal cord (Greenfield,
1993).
Peroxisomes. These small membrane-limit-
ed organelles are similar in appearance to lyso-
somes but have different functions. Peroxisomes Figure 3-7. Motor neuron; pentral horn cell from a
contain enzymes that break down fatty acids, human cerpical spinal cord, demonstrating the Nissl
amino acids, and the enzyme catalase, which substance (rough endoplasmic reticulum), axon
degrades the deleterious hydrogen peroxide hillock, and nucleolus. (Nissl stain, <X>600.)
NEUROCYTOLOGY 3-7
the cytoplasm to ADP, providing the energy Glycogen (Fig. 3-11B). Glycogen is a poly-
required for cellular metabolic functions. In the mer made up of D-glucose monomers and is
cytoplasm are found enzymes that break down commonly seen in electron micrographs of nerve
glucose into pyruvic and acetoacetic acid. These cells and glia. Glycogen appears in the form of
substances are taken into the mitochondrial electron-dense rosettes, which are much larger
matrix and participate in the Krebs citric-acid than the RNA rosettes. It is a local source of
cycle, which allows the mitochondria to metabo- energy.
lize amino acids and fatty acids. Lipid Droplets (Fig. 3-11). Lipid droplets
Centrosomes. Centrioles within the centro- are also seen in the soma. They represent a local
some are seen in the immature dividing neurob- store of energy as well as a source of carbon
last as well as the adult neuron. However, since chains for membrane formation.
mature neurons are incapable of dividing, the Neurosecretory Granules. Neurons in the
function of centrosomes there is not clear. supraoptic and paraventricular nuclei of the
Inclusions. Substances stored in a cell hypothalamus form neurosecretory material
include pigments, glycogen, and lipid droplets. (Bodian, 1963 and 1966; Palay, 1957; Scharrer,
Pigment granules (melanin) are common in cer- 1966). The axons of these cells form the hypo-
tain parts of the brain, particularly the substantia thalamic-hypophyseal tract, which runs through
nigra, locus ceruleus, and reticular formation. In the median eminence, down the infundibular
humans, lipochrome pigment (lipofuscin) is stalk to the neurohypophysis (pars nervosa),
found in most cells (Fig.3-11A). The amount where the axons end in close proximity to the
appears to increase with age. Lipofuscin consists endothelial cells. The secretory granules are 130
of pigment combined with fatty material and to 150 millimicrons in diameter and are found in
probably is a metabolic by-product of lysosomal the tract (Fig. 3-13). They increase in size as one
activity that is not readily disposable. It is approaches the endothelial end of the axons.
commonly referred to as the "wear-and-tear" The protein in the secretory granules is made
pigment. in the Nissl substance; the granules are formed in
the Golgi apparatus and transported by the axons
of the hypothalamic-hypophyseal tract to the
infundibulum, where they are stored in the neur-
allobe. The sites of storage are called Herring
bodies (Fig. 3-14B). Interruption of the hypo-
thalamic-hypophyseal tract produces diabetes
insipidus.
Neuronal Cytoskeleton
In silver-stained sections examined in a light
microscope, a neurofibrillary network can be
seen in the neurons (Fig. 3-14). Electron micro-
graphs can distinguish microtubules, 3 to 3 nm
in diameter, and neurofilaments, 1 nm in diame-
ter. It appears that fixation produces clumping of
the tubules and filaments into the fibrillar net-
work seen in light micrographs.
Neurons in common with other eukaryotic
cells contain a cytoskeleton that maintains it
shape. This cytoskeleton consists of at least three
types of fibers:
1. Microtubules 30 nm in diameter
Figure 3-8. Elearon murograph of neuron in the rat
sensory cortex, demonstrating the nucleus and nucleo-
3. Microfilaments 7 nm in diameter
lus (arrow). (<X>10,OOO.) 3. Intermediate filaments 10 nm in diameter.
3-8 CHAPTER 3
the mechanism of transport in the central ner-

vous system (Brady, 1985; Vale et al., 1985 and
1987). The products transported down the
microtubules probably move like an inch worm
and not like a train on a track. During mitosis,
microtubules disassemble and reassemble; how-
ever, a permanent cytoskeleton lattice of micro-
tubules and intermediate filaments in the neuron
is somehow maintained. It is not yet known how
long each microtubule exists, but there is evi-
dence of a constant turnover.
Neruofibrillar tangles are bundles of abnor-
mal filaments within a neuron. They are helical
filaments, that are different from normal
Figure 3-9. Motor neuron from the ventral horn ofa cytoskeletal proteins and they contain the tau
female squirrel monkey. Note the nucleus, nucleolus, protein a microtubule binding protein (MAP)
and accessory body ofEarr (arrow). (One-micron that is a normal component in neurons. In
epo»] section, <.X>1400.) Alzheimer's disease there are accumulations of
If the plasma membrane and organelle mem- abnormally phosphorylated and aggregated
brane are removed, the cytoskeleton is seen to forms the microtubule binding protein tau.
consist of actin microfilaments, tubulin-contain- These large aggregates form the tangles that can
ing microtubules, and criss-crossing intermediate be physical barriers to transport, may interfere
filaments. with normal neuronal functions, and are proba-
Neurotubules (microtubules) predominate bly toxic. Mutations in the human tau gene are
in dendrites and in the axon hillock, whereas found in autosomal domininant neuronal degen-
microfilaments are sparse in dendrites and most erative disorders isolated to chromosome. 17.
numerous in axons (Fig. 3-15). Microtubules These familial disorders are characterized by
and intermediate filaments are found throughout extensive neurofibrillar pathology and are often
the axon. called "taupathies" (Hutton 2000). Functions of
The microtubules help to transport mem- neuronic organelles are listed in Table 3-3.
brane-bound vesicals, protein, and other macro- Axon and Axon Origin
molecules. This orthograde transport, or antero- The axon contains some elongate mitochon-
grade axonal transport, is the means whereby dria, many filaments oriented parallel to the long
these molecules formed in the soma are trans- axis of the axon (Figs. 3-15, and 3-16), and some
ported down the axon into the axonal teloden- tubules. In contrast, a dendrite contains a few fil-
dria. aments and any tubules, all arranged parallel to
The individual microtubules in the nervous the long axis of the dendrite (Fig. 3-5).
system are 10 to 35 nm in length and together Polyribosomes are present, but the highly orga-
form the cytoskeleton. The intermediate fila- nized, rough endoplasmic reticulum is absent.
ments are associated with the microtubules. The Axon Hillock. The axon hillock is a slender
wall of the microtubule consists of a helical array process that usually arises from a cone-shaped
of repeating tubulin subunits containing the A region on the perikaryon (Fig. 3-16). This
and B tubulin molecule. The microtubule wall region includes filaments, stacks of tubules, and
consists of globular subunits 4 to 5 nm in diam- polyribosomes (Fig. 3-16B). The initial segment
eter; the subunits are arranged in 13 protofila- of the axon, arising from the axon hillock, is cov-
ments that encircle and run parallel to the long ered by dense material that functions as an insu-
axis of the tubule. Each microtubule also has a lator membrane at the hillock is covered by an
defined polarity. Associated with the micro- electron dense material (Fig. 3-16).
tubules are protein motors, kinesins and dyneins, Myelin. In the nervous system axons may be
which when combined with cAMP may well be
NEUROCYTOLOGY 3-9
TABLE 3·3. FUNCTIONS OF DYNAMIC ORGANELLES IN
THE NEURON
Microtubules Provide the structural basis for transport,

and axoplasmic flow. Found throughout
the neuron; part of the neuronal
cytoskeleton.
Microfilaments Form much of the cytoskeleton

of the entire neuron.
Nissl substance Protein manufacturing unit in the nerve

(rough cell. The most commonly stained
endoplasmic organelle with basophilic dyes;
reticulum) very sensitive to cell injury.
Golgi bodies Form the lipophilic portion of all the memo

branes In the neuron.
Nucleus Chromatin is dispersed as nerve cells

are very active metabolically. Eukaryotic
in the adult nerve cell; important in all
normal cell functions. Demonstrable
abnormalities in many diseases, Figure 3-10. Electron micrograph of a small pyra-
including trisomies, Alzheimer= s, midal neuron in the rat cerebral corwx, demon-
Huntington= s, and Parkinson= s. strating the following organelles: Golgi apparatus,
mitochondria, lysosome, and Nissl substance. Note
Nucleolus Contains the messenger RNA that the nuclear pore (arrow). (<1(>60,000.)
is activated by chromatin.
myelin sheaths by wrapping around the axon.
The space between the axonal plasma membrane
myelinated or unmyelinated. Myelin is formed and the forming myelin is reduced until most of
by a supporting cell, which in the central nervous the exoplasmic and cytoplasmic space is finally
system is called the oligodendrocyte and in the forced out. The result is a compact stack of
peripheral nervous system, the Schwann cell. membranes. The myelin sheath is from 3 to 100
The immature Schwann cells and oligodendro- membranes thick and acts as an insulator by pre-
cyte have on their surface the myelin-associated venting the transfer ofions from the axonal cyto-
glycoprotein that binds to the adjacent axon and plasm into the extracellular space.
may well be the trigger that leads to myelin for- Myelin Sheath. Myelin sheaths are in con-
mation. Thus, the myelin sheath is not a part of tact with the axon. In light microscopy they
the neuron; it is only a covering for the axon. appear as discontinuous tubes 0.5 to 3 mm in
Myelin consists of segments approximately 0.5 to length, interrupted at the node (Fig. 3-29). The
3 mm in length. Between these segments are the axon is devoid of myelin at the site of origin (the
nodes ofRanvier. The axon, however, is contin- nodes) and at the axonal telodendria. At the site
uous at the nodes, and axon collaterals can leave of origin the, axon is covered by an electron-
at the nodes. The myelin membrane like all dense membrane, and at the site of the synaptic
membranes contains phospholipid bi-Iayers (Fig. telodendria the various axonal endings are isolat-
3-17). In the central nervous system myelin ed from one another by astrocytic processes.
includes the following proteins: In electron micrographs each myelin lamella
Proteolipid protein (50%) actually consists of two-unit membranes with the
Myelin basic protein (40%) entire lamella being 130 to 180 A thick (Fig. 3-
Myelin-associated glycoprotein (1%) 17). Myelin is thus seen to consist of a series of
3,3-cyclic nucleotide (4%) light and dark lines. The dark line, called the
The oligodendrocytic process forms the major dense line, represents the apposition of the
3-10 CHAPTER 3
Figure 3-11. Electron micrographs showing inclusions.

A, Lipofuscin. B, Glycogen, lipid, and Nissl substance.
(<.1l>30,000.) Figure 3-12. Electron micrographs of a pyramidal
inner surface of the unit membranes. The less neuron in the rat cerebral cortex. A, Soma and
nucleus. B, Dendrite. Note the iar.qe amountofNissl
dense line, called the interperiod line, represents
substance in the soma, but the dendrites have less Nissl
the approximation of the outer surfaces of adja- substance and many microt'Ubules. (<'x>35,000.)
cent myelin membranes.
Only at the node of Ranvier is the axonal with the diencephalon and cerebrum last. A
plasma membrane in communication with the delay in myelination can result from many fac-
extracellular space. The influx of Na+ at each tors, including genetic and nutritional ones, and
node causes the action potential to move rapidly is usually very harmful to the fetus.
down the axon by jumping from node to node Peripheral Nervous System
(see Chapter 5-Part II). In the peripheral nervous system, there is
Myelination. The process of myelination usually only one Schwann cell for each length or
has been followed with the electron microscope. internode of myelin. In the central nervous sys-
An axon starts with just a covering formed by the tem each oligodendrocyte may form and main-
plasma membrane of either the Schwann cell or tain myelin sheaths on 30 to 60 axons.
the oligodendrocyte. More and more layers are The unmyelinated axons in the peripheral
added until myelination is complete. One theory nervous system are found in the cytoplasm of the
is that myelin is laid down by the processes of the Schwann cell. There can be as many as 13
Schwann cell twisting around the axon (Geren, unmyelinated axons in one Schwann cell. The
1956; Robertson, 1955); this indeed occurs in unmyelinated axons in the central nervous sys-
the peripheral nervous system. In the central ner- tem are usually found in small bundles without
vous system each oligodendrocyte enwraps many any special covering.
axons, and they also appear to twist around the
Axoplasmic Flow (Fig. 3-18).
axons as they myelinate.
The sequence of myelination has been stud- With the protein manufacturing apparatus
ied in great detail; it begins in the spinal cord, present only in the soma, and to a lesser degree
moves into the brain stem, and finally ends up in the dendrites, a mechanism must exist to
NEUROCYTOLOGY 3-11
Figure 3-14. Cytoskeleton. Neurofibrillar stain of a

ventral horn cell in the cervical spinal cord of the cat,
showing neurofibrillar network in soma and den-
Figure 3-13. Electron micrograph of a rat neurohy- drites(A): and in axons(B). X400
pophysis. A shows neurosecretorygranules in the axo-
plasm offibers of the hypothalamo-hypophyseal tract This mechanism of transport is not diffusion
(<1(>30,000). B demonstrate a Herring body, a stor- but rather retrograde axonal transport associated
age site of neurosecretory material. (<1(>8,000.) with the microtubule network that exists
Figure 3-16. Cytoskeleton. Neurofibrillary stain of a throughout the nerve cell. The rate of flow varies
ventral horn cell in the cat spinal cord, showing neu- depends upon the product being transported
rofibrillary network in soma and dendrites (A) and and ranges from more than 300 mm/day to less
in the axons (B). (<1(>400). than 1 mm a day. The main direction of the flow
transport proteins and other molecules from the is anterograde, from the cell body into the axon
soma, down the axon, and into the presynaptic and synapse. There is also a very active retro-
side. Weiss and Hisko (1948) demonstrated by grade flow from the synaptic region back to the
tieing off a peripheral nerve, which caused cell body that may be a source for recycling many
swelling proximal to the tie, that material flows of the substances found at the synaptic ending.
from the soma, or trophic center, into the axon The particles that move the fastest consist of
and ultimately to the axon terminal. The devel- small vesicles of the secretory and synaptic vesi-
opment of techniques that follow this axoplasmic cles, and the slowest group is the cytoskeletal
flow has revolutionized the study of circuitry components. Mitochondria are transported
within the central nervous system. The ability to down from the cell body at an intermediate rate.
map this circuitry accurately has given all neuro- The retrograde flow from the synaptic teloden-
scientists a better understanding of the integra- dria back into the soma, returns any excess of
tive mechanisms in the brain. There are many material for degradation or reprocessing. The
compounds now available to follow circuitry in retrograde flow permits any excess proteins or
the brain and they include horseradish peroxi- amino acids to recycle. It also permits products
dase, wheat germ agluttin, tetanus toxin, fluores- synthesized or released at the axonal cleft to be
cent molecules and radiolabeled compounds. absorbed and then transported back to the cell
3-12 CHAPTER 3
body, where they can affect the basic function of TABLE 3-4. CONTENTS OF A PERIPHERAL NERVE
the cello-the signaling process. BUNDLE
Fast axonal transport is associated with the
microtubules. The slower components including Epineurium The outer layer, covering the nerve trunks
and filling between the individual fascicles
membrane associated proteins (MAPS) are trans-
consists of connective Hssue cells,
ported inside the microtubules, but the mito- collagen, and some fat cells.
chondria actually descend the axonal cytoplasm
(Table 3-3). Perineurium Aconnective tissue layer that surrounds
TABLE 3-3. RATE OF AXONAL TRANSPORT OF CELLULAR the nerve fascicles
STRUCTURES (DATA FROM GRAFTSTEIN AND FORMAN, Endoneurium Strands of collagen and fibroblasts
1980; MCQUARRIE, 1988; WWEK AND LASEK, 1983.) (sheath of between individual axons. Endoneurium
Key-Retzius) also refers to the delicate trabeculum
TransQort Rate (mm/da~) Cellular Structure surrounding each nerve fiber.
Fast 300<->400 Vesicles, smooth Sheath of Engulfs each individual axon
endoplasmic reticulum, Schwann and forms myelin.
and granules
Intermediate 50 -- Mitochondria the epineurium and perineurium and capillaries

15 --Filament proteins are seen in the endoneurium.
Fibers can vary in diameter from less than 0.5
Slow 3<->4 Actin, fodrln, enolase,
component CPK, calmodulin, microns to 33 microns (see Chapter 5 Part II).
B and clathrin Axons can be classified by size and function into
three major groups (Table 3-5).
Slow 0.3<->1 Neurofilament protein, Central Nervous Structure. Axons in the
component tubulin, and MAPS central nervous system also vary in size (5 to 33
A
microns) and in length (0.5 mm to 1 m), but
these axons cannot be separated into functional
categories based on axonal diameter. The axons
Peripheral Versus Central Nerve Structure in the central nervous system run in groups
Peripheral Nerve Structures. The struc- called tracts that are enwrapped by the processes
ture of a peripheral nerve is different from that of of fibrous astrocytes. However, no specific cov-
fiber bundles in the central nervous system
(Table 3-4). Peripheral nerves consist of many TABLE 3-5. FUNCTIONAL COMPONENTS
axons held together in a fascicle by connective OF PERIPHERAL NERVES
tissue of mesodermal origin (Fig. 3-19). The
outer layer that covers the nerve trunks and fills Fiber DeSCription Diameter Conduction
between the individual fascicle is called the
Type (microns) Speed
(meters
epineurium. It consists of connective tissue cells, ~er second)
collagen, and some fat cells. Each of the fascicles Type Myelinated somatiC 1<->33 5<->130
is wrapped in a dense layer of connective tissue, A afferent and
which is called the perineurium. Strands of col- efferent fibers.
lagen, fibroblasts, and other cells that run
between the individual nerve fibers are called the Type Myelinated efferent 1<->3 3<->15
B preganglionic
endoneurium. The term endoneurium is also autonomic fibers.
applied to the delicate trabeculum surrounding
each nerve fiber, which is also called the sheath of Type Unmyelinated 0.3<->1.3 0.5<->3
Key-Retzius. The peripheral nerve fiber or axon C afferentor efferent
is engulfed in the Schwann cytoplasm (the fibers, pain fibers,
neurilemmal sheath), which also forms the and postganglionic
sympathetics fibers.
myelin sheath. Large blood vessels are found in
NEUROCYTOLOGY 3-13
Figure 3-15. Electron micrograph of the rat cerebral cortex, demonstrating the difference between a myelinated
axon and a dendrite. Note the axon has numerous microftlaments while the dendrite has numerous microtubules.
«]630,000.)
ering corresponds to the sheath of Schwann in axon, some axons run very long distances. For
the peripheral nervous system. Each tract has a example, from the type I pyramidal cell in the
distinct function in the nervous system. cerebral cortex to the ventral hom cells in the
The axonal arborization of neurons is not as sacral spinal cord, or from a ventral hom cell in
elaborate as that of the dendrite, but it can be the spinal cord, down a peripheral nerve to a
very extensive. Although the surface area of foot muscle.
many dendrites may total more than that of an Action Potentials. The action potential is
3-14 CHAPTER 3
generated at or near the axon hillock and is then ron either below or above the firing threshold.
propagated down the axon as an all-or-none phe- Synapse: Synapses can be seen at the light
nomenon to the synapse (see Chapter 5 - Part microscopic level (Fig 3-20), however to identifY
II). Several axon terminals that come from many all the components of a synapses the electron
different sources are found on any neuron. microscope must be use. At the electron micro-
Unlike the axon, the dendrite does not respond scopic level the synapse consists of the axonal
in an all-or-none fashion like the axon. Instead, ending, which forms the presynaptic side, and
each nerve impulse at a given site on the dendrite the dendritic zone, which forms the postsynaptic
produces a change in the electrical activity. The side (Fig. 3-21). Collectively, the pre- and post-
sum total of all these electrical changes result in a synaptic sides and the intervening synaptic cleft
variation in the membrane potential in the neu- are called the synapse.
Figure 3-16. Appearance of the axon hillock: A, after Nissl staining (<1(>400), B, in an electron micrograph
(<1(>15,000), and C, after Golgi rapid staining (<16350).
NEUROCYTOLOGY 3-15
Figure 3-18. Demonstration of the cells of origin of

callosal RXOns with the horseradish peroxidase<-
>diaminoben.zidine reaction method in layers III,
and V of the somatosensory cortex. The horseradish
peroxidase was injected into the contralateral cortex
Figure 3-17. Electron micrograph of myelin .sheath 34 hours pretliously. The predominant cell type is
from the optic nerve of the mouse demonstratmg pyramidal. (Darkfield, <.16100.)
repeating uni# of the myelin sheath, consisting of a
series of light and dark lines. The dark line, called the has revealed many new details in synaptic struc-
major dense line (MDL), represen# the apposition of ture (Bodian, 1970; Colonnier, 1969; Gray,
the inner surface of the unit membranes. The less 1959; Palay, 1967). In an electron micrograph,
dense line, called the interperiod line (IPL), represen# the presynaptic or axonal side of the synapse con-
the approximation of the outer surfaces of adjacent
tains mitochondria and many synaptic vesicles
myelin membranes. (<X>67,000.) (Courte? of~n
Peters, Department of anatomy, Boston UmllerSfty (Fig. 3-21). Synaptic vesicles are concentrated
School of Medicine) near the presynaptic surface with some vesicles
actually seen fusing with a membrane (Fig. 3-
At the synapse the electrical impulse from 21), illustrating that this site releases neurotrans-
one cell is transmitted to another. Synapses vary
mitters. Neurofilaments are usually absent on
in size from the large endings on motor neurons
the presynaptic side. Pre- and postsynaptic mem-
(1 to 3 microns) to smaller synapses on the gran-
branes are electron-dense and are separated by a
ule and stellate cells of the cortex and cerebellum
30 to 40 nm space, the synaptic cleft, which is
(less than 0.5 microns). Synapses primarily occur
continuous with the extracellular space of the
between the axon of one cell and the dendrite of
central nervous system.
another cell. Synapses are usually located on the
Synaptic Types. Two types of synapses, elec-
dendritic spins but are also seen on the soma and
trical and chemical, differ in location and appear-
rarely between axons. At the synapse the axon
ance. Most of the synapses in the mammalian
arborizes and forms several synaptic bulbs that
central nervous system are chemical.
are attached to the plasma membrane of the
Electrical synapses are connected by mem-
opposing neuron by intersynaptic filaments (Fig.
brane bridges, gap junction connections, which
3-21).
permit the electric impulse to pass directly from
Structure. Synapses can be identified by
one cell to the other. Electric synapses have
light microscopy, but the electron microscope almost no delay and little chance of misfiring.
3-16 CHAPTER 3
Figure 3-20. Silver stain of a one-micron plastic

embedded section. A demonstrates synaptic boutons on
neurons in the reticular formation. B demonstrates
houtons on ventral horn cells. (<16400.)
postsynaptic bush with presynaptic vesicles (Fig
3-21). This type of synapse is most commonly
Figure 3-19. Peripheral nerve of a cat. A shows seen on dendrites. Glutamate has been identified
wrapping of the nerve trunk, the epineurium; each in excitatory synapses. At the excitatory synapse
nerve fascicle is surrounded by the perineurium while there is a change in permeability that leads to
each nerve fiber is embedded in endoneurium depolarization of the postsynaptic membrane
(Bodian stain, <16100). In B, 1 demonstrates a lar:ge
and which can lead to the generation of an action
myelinated axon; 3 points to a small myelinated and
unmyelinated axon (Bodian stain, <X>350). potential. Glutamate has been identified in exci-
tatory synapses.
These synapses are seen in many fish. Inhibitory synapses in the central nervous
Chemical synapses have a presynaptic side, system are symmetrical with thickened mem-
containing vesicles and a gap, and the postsynap- branes on the pre- and postsynaptic side and vesi-
tic side with membrane receptors. The neuro- cles only on the presynaptic side. GABA has
transmitter released by the action potential is been identified in the inhibitory synapses. At an
exocytosed and diffuses across the synaptic cleft inhibitory synapse the neurotransmitter binds to
and binds to the specific receptor on the postsy- the receptor membrane, which changes the per-
naptic membrane. meability and tends to block the formation of the
Synapses are either excitatory or inhibitory. action potential. Synapses on the soma are sym-
Synapses that depolarize the membrane potential metrical and they are considered inhibitory.
(make it more positive) are excitatory. Synapses Throughout much of the central nervous sys-
that hyperpolarize the membrane potential tem, spines are found on the dendrites. These
(make it more negative) are inhibitory. dendritic spines are bulbous, with a long neck
Excitatory synapses in the central nervous connecting to the dendrite. Many axon termi-
system are asymmetrical, having a prominent nals are located on the spines. In the cerebral
NEUROCYTOLOGY 3-17
cortex, a spine apparatus is found within the affects the shape of a vesicle. Bodian (1970) has
spine, which seems to function like a capacitor, shown that osmium fixation produces only
charging and then discharging when its current spheroidal vesicles. Aldehyde followed byosmi-
load is exceeded (see Fig. 3-2, 3-15). um produces spheroidal and flattened vesicles.
Synaptic Vesicles. The synaptic vesicles dif- The shape of flattened vesicles may also be mod-
fer in size and shape and may be agranular, spher- ified by washing the tissue in buffer or placing
ical, flattened, or round with a dense core. The the tissue directly from the aldehyde into the
method of fixation for electron micrographs osmium. The spheroidal vesicles retain their
Figure 3-21. Synapse in the sensory cortex of the rat tkmonstrating agranular synaptic vesicles (300 to 400 A) in
the presynaptic axonal sitko Note the electron-tknse synaptic membranes and the intersynaptic filaments in the
synaptic cleft. Electron micrograph (<'x>65,000.)
3-18 CHAPTER 3
shape regardless of any manipulation. cleft produces the same change in the resting
There are four basic categories of synaptic membrane potential as stimulation of the presy-
vesicles (Palay, 1967), as described in Table 3-6. naptic axon; the compound is rapidly degraded,
Treating the Type 1 vesicles with high osmo- and the membrane potential returns to the rest-
lality aldehyde fixatives produces the commonly ing state.
seen spherical vesicles and also a group of flat- The neurotransmitters are either amino acids,
tened, ovoid, or disc-shaped vesicles. Flattened derived from amino acids, or small neuropep-
vesicles are known to be inhibitory synapses, and tides. The classic neurotransmitters in the central
the spherical vesicles are assumed to be excitato- nervous system include acetylcholine, epineph-
ry synapses. rine, norepinephrine, serotonin, glycine, gluta-
Synaptic Transmission. Current evidence in mate, dopamine, and GABA At certain synaptic
the mammalian central nervous system suggests sites the following compounds may also function
that synaptic transmission is primarily a chemical- as modulators (usually a slower transmitter) form
ly and not an electrically mediated phenomenon, of neurotransmission: adenosine, histamine,
based on the presence of: octopamine, B-alanine, ATP, and taurine. Many
1. A 30 to 40 nm cleft of the neuropeptides, such as substance P,
3. Synaptic vesicles vasoactive peptide, peptide Y, and somatostatin
3. Appreciable synaptic delay due to are also active in neurotransmission or neuro-
absorbance of the chemical onto the postsynap- modulation. Catecholamines and 5-hydrox-
tic receptor site. ytryptamine are transmitters linked to synaptic
In contrast electrical synapses have cytoplas- transmission in the central nervous system.
mic bridges that interconnect the pre- and post- Noradrenaline is a transmitter at the pregan-
synaptic membranes resulting in a minimal glionic synapses.
synaptic delay as transmission is ionic rather than Many steroids and hormones have also been
by release of chemical from a vesicle. linked to synaptic transmission. It is still uncer-
Neurotransmitters tain whether these compounds playa direct role
in nervous transmission or if they are just related
Many compounds have been identified as
by their importance to the ongoing functions of
neurotransmitters. These substances are found
the entire nervous system (Table 3-7).
in synaptic vesicles on the presynaptic side.
At excitatory synapses the following com-
Introduction of the compound into the synaptic
TABLE 3-6. CATEGORIES OF SYNAPTIC VESICLES
Type Diameter Locations

1. Spheroidal or naHened wtth a 30 to 40 nm At neuromuscular junction and throughout
clear center; most common type central nervous system.
(Figs. 3-33 and 3-34).
2. Spheroidal with 38 nm 40 to 80 nm Found in autonomic endings in the Intestines,

electron-dense granule in the center vas deferens, and pineal body; contains catecholamines.
3. Spheroidal with a 50 nm 80 to 90 nm Found aI preganglionic sympathetiC synapses, at

electron-dense granule in the center neuromuscular junctions in smooth muscle, and in pari
of the hypothalamus, basal nuclei, brain stem, and
cerebellum; calecholamlnes present in vesicles.
4. Spheroidal with a large droplet Characteristic of nerve endings in the hypothalamus
thai nearly fills the vesicle (Fig. 3-15). 130 to 300 nm and neurohypophysis; also found in the soma, axons,
and presynaptic endings of nerve cells of the
hypotholomic-hypophyseoltroc!;
vesicles contain vasopressin and oxytocin.
NEUROCYTOLOGY 3-19
TABLE 3-7. LOCATION AND FUNCTION OF NEUROTRANSMITTERS
Agent location Function

L-Glutamine Excitatory neurons ExcHation
GABA Inhibitory neurons Inhibition (fast/slow)
Acetylcholine Motor neurons, basal forebrain, and Excitation and modulation

midbrain and pontine tegmentum
Monoamines Brain stem and hypothalamus Modulation

-- Norepinephrine --Locus ceruleus
-- Serotonin --Raphe nuclei
-- Histamine --Hypothalamus
Neuropeptides limbic, hypothalamus, autonomics, Modulation

and pain pathways
tern end in skeletal muscles and form the motor

end plates (see Chapter 6). Nerve endings in
smooth and cardiac muscle and in glands resem-
ble the synaptic endings in the central nervous
system. Visceral motor endings are found on
muscles in arterioles (vasomotor), muscles in hair
follicles (pilomotor), and sweat glands
(sudomotor).
Sensory Receptors. A stereogram of the
skin is shown in Figure 1-3. Table 3-8 lists the
mechanicoreceptors in the body.
Sensory Endings (Fig 1-3). Sensory end-
ings, found throughout the body, subserve pain,
Figure 3-22. Degenerating synaptic ending in the touch, temperature, vibration, pressure, heat,
sensory cortex of the adult rat, showing dense vesicles and cold in the skin, muscles, and viscera as well
and filaments replacing the normal appearance seen
as the specialized somatic and visceral sensations
in Figure 3-21. Electron micrograph <1(> 115,000
of taste, smell, vision, audition, and balance.
pounds have been found: acetylcholine, norepi- Visceral sensory receptors are similar to somatic
nephrine, dopamine, serotonin, glutamate, and
sensory receptors associated with the somatic
aspartate. Inhibitory neurotransmitters include
nervous system, except that they are located in
GABA, histamine, neurotensin, and angiotensin.
the viscera and their accessory organs.
Acetylcholine, the best documented trans-
Free Nerve Endings (Fig. 1-3). Free nerve
mitter in the peripheral nervous system, has been
isolated in synaptic vesicles. Acetylcholine TABLE 3-8. MECHANICORECEPTORS
esterase has been found throughout the central
and peripheral nervous systems and at postgan- Modality Receptors
glionic sympathetic endings. light touch and vibration Encapsulated endings--
Effectors and Receptors Meissner=s and
Pacinian corpuscles
Each peripheral nerve, whether sensory,
motor, or secretory, terminates by arborizing in a Proprioception Muscle spindles and Goigi
peripheral structure (Fig.1-3). tendon organs in joints
Effectors Pain and temperature Free nerve endings
The motor nerves of the somatic nervous sys-
3-20 CHAPTER 3
endings are formed by sensory fibers and Remember that all of the sensory endings
arborize in various tissues, including the stratified form the primary neurons in the sensory system.
epithelium, muscles, tendons, connective tissues, Their cell bodies are located in the spinal dorsal
mucosa, and serous membranes in joints. They root ganglia or cranial nerve ganglia, and their
are considered to be pain receptors because they axons enter the central nervous system. The
are found in tissues where pain is the primary motor or effector axons represent the lower
sensation, such as tooth pulp, dentin, and the motor neuron or final neuron in the motor
cornea. Crude touch may also be subserved by system.
these receptors. Supporting Cells of the Central
Free nerve endings are also found in terminal Nervous System
networks around the disc-shaped tactile cells of
The central nervous system has billions of
Merkel and around the hair follicles in the dermal
neurons, but the number of supporting cells
sheath and outer root sheath. These structures
exceeds them by a factor of five or six.
appear to subserve touch.
Supporting cells form a structural matrix and
Encapsulated Sensory Endings (Fig. 1-3).
playa vital role in transporting gases, water, elec-
In these endings, the nerve is surrounded by a
trolytes, and metabolites from blood vessels to
specialized connective tissue capsule of varying
the neural parenchyma and in removing waste
thickness. Encapsulated endings include
products from the neuron. In contrast to the
Meissner=s and pacinian corpuscles, muscle and
neuron, the supporting cells in the adult central
tendon spindles, the cylindrical end bulb of
nervous system normally undergo mitotic divi-
Krause, and the end bulb ofGolgi-Mason.
sion. The supporting cells are divided into
Meissner's Corpuscles(Fig 1-3).
macroglia and microglia.
Meissner=s (tactile) corpuscles are presumed to
The macroglia, which include astrocytes,
subserve touch. They are elliptical and may have
oligodendrocytes, and ependyma, are the sup-
from one to five myelinated nerve fibers arboriz-
porting cells or neuroglia (nerve glue) of the cen-
ing in their lamellated capsule. These end organs
tral nervous system (fig 3-23). Schwann cells,
are found in dermal papillae, being most numer-
satellite cells, and fibroblasts are supporting cells
ous in the fingertips, soles, palms, lips, glans
of the peripheral nervous system. Mesodermal
penis, and clitoris.
microglia cells include the perivascular cells and
Pacinian Corpuscles (fig 1-3). These cor-
any white blood cells found within the parenchy-
puscles resemble a sliced onion. Many concen-
ma of the central nervous system. Functions of
tric layers built upon the centrally placed axon.
the different supporting cells in the nervous sys-
They are found throughout subcutaneous tissue
tem are summarized in Table 3-9.
and are especially numerous in the hand, foot,
mammary glands, clitoris, and penis. Pacinian Astrocytes (Figs. 3-23, 3-24, and 3-25)
corpuscles are pressure-sensitive receptors. Astrocytes are of two types: fibrous (most
Herbst=s corpuscles are similar to pacinian cor- common in white matter) or protoplasmic (most
puscles but smaller.
End Bulbs of Krausse and Golgi-Mason(fig
1 -3). These endings are found throughout the
body and contain a single, extensively ramified
axon within the matrix. Many variants of this
structure have been identified. This organ is pre-
sumed to record changes in heat and cold.
Muscle and Tendon Spindles (fig 7-20). OLl~
•
The muscle spindles and annulospiral endings . ASTRO
(see Chapter 5), as well as the tendon spindles, •
transmit information concerning muscular activ-
ity and tendon stretching to the central nervous Figure 3-23. Appearance of neuron, astrocyte (astro),
system. and oligodendrocyte (oligo). Nissl stain. (<X>300.)
NEUROCYTOLOGY 3-21
TABLE 3-9. FUNCTIONS OF SUPPORTING CELLS
Cell Type Functions

Aslrocytes Major supporting cells in the brain,
--Fibrous type forming microenvironment for
(white matter) neurons; act as phagocyte; Isolate
--Protoplasmic synapses, enwrap blood vessels, and
type (gray matter) form membranes on brain=s
inner and outer surface.
Oligodendrocytes Form and maintain myelin
Ependymal cells Ciliated lining cells of the

ventricular system
Figure 3-24. Dendrite with dendritic spine. The spines
Endothelial cells lining cells of blood vessels in the greatly increase the surface area of many neurons.
brain that form blood-brain barrier. Note the many microtubules in the dendrite and the
neck of eh dendritic spin conmining a spine appara-
Microglia Supporting cells and multi potential tus. The3re are several synapses on the spine. EleCUJrn
(pericytes) cells found in the basement micrograph <X> 80,000.
membrane of blood vessels and
within brain parenchyma
Astrocyte
Mononuclear White cells from the Circulation that ~~~~~~---d

cells readily enter the brain (lymphocytes,
monocytes, and macrophages)
and function as sentinels for the
immune system
common in gray matter). All astrocytes are larg-

er and less dense than the oligodendrocytes. The
astrocytes fonn a complete membrane on the
external surface of the brain called the external
glial limiting membrane, which surrounds all
blood vessels, fuses with the ependymal process-
es, and isolates neuronal processes.
In light micrographs astrocytes appear as pale
cells with little or no detail in the cytoplasm. The
nuclei are smaller than those of a neuron but
larger and less dense than those of an oligoden-
drocyte (Fig. 3-24). Electron micrographs
demonstrate that fibrous astrocytes have many
filaments, which in places appear to fill the cyto- Figure 3-25. Electron micrograph demonstrating
plasm. There are few microtubules, and the appearance of the neuron, astrocyte (astro), and oligo-
dendrocyte (oligo). (<X> 18,000.)
processes appear pale. The nuclei of these cells
have some condensed chromatin adjacent to the synapses and help form the blood-brain barrier
nuclear membrane. Glycogen is also common in by enwrapping brain capillaries (outer and inner
astrocytic processes. Protoplasmic astrocytes limiting membranes). If the brain is damaged by
have nuclei that are a little darker than those of a infarction, for example, astrocytes proliferate and
neuron. They resemble fibrous astrocytes except form scars.
that they have just a few filaments. Astrocytes and adjacent neurons fonn the
Astrocytes not only form the skeleton of the microenvironment of the nervous system. There
central nervous system but also tend to segregate are approximately 100 to 1,000 astrocytes per
3-22 CHAPTER 3
neuron, depending on the size of the neuron. In

areas with high glutamate concentration, such as
the cerebral cortex, or areas with high dopamine
content, such as the basal nuclei, the glia take on
the chemical characteristics of the adjacent neu-
ron. Glia are involved in neuronal functions
because they absorb transmitters and modulators
in their environment and often release them back
into the synapse.
When central nervous system diseases affect
only astrocytes, the reaction is called primary
astrogliosis. More commonly, the disease
process affects nerve cells primarily, which is
called secondary astrogliosis. When an injury
occurs to the nerve cell in the central nervous
system without concomitant injury to blood
vesicles and glia, the nerve cells are phagocytized
and the astrocytes proliferate and replace the
neurons, forming a glial scar (replacement glio-
sis). In the case of a more severe injury to the
nervous system, such as an infarct that damages
glia, nerve cells, and blood vessels, the astrocytes
proliferate along the wall of the injury, and the Figure 3-26. Electron micrograph of a human cere-
dead neurons and glia are phagocytized, leaving bral cortex demonstrating diffirences in the density of
only a cavity lined with meninges. In all other the DNA in the nuclei of oligodendrocytes (oligo) and
organs there are enough fibroblasts to proliferate microglia. (<X>30,OOO.)
and form a scar, but in the central nervous sys- pIe sclerosis). The formation of myelin is under
tem there are only a few fibroblasts, so cavitation genetic control. Oligodendrocytes are usually
is a common sequela to extensive destruction. seen in close proximity to astrocytes and neu-
Oligodendrocytes rons, and all three cell types are important in
In light micrographs the oligodendrocyte forming and maintaining myelin.
has a small darkly stained nucleus surrounded by Endothelial Cells
a thin ring of cytoplasm (Fig. 3-23). In electron Endothelial cells form the lining of the capil-
micrographs oligodendrocytes are dense cells laries in the central nervous system(fig 3-25).
with many microtubules and few neurofilaments They are of mesodermal origin and bound
(Figs. 3-25 and 3-26). Dense clumps of rough together by tight junctions. Their tight junc-
endoplasmic reticulum and clusters of polyribo- tions and apinocytosis provide the basis of the
somes are seen in the cytoplasm, which is denser blood-brain barrier (see below).
but scantier than that in neurons. The nucleus
tends to be located toward one pole of the cell; Mononuclear Cells
the nuclear chromatin tends to be heavily Mononuclear cells--Iymphocytes, mono-
clumped. In electron micrographs oligodendrocytes, and histiocytes--are found in the central
cytes can be distinguished from astrocytes nervous system, where they seem to act as
because they have a darker cytoplasm and nucle- phagocytes, breaking down myelin and neurons.
us, few if any filaments, and more heavily con- Myelin destruction always triggers intense
densed chromatin (Fig. 3-26). macrophage reaction within 48 hours, followed
The role of the oligodendrocyte is to form by infiltration of monocytes first and then lym-
and maintain myelin (although they may also be phocytes. Note that astrocytes have also been
responsible for breaking down myelin in multi- shown to engulf degenerating myelin sheaths,
axonal processes, and degenerating synapses.
NEUROCYTOLOGY 3-23
The central nervous system was once consid- TABLE 3·10. lYPES OF MICROGLIA CELLS
ered an Aimmunologically privileged site@
because: Cell Type Function
1. No specific lymph drainage from the cen- Monocytes Enters brain during early
tral nervous system alerts the immune system of development and is the stem
infection. cell of microglia.
2. Neurons and gIia do not express the major Perlcytes Found inside the brain in the
histocompatibility complex. (perivascular cell) basement membrane of the blood
3. The major cell for stimulating the immune vessel; can act as a macrophage.
response (leukocyte dendritic cells) is not nor-
mally present in the disease-free nervous system. Amoeboid microglia Transitional form leads to
resting microglia.
However, recent studies have shown that
there is a regular immune surveillance of the cen- Resting microglia Down-regulated from amoeboid
tral nervous system, which is sufficient to control (ramified) microglia; probobly the sennneis In
many viral infections (Sedgwick and Dorries, the brain that raise the alarm for
1991). It is now known that immune cells reg- invasive diseases.
ularly enter the brain through the capillaries and Activated microglia Upregulated resting cell changes
that macrophages infected with human immun- into parHally acHvated macrophage
odeficiency virus (HIV), for example, can infect with MHC class I.
the brain directly, the so-called Trojan-horse
phenomenon (Haase, 1986; Price et al., 1988). Reactive microglia Fully acHvated macrophage with
MHC class II and phagocytic
Miaoglia properHes.
Neurons, astrocytes, and oligodendrocytes
are ectodermal in origin, but microglial cells are Giant Forms from fusion of reacHve cells;
multinucleated cells associated with viral brain infecHons
mesodermal in origin (Fig. 3-26). The ovoid and Creutzfeld-Jakob disease;
microglia cells are the smallest of the supporting hallmark of AIDS dementia.
cells and are divided into two categories: (1)
those that form the perivascular cells and (3) the
the brain and, after formation of the blood-brain
resting microglial cells in the brain parenchyma.
barrier, become trapped (Davis et al., 1994; ling
Microglial cells originate from monocytes that
enter the brain (Table 3-10). and Wong, 1993). The monocytes pass through
Pericytes are found in relation to capillaries an intermediate phase of development, the
amoeboid microglia, which evolve into a down-
but external to the endothelial cells and
enwrapped in the basal lamina. In electron regulated resting form, the ramified microglia.
micrographs they are not as electron-dense as These resting microglia are found throughout
oligodendrocytes and lack the neurofilaments of the central nervous system and may well be the
the astrocyte and the tubules of the oligoden- sentinels that alert the immune system to disease
drocyte. The cytoplasm is denser than that of in the brain. With the appeearance of any cen-
astrocytes and contains fat droplets and laminar tral nervous system disease (e.g., multiple sclero-
dense bodies. The granular endoplasmic reticu- sis, stroke, trauma, or tumors), the resting
microglia are upregulated and become activated
lum consists of long stringy cisterns. Microglia
microglial cell. The factor or gene that upregu-
are considered multipotential cells because with
the proper stimulus they can become lates or down-regulates these cells is currently
unknown. Once the disease process has been
macrophages (Vaughn and Peters, 1968). The
resolved, the activated microglia can revert to
pericyte contains actin, and this cell may well be
important in controlling the channels entering resting microglial cells.
the endothelial cells (Herman and Jacobson, The activated microglia cell is a partially acti-
1988). vated macrophage containing the CR3 complex
During early development, monocytes enter and class I major histocompatibility complex
(MHC). The active microglia then become a
3-24 CHAPTER 3
reactive microglial cell, which is a fully active

macrophage containing class II MHC and
phagocytic activity. These cells are very active
during all major disease states in the brain.
Activated microglial cells can also evolve into
giant multinucleated cells by the fusion of reac-
tive cells. They are seen in viral infections and are
considered the hallmark of AIDS dementia. Also
called gitter cells, giant multinucleated cells are
often found in patients with Creutzfeldt-Jakob
disease (Fig. 3-31), a disease caused by proteina-
ceous infectious particles, or prions.
Figure 3-28. Sensory ganglion of the rhesus monkey,

demonstrating pseudounipolar cells surrounded by
their satellite cells (arruw). (<'x>300.)
al crest) in the peripheral nervous system and
function like oligodendrocytes, forming the
Figure 3-27. Ependymal lining cells in the third ven-
myelin and neurilemmal sheath. In addition, the
tricle ofa rat. Note prominent cilia (arruws) in this
one-micron thick plastic-stained section. (<.X>1,400.) unmyelinated axons are embedded in their cyto-
plasm. Schwann cell cytoplasm stops before the
Ependymal Cells (Fig. 3-27) nodes of Ranvier (fig 3-33), leaving spaces
between the node and Schwann cells. In an
Ependymal cells line all parts of the ventricu-
injured nerve Schwann cells can form tubes that
lar system. They are cuboidal, ciliated, and con-
penetrate the scar and permit regeneration of the
tain filaments and other organelles. The process-
peripheral axons. Nerve growth factor is impor-
es of these cells extend in the central nervous sys-
tant to proliferation of the Schwann cells.
tem and fuse with astrocytic processes to form
the inner limitingglial membrane. Highly mod- Neural Crest Cells
ified ependymal cells are found attached to the These cells originate embryologically as neu-
blood vessels in the roof of the body of the later- roectodermal cells on either side of the dorsal
al ventricles, the inferior hom of the lateral ven- crest of the developing neural tube but soon
tricles, and the third and fourth ventricles. There drop dorsolaterally to the evolving spinal cord
they form the choroid plexus, which secretes area. Neural crest cells migrate out to form the
much of the cerebrospinal fluid (Fig. 3-35). following: dorsal root ganglion cells, satellite
Ependymal cells originate from the germinal cells cells, autonomic ganglion cells, Schwann cells of
lining the embryonic ventricle, but they soon the peripheral nervous system, chromaffin cells
stop differentiating and stay at the lumen on the of the adrenal medulla, and pigment cells of the
developing ventricles. integument.
Satellite Cells (Fig. 3-28) Response of Nervous System to Injury
Satellite cells, which are found only in the Degeneration
peripheral nervous system among sensory and
Neuronal death or atrophy may result from
sympathetic ganglia, originate from neural crest trauma, circulatory insufficiency (strokes),
cells. Many satellite cells envelop a ganglion cell.
tumors, infections, metabolic insufficiency, devel-
Functionally, they are similar to the astrocytes,
opmental defects, and degenerative and heredo-
although they look more like oligodendrocytes.
degenerative diseases. These neuropathologic
Schwann Cells processes produce a range of responses in the
Schwann cells are ectodermal in origin (neur- neurons and glia (Ramon y Cajal, 1938; Young,
1943). In this section, the neuronal response to
NEUROCYTOLOGY 3-25
following series of responses in the soma:
1. The nucleus, cell body, and nucleoli swell.
The nucleus is displaced from the center of the
cell body and may even lie adjacent to the plasma
membrane of the neuron.
2. A slow dissolution ofNissl substance starts
centrally and proceeds peripherally, until only the
most peripherally placed Nissl substance is left
intact (which is probably essential to the protein
metabolism of the rest of the cell). This dissolu-
tion of the Nissl substance (ribosomal RNA),
called chromatolysis, allows the protein-manu-
Figure 3-29. Longitudinal section of a peripheral
nerve fixed in osmium, demonstrating the nodes of facturing processes to be mobilized to help the
Ran'Vier (arrows). (<X>1,000.) neuron survive the injury. The mRNA then
begins the manufacturing of membrane that is
injury will be examined in the cell body and transported down the intact tubules into the
axon. growing axonal ending (growth cone).
Retrograde Changes in the Cell Body 3. All other organelles in the cell body and
(Fig. 3-30). Section of the axon obr direct dendrites also respond to the injury. The mito-
injury to the dendrites or cell body produces the chondria swell, and the smooth endoplasmic
c D
Figure 3-30. Ventral horn cells in the human lumbar spinal cord. A, Normal. B to D, Wallerian retrograde
chromatolytic changes in 'Ventral horn cells following injury to the peripheral nerve. B, Chromatolytic neuron with
eccentric nucleus and some dissolution of the Nissl substance. G Chromatolytic neurons, shuwing a peripheral ring
of Nissl substance (peripheral chromatolysis). D, Chromatolytic neuron, shuwing eccentric nucleus and only a
peripheral ring of Nissl substance. (Nissl stain, <X>400.)
3-26 CHAPTER 3
reticulum proliferates to help in the formation of

new plasma membrane and new myelin.
These responses represent the increased ener-
gy requirements of the nerve cell and the need to
form plasma membrane during the regenerative
process. If the cell survives the injury, all
organelles return to normal: the nucleus returns
to the center of the cell body, and the soma
returns to its pretraumatic size. If the injury is
too extensive, the neuron atrophies or dies. The
responses of neuronal soma to injury (chroma-
tolysis) can be summarized in three steps:
I. Swelling of nucleus, nucleolus, and cyto-
plasm with nucleus becoming eccentric as a
direct response to injury of the axon or dendrite.
Nissl substance appears to dissolve.
2 Proliferation of metabolic processes in the
nucleus including mRNA occurs. Endoplasmic
reticulum and mitochondria starts manufactur-
ing membranes and increasing the energy avail-
able in the cell.
3. With successful recovery, the cell returns
to normal size. If seriously injured, the cell
becomes atrophic or may be phagocytized. Figure 3-31. A and B, Electron micrograph of a
Atrophic Change. In atrophic change, the reactive astrocyte in the cerebral cortex of a person
nerve cell is too severely damaged to repair itself with Jakob-Creut:ifeldt disease. Note the prominent
Consequently, the cell body shrinks and becomes digestion vacuoles shown in higher power in B. (A,
smaller. This response is similar to the response <X>8,000; B, <X> 35,000.)
of a nerve cell to insufficient blood supply, which and 3-32), and it may take several months before
produces an ischemic neuron. If necrosis occurs, all of the fragments are ingested. In the proximal
the neuron cannot survive. The Nissl substance portion degenerative changes are noted back to
begins to disperse, and after 7 days the nucleus the first unaffected node. As the myelin degen-
becomes dark and the cytoplasm eosinophilic. erates, it is broken up into smaller pieces that can
Within a few days, these cells are phagocytized. be ingested more easily (Figs. 3-32 and 3-33).
Wallerian Degeneration. When an axon is
REGENERATION
sectioned, the distal part that is separated from
the trophic center (cell body) degenerates, a Peripheral Nerve Regeneration
process called wallerian, or anterograde, degener- Within a few days after section, the proximal
ation. At the same time, the cell body undergoes part (attached to a functional neuronal soma) of
a process called axonal, or retrograde, degenera- the nerve starts regrowing. Nerve growth factor
tion. If the cell body remains intact, the proximal is produced after injury to the axon, and it pro-
portion begins to regenerate. The distal stump is motes the axonal sprouting. If the wound is
usually viable for a few days, but its degeneration clean, e.g., a stab sound, sewing the nerve ends
begins within 13 hours of injury. The axon starts together can dramatically increase the rate of
to degenerate before the myelin sheath. In 4 to recovery in the affected limb. The regenerating
7 days, the axon appears beaded and is beginning nerves may cross the scar within several weeks
to be phagocytized by macrophages, which enter (Fig. 3-34). The crossing is helped by the
from the circulatory system (Fig. 3-4). Schwann cells and fibroblasts, which proliferate
Fragments of degenerating axons and myelin are from the proximal end of the nerve. The
broken down in digestion chambers (Figs. 3-31 Schwann cells form new basement membrane
NEUROCYTOLOGY 3-27
As the regenerating axon grows, the axonal
end sprouts many little processes. If one axonal
sprout penetrates the scar, the other sprouts
degenerate, and the axon follows the path estab-
lished by the penetrating sprout. If an axon
reaches one of the tubes formed by the Schwann
cells, it grows quickly and after crossing the scar
descends the distal stump at a rate of approxi-
mately 1 nun/day (Jacobson and Guth, 1965;
Guth and Jacobson, 1966).
When the motor end plate is reached, a delay
occurs while the axon reinnervates the muscle
and reestablishes function. At this stage the
average rate of functional regeneration is 1 to 3
nun a day.
Only a small percentage of the nerves reach
the effectors or receptors. The basal laminae
helps direct the regenerating nerve to the motor
end plate. If a sensory fiber innervates a motor
end plate, it remains nonfunctional and probably
degenerates, and the cell body atrophies. A sen-
sory fiber that reaches a sensory receptor may
become functional, even if the receptor is the
Figure 3-32. Elearon micrograph of degenerating wrong one. For example, after nerve regenera-
axons in slWeral fascicles of the medullary pyramid of tion some patients complain that rubbing or
a rat 15 days after a cortical lesion. A, Arrows point pressing the skin produces pain. In these cases it
to degenerating axons (<.1&8,000). B, Detail of would appear that fibers sensitive to pain have
degenerating axons (<'x>30,000). Note the collapsed
reached a tactile or pressure-sensitive receptor. A
axons and dense axoplasm and that many axons were
unafficted by the lesion.
and provide tubes through which the regenerat-

ing axons can grow.
In certain peripheral nervous system diseases
only segmental degeneration occurs. One
example is diphtheria: the myelin sheath degen-
erates but the axon remains intact. Phagocytes
break down the myelin, and Schwann cells rapid-
ly reform myelin.
The rate of movement of the slow compo-
nent ofaxoplasmic flow probably accounts for
the rate of axonal regrowth, which is limited to
about 1 nun a day. Slow components of the axo-
plasmic flow (-Scb) carry actin, fodrin, calmod-
ulin, clathrina, and glycolytic enzymes that form
the network of microtubules, intermediate fila-
ments, and the axolenuna, which limit the rate
of daily axonal regeneration, although function- Figure 3-33. Elearon micrograph of a degenerating
al recovery may be a little faster (McQuarrie and myelin sheath in the medullary pyramid of a rat 30
Grafstein, 1983; Wujek and Lasek, 1983; days after a cortical lesion. Note the unralleling and
McQuarrie, 1988; Kandel and Schwartz 2000). lIacuolization of the myelin. (<'x>30,000.)
3-28 CHAPTER 3
motor fiber may also reinnervate the wrong Central Nerve Regeneration
motor end plate, as when a flexor axon inner- After an injury, axons in the central nervous
vates an extensor. In such a case, the patient has system regenerate, but there seems to be no
to relearn how to use the muscle. equivalent to the Schwann cell because oligo-
Muscle that is denervated assists the regen- dendrocytes and astrocytes do not form tubes to
erating axons by expressing molecules that influ- penetrate the scar. Instead, they form a scar that
ence the regenerating axons. Some of the mol- is nearly impenetrable. Even if the axons pene-
ecules are concentrated in the synaptic basal lam- trate the scar, they have no means of reaching
ina of the muscle. Other molecules are upregu- the neuron to which they were originally con-
lated following denervation and help in attract- nected.Horner and Gage (2000)have reviewed
ing and reestablishing the synapse in the muscle. the question of how to regenerate the damaged
These upregulated molecules include: growth central nervous system in the brain that is
factors (IGF-3 and FGF-5), acetylcholinesterase inherelty very plastic. The y have noted that it is
(AChE), agrin, laminin, s-laminin, fibronectin, not the failure of neruoaln regeneration , but it
collagen a3, and the adhesion molecules N- is rather a feature of the dmaged environment;
CAM and N-cadherin (Hall and Patterson, and it is now possible to reintroduce the factors
1993; Horner and Gage 3000). preent in the developing nervous system tha
Successful nerve regeneration also depends produced this wonderful organ. The gene
on an adequate blood supply. For example, in a responsible for needed growth factors is proba-
large gun shot wound, nerves attempt to regen- bly missing or inactivated in adult tissue.
erate but may not succeed. A summary of the Recently a brain-derived neurotrophic factor has
sequence of regeneration in the peripheral ner- been identified, which may eventually help in
vous system can be broken down into seven finding a way to guide the axon (Goodman,
steps: 1994).
1 The peripheral nerve is sectioned by an Animal studies have shown that neurons
injury. have considerable plasticity. That is, if some
2 The axon dies back to the first unaffected axons in a region die off, bordering unaffected
node ofRanvier, with the myelin and distal axon axons will sprout and form new synapses over
beginning to degenerate within 34 hours. many months, filling in where the synapses were
3 At the site of injury, the axon and myelin and resulting in major functional reorganization.
degenerates to form a scar. Phagocytosis begins This reorganization may eventually produce
within 48 hours. some recovery of function.
4 Axons separated from the cell body degen- Stem Cells. In the Adult Brain neuronal
erate. With an adequate blood supply the por- stem cells have been identified in the adult brain
tion of the axon still connected to the intact cell and spinal cord. These cells under the right con-
body begins regenerating by sprouting. ditions may well be activated and help to reverse
5 Within 73 hours, Schwann cells begin to the effects of lesions in the CNS (Kornack &
proliferate and form basement membranes and Rackic 1999). After the implantation of imma-
hollow tubes. Nerve growth factor is also ture neurons (neuroblasts) in regions affected by
formed and released, which further encourages certain diseases (e.g., the corpus striatum of
sprouting. patients with Parkinson's disease), there has
6 From each of the severed axons, sprouts been some recovery (Sladek and Gash, 1984;
attempt to penetrate the scar. After one sprout Gage et al., 1991). In Parkinsonian patinet's the
successfully grows through the scar the other age of the individual receiving the transported
sprouts die. Nerves take a month or more to cells seems to effect the outcome with younger
grow through the scar. patients(less than 50 years of age) more likely to
7 Once an axon penetrates the scar, it grows show some improvement. Regenerating axons
at 1 mm/day; about a third of the severed axons in the central nervous system may also grow and
actually reinnervate muscle and skin. form a nonfunctional neuronal ball, or neuroma.
Similar long-lasting neuromas may form in the
NEUROCYTOLOGY 3-29
peripheral nervous system and may be a source
of pain. In time, the dead neurons and axons are
phagocytized by the glia and macrophages, but
the astrocytic scar remains.
Factors that promote neuronal survival and
axon outgrowth (e.g. brain derived neurotroph-
ic factor-BDNF) have been identified and the
focus is now on getting these cells to produce
axons to grow into the injured areas and then to
grow through into the uninjured area.
Nerve Growth Factors. The first nerve
growth factor was isolated by Levi-Montalcini
and Angeletti in 1968, but only recently have
biotechnology techniques been able to produce
these factors in large quantities. Attempts have
been made to help regeneration in the central
nervous system, for instance, by placing Teflon
tubes on Schwann cells through the scarred por-
tion of the spinal cord in the hope that the
nerves would follow these channels. However,
even though nerves do grow down these chan-
nels, no functional recovery occurs. Further
information is needed to understand better the
chemical nature of scar tissue that retards axonal
regeneration. Figure 3-34. Sciatic nerve of a rat, demonstrating
With the identification of neurotrophic fac- the appearance of regenerating nerves 3 weeks after a
crushing injury. A, At the site of the crushing lesion,
tor (netrins 1 and 3) that produces axonal
the nerves look normal with regenerating aJ«JnS
growth (Serifini et al., 1994) and with the stud- grown past the site of the injury; arrow indicates
ies of programmed cell death beginning to iden- Schwann cell nucleus. B, About 30 mm distal to the
tifY genes that may be responsible for premature site of injury, note some regenerating aJ«JnS and still
neuron death (Oppenheim, 1991), we may be many tkgenerating axon fragments. C, About 35
entering an era of brain research that offers great mm distal to the crush site the transition from regen-
promise to help patients with neurodegenerative erating axons to only degenerating axons is shown.
diseases, Huntington=s, Parkinson=s and (&dian silver stain, <X>500.)
Alzheimer=s. Large infarcts may take several years before
phagocytosis is complete. If the lesion is huge,
Glial Response to Injury
such as a large infarct in the precentral gyrus, a
Neuronal death triggers an influx: of phago-
cavity lined by astrocytic scar will form. In small
cytic cells from the blood stream and the
lesions the neurons are phagocytized glia prolif-
microglia proliferate and break down the dying
erate, a process called replacement gliosis. In
neurons.
organs with numerous fibroblasts, necrotic areas
Necrosis. Within a few days of an ischemic
are soon filled with proliferating fibroblasts, but
attack with infarction, neutrophils are seen at the
in the central nervous system there are few
site of injury. Shortly thereafter, microglial cells fibroblasts for this, and the astrocytes do not
and histocytes are seen in the region of the dying
proliferate in sufficient numbers.
cells. Since the blood-brain barrier is usually
compromised, monocytes may now migrate into Blood-Brain Barrier
the parenchyma of the central nervous system in In the peripheral nervous system the endothe-
greater numbers and assist in phagocytosis. lial cells are fenestrated and very active in pinocy-
The time it takes for the complete removal of tosis: these two factors increase the ability of
injured cells depends on the size of the lesion. compounds to readily enter the nerves. Also,
3-30 CHAPTER 3
molecules move through peripheral endothelial

cells by fluid phase, or receptor-mediated, endo-
cytosis. Fluid phase endocytoiIs is relatively non-
specific; the endothelial cells engulf molecules
and then internalize them by vesicular endocy-
tosis. In receptor-mediated endocytosis, a ligand
first binds to a membrane receptor on one side
of the cell. After binding to the ligand the com-
plex is internalized into a vesicle and transport-
ed across the cell, the ligand is usually released.
In the central nervous system endothelial
cells that line the capillaries and the choroid
Figure 3-35. Site of cerebrospinal fluid formation:
plexus are joined together by tight junctions, the choroid plexus in the fourth ventricle. Note the
zonula occludens(fig 3-25). The capillaries are blood vessel (BV) in the center and the cuboidal
not perforated, and the endothelial cells show epithelial cells (arrow) on the outside of the vessel.
very little pinocytosis or receptor-mediated (<.JD300.)
endocytosis (Brightman, 1988). This endothe- cumventricular organs include: pituitary, medi-
lial lining is called the blood-brain barrier an eminence, organum vasculosum, subfornical
because it is very selective to certain large mol- organ, subcommissural organ, pineal gland, and
ecules and dyes and limits the entry of other the area postrema of the fourth ventricle. These
substances, including amino acids, water, glu- open connections between the brain and the
cose, and electrolytes into the brain parenchy- ventricular system permit neuropeptides from
ma. the hypothalamus, midbrain, and pituitary to
Plasma in blood vessels is separated from the enter the cerebrospinal fluid and to be widely
central nervous system tissue by the endothelial distributed in the brain and spinal cord, thus
lining of the blood vessel and the basement forming an alternate pathway in the neuroen-
membrane. Pericytes (perivascular) cells are docrine system.
also found within the basement membrane of Large molecules (such as ferritin and horse-
the capillary wall. The extracellular space of the radish perioxidase) injected invascularly do not
central nervous system lies external to the base- pass through the endothelium; instead, they fill
ment membrane. All vascular branches within the extraceUular spaces between the glia and
the central nervous system are surrounded by a neurons and do not reenter the blood vessels
thin covering formed by astrocytic processes (Reese and Karnovsky, 1968). Studies have
(Fig. 3-25). However, the astrocytic processes shown that the blood-brain barrier is imperme-
do not fuse with the endothelial lining of the able to certain large molecules including pro-
blood vessel or with the processes of other cells, teins, but substances such as smalllipid-soluable
so they have minimal effect on limiting the compounds, including alcohol and anesthetics,
entry of solutes into the brain parenchyma. gasses, water, glucose, electrolytes (NA+, K+,
Thus the extracellular space can be entered once and CL-), and amino acids, can pass from the
the materials pass through the endothelium. plasma into the intracellular space (inside neu-
The intravenous perfusion of various dye rons and glia) or into the extracellular space
compounds (trypan blue, Evans blue, proflavin between neurons and glia.
H CI, and horseradish peroxidase) demonstrates Acute lesions of the central nervous system,
passage through the blood-brain barrier. These including those caused by infections, usually
dyes demonstrate that the blood-brain barrier is increase the permeability of the barrier and alter
leaky in certain midline regions of the third and the concentrations of water, electrolytes, and
fourth ventricle, the circumventricular organs, protein. In viral diseases the infected leukocytes
and in the choroid plexus and locus ceruleus (macrophages) more easily penetrate into the
(Brightman, 1989; Dempsey and Wislocki, brain by passing between the normally tight
1955; Wislocki and Leduc, 1953). The cir-
NEUROCYTOLOGY 3-31
junctions in the endothelial cells, which is one cellular fluid. Cerebrospinal fluid may also be
way that HIV enters the brain directly from the reabsorbed after temporary storage in the extra-
blood. Tumors within the central nervous sys- cellular space. Fat-soluble compounds that
tem produce growth factors that cause blood readily pass through the blood-brain barrier can
vessels to sprout. These new blood vessels have enter the extracellular space and may be useful
immature tight junctions that are also quite in resolving infections in the central nervous
leaky. The leakiness of the capillaries within system or in improving the function of certain
tumors has been exploited with some success to brain cells.
deliver chemotherapeutic agents specifically to
the tumor (Neuwelt and Dahlborg, 1989).
There have also been attempts to interfere with
the formation of the blood vessel growth factors
as a way to starve tumors.
Stress has been shown to open the blood-
brain barrier by activating the hypothalamic-
hypophyseal-adreanal axia and releasing CRR
(Esposito et al. 2001). Acute lesions of the cen-
tral nervous system including those caused by
infections usually increase the permeability of
the barrier and alter the concentrations ofwater,
electrolytes, and protein. In some viral diseases,
for example, infected leukocytes (macrophages)
more easily penetrate directly into the brain by
passing between the normally tight junctions in
the endothelial cells. This is one way HIV
enters the brain from the blood. Also, central
nervous system tumors produce growth factors
that cause blood vessels to sprout. These new
capillaries have immature tight junctions that
are also quite leaky and have been studied with
some success as a way to deliver chemothera-
peutic agents specifically to the tumor (Neuwelt
and Dahlborg, 1989).
Extracellular Space
Between the cells in the central nervous sys-
tem is the extracellular space, measuring
between 30 and 40 nm and filled with cere-
brospinal fluid( CSF) and other solutes. The
CSF is formed primarily by the choriod plexus
in the lateral ventricle, IIIrd ventricle, and IV
ventricle (Fig 3-35). The amount of extracellu-
lar space in the brain is still a matter of contro-
versy. Some solutes can readily pass from the
blood plasma through the endothelial lining
into the extracellular space, and the solutes pre-
sent in this space (whether deleterious or not)
affect the functions of the central nervous sys-
tem. A portion of the cerebrospinal fluid
appears to be formed by the diffusion of extra-
CHAPTER 4
Neuroembryology and Congenital Malformations
Introduction of ectodermal cells can be noted at the caudal

The brain undergoes a series of incredible end of the embryonic disc. This accumulation of
changes in utero as it changes from a flat plate cells is known as the primitive streak (Fig.4-1A).
into a tube and then evolves into the convoluted As development continues, surface ectodermal
cerebral hemisphere. This complex evolution cells involute through the primitive streak and
results in several structures that start very close migrate laterally, forming the intraembryonic
together (particularly the fornix, stria terminalis, mesoderm, interposed between the surface ecto-
corpus callosum and anterior commissure) mov- derm and subjacent endoderm. As the intraem-
ing quite a distance apart. bryonic mesoderm forms, another thickening of
The in utero development of the central ner- ectodermal cells called Hensen's node occurs at
vous system can be divided into three periods the cephalic end of the primitive streak (Fig. 4-
that roughly correspond to the first, the second, lA). Cells migrate inward through this zone and
and the third trimester of gestation (Table 4-1). extend between the surface ectoderm and subja-
cent endoderm, forming the notochord plate.
TABLE 4-1. IN UTERO BRAIN DEVELOPMENT The notochord is the primary "inductor" for the
thickening of the ectoderm overlying and on
First Establishment of basic organizalion of the either side of the notochord to form the neural
Trimester eNS beginning as the neural plale, the
plate, that is the origin of the central nervous sys-
neural plale sinks inward 10 form the neural
groove. The neural groove conlinues 10 tem. The many factors in the notochord that
deepen unlillhe dorsal lips of the mee! and underlie the formation of the neural tube and the
fuse, forming the neural lube, Ihe beginning transformation of embryonic cells into adult cells
of the hollow dorsally placed central are currently being identified. The notochord
nervous system. ultimately degenerates as the body of the verte-
brae appears and it persists as the nucleus pulposi
Second Tubular like nervous system is changed by
Trimester the massive waves of migration of neuroblasts of the intervertebral disc.
from Ihe germinal cell lining producing an On either side of the neural plate is a thin
immature model of the adult nervous system strip of ectoderm known as the neural crest. As
with the beginnings of much of the circuitry development proceeds, the neural plate sinks
in place. inward to form the neural groove (Figs. 4-1B and
Third Neuronal processes mature, and Ihe gyri 4-2). At the beginning of the forth week this
Trimester enlarge, myelination begins, and the basic midline groove continues to deepen until the
circuitry continues 10 form preparing the dorsal lips of the groove meet and fuse, forming
infanl for funClioning outside the womb. the neural tube, neurulation (Figures 4C and 4-
2). The adjacent neural crest separates from the
Newborns, through genetic inheritance, can overlying ectoderm and comes to lie lateral to the
make about 40 different sounds, and distinguish neural tube (Fig. 4-2). The central nervous sys-
some sounds as being either safe or dangerous. tem is derived from the neural tube; the neural
They can also perceive certain shapes and usually crest yields many parts of the peripheral nervous
have enough myelin for an organized grasp and system. The remaining ectoderm becomes the
suckling reflex. epidermis of the embryo (somatic ectoderm).
I. Formation of the Central Nevous System Before the formation of the neural tube the
paraxial mesoderm begins to form the somites.
The first evidence of the differentiation of the
Fusion of the dorsal margins of the neural
nervous system appears at the end of the second
groove, forming the neural tube, begins on
week of gestation. At that time a "heaping up"
4-2 CHAPTER 4
A. Primitive streak stage B. Neural plate stage C. Beginning of neural tube D. Brain vesicle stage
(16-day presomite embfyo) (20-0ay two somlle embryo) (22.<Jay seven somite embfyo) (23.<Jay ten somite embryo)
Figure 4-1. Dorsallliew of human embryo. A, Primitille streak stage (16-day presomite embryo). B, Neural plate
stage (20-day two-somite embryo). C, Beginning of neural tubes (22-day SC1Ien-somite embryo). D, Brain lIesicles
stage (23-day ten-somite embryo).
about the twenty-second day in the region of ectoderm, the neural crest cells appear as an
somites 4 to 6 (Fig. 4-1 C). Fusion continues in almost continuous column of cells along the dor-
both cranial and caudal directions, and by the sal surface, crest, of the neural tube from the
twenty-fifth day, only the cranial and caudal ends mesencephalic level through all spinal cord levels
of the neural tube remain open (called the ante- (Fig. 4-2). The neural crest cells are the pri-
rior and posterior neuropores respectively). The mordium of the sensory ganglia, the cranial
lumen in the neural tube will become the ven- nerves and the spinal ganglia, the neurilemmal
tricular system of the central nervous system. cells, satellite cells, the autonomic ganglia, and
After delineation of the neural and somatic probably the pia-arachnoid membrane. Shortly
after the closure of the neural tube, processes
from the neural crest cells enter the spinal cord or
brain stem and form the sensory roots of the
spinal and cranial nerves.
Histogenesis
The walls of the neural tube throughout the
nervous system consist of germinal epithelial cells
that form a pseudostratified epithelium. After
closure of the neural tube, another cell type is
found external to the germinal cell layer. This
new cell is the neuroblast (or immature neuron),
these cells originate from the mitotic divisions of
Neural Tube the germinal cell and form a new layer, the man-
Surface Ectoderm tle or intermediate layer, and external to the
Neural crest cells
mantle layer is seen a cell-free zone, the margin-
~ Spinal cord
MeduliaIPons
Midbrain
Telencephalon
Dtencepahalon
allayer. Subjacent to the germinal layer the sub-
ventricular region develops.
The glia are instrumental in the final forma-
tion of the central nervous system. They migrate
out from the subventricular layer prior to the
Figure 4-2. Coronal seaion showing differentiation neuroblasts and form processes that reach the
of neural ectoderm in the neural plate stage, the neur-
submeningeal surface and remain connected to
al growe stage, the neural fold stage, and the neural
tube stage. the ventricular surface. The neurons migrate out
NEUROEMBRYOLOGY AND CONGENITAL MALFORMATIONS 4-3
into the region formed by the glia. plant research holds great promise not only for
Initially the neuroblasts are connected to the the nervous system but also for pancreas, adren-
lumen by an elongate process, a transient den- al, pituitary.
drite. As they migrate into the subjacent mantle The implantation of fetal stem cells seems
layer they lose this process and become apolar especially promising, but there is much public
neuroblasts. Shortly thereafter two new process- controversy over the use of fetal or aborted mate-
es appear; one becomes the axon, the other the rial. Recently adult stem cells have been harvest-
dendrite. The axonal process elongates and ed from surgical specimens and at postmortem
more dendritic branches appear, forming a mul- examinations; this approach also shows much
tipolar neuroblast. promise.
Some neurons form only a single process; Principles of Differentiation
e.g., these are the sensory ganglion of the spinal within the CNS:
cord and cranial nerves, and the mesencephalic
The following are certain rules that can be
nucleus of cranial nerve V. Some neurons remain
applied to the differentiation within the CNS
bipolar, e.g., the olfactory receptor cells, rods,
(after M. Jacobson 1978):
and cones of the retina, the bipolar cells in the
1..Spatial and temporal gradients of prolifer-
retina, and the receptor cells in the vestibular and
ation exist in the neuroepithelial germinal zone.
cochlear ganglion.
2. Neighboring regions have separate origins
It should be noted that the germinal cells also
and are different cytoarchitectonically.
form the supporting cells in the central system
3. In an orderly sequence large neurons are
(Fig 4-3). Throughout the central nervous sys-
produced first, then intermediate-sized neurons,
tem neurons migrate into the intermediate
and finally small neurons.
(mantle) zone to become the definitive struc-
4. Glial cells tend to originate before neurons
tures of the spinal cord, much of the brain stem,
in any particular region of the brain.
and the basal nuclei. Sidman and Miale (1959)
5. Phylogenetically older parts of the brain
using tritiated thymidine identified this migra-
are predisposed to arise earlier in ontogenesis.
tion. In these regions the cells in the mantle layer
become the gray matter, while their axons form Growth Cone Guidance.
the marginal zone or white matter. By contrast, Ramon y Cajal at the turn of the last century
the cerebral cortex and cerebellar cortex are identified the growth cones that form connec-
formed by the migration of neuroblasts through tions in the developing nervous system. Since
that time neurobiologists have been searching for
Germinal Cells the mechanisms that permit the formation of
+
Neuroblast
i
Glioblast +
Ependyma
these synapses. Several mechanisms have been
proposed including cell adhesion, repulsion and
Nelon
,AstrocyteI ,
Oligodendrocyte
chemoattraction. Recently a diffusible factor that
promotes outgrowth ofaxons in vitro has been
found in the floor plate of the embryonic spinal
Figure 4-3 Evolution of Germinal Cells. cord (Serfanin et al, 1994; Kennedy, 1994)).
Two membrane-associated proteins were puri-
the mantle zone into the marginal zone. fied from the embryonic chick brain, nettin-1
and nettin-2, and each protein promotes growth
Repair of Damaged Nervous System.
cone outgrowth. Cloning cDNA encoding the
Since immature cells from fetuses are not as
nettins showed that they were homologous to
easily rejected, it has been proposed to recover
UNC-6 a larninin-related protein (found in the
neuroblasts from the brains of aborted human
extracellular matrix) required for migration of
fetuses. These fetal stem cells from human
cells and axons in the nematode Coenorhabditis
embryos would be implanted in adults replacing
elegans.
damaged neurons in patients with Huntington's
This homology suggests that growth cones
chorea and Parkinson's disease. This line of trans-
in the vertebrate and nematode respond to a sim-
4-4 CHAPTER 4
TABLE 4-2 LISTS THE FATE OF THE LAYERS degeneration is normal and planned, called apop-
IN THE NEURAL TUBE: tosis (a Greek term referring to the seasonal
falling off of leaves) begins with condensation
Marginal zone -at the surface covered by the and degeneration of the chromatin, blebs of the
presumptive pia contains pathways plasma membrane, shrunken cytoplasm with the
in the adult spinal cord and neurons organelles intact (Oppenheim '91 ,Schwartzman
in the cerebrum and cerebellum & Cidlowski '93, Taylor '93). Caspases (cys-
Intermediate or -becomes gray maHer of the adult teine-dependent, aspartate-specific proteases) are
manHe zone spinal cord, brain stem and endoproteases that are integral to the disassem-
diencephalon, and contains white bly of the cell (Cohen 1997;Cortese 2001).
maHer of the cerebrum and cerebellum These enzymes exist normally in an inactive
form, but once they are activated they set off a
Subventricular -forms the macroglia
zone (astrocytes,Oligodendrocytes ). proteolytic cascade that spreads and destroys the
cell. In both of these events glia and
Ventricular -early on has germinal cells, macrophages phagocytose the nerve cells, but in
lining zone that form neuroblasts; apoptosis the nerve cells die quietly without any
-in mature brain becomes inflammatory response or major activation of the
ependymal lining of ventricles.
phagocytes. With necrosis, there is an inflamma-
tory response with phagocytes activated, while in
ilar molecule. Further studies with UNC-6 and apoptosis there is no injury or interruption of the
the netrins have shown that these molecules may blood supply and yet the cell begins to degener-
be guidance and targeting signals rather than just ates with the cell bodies appearing pyknotic.
attractive versus repulsive molecules (Goodman Researchers have become more aware of this
1994). We must expect that further investiga- "natural" type of cell death and have also called
tions of these molecules will lead to a better it programmed cell death, biological/physiolog-
understanding of how the nervous system actu- ical cell death, or even cell suicide. Many areas in
ally forms and connects. An understanding of the vertebrates and invertebrates nervous system
how the nervous system forms connections are now known to have apoptosis. It is also well
which may ultimately lead to better methods to established that programmed cell death occurs in
repair damage in the brain. most other tissues and organs and is an impor-
Programmed Cell Death. tant means to shape the final form of the body.
During the development of both the central There have also been studies with hormones and
and peripheral nervous system, the number of other compounds that have decreased the num-
immature neurons formed is actually double that ber of immature neurons dying by apoptosis.
that will ultimately survive (Cowan et al '83). With the recognition that apoptosis is a nor-
This apparent excess in formation of neurons is a mally occurring phenomenon, neurobiologists
mechanism whereby the size of the neuronal using molecular probes have identified genes that
pool is ultimately matched to the amount of tis- regulate this process (Kane 1995). The finding of
sue actually innervated (Kane 1995, Lee '93, genes that control these phenomena has also per-
Majno & Joris 1995). mitted researches to questions whether diseases
Neuronal Death such as Huntington's chorea, Parkinson's disease
and even Alzheimer's are a consequence of this
1. Necrosis. Neuronal death is necrosis and it
same gene pool being activated later in life to
is unplanned cell death characterized by cellular
produce the resultant neuronal death. This
edema and destruction of the neuronal
promising research may well lead to gene thera-
organelles and membranes. Necrosis is com-
py which permits treatment of these presumed
monly accompanied by the inflammatory
programmed cell death caused disease by turning
response. This occurs usually following an injury
off the offending genes.
(e.g. stroke, trauma, and tumor).
2. Programmed cell death. This type of Development of Blood Vessels in the Brain.
The blood supply to the developing brain the diencephalon -- the third ventricle -- narrows
begins by the invasion of solid cords of mesoder- as the parenchyma of the diencephalon forms.
mal endothelial cells, called WIlson's Buds, which Cerebral Aqueduct. In the midbrain the tec-
over a period of several days develop a lumen and tum and tegmentum expand greatly and con-
a basement membrane. These arteries develop in strict the lumen so that only the narrow cerebral
the pharyngeal arches during the fourth week aqueduct remains.
and are derived from the third pair of aortic arch- Fourth Ventricle. In the metencephalon
es and dorsal aortae and by 6 weeks there are (cerebellum and pons) and myelencephalon
well-established internal and external carotid ves- (medulla), the tegmentum undergoes a series of
sels. These buds of growing endothelial cells are flexures and expands laterally, and is overgrown
especially prominent as the intermediate and by the cerebellum. As a result, the cavity in the
marginal layers evolve. The blood supply evolves myelencephalon and metencephalon called the
in direct relationship to the maturation of the fourth ventricle assumes a rhomboid-shaped.
eNS and as a consequence of the many factors The fourth ventricle is continuous with the nar-
released into the developing parenchyma of the row cerebral aqueduct above and the constricted
eNS. As the astrocytes form within the eNS, spinal canal below.
some of their end-feet surround the basement Spinal Canal. In the spinal cord, the expand-
membrane of the brain capillaries and begin to ing gray and white matter nearly obliterates the
form a blood-brain barrier. The actual tight junc- ventricular cavity so that only the small spinal
tions between the endothelial cells that delineate canal remains.
the definitive blood-brain barrier are not com- Fonnation of Peripheral Nervous System
plete until just before birth.
Peripheral structures are innervated from
Ventricular System nuclei in the brain stem (by the cranial nerves)
When the neural folds fuse, a neural tube is and from nuclei in the spinal cord (by the spinal
formed. At the rostral end of the nervous system nerves). The twelve cranial-nerve nuclei inner-
two lateral dilations appear: the primordia of the vate skin, glands, viscera, striated muscles, and
cerebral vesicles. These regions will grow rapid- special sense organs (eye and ear) in the head and
ly, extending anteriorly, inferiorly, and posterior- neck. The spinal nerves innervate skin, glands,
ly as they form the ventricles in the cerebral and striated muscles in the upper and lower
hemispheres. extremities and in the thorax, abdomen, and
Lateral Ventricles. The cavity in each cerebral pelvis.
vesicle is called a lateral ventricle. As the cerebral Spinal Cord Differentiation
hemispheres grow by continued outward migra-
The origin of the spinal cord can be traced to
tion of nerve cells, the ventricles take up less and
the twentieth day. The neural plate then has two
less space in the brain and are modified into a C-
distinct regions: caudally, a single elongate cylin-
shaped structure with a spur extending occipital-
drical region, which will become the spinal cord;
ly. Each lateral ventricle in its final form is divid-
and, cranially, a shorter broader region, which
ed into an anterior hom, body, inferior hom, and
will become the brain (Fig. 4-1B).
posterior hom.
Until the third month the spinal cord fills the
Foramen of Monro. Early in development,
vertebral column. From then on the cartilage
the lumen in the paired telencephalic vesicles is
and bone grow faster than the central nervous
continuous with that of the neural tube. As the
system, and by birth the coccygeal end of the
telencephalon differentiates into cerebral cortex
spinal cord lies at the level of the third lumbar
and basal nuclei, the ventricles take up relatively
vertebra. In an adult it is found at the level of the
less space. A narrow channel, called the inter-
first lumbar vertebra.
ventricular foramen of Monro, persists between
At the end of the somite period (days 30 to
the cerebral ventricles and the third ventricle (Fig
35), mitotic divisions in the spinal cord region
1-21).
produce thickened walls and a thin roof and
Third Ventricle. The centrally placed cavity in
floor; with almost complete obliteration of the
4-6 CHAPTER 4
TABLE 4-3 STRUCTURE INNERVATED

Alar Plate
BY CRANIAL NERVES
Sulcus Limitans
STRUCTURE
Basal Plate INNERVATED BY
CRANIAL NERVES CRANIAL NERVE
1. Muscles of somite origin XII, VI, IV, and most of III.
Roof Plate 2. Muscles and skin V, VII, IX, Xand XI.

of pharyngeal arches
Ependyma
3. Preganglionic IX, X, VII, V, and a
Sulcus Limitans parasympathetic small part of III.
4. Special Sensory I, II, VII, VIII, IX, and X.

Dorsal Column cranial nerves
Posterior Hom
parasympathetic neurons
Anterior Horn Axons of developing motor neurons in the
basal plate enter the adjoining somites, while sen-
Ventral Column sory roots derived from the adjacent neural crest
zone enter the dorsal or alar plate. In the spinal
Lateral Column
cord (Fig. 4- 3) the plate will become the dorsal
or sensory associative hom, and the basal plate
Ependyma will become the ventral or motor hom. In the
medulla (Fig. 4-5), pons (Fig.3-6), and midbrain
Anterior Fissure (Fig. 4-7) the alar and basal plates are restricted
to the floor of the developing ventricular system.
Figure 4-4. &hematic represenmtion of the develop- The remaining bulk of these zones consist of
ment of the spinal cord. (After Hamilton, W]. Boyd, nuclei and tracts that are related to the head,
J.D., and Mossman, H w.: Human Embryology.
neck, and special senses.
Cambridge, England, Heifer and Sons, 1964).
In the spinal cord the marginal zone also
central canal (Fig. 4-4). The ventral portion of increases in width as axons that form the ascend-
the lateral walls develops and expands earlier than ing and descending tract enter (Fig. 4-4). The
the dorsal region. The ventral portion is called formation of the dorsal and ventral horns delim-
the basal plate and the dorsal portion is called the its the dorsal, ventral, and lateral columns or
alar plate. Processes from cells in the mantle layer funiculi in the marginal zone. An intermediate
enter the external-most region of the cord, which hom develops dorsal and lateral to the anterior
is called the marginal zone. hom in the thoracic and lumbar levels of the
Gray matter. Four columns appear in each spinal cord. Cells in this hom are the pregan-
half of the gray matter of the spinal cord: two glionic sympathetic neurons. The postganglionic
motors and two sensory (Table 4-3). The visceral neurons are in the paravertebral sympa-
somatic afferent and efferent column innervates thetic chain or in ganglia associated with the vis-
skin and muscle related to the somites, while the ceral organs. The preganglionic parasympathet-
visceral afferent and visceral efferent columns ic innervation originates from the motor neurons
innervate the mucosa, glands and smooth mus- in cranial nerves III, VII, IX and X and the sacral
cles in the visceral structures. The somatic effer- spinal cord and innervates ganglia that connect
ent cells are the motor neurons in the ventral the appropriate organ or gland. Again, these
horn of the spinal cord; the somatic afferent cells ganglia differentiate very close to the appropriate
are the neurons in the spinal ganglia. The vis- structure. In the dorsal or sensory hom of the
ceral efferent cells consist of sympathetic and spinal cord there are sensory neurons that pro-
wne at the upper end of the developing central
Roof Plate nervous system with three distinct vesicles- the
prosencephalon, the mesencephalon, and the
Alar Plate rhombencephalon.
Sulcus Limitans Rhombencephalon (Hind Brain)
Basal Plate The rhombencephalon differentiates into the
metencephalon (Fig.4-6) and myelencephalon
(fig 4-5). This region is further divided by their
relationship to the ventricular system. That por-
Alar Plate tion forming the floor of the ventricle is called
the tegmentum, while that forming the roof of
Basal Plate
the ventricle is called the tectum. In the spinal
cord the basal plate was ventral and the alar plate
dorsal. In the medulla, pons, and midbrain both
basal and alar plates are restricted to that portion
of the tegmentum that forms the ventricular
floor. The alar or sensory region is lateral, while
the motor region is medial. The sulcus limitans,
on the ventricular floor, separates the medial
Olivary Nucleus
motor region from the lateral sensory region.
In the spinal cord the neurons are in the gray
Figure 4-5. Schematic representation of the develop-
ment of the medulla. (After Hamilton, WJ. Boyd,
ID., and Mossman, H. w.: Human Embryology. Alar Plate
Cambridge, England, Heffer & Sons, 1964). ~_- Sulcus lImitalls
vide connections throughout the spinal cord or Basal Plate

brain stem.
The segmental arrangement of the central
nervous system stops at the spinomedullary junc-
tion, which marks the site of transition from the
spinal cord to the brain stem. The brain stem
and cerebrum are suprasegmental with no evi- Bulbo-pontine
dence of segmentation present. These regions of extension
the central nervous system are specialized to con-
trol structures in the head and neck as well as
exerting control over the entire body.
During development the spinal cord and the
somites lie close together, so the distance the
axon must travel to reach its appropriate muscle
is very short. Undoubtedly, chemical factors
help direct the axon to the correct muscle. The
Pontine Nudei
sensory fibers also have only a short distance to
run from the ganglia into skin or muscle and
their axon into the central nervous system; again,
probably by chemical mediation they establish Figure 4-6. Schematic representation of the develop-
the connection with the correct dorsal hom cells. ment of the pons. (After Hamilton, WJ., Boyd, ID.,
and Mossman, H. w.: Human Embryology.
Brain Differentiation Cambridge, England, Heffer and Sons, 1964).
The brain begins development as a broad
4-8 CHAPTER 4
matter, in the center of the spinal cord while the neurons are migrating into their definitive place,
fiber tracts are on the outside. In the brain stem they form many of the connections necessary for
motor nuclei migrate to a medial position and their specialized functions.
sensory nuclei to lateral. The fiber tracts are on The factors which control the migration of
the external and medial surface; some tracts actu- cells into the cerebellum and cerebrum and
ally in the center of the brain stem. which provide the connections that are necessary
The dorsal portion of the alar plate in the for the proper function of these structures are
metencephalon (pons) forms the primordium of only now being identified. (These factors pro-
the cerebellum. This region, the rhombic lip, duce some of the following changes- the glia and
thickens and the cerebellum continues to expand neurons migrate and elongate at certain critical
laterally and then medially so that pair of lateral times and is supplied with an adequate blood
regions, the cerebellar hemispheres, and a medi- supply that permits all this to happen).
al wne, the vermis, is now formed. The ependy- Mesencephalon
mal lining and pia form the roof of the lower The mesencephalon (fig 4-7) begins as a
medulla, the tela choroidea. wide tube with a conspicuous floor (tegmentum)
On the anterior surface of the medulla, pons, and a thin roof (tectum). The addition of fibers
and midbrain is the basilar region, which include and nuclei in the mantle wne of the tegmentum,
the more recently phylogenetically added concomitant with the formation of the superior
descending cortical fibers. In the medulla these and inferior colliculi in the tectal area, produces a
fibers consist of the pyramids, and, in the pons, narrow cerebral aqueduct with a large tegmen-
consists of the middle cerebellar peduncle and tum and tectum.
pyramids, and in the midbrain they consist of the The tectum consists of neurons that receive
cerebral peduncles. Other tracts and nuclei form
the bulk of the tegmentum of the pons, medul-
la, and midbrain. Roof Plate
The ventricular lumen in pontine and
.~T--- Alar Plate
medullary levels is called the fourth ventricle. Ventricle
The neural tube in these zones changes from a
Basal Plate
tube to a rhomboid-shaped fossa as a result of the
broadening of the tegmentum and the over- --0:::::'"",,- _ Floor Plate
growth of the cerebellum. Tectal Nuclei
The cerebellum and deep cerebellar nuclei
are formed by the migration of cells ( Fujita et. Aqueduct
al., 1966). In the cerebellum there are two dis-

tinct germinal centers:
1) a region in the roof of the IV ventricle Sulcus Limitans
gives origin to the germinal Purkinje and Golgi
II cells and glia which migrate into the mantle
layer of the cerebellum, and
2) The external granule wne that forms Red NUCleus
beneath the pia of the cerebellum, the external Substantia Nigra

granule zone. This region gives origin to the
granule cells, stellate, and basket cells and some
of the glia.
Cerebral
The Purkinje cell layer is the first to form. A Peduncle
little later cells migrate inward from the more
external layers to form the granular layer. In the Figure 4-7. Schematic representation of the dnelop-
adult the molecular layer has only a few cells, but mentofthe midbrllin. (After Hllmilton, WJ. Boyd,
the Purkinje layer and granule cell layer have J.D., lind MOSS1nIln, H. w.: HUmiln Embryology.
many neurons. It appears that as the primitive Ca.mbridge, Engla.nd, Heifer and Sons, 1964).
input from the cranial nerves that relay auditory anterior portion of the prosencephalon. In front
(inferior colliculus) and visual information (supe- of and above the optic stalk a pair of cerebral vesi-
rior colliculus). The cerebral peduncles form the cles form. The cerebral vesicles expand superior-
anterior surface or basis of the midbrain, with the ly, anteriorly, and posteriorly.
tegmentum located between the basis and tec- Diencephalon.
tum. The cerebral peduncles consist of fibers
The diencephalon originates from the caudal
descending from the cerebrum to the brain stem
portion of the prosencephalon (Fig. 4-2D) and
and spinal cord.
represents the thickened lateral wall of the pri-
Prosencephalon mordium of the third ventricle. The dorsal half
Three primary vesicles of brain regions are of the diencephalon will become the thalamus
seen as the neural tube begins to close; prosen- and epithalamus, while the floor differentiates
cephalon (forebrain), Mesencephalon( midbrain) into the hypothalamus and neurohypophysis.
and rhombencephalon (hindbrain. The prosen- The alar and basal plates are no longer found at
cephalon (Fig. 4-9) begins to differentiate at diencephalic levels although functionally the
about 30 days as a dilation of the cranial end of basal plate may well be represented as the hypo-
the neural tube (Fig. 4-2C, and D) this dilation thalamus. Fibers to and from the telencephalon
evolves into a right and left dilation. Early in will form the lateral limit of the diencephalon.
development optic vesicle, which will become These fibers are the internal capsule.
the eye, appear as a lateral diverticulum of the
~~:
NEURAY' ~ . PLATE
PRESUMPTIVE
NEURAL
t ~ .
,
CREST---""::I'!\
Figure 4-8. Diffirentiation ofembryonic brain areas into adult brain regions.
4-10 CHAPTER 4
Telencephalon
Choroid Plexus
Cerebral Cortex
Corpus Striatum
--...-- Diencephalon
Ventride III
Lateral Ventride
.,...... .r-. - Cortex
Choroid Plexus
Caudate Nudeus
Lenticular Nudeus
Vagus Nerve
r1I....tr-- Thalamus Ungual Br. CN IX
Ventricle III Figure 4-10. Lateral sUrface of ll-week human

embryo demonstrating the cranial and upper spinal
nerves. (After Patten, B.M.: Human Embryology,
New York, McGraw-Hill, 1953).
Caudate Nudeus
Nerve IV (trochlear) is a purely motor nerve
Internal Capsule
Claustrum and innervates the superior oblique muscle of the
~""'f-,lF-Globus Pallidus eye. This is the only cranial with rootlets that
Putamen
Fornix leave the central nervous system from the poste-
rior surface of the brain.
Nerve VI (abducens) is a purely motor nerve
and innervates the lateral rectus muscle of the
eye.
Figure 4-9. Schematic representation of the develop- Nerve XII (hypoglossal) is a purely motor
ment of the telencephalon and diencephalon. (After nerve and innervates the extrinsic and intrinsic
Hamilton, WJ., Boyd, J.D., and Mossman, H. w.: muscles in the tongue. Occipital myotomes
Human Embryology. Cambridge, England, HeJfrr migrate ventrally and form the tongue muscula-
and Sons, 1964).
ture that is innervated by nerve XII. The epithe-
Cranial Nerves lium and general connective tissue of the tongue
The cranial nerves form connections to mus- arises by the fusion of pharyngeal endoderm and
cles, skin, glands, and blood vessels in the head branchial mesoderm that are innervated by
and neck. A detailed discussion of the individual nerves VII, IX and X. -
cranial nerves can be found in Chapter 11. In 2. Cranial Nerves Innervating Muscles
this section, the cranial nerves Table 4-3 and (Skeletal) and Skin in the Pharyngeal
Figure 4-10 will be categorized on the basis of Arches.
the embryonic derived structures they innervate: Cranial nerve innervation of the pharyngeal
1. Cranial Nerve Innervation for Muscles of arches is shown in Table 4-4. After somites begin
Somite Origin to form, five ectodermal grooves appear lateral to
Nerve III (oculomotor) is a purely motor the embryonic pharynx and caudal to the soma-
nerve that innervates the inferior oblique, medi- toderm, or primitive mouth. The grooves are
al, superior, inferior recti muscles and levator separated from one another by elevations, which
palpebrae superior muscles. The extrinsic eye gradually elongate, fuse with the opposite side,
muscles develop from mesenchyme in the orbital and extend laterally and anteriorly around the
region. pharynx, forming arches. In lower vertebrates
these arches form the gills, while in vertebrates the iris, which constricts the pupil in bright light.
without gills they are called pharyngeal arches. Nerve VII provides innervation to the sub-
Many of the muscles and bones in the face and maxillary and lacrimal ganglia associated with the
neck originate from these arches. following glands: submaxillary, sublingual, nasal,
Mammals have a total of six arches: and lacrimal.
1. First and second arches named respective- Nerve IX provides innervation to the parotid
ly the mandibular and hyoid and the lower four gland via the otic ganglion.
unnamed (the sixth arch is rudimentary). Nerve X provides innervation to the heart,
a. The trigeminal nerve innervates the first lungs, and gastrointestinal system up to the
arch - muscles of mastication form here; transverse colon and the axons from the vagus
b. The facial nerve innervates the second arch synapse upon ganglia associated with these
- the muscles of facial expression form here; organs.
c. The glossopharyngeal nerve innervates the 4.Cranial Nerves Associated with the
third arch - the stylopharyngeus forms in the Special Senses.
third and, Nerve I (olfactory) cell bodies are located in
c. The vagus nerve innervates the fourth, the nasal placode in the upper fifth of each nasal
fifth and sixth arches- the laryngeal forms here. cavity. The neuroblasts in the olfactory epitheli-
Nerve V (trigeminal) is a mixed nerve um differentiate into olfactory epithelial cells.
(motor and sensory) that innervates the first or The axons of these cells grow toward the cerebral
mandibular arch and also contains a portion hemisphere, pierce the roof of the nasal cavity
(ophthalmic) that distributes to the skin up to and enter the region of the hemisphere that will
the vertex of the skull. The motor division of this become the olfactory bulb. The primary fibers
nerve innervates the muscles of mastication synapse in the olfactory bulb. The secondary cell
derived from the first arch. The sensory division bodies are located in the olfactory bulb and form
innervates the skin on the face and forehead. the olfactory tracts.
Nerve VII (facial) is a mixed nerve that dis- Nerve II (optic) originates from tertiary gan-
tributes to the second pharyngeal or hyoid arch. glion neurons in the retina. These axons are real-
The motor division of this nerve innervates the ly a tract in the central nervous system and do
muscles offacial expression. The sensory division not constitute a peripheral nerve. The axons
innervates the taste buds on the anterior two- synapse in the lateral geniculate nucleus of the
thirds of the tongue. thalamus. (Students may also want to review the
Nerve IX (glossopharyngeal) is a mixed nerve details of the formation of the eye from the optic
that innervates structures associated with the vesicle and lens vesicles in a standard embryolo-
third arch. The motor division of this nerve gy test.
innervates the stylopharyngeus muscles. Nerve VIII (vestibulocochlear) primary cell
Nerve X (vagus) is a mixed nerve that inner- bodies are located in the cochlea (auditory divi-
vates structures associated with the fourth and sion) and vestibule (vestibular division) of the
sixth arches (the fifth arch regresses). As well as inner ear. (Students may also want to review the
providing afferent and efferent components to details of the formation of the inner ear from the
the heart, lungs, and much of the gastrointestinal otic placode in a standard embryology text-
system. book).
Nerve XI (accessory) is purely motor and Nerves VII, IX, and X provide innervation to
innervates the sternomastoid and trapezius mus- the taste buds on the tongue and pharynx.
cles, which originate from somatic and branchial
Telencephalon
mesenchyme in the cervical region.
The Telencephalon, part of the forebrain,
3. Preganglionic Parasympathetic consists of two regions a cortical wne that
Innervation to Smooth Muscle. becomes the cerebral hemispheres and a deeply
Nerve III innervates the ciliary ganglion; placed nuclear region the corpus striatum that
postganglionic fibers then pass to the sphincter of becomes the caudate, putamen, and globus pal-
4-12 CHAPTER 4
lidus. appear at about 19 weeks; they are initially the

The telencephalon begins at 10 weeks as lateral or Sylvian sulcus, on the lateral surface
paired small smooth telencephalic vesicles. By (Fig. 4-11), and the parieto-occipital sulcus, on
birth a large, convoluted cerebral cortex is pre- the medial surface (Fig. 4-12). By the 24th
sent. The first prominent features seen in the week, the Sylvian sulcus is more pronounced on
hemisphere are the formation of the primary the lateral surface and the calcarine sulcus is
sulci or depressions. prominent on the medial surface becomes
prominent (Fig. 4-11). Shortly thereafter the
Primary Sulci.
other primary sulci-the central, callosal, and
The first of these sulci, the primary sulci, hippocampal-appear.
Figure 4-11. Development of the lateral surface of the brain during fetal life· Numbers represent gestation age in
weeks. (From Larroche, J. CI: The Development of the Central Nervous System During Intrauterine Life. In
Falkner, F. (ed.): Human Development, Philadelphia, W.B. Saunders, 1966, p. 258).
to grow and by late childhood reaches its final
weight of approximately 1500 g.
Development of Cerebral Cortex
The development of certain areas is of special
importance in understanding the final form of
the brain. As the lateral sulcus forms, the cortex
above and below the lateral fissure overgrows the
cortex deep in the lateral/Sylvian fissure. This
cortex, the insula, soon disappears from view and
is covered over by this overgrowth of frontal,
parietal, and temporal cortex. .
Formation of the cerebral cortex begms
around the seventh week and is completed in the
first year of life. Developing from the inside to
out, the first layer to form is layer VI and the last
to form is layer II (tritiated thymidine studies-
Angevine and Sidman, 1961; Berry and Rogers,
1965). The pyramidal cells in the cerebral cortex
Figure 4-12. Development of the medial surface o! the
appear to mature prior to the stellate cells
brain during fotallift. Numbers represent gestatJOn
age in weeks (From Larroche, J. CI.: The Development (Altman, 1966). Radial glial fibers form connec-
of the Central Nef"llous System During Intrauterine tions from the luminal surface to the pial surface
Life. In Falkner, F. (ed.): Human Development. that helps the primitive neurons migrating later
Philadelphia, W.B. Saunders, 1966, p. 259). into the more superficial layers to traverse the
increased cell densities in the deeper layers. The
After about 30 weeks the primary sulci are formation of the cerebrum from inside to outside
formed, and there is a rapid increase in the sec-
permits much of the circuitry to form and also
ondary sulci and gyri. By term, formation of the
permits the columnar arrangement in the cortex
gyri and sulci is complete. After birth the gyri
to evolve.
increase in bulk as the neurons continue to dif-
The development of the six-layered cerebral
ferentiate.
cortex starts with the migration of neuroblasts
The telencephalic vesicle rapidly changes into the deepest layer (VI-IV) first, then the cells
shape as the frontal lobe forms and pushes ante-
into the external layers (I-III) last- "inside-out".
riorly, the temporal lobe grows inferiorly, and the
Tritiated thymidine studies have been used on
occipital and parietal regions expand. The olfac-
rodents and primates for labeling nerve cells in
tory bulb forms at the base of the frontal lobe by
the germinal layer of the ventricle on their "birth
an evagination of cells that quickly obliterates any
days" and following them into the cerebrum and
trace of the ventricle in the olfactory bulb.
identifYing their final destination (Sidman and
The sulci begin as rather shallow depressions.
Feder 1959; Sidman and Miale, 1959; Rakic,
However, as the neurons continue to migrate in
1972).
from the ventricular surface, more and more cells
Commissures. Fiber bundles, called com-
are added and the gyri become larger and the
missures (Fig. 4-13 A, B, C, and D) interconnect
sulci become deeper. In the term and adult brain
the two cerebral hemispheres. The anterior
more than 70% of the cortical surface is hidden
commissure interconnects the olfactory bulbs
from view, deep in the banks of the sulci.
and anterior parts of the temporal lobe. The
Therefore, when we speak of the total surface of
huge corpus callosum interconnects the remain-
the cerebral hemispheres we must include not
ing portions of the hemisphere. The hippocam-
only the superficial cortex but also the hidden
pal commissure interconnects the hippocampus
sulcal cortex.
and adjacent portions of the hippocampal gyrus.
The brain at birth weighs 300 to 400g; by 1
These commissures form in the lamina terminalis
year it weighs 1000 grams. The brain continues
4-14 CHAPTER 4
Hippocampus
Olfactory
Iwa
CoI'pus Callosum
Olfactory Area Uncus Hippocampus
Figure 4-13. Development of the fornix and commissures of the cerebral hemispheres. A, 3-monthfetus. B, 4-month
fetus. C, Fetus at beginning of 5th month. D, Fetus at end of 7th month. (After Keibe~ B, and Mal~ BP.: Manual
of Human Embryology, Philadelphia, Lippincott, 191(}-12).
that marks the site of the closure of the anterior as the preplate (the primordial plexiform layer).
neuropore. The ventral surface of the hemi- Later formed neurons divide the preplate into 2
spheres at this place fuse, and the fibers can then layers: the marginal zone (future layer 1) and the
cross and interconnect the two hemispheres. subplate (the future neurons of layer 6 and the
Initially, the anterior commissure, corpus cal- white matter). Between the marginal rone and
losum, and fornix (which connects the hip- the subplate a transient layer the cortical plate is
pocampus and hypothalamus) are close to one formed beginning approximately at embryonic
another (Fig. 4-13A), but as the brain grows, the day 52.
corpus callosum expands anteriorly, inferiorly, Neuronal Migration. The migration of neu-
superiorly, and caudally with only the rostral tip rons is facilitated by the presence of special prim-
remaining attached to the lamina terminalis. 1 itive radial glial cells that extend between the ven-
PRENATAL DEVELOPMENT tricular surface and the pial surface. These glial
OF CEREBRAL CORTEX: cells essentially serve as guide wires for the
migrating neurons. This radial or vertical orien-
The developing cerebral hemispheres initially
tation provides the basis for the columnar orga-
show the three regions common to the neural
nization that is a characteristic of cerebral cortex.
tube, ventricular, intermediate and marginal
The initial migrating neurons travel through the
rones. Then the subventricular zone appears.
entire marginal layer and form a temporary orga-
Cells of the intermediate rone migrate into the
nizing layer in what will eventually become the
marginal rone and form the cortical layers. So
relatively acellular molecular layer. This organiz-
that the gray matter is on the periphery and the
ing layer apparently secretes an extracellular pro-
while matter, medullary center, is located cen-
tein: Reelin. (Reelin is named after the mutant
trally.
mouse -reeler-which has ataxic reeling move-
The initial progenitor neurons first appear in
ments due to the absence of this protein and in
the matrix/germinal area a proliferative cell layer
which there is total disorganization of the usual
around the ventricle at approximately 33 - 42
laminar pattern). When the successive waves of
days of development and form a structure known
migrating neurons encounter the organizing
1 The hippocampus anteriorly is disrupted by the layer, the Reelin provides a signal to detach, from
formation of the corpus callosum and a smaU the glial guide wires. The initial cells to detach
dorsal hippocampus or indusium griseum form the neurons oflayer 6. The apical dendrites
remains on the dorsal surface of the corpus cal- of these pyramidal cells in layers 6 and subse-
losum. quently layer 5 will extend to the pial surface.
Subsequent waves of neurons detach at succes- increasing complexity of the primary and sec-
sively higher levels. In addition to the putative ondary fissures. This process continues after the
role of the protein Reelin, other factors also influ- second year with the development of tertiary fis-
ence this process of migration. The radial guided sures.
migration is blocked by NMDA-antagonists Myelin formation is necessary for the func-
suggesting a role for the transmitter glutamate. tioning of the nervous system. The following
In addition calcium ion channels may also be table lists the chronological sequence of myelina-
involved in migration. Although the previous tion in the brain Table 4-4. and by implication
discussion has emphasized the radial movement the beginning of functions in many of these
of neurons it is also evident that some neurons same regions.
may migrate in a direction perpendicular to the At birth most of the intrinsic fiber systems of
radial glial fibers. Thus there are horizontal con- the spinal cord and brain stem have myelinated.
nections in addition to the vertical organization. The long corticospinal tracts and corpus callo-
The process of neurogenesis and migration is sum begin to myelinate during the first postnatal
completed in the human fetus by approximately months. The frontopontine, temperopontine,
week 24. The subsequent step in the process of and thalamocortical projections myelinate during
cortical development is a removal of those neu- the second postnatal month.
rons in the molecular layer that served as the ini- Myelination within the cerebral hemisphere
tial organizing layer by the process of apoptosis. and within the cerebral cortex occurs at different
The neurons in the ventricular zone, the subven- rates in different areas paralleling the changes in
tricular zone and the white matter (which have psychomotor development. Flechsig demon-
failed to reach the cortical plate forming layers 2- strated that the sequence of myelination in cere-
6) also die off by this same process. The radial bral cortex followed a logical pattern (Fig. 17-
glial cells lose their long fibers and differentiate 21).
into astrocytes. Although myelination of the cerebral cortex
The mature cerebral cortex is laminated and begins during the early postnatal months, it is
consists of the following six layers: evident that this process is not completed at this
Layers 1,2 and 3- supragranular phylogenet- time (Fig. 17-22). The initial myelination begins
ically newest layers and last layers to form in the vertically oriented fibers of the infragranu-
Layer 4 - granular layer, TABLE 4-4. MYELINATION Of BRAIN REGIONS.
Layers 5 and 6 - infragranular layers phyloge-
netically are first layers to form BRAIN WHEN
REGION MYELINATES
n. CHANGES IN CORTICAL
ARCHITECTURE AS A FUNCTION Spinal Cord Lastlrimester
OF POSTNATAL AGE Brain Stem last Trimester
During postnatal development the brain
increases significantly in weight from an average Fronto, parieto, tempero, occlpHo- Flrst- 2 month
pontine fibers postnatal (PN)
of 375 to 400 grams at birth to 1000 grams at 1
year, to a maximum of 1350 to 1410 grams at Primordial Cortical Fields : PN 1-2 Month
age 15 years (males). This increased growth does Motor -Sensory Strip
not affect all areas of the brain to an equal extent.
Thus this growth involves a rapid expansion of Intermediate Cortical Fields: PN 2-4 Month
Association areas adjacent to
the convexities of the frontal, parietal, and tem-
primary motor and sensory cortex -
porallobes. This results in a completion of the Premotor and Superior Parietal lobule-
covering of the insular lobe by the surrounding
operculum and a relative displacement of the Terminal Cortical fields: PN 4th month
parahippocampal gyrus and occipital lobe. In Association or integration areas -
addition, the cortical surface area is in a sense Prefrontal, Inferior parietal,
posterior temporal cortex
being increased by the deepening of sulci, with
4-16 CHAPTER 4
lar layers and then extends into the supragranular organ system. Of the 0.5% of newborn infants
layers. The myelination of horizontal plexuses with a major malfunction, roughly 60% affect the
occurs at a later stage. Myelination continues to nervous system.
increase beyond 15 years of age even until age 60 Many defects in the brain and spinal cord are
with a gradual increase in density of the myeli- evident at birth (Table 4-5). Some defects may
nated fibers particularly in the horizontal plexus- be limited to only the nervous system, but others
es. It is important to note that even in the adult may include overlying ectodermal and mesoder-
not all cortical areas will reach the same density mal structures (bone, muscle, and connective tis-
of myelinated fibers since the underlying pattern sue). Many of the malformations are due to
of distribution and density of pyramidal cells and genetic abnormalities. Other categories of
their processes will differ significantly among dif- defects can be acquired from the maternal envi-
ferent cortical areas. ronment: infections (syphilis, rubella, AIDS),
Neuronal Maturation. In addition to drugs (including alcohol, cocaine etc.), ionizing
changes in the degree of myelination, more basic radiation, environmental toxicants, metabolic
changes in the relationship between nerve cells disease and poor nutrition. The most serious
are occurring. Thus the neocortex has received defects are fatal, but even the less severe abnor-
its full complement of neurons by the end of the malities may significantly impairment function.
6th fetal month. During post natal development The following discussion covers many of the
as shown in silver stains there is a progressive major groups of malformations of the peripheral
growth of the apical and basilar dendritic and central nervous system. More complete lists
arborizations. The studies of Conel [25] have can be found in pathology textbooks.
demonstrated that the more primitive allocortex Malformations Resulting from
(e.g. hippocampus) attains its final structural Abnormalities in Growth and Migration
form at an earlier stage than the neocortex. The with incomplete development of the brain.
process of maturation however involves more
Heterotopias. Displaced islands of gray mat-
than a progressive growth and elaboration of
ter appear in the ventricular walls or white matter
dendrites and synapses. In addition, a re-model-
due to incomplete migration of neurons and this
ing of neuronal connections occurs in large part
based on neuronal activity. In the early perinatal TABLE 4-5. CONGENITAL NEUROLOGIC MALFORMATIONS
period, there may be an excessive projection of
axons to their targets. Maturation in part consists CATEGORY RESULTANT DEFICITS
of the elimination of these aberrant collateral 1. AbnonnalHles Heterotopias; anencephaly;
axon branches. In the primate there are estimat- in growth and holoprosencephaly; lissencephaly;
ed to be 3 to 4 times as many axons within the migration mlcro-, macro-, or polygyria;
corpus callosum at birth compared to the adult porencephaly; schizencephaly;
state. In this process the NMDA receptor may agenesis; fetal alcohol syndrome
have a considerable role in both neocortex and
2. Chromosomal Down's, Edward's, and
hippocampus, with the same cascade of the trisomy and Patau's syndromes
events that occur in long-term potentiation also translocation
responsible for the remodeling and synaptic plas-
ticity. Abnormalities in development or senso- 3. Defective fusion Spina bifida, cranial bifida,
ry/ environmental deprivation may retard the Amold-Chiari malformation
structural and functional development of these 4. Abnormalities Tuberous sclerosis,
processes. with excessive neurofibromatosis (von
m. ABNORMAL DEVELOPMENT growth of
ectodennaland
Reckiinghausens=Dlsease),
Sturge-Weber syndrome,
The complexity of development of the ner- mesodermal tissue.
vous system means that there is a great chance for
things to go wrong. In fact, more malformations 5. Abnormalities Syringomyelia, syringobulbia,
occur in the nervous system than in any other in ventricular system hydrocephalus
defect in neuronal migration may be seen in in males. Severe psychomotor retardation and
many of the following abnormalities. In this cat- seizures are the result of this process. Since
egory of malformation, the neurons or gJia have females have 2 X chromosomes the effects of a
f.riled to migrate, and consequently the brain single mutant X chromosome, are less severe.
development is incomplete. In the normal devel- The double cortex (subcortical band hetero-
opment of the cerebrum the neurons which form topia, or laminar heterotopia or diffuse cortical
the deeper cortical layers arrive first and then cells dysplasia) syndrome is the result. There is only a
destined for outer layers appear. In this abnor- partial migration defect. Some neurons arrest in
mality the later waves of migration stop. The the subcortical white matter but sufficient neu-
axons from the first cells to arrive begin to extend rons reach the intended targets so that a normal
throughout the brain and actually form a barrier 6-layered laminar pattern is present. Cognitive
that interferes with the next wave of migration. function fully develops but seizures are present.
The newly arriving neurons, which were destined 2) Mil~Dieker syndrome. This different
for the superficial layers, instead now form a dis- genetic type of lissencephaly occurs in the auto-
organized mass of neurons deep to the cortex. somal recessive with linkage to locus
The disruption of the normal pattern of cerebral 17p13.3.Infantile spasms and mixed seizures are
cortical development results in an imbalance in associated with motor and mental retardation
the equilibrium of excitation-inhibition. Seizures and a characteristic facies.
often result. The routine use ofMRI for the eval- 3) Bilateral nodular perivenmcular
uation of patients with epilepsy, has demonstrat- heterotopia is another X -linked dominant, [24] a
ed the high frequency of migration disorders par- relatively continuous series nodules composed of
ticularly in the pediatric and young adult age neurons is present in the ependymal layer and
group. Depending on the severity of the disor- subventricular zone, the former proliferative
der, the neurological examination and intellectu- zone for neurons during development. The cor-
al development may be normal. Areas of micro- tical lamination pattern is normal. In these cases,
gyria, macrogyria or polygyria may be encoun- 4) Cortical microdysgenesilU is a subtle
tered. For some migration disorders, a genetic form of neuronal migration disorder. It has been
basis has been established as summarized in described in many patients with idiopathic
Figure 4-18 derived from Walsh [23]. Various epilepsy: absence, juvenile myoclonic epilepsy
seizure types are present, but neurological devel- and primary generalized tonic-clonic. This disor-
opment, examination and intelligence are nor- der reflects events at a late stage of prenatal cor-
mal. (17-20). A recent review by summarizes tical development. Neurological examination
other genetic disorders with cerebral cortical and psychomotor development are normal,
changes. although subtle changes in cognitive function
Genetically Linked Migration Disorders may be present.
In the following malformations, neurons or
1) Type 1 X-linked dominant lissencephaly.
Most of the neurons never reach their expected gJia have f.riled to migrate, and consequently the
destination but instead are arrested in the sub- brain's development is incomplete. In the normal
cortical white matter and the subventricular pro- development of the cerebrum the neurons that
liferative wne. The cortex is smooth, since devel- form the deeper cortical layers arrive first and
opment never proceeds to the stage of develop- then cells destined for outer layers appear. In this
abnormality the later waves of migration stop.
ment of sulci and gyri that is necessary to accom-
modate the large numbers of cortical neurons The axons from the first cells to arrive begin to
extend throughout the brain and actually form a
that would otherwise be present in a normally
developed cerebral cortex. In this mutation, the barrier that interferes with the next wave of
cortex per se is thin with the lamination pattern migration. The newly arriving neurons, which
consisting of a rudimentary molecular layer 1 were destined for the superficial layers, instead
now form a disorganized mass of neurons deep
and a thin layer 5/6. Since males have only one
X chromosome this type of lissencephaly occurs to the cortex. The following case is an example of
abnormal migration.
4-18 CHAPTER 4
Case 4- 1: Bilateral subcortical band hetero- Comment: The description of the initial clin-
topias: double cortex SEE Details on CD ical phenomena and the subsequent evolution
This 24 year old right handed mother of 2 suggest initial discharge in the left frontal eye
children and home health aide was admitted to field (area 8) with subsequent spread to the (left)
the neurology service after a recurrence of supplementary motor cortex (an area where
seizures with a flurry of 4 seizures on the day of there is bilateral representation of the lower
admission. Seizures had begun at age 11 and extremities) .In contrast to the primary motor
would occur every 2 months. She described the cortex where simple clonic movements occur on
seizures as beginning with an involuntary driving stimulation, complex postures and bilateral leg
of the head and eyes to the right "as though she movements occur on supplementary motor cor-
was going to look over her right shoulder." At tex stimulation .The tonic posture or movement
this point she might experience a sensation of of the right arm would also be consistent with
fear. She was aware that involuntary movements such a pattern of spread. The clonic movements
of both legs would then occur as well as clonic or of the upper extremity would be consistent with
tonic movements of the right upper extremity. additional spread to the left motor cortex. The
On some occasions, she would then lose con- sensation of fear could have reflected spread to
sciousness and a secondarily generalized tonic- the limbic system possible by means of the adja-
clonic seizure would then be witnessed. She had cent cingulate gyrus eventually involving the
been initially treated with anticonvulsants: amygdala. The actual pathology in these areas of
phenytoin and phenobarbital, without control of frontal lobe consisted of heterotopias of gray
seizures. Carbamazepine was then utilized but matter, (termed double cortex or subcortical
produced side effects. She had discontinued all band heterotopia) a long-standing migration dis-
medications 14 months prior to admission. order. With the increasing use of the MRI to
Family history: negative for neurological or investigate patients with seizure disorders, there
seizure disorders. has been increasing recognition of such migra-
Past history: head trauma right frontal with tion disorders. This is an X chromosome linked
short period of unconsciousness at age 9 years. disorder. In the female with 2 X chromosomes,
She had a tubal ligation and bilateral carpal tun- this is a relatively benign disorder. In contrast in
nel surgery, 5 years prior to admission. the male with only 1 X chromosome, the effects
Neurological examination: mental status, are much more severe, most neurons never reach
cranial nerves, motor system, reflexes and senso- their expected destination but instead are arrest-
ry system were all normal. ed in the subcortical white matter. The result is
Clinical diagnosis: Focal seizures (partial type 1 X linked lissencephaly. The cortex is
epilepsy) originating left frontal eye field with smooth (lissencephalic) since development never
subsequent spread to left supplementary motor proceeds to the stage of sulci and gyri. Sulci and
cortex and amygdala (or possibly cingulate gyri develop normally in the process of accom-
gyrus). modating the large number of neurons that
Laboratory data: would under normal circumstances reach the
1.Electroencephalogram: normal cortical layers. Such males have severe psy-
2.MRI: bilateral triangular shaped foci of chomotor retardation as well as seizures.
heterotopic gray matter were present in the Anencephaly. Anencephaly is a lethal condi-
frontal white matter extending from the supero- tion in which skull, cerebral hemisphere, dien-
lateral aspect of the frontal horns to the gray cephalon, and midbrain can be absent. The noto-
white junction superiorly (see MRI Fig 4-1.). chord does not induce the anterior neuroecto-
Subsequent course: Anticonvulsant medica- derm and the anterior neuropore does not close.
tions were re-adjusted. Valproic acid was added The cerebral cortex and upper brainstem are rep-
to the carbamazepine. Compliance continued to resented by a tangle of meninges, glia and vessels
be a problem. She continued to have at least 1 at the base of the skull. The amount of brain tis-
generalized tonic-clonic and possibly several sim- sue absent can vary from only the cerebrum to all
ple partial seizures per year over the next 4 years. of the diencephalon and telencephalon. Part of
had trisomy l3y. In some cases these children
have had only one eye, cyclopia, and a proboscis
like nose with only a single nostril.
Lissencephaly (Agyri-Pachygyri). The brain
has failed to form sulci and gyri and corresponds
to a 12-week embryo. There are usually also dys-
morphic facial features. In some cases a few gyri
do form. Neuronal migration has been arrested
at this stage due to a chromosomal defect,
ischemia, or infection. The studies of Reiner et al
(1993) have identified a specific gene deletion at
chromosome 17 region pl3.3, the LIS-1 gene.
Figure 4-14. Micropolygyria. (Courtesy of Dr. John
Micropolygyria (Fig. 4-14). The gyri are
Hills, New England Medical Center Hospitals). more numerous, smaller, and more poorly devel-
oped than normal.
the brainstem, and remnants of higher structures Macrogyria. The gyri are broader and less
are usually present. The pituitary gland and numerous than in the normal brain.
other endocrine glands are small or absent. The Microencephaly. This is another abnormal
eyes and ears are well developed, but the optic defect in which development of the brain is rudi-
nerves are usually absent. These children are mentary and the individual has a low-grade intel-
usually born alive, but do not survive the first few ligence.
days. This category of almost complete absence Porencephaly. There are symmetrical cavities
of the brain has been used extensively for trans- in the cortex due to the absence of cortex and
plants of the normally formed heart, lung or kid- white matter in these sites.
ney into infants in need of organ donors. Schizencephaly (Fig 4-15). There is an incom-
In this condition the brain has failed to form plete development of the cerebral hemispheres
two distinct cerebral hemispheres. Instead, there with the presence of abnormal gyri. The patient
is a single partially differentiated hemisphere. is usually retarded.
The patient has a single ventricle, representing Agenesis of Corpus Callosum (Fig 4-16).
both lateral ventricles and the third ventricle. There is a complete or partial absence of the cor-
There are grades of severity of the malformation. pus callosum and septum pellucidum (See also
In some cases ofholoprosencephaly the children Fig 21-1)).
Figure 4-15. &hizencephaly. A. 3D reconstruction and B coronal view. MRI, 12 (Courtesy of Dr. Val Runge,
University of Kentucky Medical Center).
4-20 CHAPTER 4
panied by a deficit in medial facial development

(Fig 4-17).
Figure 4-3 on CD. This lOmonth old white
male had severe spastic diplegia (a form of "cere-
bral palsy") and severe developmental delays. CT
scan demonstrated a fusion of the two lateral
ventricles and no frontal horns . A large cystic
area extended superiorly and posteriorly.
Cerebellar Agenesis. Portions of the cerebel-
lum, deep cerebellar nuclei, and even the pons
are either absent or malformed. In some
instances portions of the basal ganglia and brain
stem and spinal cord may also be malformed or
Figure 4-16. Agenesis ofcorpus callosum. (Courtesy of absent.
Dr. John Hills, New England Medical Center The cerebellar cortex forms differently than
Hospitals). the cerebrum by migration of primitive cells
The following case Case 4-2 is an example of from the rhombic lip of the brainstem. These
Agenesis of the Corpus Callosum. cells form a layer called the external granular cell
Case 4-2. Agenesis of corpus callosum: layer. From this layer, cells then migrate inward
Patient of Dr. Sandra Horowitz) to form the internal granular cell layer.
This 20-year-old female warehouse employee Environmentally Induced Migration
was referred for re-evaluation of generalized con- Disorder. Fetal Alcohol Syndrome. Fetal alco-
vulsive seizures that had developed at age 3 years. hol syndrome (FAS), mothers drinking alcohol
She had been seizure free for 5 years. She had during pregnancy cause one of the more com-
mild developmental delays. Full scale Wechsler mon nongenetic causes of mental retardation
Adult Intelligence score IQ was 82, with a verbal (one out of300 to 2000 live births, or up to 2%).
score of 88 and a performance score of 77(all There are other environmentally generated dis-
were within low average range). MRI (Fig. 4-20n orders but the FAS has the clearest etiology. The
CD) demonstrated complete agenesis of the cor- current recommendation is for pregnant women
pus callosum. With associated alterations of gyral to avoid all alcohol, especially during the first
and sulcal patterns. Midline sagittal section T 1 trimester, or to cut back to no more than two
weighted. drinks per day. Pregnant alcoholics are at high
Holoprosencephaly. Only a single forebrain risk for premature delivery.
has formed. This deficit is also commonly accom- In FAS, pre- and postnatal growth retarda-
Figure 4-~7. Holoprosencephaly. A, view offrontal poles, B, coronal section. Note the absence of any differentiation
of the hemISpheres. (Courtesy of Dr. John Hills, New England Medical Center Hospitals).
tion occurs along with cardiovascular, limb, and about 5% of children in institutions for the men-
craniofacial abnormalities, such as a short palpe- tally retarded.
bral fissure, thin vermillion border, and smooth The brains of these children show little gross
philtrum. Children often have impaired fine and abnormality. The frontal and occipital poles are
gross movements and developmental deficits. rounder than normal and the superior temporal
Microcephaly, heterotopias, and lissencephaly gyrus is thinner. Conventional stains show the
have been reported (Greenfield, 1992; Diminski brain to be normal histologically, but the Golgi
and Kalens, 1992). Related to the problem of stain, which specifically impregnates axons and
FAS is the huge rise in "cocaine babies," which dendrites, shows sparser dendritic arborizations,
have similar deficits that require lifetime care. fewer dendritic spines, and more anomalous
Malfonnations Resulting from
spines (Marin-Papilla, 1972; Purpura, 1974;
Chromosomal Trisomy and Translocation
Becker et al., 1986).
Patients who reach middle age may develop a
Through advances in molecular biology,
degenerative disease of the nervous system called
more and more genetic defects are being local-
Alzheimer's disease (see chapter on dementia).
ized to specific genes. For example, in transloca-
tion syndromes like trisomy 21 (Down's syn- Malfonnations Resulting from Defective
drome), one chromosomal segment is trans- Fusion of Dorsal Structures
ferred to a nonhomologous chromosome; this is Spinal Biftda. In spinal bifida, the most
called a Robertsonian translocation and most common malformation in this category, the arch-
commonly affects chromosomes 13, 14, 15, 18, es and dorsal spines of the vertebrae are absent.
21, and 22. Figure 4-19 shows the clinical fea- Often the bony deficit alone is present. The
tures of trisomy 21. Other defects, such as tri- spinal cord, however, may be malformed either at
somy 18 (Edwards' syndrome) and trisomy 13 one level or at many levels. In some instances the
(Patau's syndrome), have similar neurologic find- spinal cord, nerve root, and meninges have her-
ings. niated through the midline defect in the skin and
Most children with Down's syndrome are bone -- meningomyelocele (Fig. 4-18). In other
moderately mentally retarded and of short instances only the meninges have herniated
stature. They have hypoplastic faces with short through the midline defect, the sac is called a
noses, small ears with prominent antihelices, and meningocele.
prominent epicanthal folds (which perhaps sug- Cranial Biftda. Cranial bifida is less com-
gested the now outdated term mongolism). mon the spinal bifida and usually occurs only in
Other defects include a protruding lower lip, a the suboccipital region. The cranial bones either
fissured and thickened tongue, and a simian fails to fuse or do not form . The abnormality
crease on the palm. A predisposition to leukemia may only be restricted to the underlying portion
and congenital heart defects often prove fatal. of the cerebrum or it may be accompanied by a
Children with Down's syndrome constitute herniation of meninges -- meningocele -- or
Figure 4-18. Meningomyelocele at sturallevel of the spinal cord. Arrow reftrs to Stu, meninges, neural tissue, and
overlying skin. (Courtesy ofDr. John Hills, New England Medical Cenwr Hospitals).
4-22 CHAPTER 4
meninges and brain tissue -- encephalocele. order is characterized by the proliferation of

Cranial bifida is commonly associated with cells derived from the neural crest. The cells
hydrocephalus and extensive brain damage. identified in this defect include Schwann cells,
Arnold-Chiari Malformation. In this condi- melanocytes and endoneurial fibroblasts. The
tion there is elongation and displacement of the presence of melanocytes produces multiple areas
brain stem and a portion of the cerebellum ofskin with hyperpigmented (cafe au lait spots).
through the foramen magnum into the cervical Multiple tumors form in the cutaneous and sub-
region of the vertebral canal. Hydrocephalus, cutaneous tissues. The subcutaneous lesions may
spina bifida with meningocele, or meningomye- be discrete tumors and may be attached to a
locele may also be associated with this abnormal- nerve or more diffuse-described as plexiform
ity, which may be fatal or produce neurological neuromas. The latter may produce considerable
symptoms due to compression of the cervical distortion of face and body. Tumors may involve
roots and the overcrowding of the neural tissue peripheral, spinal or cranial nerves. Tumors of
in the posterior fossa (Fig. 15-7). glial and meningeal origin also occur within the
Malformations Characterized by Excessive central nervous system.
Growth of Ectodermal and Mesodermal Type II is characterized by bilateral acoustic
Tissue-affecting skin, nervous system and neuromas and has been identified with a gene
other tissues. locus on chromosome 22. (Case history exam-
These neurocutaneous disorders are referred ples and additional discussion will be found in
to as phacomatosis (mother spot). They are all Chapters 9,15, and 27.)
characterized by hereditary transmission, Cutaneous Angiomatosis with associated
involvement of multiple organs, and a slow evo- malformations of the central nervous sys-
lution of the disorder during the childhood and tem.
adolescent years. Due to maldevelopment, Various disorders are included in this catego-
benign tumors are formed-referred to as hamar- ry, often some type of vascular anomaly affecting
tomas (body defect tumor). There is moreover a skin (a vascular nevus), is associated with a mal-
tendency to malignant transformation. formation in the affected areas of the nervous
Tuberous Sclerosis. The triad of seizures, men- system. Hemangiomas of the spinal cord may be
tal retardation and a skin disorder called "adeno- associated with a congenital vascular nevus in the
ma sebaceum" characterizes this autosomal corresponding dermatome.
dominant disorder. The skin disorder involves Sturge- ~ber Syndrome. Patients with this
the formation of nodules over the face-com- abnormality have a large, deep port red wine
posed of angiofibromas. Within the nervous sys- nevus over much of the forehead corresponding
tem, the nodules are usually present in a periven- to the distribution of the ophthalmic branch of
tricular subependymal location composed of the trigeminal nerve. The vascular malformation
glioblast and neuroblasts. Other nodules may be involves the meninges overlying the parieto-
present in the cerebral cortex. Giant neurons and occipital cortex. In this cortical region there is
astrocytes may be present. As these nodules calcification of the second and third layers with
(tubers) expand the ventricular system may be neuronal degeneration and proliferation of reac-
blocked. Rarely malignant transformation tive glial. Atrophy occurs in the cerebrum. The
occurs. The abnormal gene has been isolated to specific genetic basis of this syndrome is uncer-
chromosome 9. In some manner this gene loca- tain.
tion may control an inhibitory factor. When Malformations Resulting from
defective, excessive growth occurs. Abnormalities in the Ventricular System
Neurofibromatosis (von Recklinghausen)s Syringomyelia. In this condition the spinal
Disease). canal is abnormally large. The cavity may enlarge
Two types of neurofibromatosis have been
to destroy parts or all of the gray matter and
described. Type I is related to a gene locus on adjacent white matter producing a characteristic
chromosome 17. This autosomal dominant dis- "cape like deficit" in pain sensation (Chapter 9).
noid space into the venous channels (via the
arachnoid granulations) or the malformation of
the arachnoid villi, produces excess fluid in the
subarachnoid space with resultant pressure on
the central nervous system. Obliteration of the
subarachnoid cisterns or of the subarachnoid
channels may produce this syndrome.
Hydrocephalus can produce thinning out of
the bones of the skull with a prominent forehead
and atrophy of the cerebral cortex and white
matter, compression of the basal ganglia and
diencephalon, and herniation of the brain into
the foramen magnum. Prior to closure of the
sutures such pressure will result in an increase in
the size of the head. Depending on the severity
of the brain damage the infant may die or survive
with mental retardation, spasticity, ataxia, and
other defects.
Figure 4-19. Noncommunicating hydrocephalus,

Dandy-Walker syndrome. (Courtesy of Dr. John Hills,
New England Medical Center Hospitals).
Syringobulbia. In this condition there are
abnormal slit like cavities extending from the
fourth ventricle into the subjacent tegmentum of
the medulla (most common) and pons disrupt-
ing gray and white matter with accompanying
cranial nerve and long tract signs (Chapter 9).
Hydrocephalus. Any abnormality in absorp-
tion of cerebrospinal fluid that produces
increased cerebrospinal fluid pressure and dila-
tion of the ventricular system is called hydro-
cephalus. Blockage of the flow in the ventricular
system is called noncommunicating hydro-
cephalus, while blockage of the cerebrospinal
fluid in the subarachnoid space is called commu-
nicating hydrocephalus.
Noncommunicating hydrocephalus may be
caused by a CSF blockage at the interventricular
foramen, the cerebral aqueduct, or in the fourth
ventricle, as well as by a malformation of any por-
tion of the ventricular system. The passageways
connecting the fourth ventricle to the subarach-
noid space (foramina of Luschka and Magendie)
may be blocked or ill formed (as in the Dandy-
Walker malformation, Fig. 4-19).
Communicating hydrocephalus is caused by
the inability of fluid to pass from the subarach-
CHAPTER 5
Physiology
PART I. CELL PHYSIOLOGY

The cell is the basic building block of the ner-
vous system and indeed, the whole body. On
our way to an understanding of the nervous sys-
tem, a working knowledge of the capacities of
individual cells will be most helpful. The cell
membrane (Chapter 3) delimits the cell and is FIG 5-1. A drawing of the phospholipids bilayer that
the boundary between the sodium and chloride comprises the bulk ofplasma membranes. The lipid
rich extracellular fluid and the potassium and soluble tailsface each other while the more water-solu-
protein containing intracellular fluid. ble heads face the extracellular fluid and the cyro-
plasm. Most membranes are covered with a thin pro-
The Cell Membrane teinskin.
The membrane is composed of lipids, partic-
stretching its membrane comes from a difference
ularly lecithin, cholesterol, cephalin and sphin-
in the concentration of water on the two sides of
gomyelin, arranged as a bimolecular leaflet (Fig.
the membrane and a tendency for any substance
5-/) with the non-polar, water insoluble, ends in
to diffuse from a region of higher to a region of
the center and the polar, water soluble ends fac-
lower concentration. Concentration of water
ing the aqueous solutions of the extra and intra
you say? Certainly! '
cellular fluid compartments. The outside is cov-
. Pure ~ater contains 55.56 moles H20 per
ered by a thin layer of protein; the total about 5-
liter and IS 55.56 molar. As substances are dis-
5 nm thick. Similar bimolecular leaflets can be
solved in the water they replace and displace H20
formed in the laboratory. Such a membrane
~olecules, the number of moles of water per liter
would easily pass substances (such as ethanol)
IS reduced. When red blood cells are placed in
which were soluble enough in water to reach it
distilled water, the concentration of water out-
and also soluble enough in lipid to pass through
side the cells is much higher than inside where
it. The membrane would be permeable to such
the water is diluted by ions and proteins. As a
a substance. Highly water-soluble substances
consequence of this difference in concentration
such as glucose and ions such as sodium or potas-
water moves into the cell. The cell swells and
sium would not pass through; the membrane
because the inward force is so great, it bursts.
would be impermeable to them.
This is n?t just a laboratory curiosity, the person
Such a membrane would also be imperme-
who aspIrates fresh water into their lungs when
able to water, yet we can easily demonstrate
drowning will burst many red blood cells in the
water movement into and out of cells by observ-
~ulmonary circulation and liberate potassium
ing volume changes and eventual bursting of
mto the blood heading back to the heart.
cells. Water apparently moves through the cell
We should digress to develop an intuitive
membrane in protein-lined pores or channels 0.3
approach and a few simple equations describing
to 0.5 nm in effective diameter. The changing
the forces acting on the water molecules as they
cross sections of a single muscle fiber shown in
move through the cell membrane. Any text of
Fig. 5-2 are but one example of water movement.
physical chemistry will provide a more rigorous
Even though we can study water movement eas-
approach to the derivation of the same
ily by observing volume changes, we have made
equations.
very little progress in characterizing the pores or
channels through which it moves. Finkelstein Energy
(1987) summarizes both the theory and reality. We know intuitively that a reservoir full of
The force moving water into the cell and water contains a certain amount of energy; it has
5 -2 CHAPTER 5
... an understanding of the direction in which a sys-

... .' tem can go. Of its own accord, a stone can only
.. ltfj ~oll downhill. If we find rocks moving uphill we
infer that some form of energy is (or has been)
expended.
Chemical potential. Cells exist in aqueous
solutions. Consequently, it is the energy of aque-
.....--
••~~-7,~,,~,~,-~~ ous systems and they're potential for doing work
that is of interest to us in the study of cell physi-
ology. The potential factor, called the chemical
Figure 5-2. The influence of osmotic strength of the
bathing solution on the cross-section area and 1'0lume potential, is analogous to all the other potential
of a~ isolated single muscle fiber. (From Blinks, J.: J. factors, such as height, temperature, pressure, or
PhYSlOI., 177: 52, 1965.) voltage. The capacity factor is the number of
moles involved in the reaction.
the potential to do some work as it flows from
Metallic sodium reacts with water to form
the reservoir. Whether this work is the frictional
sodium hydroxide, hydrogen, and heat. The
heat of water falling on rock or the rotation of
chemical potential of pure sodium is greater than
the turbine of an electric generator is largely a
that of sodium hydroxide and hydrogen.
measure of the cunning of the engineer. We
Consequently, the reaction proceeds sponta-
know, however, that the energy of the reservoir is
neously and energy (heat) is liberated. The reac-
conserved; it goes somewhere and is turned into
tion proceeds from a state of higher chemical
some kind of work.
potential to a state of lower chemical potential;
As water flows from a reservoir, the distance
all spontaneous reactions do. The reactants have
the waterfalls are the potential of the system to
a higher chemical potential than do the products.
do work. The amount of work done is also
The total amount of energy liberated as you
dependent on the size or capacity of the reser-
might expect, depends on the number ~f moles
voir. The total extractable work, the energy of
of sodium that react.
the system, is proportional to the distance (i.e.,
The chemical potential La) of a simple,
potential) the water can fall and the amount (i.e.,
uncharged reactant (a) is, to a first approxima-
capacity) of water available to fall.
tion, a very simple function of concentration.
Similarly, the total energy of any system is
a = O(a)+ RT In Ca
equal to the product of a potential factor and a
Where
capacity factor. Several examples are given in the
R = the gas constant
following table:
T = absolute temperature of the solution
Ca = molar concentration of the reactant
Potential Capacity
(or Extrinsic)
O(a) = standard state chemical potential
(or Intrinsic)
Type of Energy Factor Factor O(a) is the chemical potential of a I molar
solution of the reactant at 273°K (O°C) and 760
mm Hg pressure. It enters the equation because
Gravitational Height Weight
Expansion Pressure Volume of the units chosen for concentration. Note that
Electrical Voltage Current when Ca = I mole, = 0, because In 1= O.
Heat Temperature Caloric Content Because we are usually interested in the dif-
ference in u between two solutions on either side
(i and 0) of a membrane, 0 drops out and to =
It is the potential factor that determines
whether work will proceed at all. We can get RT In (q/Co )'
In the study of the movement of a substance
work from two reservoirs ofwater only if they are
through cell membranes, an important factor is
at different heights. Heat will flow between two
the difference, if any, in chemical potential
bodies only if they are of different temperatures.
between the substance inside the cell and the
The idea of a difference in potential is crucial to
substance in the outside solution. Unless this is
PHYSIOLOGY 5-3
known, only conjectures can be made about the D = constant C;X = concentration gradient
nature of the process by which the substance The number of moles of glucose per minute
enters the cell. If the substance is moving from a that will flow from a solution of 2 molar glucose
region of high chemical potential to a region of to a solution of 1molar glucose is dependent on
low chemical potential, a permeable membrane is the area of contact between the two solutions.
all that is required. If the substance is moving Clearly, the greater the area exposed, the greater
from a region oflow chemical potential to one of the flow. M. H. Jacobs (1967) discuss specific
high chemical potential, we know immediately solutions to the diffusion equation for various
that energy must be expended, an active trans- boundary conditions (physical situations).
port. Linear Diffusion. When a substance is dif-
To sum up, the chemical potential is, as the fusing in a long tube, the rate of diffusion
name implies, a potential function. We expect depends on the square of the distance. After dif-
that energy will flow from a phase of greater fusion has progressed a while, the concentration
chemical potential to a phase of lower chemical at any point along the tube will be proportional
potential. This principle is the cornerstone of to the square of the distance from the original
thermodynamics. The maximum work we can interface.
get from a system is equal to the product of the An example oflinear diffusion is shown in the
difference in chemical potential times the num- following table. One million sugar molecules
ber of moles involved. were concentrated in a very fine layer at the bot-
If, however, the chemical potential of a sub- tom of a graduated cylinder. One hour later the
stance is equal in two phases, we do not expect a distribution was:
net flow of the substance. Two solutions are, by
definition, in equilibrium when the chemical Distance Number of Molecules
potentials of all the substances in the two solu- O-Imm 553,000
tions are equal. In the case of a semi-permeable 1-2 mm 319,000
membrane, only permeable substances are con- 2-3 mm 157,000
sidered when determining equilibrium across the 3-5 mm 55,000
membrane. Water is usually in equilibrium across 5-5 mm 13,000
the membrane. 5-6 mm 2,000
Diffusion 6-7 mm 170
The flow of mass is one form of work in Over 7 mm 20
which energy in the form of chemical potential
can be expended; in which a difference in chem-
ical potential can be put to work. All ofyou have As you can see, almost half the molecules
seen the classic demonstration of a crystal of have not moved 1mm from the starting position.
potassium permanganate dropped into a cylinder A handy rule of thumb for simple electrolytes in
of water. The purple color gradually spreads water is that it will take 1 millisecond for a sub-
throughout the cylinder. The color change indi- stance to diffuse 1jJlll.
cates that permanganate ions are spreading Diffusion into a Cylinder. The second case
through the water by the mechanism of diffu- concerns the diffusion of nitrogen into a cylin-
sion. The permanganate ions are moving from a drical muscle fiber. Consider, for example, that
region where they have a high chemical potential pure nitrogen is suddenly bubbled into the fluid
(high concentration) to a region where they have surrounding a muscle fiber. How long will it
a low chemical potential (low concentration). take before the concentration reaches 90 percent
Diffusion is an irreversible process and is of its final value at the center of the cell? That
described by the equation depends on the diameter of the cell. Values for
moles/time = -DA q;X both 50 percent and 90 percent of the value at
where the surface for cylindrical cells of varying diame-
t = time A = area available for diffusion ter are given in the following table:
5-4 CHAPTERS
Time (sec) for Time (sec) for Osmolarity.

We describe the degree of dilution of water
Diameter 50 percent 90 percent
Saturation Saturation by the number of particles diluting it and express
this in milliosmoles. Human plasma osmolarity
20~m 0.008 0.055 is 28S-29S mosmjl and is made up of Na+,
ISOmM; K+, 3mM; Ca++ (2xSmM=IOmosm);
50~m 0.035 0.177
Cl-, 100mM; HC03 -, 2SmM; with the remain-
100~m 0.213 1.11 der from serum proteins. Because the osmolari-
ty of a solution is a function of the number of
200~m 0.852 5.55 particles, osmolarity belongs to the much larger
Imm 21.3 III
and well-studied group of colligative properties
of water such as vapor-pressure lowering, freez-
2mm 852 5500 ing point depression and boiling point elevation.
The standard, commercial osmometer really
Since the situation for other small molecules, measures freezing point depression, but is cali-
such as 02 or Ca++, is similar, it can readily be brated in milliosmoles. We describe solutions
seen that large cells are at a considerable disad- that maintain cell volume as isotonic, such as iso-
vantage since they must obtain all their nutrients tonic saline for injection. Hypertonic solutions
and excrete all their waste products by diffusion. contain more particles, particularly particles that
The time it takes the large cell to move even cannot enter cells, and cause cells to shrink.. As
small quantities of these substances is so long that the cell shrinks due to water movement down its
they cannot metabolize at a reasonable rate. For chemical potential gradient, the concentration of
that reason large (200 Jlill) cells are very rare and the cell contents increases until the chemical
cells which move substances rapidly, such as red potential of water is equal on both sides of the
blood cells, are small (7Jlill). membrane. Hypotonic solutions contain fewer
Furthermore, calculations such as these show diluting particles and cause cells to swell.
that the distance between a cell and the nearest Osmotic pressure refers to the ability of phys-
capillary must be fairly short to provide rapid dif- ical pressure to alter the chemical potential of
fusion. water and hence balance the chemical potential
Water Movement of H20 by pressure rather than concentration.
The energy to drive water into cells and Plants and bacteria have cell walls that allow the
change their volume comes then from differ- creation of a pressure within the cell, indeed it is
ences in chemical potential of water between the the only way a cell can survive in distilled or fresh
solutions inside and outside the cell and the water. Animals have no cell wall and are unable
speed is described by the diffusion equation. The to maintain pressure within individual cells.
single muscle fiber shown in Fig. S-2 maintained The adult brain, however, is encased in the
its normal volume when placed in a 120 mM nonexpendable skull and does maintain a small
NaCI solution. The chemical potential of water physical pressure, the cerebrospinal fluid pres-
is equal on both sides of the red cell membrane. sure, normally 70-80 mm H2O or S-7 mmHg.
When placed in an 80 mM NaCI solution, the A large number of conditions, including trauma,
fiber swelled. The chemical potential of water is cause the brain to swell and hence increase
slightly greater in the 80 mM NaCI solution; it is intracranial pressure and decrease consciousness.
diluted less. Water will move down the chemical Intracranial pressure can be reduced by adding
potential gradient, swell the cells and dilute the particles to the plasma which cannot cross capil-
cell contents until the chemical potential of water laries or get into brain cells. Fig. 5-3 is an exam-
on both sides of the membrane is the same, an ple where isosorbide was added to plasma, serum
equilibrium reached and a new volume estab- osmolarity was increased and water moved from
lished. brain cells into plasma. Intracranial pressure was
reduced dramatically and the patient's condition
PHYSIOLOGY 5-5
improved. Mannitol is more commonly used for Recording from such a channel (Fig S-4A)
reducing intracranial pressure. shows it opening and closing rapidly. This par-
ticular channel was recorded from a small patch
of membrane attached to a pipette by mild suc-
':50:s,OI"O[ nUDY ~ ,,'/66 tion and pulled off the cell so that the inside sur-
.AIIING '01 2 HOUtS
WEIGH: sa'll, face of the membrane is exposed to the bathing
solution (here 150 mM K+), a so-called inside out
~ __ .... _______ ::'!':.~'::~•.!"!. __ jloo patch.
These channels are quite selective for potassi-
J2.IO um. In Fig. 5-4B the solution against the inside
.. of the membrane was changed to one containing
150 mM Rh+ and the number of ions flowing
g
200
I~O
through the channel (the current) dropped dra-
u
matically. On the basis of whole cell recording,
'00 the selective permeability series is
JO~ lII.ellAU
IN" (U PUUUI.
K+>Rh+>NH5+»Na+ or Li+. High ionic
)0
IN I HI., 11 MIN$.
selectivity is characteristic of most channels.
I ,
" 30 .$ 6D 7.) '0 10) 170
UMf IN MINUUS
Figure 5-3. The effict of increased serum osmolarity

(dashed line) on intra&ranial pressure (solid line).
(From Wise, B.L., and Mathis, ].L.:]. Neurosurgery.
28:125, 1968.)
Potassium Channels
Cells contain a high concentration of potassi- Figure 5-4. A cartoon of a voltage gated potassium
um (150 mM) while the extracellular fluid con- channel inserted in a lipid bilayer. S represents the
tains a low (3 mM) concentration; there is a sig- selectivity gate or filter that discriminates between
nificant difference in the concentration of potas- potassium and other monovalent ions. The dotted
sium across the cell membrane. The lipid bilayer sphere represents the voltage sensor and V the voltage
membrane discussed earlier would not allow modulated gate.
potassium to move across the membrane because
Potassium equilibrium voltage. Most cells
potassium ions are insoluble in lipid. Soon after
contain several thousand such potassium chan-
adding radioactive potassium to the extracellular
nels on their surface; indeed, it is very difficult
space, however, the cells contain radioactive
with a 0.1 J.lIIl pipette to find a place with only
potassium and when these cells are returned to a
one channel. On a statistical basis, then, a large
non-radioactive solution, the radioactivity leaves
number of these channels are open at anyone
the cells; the cell membrane is clearly permeable
time and provide a sizable pathway for potassium
to potassium ions.
ions to move down their concentration gradient.
Potassium ions cross the cell membrane via
Yet the potassium ion concentration of cells
specialized protein channels in the cell mem-
remains constant and the potassium flux leaving
brane (Fig. 5-4). These potassium channels and
the cells is quite small. Why with a sizable path-
all channels that have been studied are constant-
way and an equally sizable concentration gradi-
ly opening completely and after an apparently
ent (150 mM > 3 mM) doesn't potassium rush
random interval close abruptly. The channel
out of the cell (Fig 5-5)?
opens a door, some other force, concentration
Remember for a minute that potassium ions
difference, for example, provide the energy nec-
are positively charged and the equal number of
essary for the ion to move. Channels allow only
negative charges inside the cell is predominantly
a single ion species to traverse an open pore.
on proteins that do not move around and cer-
5-6 CHAPTER 5
tainly cannot leave the cell. As a positively the chemical potential of an ion (b):
charged potassium ion moves into the trans-
-b = -0 + RT lnCb + zF
membrane channel, down its concentration gra-
where z = valence, F = Faraday and = the
dient, it leaves behind a negative charge; the
absolute electric field.
inside of the cell becomes ever so slightly nega-
Once an electric field is established, the elec-
tive. As more positively charged potassium ions
trochemical potentials of the potassium ions
start down their concentration gradient through
inside and outside the cell become equal. When
the potassium channels of the membrane, the cell
only one ion is permeable, in this case potassium,
becomes increasingly more negative because of
the potassium equilibrium voltage (VK) is
the negative charges on the protein, until a stable
described quantitatively by the Nernst equation;
voltage of 0.1 volt, inside negative, is maintained.
an equilibrium between the electrical force and
As the inside of the cell becomes slightly nega-
the chemical concentration force each acting on
tive, a second force, electrostatic attraction ,
potassium ions
begins to work on the potassium ion acting to
hold it within the cell (Fig 5-5). An equilibrium zFVK = - RT In K\jK+ 0 or
is rapidly established between the concentration VK = - RT/zF In K\jK+ 0
force tending to move potassium down its con- where V is the voltage ( 0- i) across the mem-
centration gradient, out of the cell, and the elec- brane, K+i and K+o are the potassium concen-
trostatic force attracting the positively charged trations, R & F are constants, T the absolute
potassium ions back into the negatively charged temperature and z the valence of the ion. For
cell. Only about .005% of the intracellular potas- potassium ions at 200C, this equation becomes
sium moves into the membrane to establish this VK =-58 log 150mM/3 mM = -97mV
voltage, called the resting membrane voltage.
At 37°C the constant is -61.
VK is the potassium equilibrium voltage, at
this voltage and concentration ratio, K+ is in
equilibrium across the cell membrane. The
Nernst equation can be solved for any permeable
ions such as H+, Cl- or for Na+ if only that ion
was permeable; these are equilibrium voltages for
single permeable ions.
Resting membrane voltage. Actual volt-
ages across the membrane of a single muscle
Figure 5-5. A recording of ions passing through a
fiber at a varying Ka are shown in Fig. 5-6 and
single potassium channel. In Afluid facing the cYto-
plasm surface contained K+ and many ions traversed are well described by the Nernst equation that
the channel each time it opened. When Rh+ was sub- assumes that potassium is the only permeant ion;
stituted for K+ (B) the current was greatly reduced the resting membrane voltage closely approxi-
even though the channel opened as often as before. mates the potassium equilibrium voltage. The
Patch clamp data atkpted from Findley, J. Physiol. potassium ion is in equilibrium across the resting
350:179-195, 1985. membrane. There is no net force acting on it.
Because this is an equilibrium, once the work The potassium equilibrium voltage is the voltage
of putting the potassium-protein complex into across the membrane, which brings the electro-
the cell is completed, the voltage continues with- chemical potentials of potassium, inside, and
out the expenditure of energy. All nerve and out, into equilibrium.
muscle cells maintain such a negative voltage. It We find electrical potentials across the mem-
is derived from the potassium ion gradient, the branes of most types of cells, and most of these
potassium permeability of the membrane, and an potentials can be described to a first approxima-
intracellular, impermeable anion. tion by the Nernst equation for potassium and
Nemst equation. In addition to concentra- range from -80mV to -100 mv'
tion, a second factor, electric field, also influences When discussing changes in the actual mem-
PHYSIOLOGY 5-7
because the Na+ concentration gradient is into

·10
the cell. Only a voltage of +55 mV inside the cell
0 would bring Na+ into electrochemical equilibri-
·10 um across the membrane if Na+ were the only
-10 permeant ion. In a cell with a resting membrane
-30
voltage of -90 mV, sodium ions, if permeable to
__ 40 the membrane, are 135 mV away from equilibri-
>
!. -SO
um, a significant electrochemical potential
-SO difference.
~
i- The membrane is about 100 times more per-
-
60
f -70
meable to potassium ions than to sodium ions.
!
5 ·eo Each time a sodium ion manages to sneak into
the cell, the cell becomes a little less negative. A
·90
-100
potassium ion is now liberated from the con-
-100
straints of the electrostatic field and escapes from
- \10 the cell. In the steady state, the membrane volt-
• age is a little less negative than that predicted by
-'10 1-~ 10 30 ~ ",I'I.K
the potassium equilibrium. Inspection of Fig. 5-
Figure 5-6. The relationship between the external 6 shows that at Ko of2.5 and 5 the experimental
potassium coneentration and the resting membrane voltage points are less negative than predicted by
pottage fitted with the Nernst equation. (From the Nernst line.
Hodgkin, ~ and Horowicz, P.: J. Physiol., 158:127- The Goldman Equation. This is a useful
160,1959). equation describing the membrane voltage when
brane voltage of a cell, we use the term depolar- more than one ion is permeable:
ize to denote a movement to more positive volt- V(mv) = -58 log PK ~ + PNa Nao
ages (i.e. -90 to -60 mY) and hyperpolarize to PK Ka + PNa Nao
denote movement to more negative voltages (i.e. Where PK and PNa are the membrane per-
-90 to -110 mY). We use the convention that the me abilities to potassium and sodium. When PNa
outside solution is zero millivolts. = 0, it becomes the Nernst Equation for potassi-
Several Penneable Ions um. When two (or more) ions are permeable,
Sodium channels. The preceding discussion each ion influences the final membrane voltage in
of the resting membrane voltage as a potassium proportion to its ability to cross the membrane.
equilibrium voltage assumed that the membrane The equation can be rewritten as
was permeable only to potassium ions; it con- V = +58 log Ko + PNal PK Nao
tained only potassium selective channels. Real Ki + PNaiPK N~
cell membranes don't quite reach that degree of Because both the ratio PNa/pK (0.01) and
perfection. They are also permeable to sodium Nai (20) are small, the product is very small in
ions; radioactive sodium ions enter and leave cells relationship to the internal potassium (150), that
slowly. Some of the Na+ enters via K channels; term can be dropped and the equation inverted
they are only 100011 selective for K, and some to become:
Na+ enters through the Na channels we will con- V = 58 log Ka + PNa/PNa Nao
sider in the next chapter. That sodium ions enter
Ki
should be no surprise, the Na+ concentration
gradient (120 mM/20 mM) is into the cell and This equation is plotted in Fig. 5-7 together
the negative interior voltage of the cell is very with membrane potential data. The addition of
inviting to a positively charged ion. Indeed, the the PNa/PK Nao term adds greatly to the fit to
sodium equilibrium voltage is: experimental data at low potassium concentra-
VNa = -58 log 20 mM/120 mM = +55 mV tions and very negative membrane voltages. All
The sodium equilibrium voltage is positive membranes are at least slightly permeable to
5-8 CHAPTERS
more than one ion and the Goldman equation is glycosides block Na/K active transport. When
very useful in describing the observed membrane red blood cells are stored in the cold they gain
voltage. sodium and loose potassium.
l
Control of potassium Channels
At resting membrane voltages, one group of
potassium channels are opening and closing as
previously described to provide the significant
,. potassium permeability of the resting cell mem-
.
<0
i brane and the energy source for the resting
membrane voltage. This might suggest these
So
-
were static channels, the probability of opening
and closing never changing; nothing could be
farther from reality. Potassium channels come
- '''' -'00 under at least three types of control: membrane
".
1l0.';-Il-ot,-,-7If-~-,Ir-.,--+,---:,';;-0---,!;;l0-+..
..,.---.:''''~-.J
voltage, internal calcium and external neuro-
transmitters. They are the most diverse group of
Pot.anium coftCtlntr,ulon (ml'1)
channels yet studied.
Voltage Control. Some channels open
Figure 5-7. The resting membrane voltage for frog
single muscle fibers in solutions of varying potassium rapidly but transiently where the cell is depolar-
concentration fitted by the Goldman equation. The ized; because of their role in the action potential.
normal values for frog muscle are Na o = 120 mM/L, A second type of voltage sensitive potassium
Nai =20 mM/L, Ki =150 mM/L, and Ko =2.5 channels is usually open but closes a few seconds
mM/L (From Hodgkin, A.L, and Horowicz, P.: J. after depolarization. These are the channels that
Physiol., 158:127-160, 1959). provide the resting potassium permeability in
many cells.
Active Transport To understand the closing behavior when the
Just as it was clear that sodium ions were cell is depolarized, remember that any membrane
moving down an electrochemical gradient into voltage less negative than VK will result in an
the cell, any sodium ion movement out of the outward electrochemical gradient for K+ ions
cell must be up an electrochemical gradient and and if potassium channels are open, K+ ions will
must require energy; an active transport with flow out of the cell, usually in exchange for Na+
ATP as the energy source. The active transport ions. The cell must then expend energy to
of sodium out of cells has been extensively stud- actively transport the Na+ out and K+ back in.
ied (Stein, 1988) and the protein responsible iso- These K channels decrease their probability of
lated. Under most circumstances 3Na+ move opening whenever the membrane voltage is less
out for every 2 K+ moving in so there is a mild negative than VK, specifically to prevent potassi-
imbalance in charge. Other ionic pathways, usu- um loss. These channels likewise increase their
ally the potassium channel we have already dis- probability of opening when the cell becomes
cussed, make up the difference in charge (mov- more negative than VK as it might when a
ing a third K+ into the cell) and there is usually 3Na/2K active transport is working. This chan-
no component of membrane voltage attributable nel passes K+ much more easily when the potas-
to active transport. If these other pathways are sium electrochemical gradient is into rather than
blocked, a large hyperpolarization (more nega- out of the cell. We call these channels inward
tive voltage) is associated with active transport. rectifYing K channels and they probably are the
All cells leak a little sodium in and potassium major source of open potassium channels at the
out and active transport keeps the internal potas- resting membrane voltage of many cell types.
sium high and sodium low. About 10% of our These channels are also capable of great mis-
resting metabolic rate is consumed with the chief whenever the external (plasma) potassium
NajK active transport. Cold and the digitalis concentration falls as it often does in diuretic
PHYSIOLOGY 5-9
therapy. As external K falls from 2.5 to I mM the final temperature of water coming out of a
(Fig. 5-8) VK changes from -101 to -125 mV while faucet. The extremes are only hot water running
the actual membrane voltage hyperpolarizes and only cold water running and any tempera-
from -95 to only -105 mv' The difference ture in between can be achieved by the appropri-
between VK and membrane voltage increases ate mixing of flow rates of hot and cold water.
from 7 to 20 mY, a potassium electrochemical C~ Controlled. Internal Ca as showed in
gradient out of the cell. This increasing outward Fig. 5-9 controls another group of potassium
gradient decreases the probability that the inward channels. These records are from a single isolat-
rectifYing K channels will be open and conse- ed potassium channel incorporated into an artifi-
quently reduces the total potassium permeability cial bilayer so that the solution on both sides of
of the membrane. As potassium permeability of the channel can be controlled. As the calcium
the membrane decreases, the sodium permeabil- concentration increases from 3 _M to 95 _M, the
ity, which has not changed, exerts a stronger, percent open time increases until the channel is
depolarizing, force on the membrane voltage open almost all of the time.
leading to the sudden depolarization shown in
Fig 5-8. The ratio PNa/PK increases from 0.03
to 0.15. The abrupt change in PNa/PK perme-
ability ratio gives the Na ion and the Na equilib-
~L lOOms 3 j1M Ca"
rium potential (+55 mY) a greater ''voice'' in the
final membrane voltage. Such a sudden fall in
resting membrane voltage in the heart can cause
15 /LM Ca'·
cardiac stand still.
o
-u
-., •• _.)0 ••••• ; 3S/LM Ca"
~ .. to :1t:....~W if"AJ.V'.lt_T~"I..JJ..r-i;.,..!..r""'t\
:! -'1
~ -to
--v.-.
.. -lOS 95 j1M c.'·
-.,0 a - , __ . . .,,"N>., ....,......- .... -,......_.,.....,...-"""'1'.
" f'
~~.~.
fl I... It!'. It. ., • I, I' I .

-Il"
-I.ID
Figure 5-9. Records of a patch clamp of a single calci-
oL{·~~'~I--~--~--~~,~~--~:~.--~l!~. um activated potassium channel. As the calcium con-
1 ••• , .... 1 ' . , .... " .. A('. :."), (_M I centration on the cytoplasmic surface increases the
Figure 5-8. The relationship between the logarithm of channel opens more frequently and, on average,
the external potassium activity (concentration) and remains open longer until at 95 M Ca the channel is
the resting potential of heart cells. Note the abrupt almost always open. From lAtorre, R., C. ~~ora
depolarization of approximately 2 mM K/ caused by and C. HidRlgo. hoc. Nat. Acad. Sci. 79:805-809,
(1e closing ofpotassium conserving channels. Their 1982.
partial closure increases the role NR+ permeability
plays in determining the resting membrane voltage. When these C~ controlled potassium chan-
Adapted from dRta in 8hen, 8.8. et al., eirc. Res. nels are incorporated into a cell, any increase in
57:692-700,1980. intercellular Ca++ opens these channels and
increases the potassium permeability. Increasing
The Goldman equation suggests the extreme potassium permeability will hyperpolarize the
membrane voltages are VK (-100 mY) when only membrane and move the membrane voltage
K is permeable and VNa (+55 mV), when only toward the potassium equilibrium voltage of
Na is permeable. Any membrane voltage in approximately -100 mv' This hyperpolarization
between can be achieved by a judicious ratio of will stabilize the membrane and tend to inhibit
PNa and PK spontaneous or rhythmic activity. We will come
An analogy that may help you is to consider upon many examples of these channels as we
5-10 CHAPTERS
explore the cells of the nervous system. inside (-150mM) and outside the (-3mM) the
Chemically Controlled K Channels. A cell. Axons are long cylinders carrying a stereo-
third major type of potassium selective channel is typed electrical message, an action potential,
controlled by chemicals applied to the exterior of from cell body to synaptic region of the nerve
the cell; particularly those released by nearby cell. like most cells, the axon maintains a nega-
nerves. The classic example is the slowing of the tive resting membrane voltage (Fig. 5-11)
heart by acetylcholine released from the vagus derived from the potassium ion gradient (Ch. 5-
nerve. The acetylcholine does not act directly on 1). Whenever the axon is stimulated (Fig. 5-U),
the channel but through an intermediate G pro- in this case by a brief electrical shock, the voltage
tein step (Fig.s-lO). Acetylcholine binds to the across the membrane becomes positive and with-
external surface of the receptor and activates the in 1 msec returns to the resting membrane volt-
reaction of the G protein with GTP and Mg. age. This sudden reversal of polarity (electrical
The activated subunit binds to a nearby G gated sign) is called an action potential and his constant
K channel and increases its probability of open- throughout the axon.
ing. Increased potassium permeability moves the
resting potential (-70 mV) of the cell closer to
the potassium equilibrium voltage (-100 mV). As
we shall discuss in the next chapter, this makes
the cell less excitable and lowers the heart rate.
Figure 5-11. An intracellular recording of an action

potential from a squidgiant nxon showing (left to
right) resting membrane poltage (-45 mV), stimulus
and action potential. The electrical signal is m respect
to the bathing solution which is considered to be at
zero potential. (From Hodgkin and Hwdey, AF.: ].
Physiol. 104:176, 1954.
Figure 5-10. A tamon of a G protein gated, jHTtIISSi- The Action Potential
um seleail1e channel. Ligand binding (for example, Many types of stimuli lead to the generation
Acetylcholine) on the extracellular receptqr site of the
of action potentials but they all depolarize the
transmembrane receptqr complex catalyzes the intra-
cellular reaction of GTP with a G protein. axon membrane to a critical voltage threshold.
Ultimately the a· subunit binds with an intracellu- The action potential is propagated unchanged
lar receptqr site of the pot:tusium channeL Occupation down the axon and is remarkably similar wherev-
of this site increases the probability the K channel will er it is measured in the nervous system. Since the
open and remain open longer. The actil1e a· subunit action potential is a stereotyped event (constant
is deactipated by hydrolysis of the bound GTP. duration and magnitude), information must be
Adapted from AM. Brown and L Birnbaumer. Am. carried down the axon in the form of the interval
]. Physiol. 255: H501-H510, 1988. between action potentials, action potential fre-
quency. For example, more intense sensory
PART n. NERVE PHYSIOLOGY inputs are transmitted as higher action potential
frequencies.
All excitable cells such as nerve and muscle
Ionic Mechanism. Each patch of axonal
cells maintain a small (100 mV) voltage across
membrane participates actively in the propaga-
their surface membrane. This voltage id generat-
tion of the action potential; each section of mem-
ed across the semipermeable cell membrane uti-
brane acts as a repeater station. During the action
lizing the difference in potassium concentration
PHYSIOLOGY 5-11
potential, the ease of ionic passage through the tn'".
membrane (membrane conductance) increases II - +60
(Fig. 5-12). The positive voltage of the action
potential is derived from the sodium equilibrium
voltage (Fig. 5-13). As the sodium concentration -u
of the external solution is reduced, the peak volt-
age fulls.
_ -60
=-1 .. -
Figure 5-13. Action potentials recorded across the

membrane ofa squidgiant IIXOn whose axoplasm has
been squeezed out and replaced with an artificial
solution. In record A the solution is isotonic potassium
sulfate, 600 mM ~. In record B the internal solution
is 3/4~, 1/4 Nat, 450 mM ~. In record C the
internal solution is 1/2 ~, I/2t. The Na in the sea-
.
water is 460 mM. (From: Baker, Hodgkin and Shaw:
Nature, 190: 885, 1961).
.. .. .. . . . . . ••••n
Figure 5-12. The change in the ease ofpassage of ions channels are voltage gated; they change their
(impedance) through the membrane during an action properties from mostly closed to mostly open in
potentia~ Two superimposed records are shown. The response to depolarization of the membrane to
thin line is an action potential ofa squidgiant IIXOn the threshold voltage.
and the continuous curve is the impedance change. Sodiums Channels
(From Cole, K.8., and Curtis,H], J Gen. Physiol.
22:649,1938.) Channels consist of long stretches of a
hydrophobic helix cylinder spanning the mem-
brane. Channels can be opened by a number of
Sodium ions are suddenly and briefly able to
stimuli. Sodium channels are an excellent exam-
move down their concentration gradient,
ple of a channel opend by transmembrane volt-
through open sodium channels in the mem-
age; a voltage gated channel. The individual
brane, carrying excess positive charge into the
records in Figure 5-13A of a patch of membrane
axon, and swinging the voltage across the mem-
containing a single sodium channel show the
brane positive. Sodium channels open rapidly in
channel usually opens in response to a depolariz-
response to a stimulus, allow Na to move into
ing stimulus. Rarely (top trace) the channel
the cell, and then close quickly. Many types of
opens for 10-15 msec, sometimes for 5 msec.
stimuli lead to the generation of action potentials
and often very briefly. Axons have about 100
but they all depolarize the axon membrane to a
sodium channels/1m2, occupying about 1% of
critical voltage, threshold, which opens the sodi-
the surface area. It is the average response of
um channels and generates an action potential
many hundreds of sodium channels that is
(Fig. 5-4). Some force, external to the patch of
responsible for the action potential we record.
axon, does work upon this patch of axon to
The average can be obtained by summing either
depolarize the axon from the resting membrane
many sodium channels reacting to a single stim-
voltage (-65 mV in this case) to the threshold
ulus or one sodium channel reacting to many
voltage of -55mV. At threshold, the sodium
stimuli. Figure 5-13B is the average of 64
channels open transiently and the sodium equi-
responses to the same depolarizing stimulus and
librium voltage briefly dominates the membrane.
shows a sudden increase in the probability sodi-
In the terminology of the Goldman Equation,
um channels will be open immediately following
the ratio ofPna/ Pk becomes about 20. Sodium
5-12 CHAPTERS
tial of sodium ions inside the cell; sodium ions

1'00 (4, are nearing electrochemical equilibrium across
,v the membrane. The experiment shown in Figure
5-I3A were done with a stimulus to +50 mY, no
10
current (Nat ions) would flow through the open
channel because sodium would be in equilibrium
across the membrane. Were the sodium channels
to remain open, membrane voltage would
5 remain at +40 mV. The sodium channels do not
remain open for very long, as we saw in Figure 5-
13 SB, so the membrane voltage returns to its
resting (-80 mY) level. The closing of the sodi-
o um channels is called inactivation and will be dis-
cussed later in this chapter.
Sodium Selectivity.
These channels are highly sodium selective
with permeability ratios: PlijPna= 1, PK jPNa
-5
= 0.08 and PcajPNa = 0.016 which shows Na s
Na permeability decreasing with increasing crys-
tal radius. This suggests it is the unhydrated ion
Figure 5-14. The response ofa crab RJCOn of80-im that transits the channel. The Na+ selectivity fil-
diameters to current passage. The resting membrane ter is on the outside of the channel (Fig. 5-16)
potential was -65 mV. Depolarization is shown as the and is the site of attachment of a number of nat-
upward tkfIection. The numbers beside each trace give urally occurring paralyzing toxins including
the current strength relative to the threshold current. tetrodotoxin (TTX). These toxins bind to the
The upstroke seen in (a) is the beginning of an action
outside of the channel (they are ineffective when
potential similar to the one seen in Figure 5-1. (From
Hodgkin, A.L, and Rushton, W.A.H.: Proc. Roy. Soc., injected into the axon) and block the channel,
B133: 444,1946.). thereby preventing Na+ ions from entering and
altering the voltage across the membrane.
depolarization below threshold. The probability
of the channel being open falls rapidly, within a
few milliseconds, and then remains low, but not
zero, as long as the depolarization continues.
A
The same pattern pertains to the hundreds of
sodium channels of any patch of axon mem-
brane. Open sodium channels permit sodium
ions to move down their concentration gradient, v - -30 mV
into the cell, and carry excess positive charge into

the cell. The peak rate of influx is 150
Na+/msec/channel. The first few sodium ions
entering displace the potassium ions in the mem-
brane and allow them to move down their con-
centration gradient, out of the cell. The rest of
Figure 15. Opening of a Na channel in response to
the sodium ions bring excess positive charge a depolarization from -l00 mV to -25 mV for 30
through the membrane, into the axon, and cause msec. Notice the variability in response. If the chan-
the voltage across the cell membrane to become nel opens, it usually does so soon after the depolar-
positive. As the voltage across the membrane ization. B. The summed response (on a different
approaches the sodium equilibrium voltage (+50 time scale) of 64 consecutive depolarization ~ like
mV) the number of sodium ions entering slows the ones above. The average response is a rapid
because of the increased electrochemical poten- opening followed by closing.
PHYSIOLOGY 5-13
(Fig. 5-17) because the process is regenerative.
Once a few channels open, Na+ rushes in and
further depolarizes the patch of axon which in
turn opens more channels, which allows more
Na to enter, which in tum opens more channels;
positive feedback, a cascade. Once some external
force depolarizes the patch of membrane to
threshold, an internal process takes over which
requires only the energy in the Na ionic gradient.
Inactivation. Sodium channels close quite
soon after they open without receiving or pro-
ducing any external signal. Indeed, as we have
shown in Figures 5-15 and 5-17 the channel
closes even when the membrane remains depo-
larized and the charges that activate the voltage
Figure 5-16. A ClJrroon ofa sodium channel at rest. gate remain on the Figure 5-17A. Although not
shown in Figure 5-17, repolarization of the
Gating Currents. The axon and hence the membrane gives a transient, inward (down) cur-
sodium channel is activated by an externally rent of the same size and duration as the initial
induced voltage change across the membrane gating current. The gate that opens in response
from the resting membrane voltage (-80 to -100 to depolarization is not the one that closes to
mY) to the threshold voltage (-55 mY), a depo- block further flow of Na+. We call the gate
larization. This voltage change does work on a responsible for the early termination ofNa + flow
charged particle or dipole within the channel through the Na channels the inactivation gate.
structure. Because of its position within the The inactivation gate seems to close, and
membrane the dipole can sense voltage across block further Na+ entry, based on the number of
the membrane. Dipole movement within a Na+ ions entering through the channel. We
changing voltage field would require no energy haven't the vaguest idea of how it does it but can
beyond the externally induced voltage charge. As describe its actions, particularly in whole nerve,
the dipole moves it carries a very small, transient very well. The gate acts to limit the amount of
current, a gating current, shown in Figure 5- Na+ entering the axon and is the major cause of
17.In Figure 5-17, all ionic currents are blocked the brief duration of the action potential.
by a combination of substitution of ions imper- Once the inactivation gate is closed, it does
meable to the axon membrane and blockage of not open immediately upon repolarization. The
the sodium channel by TTX. Within 10 msec. of rate at which these gates open, remove inactiva-
depolarization, a small outward current is record- tion, is a function of both time, on the msec.
ed, the gating current. By 500 msec. all the + scale, and membrane voltage. Until the mem-
charges have moved to the outside of the membrane is repolarized to -50 mV, the rate of recov-
brane and the current signal ceases. Four positive ery is virtually zero; the inactivation gates remain
charges move outward per channel. In figure 5- closed and no further action potentials can be
17B, TTX was not added but only 5% of the usual generated. The patient paralyzed with familial
Na was present. Following the early outward gat- periodic paralysis (Chapter 5, problem 2) has
ing current, a larger inward current (Nat ions) depolarized the muscle membrane below -50
flows through the now open Na Channels. After and cannot generate further action potentials.
a few msec. the Na current declines to zero, the The heart cell, which suddenly depolarized from
channel inactivates. -65 to -40 mV, would fire a single action poten-
Threshold. tial upon depolarization but the inactivation
Individual Na channels open with 50% prob- gate, once closed, would not reopen until the
ability from -60 to -40 mV, yet threshold for a membrane repolarized to -55 mv' Consequently
patch of axon is remarkably constant at -50 mV no further action potentials would propagate
5-14 CHAPTERS
across the* ventricle and no further contraction VNI

- ----------- - -- - - - -1 +4~mV
would occur. I
I
As the membrane is further repolarized (Fig. I
5-18), the rate of resetting the gate increases, as I
ID J
does the final percent of channels open. Even at r-o
I
-80 mV when the rate is near maximum, the gate MDIBRAHE
I POTENTIAL
takes a couple of msec. to completely reopen and I
J
reset the channel. I
The inactivation gate can be enzymatically ,I--""""'~--:>l,-- _
I
_==:::::::._ _..j. -7OmV
removed by briefly applying pronase to the inside v.: __ -- _ - _ '::",,--::.-:...-.=-:.-_-::': ::!f'~82mv
of the axon. Then depolarization results in a pro- o
, ! I
1
!
1
I
longed flow ofNa- ions through the open sodi-

um channel. Because pronase is only effective Figure 5-18. The solid line shows both the rate of
when applied on the inside of the axon, we removal of inactivation of agroup ofsodium channels
believe the inactivation gate is on the inside of and the final %of these channels activated, as a func-
the Na channel (Fig. 5-16). tion of membrane voltage. R£moval of inactivation is
slow and incomplete at -50 mV, rapid and complete at
In Fig 5-19 each cartoon is identified on the
-70 mV. The dashed line shows the shift in the relation-
voltage trace below. At the second stimulus ship to more negative voltages induced by local anes-
(arrow) the reset. Inactivation gate is still closed thetics. During this time, the refractory period, a sec-
and even though the voltage sensitive gate ond stimulus will not result in a second action poten-
opens, Na+ cannot enter and further depolarize tial. Membrane voltage also determines the probabili-
the cell; the channel is refractory. ty of resetting the inactivation gate. At -60 mV, for
example, only 40% of the inactivation gates ever reset.
'The Action Potential Cycle.
The cartoon in Figure 5-19 illustrates the cycle an average sodium channel completes in
response to a brief depolarization. The mem-
brane voltage trace is shown below. The stimulus
(arrow) does external work on the resting chan-
nel (A) to bring the transmembrane voltage to
threshold (Th) and opens the voltage gate (A>
B). Na- rushes down its electrochemical gradient
and depolarizes the axon (B). The inactivation
gate closes (BA> C) at about the time the volt-
age peak is reached and the membrane voltage
slowly returns to the resting voltage. The voltage
gate closes quite rapidly (C > D) upon repolar-
ization but the inactivation gate takes its own
sweet time reopening (D>A). A second stimulus
(arrow) delivered when the inactivation gate is
still closed does not result in an action potential;
the axon (or this channel) is refractory. Only after
Figure 5-17. Sodium current and gating current
a couple of msec, when the inactive gate has reset
recorded from a voltage-clamped squid giant axon.
The RXOn was in a seawater solution containing only (opened), does the channel return to its original
5% of the normal sodium concentration (replaced by state (A) and can once again be stimulated to
tris ions), and was internally perfused with cesium generate an action potential (third arrow).
fluoride. &th trace A and trace B are the sum of the Toxins and Local Anesthetics.
current following ten positive and ten negative steps
A number of naturally occurring toxins para-
of 90 my amplitude from a holding potential of -70
mV. Tetrodotoxin (ITX) eliminates I but leaves I lyze by blocking sodium channels. Conveniently
(gating current) unaffected. Adapted from for the scientist, these toxins block by different
G.M.Armstcong, The Physiologist. 18: 93-98, 1975 mechanisms and bind firmly enough to be useful
PHYSIOLOGY 5-15
R IPIIACI'oIl Y These local anesthetics act by altering the voltage
at which recovery from inactivation occurs,
Figure 5-18, dashed line. At a low concentration
of local anesthetic, removal of inactivation might
not begin until -60 my and never is more than
20% complete. At higher concentrations,
removal of inactivation would not occur until -
120 mV, more negative than the cells' resting
membrane voltage, so recovery never occurs. In
axons, we use high concentrations to block
action potential conduction. In the heart we use
lower concentrations to delay recovery from
inactivation, particularly in damaged ventricular
cells with low resting membrane voltages which
may fire action the voltage of the resting region,
a little further down the axon, is close to the
Th potassium equilibrium voltage. Ions will flow
between these two regions of unequal voltage.
When the ionic flow crosses the membrane of the
d
resting region, it depolarizes the membrane to
threshold, the sodium permeability increases,
Figure 5-19. Cartoons ofa Na channel during.an and resulting in further depolarization, and an
action potential cycle. At A, the channel is resting and action potential is generated in this previously
primed the voltage gate is closed the inactivation gate resting region. This process continues on in each
open. Following an external stimulus (A> B) the volt- thin region of the axon. As can be seen in Figure
age gate opens and Na+ rushes through the channel
5-13, there is a short time delay between the
carrying the interior voltage to + 20 mV. B. At about
the peak of the action potential the Inactivation gate peak of the action potential at A and B. The con-
closes (B> C) Na+ .flow through the channel ceases and duction velocity is obtained by dividing the dis-
the voltage drifts back to the resting membrane volt- tance, X, by the time, t. The conduction velocity
age. Immediately upon repolarization (0.. D) the of nonmyelinated nerves is roughly proportional
voltage gate closes (DJ and afew msec. later the inac- to the square of the diameter and varies from 0.3
tivation gate opens (1» A) meters! sec for a 0.7 im axon to 25 meters/sec
for anatomic localization and biochemical tag- for a 500 im squid giant axon.
ging. Tetrodotoxin (JTX) and Saxitoxin bind to Salutatory Conduction.
the Na recognition site, the selectivity gate and In unmyelinated nerves, increased conduc-
block Na currents (Fig.5-17). Another group tion velocity is achieved by increasing the diame-
including Veratridine and Aconitine act as ter of the axon. Nature has found another way to
pronase does to remove the inactivation gate and
cause long lasting opening of the Na channel. N
_-----8
-=::::=====~
1.0
The toxins of North African scorpions and sea E
o
.....
anemones slow inactivation. A fourth group of o 5.0 6.0
E
toxins from American scorpions modifY Na chan- :: -1.0
nel activation and provide a probe for the volt- c:
~ O.IOk Procaine
age-activated gate. ; -2.0
Ep :-10 mv
Local anesthetics block nerve conduction by u
binding to the cytoplasmic end of Na channels

and prevent the Na channels opening in response Figure 5-20. The effect of 0.1% procaine at pH 7.9
to depolarization (Fig. 5-20). The early inward on the membrane currena, particularly the inward
sodium current is blocked by 0.1% procaine. (down) Na current following a tlepolarizing step.
5-16 CHAPTERS
resting axon membrane. A small efflux of sodium

v'" can be measured; sodium ions are moving up
- - - - - - - - - - - - - -- - - --1t45mV
I
their electrochemical gradient. This process must
I require energy since work is being done. This
I
I
conclusion is confirmed by the almost complete
I cessation of sodium efflux when the metabolic
rO process .of the axon are shut off by poisons such
IIEillSRAI[
CO~TAHCE
I
lO MEMBRANE as cyanide or DNP, as seen in Figure 5-14, while
I POTENTIAL
e I
injection of ATP will increase the sodium efflux
j I for a short time. The ATP is broken down while
e 10
E I providing the energy for sodium transport.
I
The efflux of three sodium ions is coupled
L..-.:...IL-4--"'::::::::::::..---l- -70mV
with the influx of two potassium ions. A third
potassium ion enters via the resting potassium
channel. When potassium is removed from
around the axon, the sodium efflux falls to very
Fig 5-21. Membrane Conductance low values.
achieve this; by increasing the distance between In a few systems the sodium is actively trans-
active regions along the nerve fiber. The time, t, ported in conjunction with an anion, thereby
between successive peaks of the action potential preserving electroneutrality. In other systems
is little affected by the distance between the only the sodium is actively transported and the
active regions. Consequently, the conduction accompanying ion is "dragged" through the
velocity will increase as the distance between membrane by an increased potential across the
active regions increases. The myelin sheath membrane.
around many nerves prevents ions from moving In nerve, active transport is a relatively slow,
across the membrane, and therefore only the continuous process that increases slightly after a
spaces between successive myelin sheaths, the large number of action potentials. Active trans-
nodes of Ranvier, are available for ionic move- port maintains the ionic gradients on an hour-to-
ment. Consequently, the action potential jumps hour basis. It is not necessary to pump out the
from node to node, about 1 mm at a jump. sodium that enters during a single action poten-
Conduction velocities in myelinated nerves run tial before a second action potential will fire. In
from 10 meters/sec for a 2 im fiber to 100 fact, the average nerve will conduct thousands of
meters/sec for a 20 im nerve. action potentials while metabolically poisoned.
Refractory Period. Dendrites and Cell Body
Immediately after an action potential, the In addition to the axon with its rapid con-
axon is incapable of carrying a second action duction mechanism, nerve cells have extensive
potential because the inactivation gates are still dendrites and a cell body. These are covered with
closed. This period lasts for about the duration of synapses and serve as the information gathering
the action potential, 1 to 2 msec. This absolute and integration portion of the nerve cell. The
refractory period is followed by a relative refrac- dendrites and cell body fluctuate in voltage. If
tory period during which a supra-normal stimu- the cell body depolarizes to -55 mY, an action
lus is necessary to evoke an action potential. This potential fires at the first node of Ranvier and
period lasts for another 2 to 3 msec. These two propagates along the axon. Most dendrites and
refractory periods put an upper limit of the cell bodies do not contain voltage gated Na
nerve's frequency response at about 200 channels so cannot fire an action potential. An
per second. anterior horn cell of the spinal cord may receive
Active Transport. upwards of 5,000 different incoming synaptic
As was previously discussed, sodium is very connections. Some of these always cause firing of
far from electrochemical equilibrium across the the axon by depolarizing it to threshold, most
PHYSIOLOGY 5-17
Activation of the contractile proteins, are a few of
the reactions activated by Ca entry. Most cells
maintain very low Ca++, liM, while Ca++ =1-5
mM; consequently Vca is greater than +100 mV.
.tQ ••••••••••••.••••• ---
Unlike the sodium ion that carries charge across

the membrane and then becomes a nuisance that
needs to be actively transported out of the cell,
calcium has a dual role, both as a depolarizing
charge carrier and as an intracellular messenger, a
universal provocateur. Ca ions carry an electrical
message on their way through the membrane
and then activate a vast array of intracellular
Figure 5-22. Decremental conduction in a dendrite.
processes. Contraction, for example, is con-
excitatory synapses acting individually only depo- trolled by intracellular free calcium, some of
larize towards threshold. Other synapses increase which enters through calcium channels in the
potassium permeability (Pk) and hyperpolarize membrane. Calcium channels are intriguing
the cell body, inhibiting the possibility of the because they exist in a number of types and a
axon firing an action potential. large number of highly specific and clinically use-
Decremental Conduction. Dendrites and ful blockers have been discovered.
cell bodies communicate via continuously vari- Transient Calcium Channels.
able voltage fluctuations that become smaller
Three major types of voltage gated calcium
with increasing distance, decremental conduc-
channels have been described. Transient (T type)
tion. These properties are similar to those oflong
channels have properties similar to sodium chan-
undersea cables, so are often referred to as cable
nels. Figure 5-23 shows the major characteristics.
properties and are illustrated in Figure 5-22.
The peak Ca current (the number of Ca ions)
Current is passed into the left hand end of
passing through the channel is small, and it is
the dendrite to hyperpolarize the dendrite. The
open 40-60 msec. Threshold (Fig. 5-23B) is at -
voltage of a nearby patch of membrane alters
50 mV (solid line, open squares) and recovery
rapidly. When the voltage is measure 2.5 mm
from inactivation (solid line, close squares)
away from the current passing electrode, the
begins at -60 mV and reaches maximum at -80
induced voltage is reduced and the voltage
mV, the resting membrane voltage of these cells.
changes more slowly. Voltage changes are more
These channels often coexist with Na channels
rapid for large structures and very slow in the
and are co activated with the Na channel. One
thin dendrites. Consequently, synapses on the
role of these channels is in cells that fire bursts of
very ends of a dendritic tree have less of an influ-
15-20 action potentials. Ca enters the cell with
ence on cell body voltage, and hence axon firing,
each action potential; Ca++ builds up and even-
than do synapses on the cell body itself. At each
tually turns on enough Ca activated K channels
synaptic region the dendritic membrane contains
to block further firing, even though the initial
a variety of receptors linked to ionic channels,
stimulus remains.
such as the potassium channel we discussed in
T channels by themselves carry enough
Part I of this chapter. We will discuss transmitter-
charge to be the sole source of action potentials
receptor interaction in both chapters 6 and 7.
in many tissues. The rise time is not so rapid and
Calciom Channe;1s the duration is longer than Na channel action
Calcium channels are widely distributed in potentials.
excitable cells. Ca channels have two important Long Lasting Calcium Channels.
potencies: Ca entry carries charge to move the
L type channels (Fig. 5-23) scarcely inactivate
membrane voltage toward VCa, + 50 mV and
even after several seconds and carry much larger
the CA++ that enters the cell activates a wide
peak Ca ion influxes. Threshold (Fig. 5-23B)
range of reactions once it is within the cell.
5-18 CHAPTERS
(dotted line, open circles), however, is quite pos- responsible for both increasing and decreasing
itive, -10mV; some other voltage sensitive the number of open calcium channels. Opening
process, such as Na channels or T type Ca chan- these channels depolarizes the cell toward the
nels, must depolarize the cell to this threshold. threshold for activation of voltage gated Na and
Once opened, these channels inactivate slowly. Ca channels and brings C+ into the cell to act as
Once inactivated, recovery (dotted line, closed a second messenger.
circles) occurs at membrane voltages well positive Regulation.
to the resting membrane voltage. The major
L type calcium channels can be recorded in
function of these channels is to bring Ca into the
whole cell preparations quite easily by the patch
cell to raise Ca and serve as an intracellular mes-
clamp method
senger. These channels are very sensitive to the
(Fig. 5-24). When the patch is pulled off the
dihydropyridine drugs including nifeedine. An
cell and the inside of the membrane exposed, L
intermediate, N type channel has a threshold at-
type channel activity quickly disappears (Fig 5-
20 mV and has an open duration of 100-200
24, at 5-7 mm). Activity does not reappear until
msec. with a peak Ca influx intermediate
the catalytic subunit of cAMP protein kinase is
between T and L type channels. They are usual-
added, together with Mg ATP, to the cytoplas-
ly found in the presynaptic region ofaxons. The
mic side of the membrane. This enzyme system
Ca++ that enters triggers neurotransmitter
phosphorylates the inner side of the L type Ca
release.
channel to reestablish voltage gating (Fig 5-24 at
Ligand gated Calcium Channels. 25-35 min). The initial loss of voltage sensitivity
Channels of this type have been demonstrat- was the result of dephosphorylation, probably
a
ed in number of tissues including CNS and catalyzed by calcineurin, a calcium and calmod-
smooth muscle. Various neurotransmitters. are ulin-dependent phosphatase. Here is a system in
continuous flux; one system to activate channels
~ fr- by phosphorylation, another system to inactivate
?
channels by dephosphozylation; a regulatory sys-
A\
,\
I
I
I
B tem operating on the scale of minutes. It regu-
lates the number of channels capable -of open-
ing in response to depolarization, allowing Ca++
to transit the membrane and bringing in positive
\ I
\ charge to depolarize the membrane and Ca ++
to activate any number of intracellular systems.
~\ The number of activated channels is con-
\ trolled by a large number of neurotransmitter
and hormones acting via receptors proteins in the
membrane to modulate c AMP and hence chan-
nel phosphorylation. The number of Ca channels
Figure 5-23. A OJ jlwc (current) through a fully in the heart ventricle is increased by epinephrine,
excited T type or L type OJ Channel. B. Ttype OJ the action potential is more positive and pro-
channels (, solid cunes) are quite similar to Na longed and more CA enters the cell. Increased
channels; threshold is near -50 mV, they open briefly CA results in a more forceful contraction. The
and then inactillate. ReCOllery from inactillation number of systems and the subtlety of their
begins at-50 mV and is rapid and complete at -80 action are expanding too rapidly to make listing
m V. L types channels have a threshold close to zero (, them all useful. Patch Clamp
dotted cunes) but once opened remain open for seconds
and allow large amounts of OJ to enter the cell.
ReCOllery from inactillation is a voltage much less
negatille than the resting membrane lIoltage.
(Adapted from Fox, AP., Nowyck, M.e. & Tsien,
R. W. ]. Physio144; 149-172).
PHYSIOLOGY 5-19
Openings. rn ... ~n
no. -:
o. =t ~ ff ~.
n"\in
S
JI~~- patch excised : inside au"
10 - ATP- Mg perfusion begins
15
20 caTalyTic subunit added
25
30
__"__~-_-_-~~-~-_--_---------~'rll-
40 <--.~~_~
pAl
:2
-C
-r
\fit, II--c
C
2 0 I'T>.
Fig 5-24. The inner surface of the channel is exposed to an artificial cytoplasm; the site is tlephosphorylated and
channel tutillity cease. Channel tutillity is regained when the phosphorylation enzyme system is added. (From
Armstrong and Eckert, Proc.Natl. Acad. Sci. USA. 84: 2518-2522, 1987)
CHAPTER 6
Skeletal Muscle and Nerve-Muscle Junction
GROSS STRUCfURE AND FUNCTION.

Skeletal muscles are the major ending of the
efferent branch of the central nervous system.
We work our will upon the outside world
through these muscles. Skeletal muscles occupy
about 80 %of the total weight of the body. They
use about 6 %of the resting oxygen consumption
to maintain ionic gradients; after strenuous exer-
cise they may use as much as 70 %of the oxygen
consumption. Each anatomic muscle is delimit-
ed by strong fascial sheets and has a characteristic
origin and insertion. The basic unit of the mus-
cle is the muscle fiber or cell that runs from one
end of the muscle to the other end and has a
diameter of 50 to 100 pm. Figure 6-1. The organization of muscle fibers into
Motor Units. structural units, muscle bundles and functional
units, motorgroups.
Anatomic muscles are subdivided into bun-
dles of many fibers (Fig. 6-1). Each muscle fiber Contraction.
is innervated by only one motor nerve fiber. The action potential travels along the muscle
Groups of muscle fibers are delimited functional- surface from the end-plate region with a conduc-
ly by their nervous innervation. As the Fig. 6-1 tion velocity of about 1meter/sec. The response
shows, the motor nerve branches and innervates to a single stimulus, either to the motor nerve or
a number of muscle fibers. The muscle fibers to the muscle surface, is called a twitch. Muscle
that are innervated by a single motor nerve are activity usually occurs in response to a series of
called a motor unit or group. All these fibers act action potentials, a partial or complete tetanus as
in the same manner since a single nerve controls illustrated in Figure 6-2B,C, and D. It can be
them. The number of muscle fibers in a motor seen that increasing the frequency of stimulation
unit varies from 300 to 400 in the gastrocnemius to a muscle increases the tension generated.
(calf) muscle to 4 to 6 in the extraocular muscles. Since motor units are in parallel, their tension is
In general, the size of the muscle group is pro- additive. The total tension a muscle produces is
portioned to the delicacy of the required move- primarily a function of the number of motor
ment. The extraocular muscles make very small, units activated.
fine adjustments; the gastrocnemius muscle, Sarcomeres and Filaments. When we study
coarse, powerful movements. the structure of the muscle fiber, the mechanism
When the motor nerve is stimulated, an of contraction becomes clearer. Figure 6-3, A-D
action potential travels down the axon until it shows the structure of a lOO-pm diameter mus-
reaches the end-plate region, where it releases a cle fiber and its component 1 pm myofibrils.
chemical transmitter, acetylcholine. The acetyl- The banded pattern (D) is clearly seen in the
choline diffuses to a specialized portion of the light microscope in either single living fibers or
muscle surface, the motor end plate, and initiates fixed and stained material. A dark A band alter-
a second action potential on the surface mem- nates with a light I band. The I band is bisected
brane of the muscle fiber. We will discuss the by a thin, dark Z disk. The basic contractile unit
motor endplate in greater detail later in the is a length of myofibril from Z line to Z line
chapter.
6-2 CHAPTER 6
Excitation Contraction Coupling

II SEC. Muscle activation begins when an action
A
potential spreads over the surface and then into
the depth of each fiber. Calcium released from
IO/SEC.
intracellular structures allows the thick and thin
filaments to interact, produce tension, and short-
B en. Contraction ceases when CA++ is transport-
ed into the same intracellular structures.
Reticular Structures. Skeletal muscle has an
enlarged and specialized reticular network that is
12/SEC. shown in Figure 6-4. It can be subdivided into
two portions: the transverse tubules or T system
c and sarcoplasmic reticulum (SR). The T system
is a tubular network that is continuous across the
whole fiber and contains extracellular fluid. If a
perfect cross section were cut across the fiber, the
T system would look like a chicken wire fence
30/SEC.
o with the fibrils running through the holes in the
wire. The sarcoplasmic reticulum wraps around
I I SEC. the myofibrils like the bun around a hot dog.
... "I The (T) system conducts the surface action
potential rapidly inward to initiate contraction.
Figure 6-2 Isometric tension in response to stimuli of When small patches of the surface membrane are
constant voltage and a varying frequency. Note that stimulated to induce local contraction, the sensi-
the total tension isgreater when the frequency ofstim-
tivity of an area depends on its location with
ulation is increased until a maximum (tetanus) ten-
sion is reached. Record from a human flexor carpi
respect to the T system. The most sensitive loca-
radialis muscle in situ. The subject's arm was held to tion varies; it is at the Z line in the frog and at the
a table with adhesive tape; stimulation was via a car- A-I junction in the lizard and many mammals
bon electrode over the muscle mass in the upper fore- (arrows, Fig. 6-4). Inward conduction is an
arm and a laflJe EGG electrode at the wrist. The ten- active, Na+ dependent process in the tubular
sion transducer was in contact with the styloid process wall, probably much like the surface action
on the wrist below the base of the thumb. Both wrist potential. Depolarization of the transverse tubu-
and finger flexors can be stimulated by this method. lar system generates a charge = movement signal
called a sarcomere. After isolation, this unit, 1 which precedes Ca++ release from the SR. This
pm in diameter and 2.5 pm long, will still con- charge = movement signal has many similarities
tract. to the gating current of the axon.
At higher magnification, in the electron The basic ionic mechanisms underlying the
microscope (Fig 6-3E), it is clear that the bulk of muscle action potential are quite similar to those
the muscle structure is made up of two types of in nerve, a regenerative increase in sodium per-
filaments. The larger of these filaments, the thick meability (to depolarize) which quickly inacti-
filament, is 10 nm in diameter and 1.5 pm long vates' followed by an increase in potassium per-
and is located entirely within the A band. meability (to repolarize). In skeletal muscle there
Indeed, all of the properties of the A band can be is also a large, but unchanging, chloride perme-
attributed to these filaments. The thin filaments ability which participates in the repolarization
are 4 nm in diameter and 1.0 pm long and run phase. Chloride is in equilibrium across the
from the Z line various distances into the A band. membrane at a resting potential of -90 mV.
During contraction the thin filaments are pulled The surface area of the T system gives the
past the thick filaments to reduce sarcomere 'surface' action potential a slow velocity (1
length. m/sec). Most of the potassium channels are in
the T = tubule membrane so the potassium efflux
SKELETAL MUSCLE AND NERVE-MUSCLE JUNCTION 6-3
during the falling phase of the action potential is face membrane.
into the lumen of the T system. After several Myotonia. In muscle fibers from myotonic
action potentials, K+ builds up in the T lumen goats the potassium buildup in the T tubules
and begins to depolarize the fiber. In normal causes a significant depolarization and action
muscles this depolarization is not large and is potentials continue to fire after stimulation ceas-
buffered by the chloride conductance in the sures. Much the same result is obtained when nor-
SKELETAL MUSCLE
Muscle Fasciculus
G-Ac:tln Molecu III

ooog
00
J
..• •.•..•
c:==:::;j~<.==~\J M
F
/ .......
" ... ... '110 . .
•••••
~
:' "'-=u
......
.:;:;:~:. N
•••• -:-:.:. LI9hl Heavy
••• Meromyolln Meromyosin
Figure 6-3 Diagram of the organization ofskeletal muscle from the gross ro the molecular level. F,G,H, and I are
cross sections at the levels indicated. (Drawing by Sylvia Colard Keene from Bloom and Fawcett: A Textbook of
Histology. Philadelphia, W.B. Saunders, 1968.)
6-4 CHAPTER 6
mal fibers are placed in chloride-free solution.

T-SR Coupling.
'The structure of the T system - terminal cis-
ternae junction is shown in Figure 6-SA. The T
Figure 6-5. A. The T system - terminal cisternae

junction. A freeze fracture study showing the T system
running vertically flanked by terminal cisternae. B.
A cross sectional drawing showing the fracture planes
at AA and BB. Fracture lines follow the hydrophobic
(center) line of the membrane. The foot processes of the
SR are stippled. (Electron micrograph courtesy of
Clara Franzini-Armstrong, Ph.D., University of
Pennsylvania, Philadelphia, PAY
tubule runs vertically in the center. The T system
is ovoid and the portion adjacent to the terminal
cisternae contains prominent particles.
The terminal cisternae (tc) of the sarcoplas-
mic reticulum shows a rich array of structures
which appear as either pits or particles depending
upon the plane of fracture. At the T-tc junction
are "feet" which create a distinct morphological
gap. The terminal cisternae are not do not par-
ticipate in any of the electrical events of the mus-
cle fiber indicating there is no ionic connection
between the two. The feet are the site of Ca++
release from the SR that initiates contraction.
After Ca++ is released from the terminal cister-
nae, the Ca++ concentration in the sarcoplasm
rapidly builds up as shown in Figure 6-6, well in
advance of tension generation.
The ultimate result of the depolarization of
Figure 6-4 Schematic representation of the distribu- the T system is Ca++ release from the terminal
tion of the sarcoplasmic reticulum around the myofib- cisternae. How depolarization induced charge
rils ofskeletal muscle. The longitudinal sarcotubules movement in the T system walls induces release
are confluent with transverse elements called the ter- of Ca++ from the SR is far from clear. One of the
minal cisternae. A slender transverse tubule (I'
author's suspects there is a chemical transmission
tubule) extending inward from the sarcolemma is
flanked by two terminal cisternae to form the so- and Ca++ is the first messenger. Other authors
called triatk of the reticulum. The location of these suggest a molecular rod that spans the foot
with respect to the cross-banded pattern of the myofib- process that controls Ca release from the SR
rils varies from species to species. In frog muscle, Dantroline sodium (Dantrium) is a muscle-
depicted here, the triatk are at the Z line. In mam- relaxing drug that acts directly upon the muscle
malian muscle there are two to each sarcomere, locat- fiber. One-half hour after a clinical dose, the
ed at the A -I junctions. (Modified after L. Peachey, twitch tension is half it normal value; recovery
from Fawcett, D. w., and McNutt, S.: J. Cell Bioi., occurs within 24 hours. Dantrolene sodium acts
25:209, 1965. Drawn by Sylvia Colard Keene.)
to reduce the amount of Ca++ released per
action potential, largely by blocking release of (Fig. 6-3,J-K). Two chains of F-actin, wound
Ca++ from the terminal cisternae. around each other, form the thin filaments along
The large particles elsewhere in the SR mem- with tropomyosin and troponin. These two reg-
brane are the site where Ca++ from the sar- ulatory proteins alter the ATPase activity of the
coplasm is taken back into the SR bringing about actin-myosin complex so that calcium ions are
relaxation. required for ATP breakdown and consequently
MOLECULAR ARCHITECTURE for muscle activity.
OF CONTRACTION The immediate energy source for contraction
is ATP and muscle converts chemical to mechan-
Muscle Proteins. Four major protein types
ical energy with an efficiency of about 50%.
have been extracted from skeletal muscle: actin,
Intact muscle contains relatively large quantities
myosin, tropomyosin and troponin. The first
of creatine phosphate, an energy storage protein.
two are the major protein constituents; the oth-
Ca++ -Troponin Interaction. Free Ca++
ers are a relatively small fraction of the protein.
binds to troponin on the thin filaments causing
Myosin has a molecular weight of 420 KD and
the troponin-tropomyosin to 'roll-back' from
contains two quite different regions; a long dou-
the active site of actin. Actin and myosin can
ble helical tail and a dual headed structure con-
now interact, bridges can form and tension is
taining both the ATPase and actin binding activ-
generated. The interaction continues for as long
ities. Figure 6-3, L-N shows the packing of the
as the Ca++ remains elevated. In the twitch
myosin molecules within the thick filaments of
shown in Figure 6-6, Ca++ is rapidly taken up by
the band. The myosin molecule can be readily
the sarcoplasmic reticulum and tension declines.
divided into two subunits - heavy and light
During tetanic stimulation, Ca++ remains elevat-
meromyosin. The heavy meromyosin retains the
ed. After the surface membrane and reticulum
adenosinetriphosphatase (ATPase) and actin
have been removed by chemical treatment, ten-
binding activity of the intact myosin. This frag-
sion generation is related to Ca++ concentration
ment forms the bridges between this and the fil-
(Fig. 6-7). Tension is maintained for as long as
aments. Light meromyosin rods aggregate to
Ca++ is present.
form a tension bearing rod, the thick filament.
Actin has a molecular weight of 60kD and Filament Interaction.
readily forms long chains of a fibrous protein A muscle fiber shortens when thin filaments
slide past thick filaments. In this manner the dis-
tance between individual Z lines (sarcomere
length) decreases. The decrease in muscle length
is proportional to the product of the decrease per
sarcomere and the number of sarcomeres per
muscle.
Cross sections through the array of thick and
thin filaments are shown in Figure 6-8, F- 1. Each
\,..... ~
set of filaments is arranged in a basically hexago-
nal array. In the region of overlap, section I, each
•• of the thin filaments has three thick filaments and
~
each neighboring thick filament has six thin fila-
Figure 6-6. The broken line shows the average light ments. Contact between the filaments is made
emission from Ca++ sensitive protein aequorin inside by cross bridges (Fig. 6-8). These bridges stick
a muscle fiber while the solid line is the twitch tension. out from the thick filaments and are arranged in
Aequorin, a protein extracted from a luminescent jel- a six-fold helix, like the treads on a spiral staircase.
lyfish, emits light in proportion to Ca++ concentra- In this case, the stairs make a complete revolu-
tion. The light emission, hence the increasing Ca con- tion in six steps.
centration within the fiber, proceeds the tension gener-
ation (solid line). From Blinks,JR, R Rudel and Cross-Bridges.
SR Taylor,J. Physiol. 277. 291-323,1978. It is the interaction between the two filament
6-6 CHAPTER 6
arrays that produces tension; the bridges (Fig. 6-

8) of the thick filaments "hook on" to and move
the thin filaments. The three-dimensional struc-
ture of the heavy meromyosin (Fig 6-3) which
contains both the actin and ATP binding sites has
recently been worked out. There is a prominent
cleft near the actin-binding site: when it is closed
(Fig 6-9A), actin-myosin binding is strong, when
it is open (Fig 6-9B) binding is weak. A lateral
pocket contains the ATP binding site; closing of
the ATP binding pocket imparts a curvature to
the head and a 5 nm movement of the actin
binding site along the actin chain (Fig 6-9 B>C).
Fig 6-9 shows a molecular model of bridge inter-
action consisting of actin-myosin dissociation
with ATP binding (A>B), curving of the bridge
with P hydrolysis to move the myosin head 5 nm
Figure 6-8. The puwer cycle of the bridge unit of
myosin. In A the cleft between the two domains of the
myosin head is closed and the myosin head is attached
to an actin monomer (speckled for identification).
The ATP binding pocket is open. As ATP begins
binding, B, the cleft opens and the myosin head
unbinds from actin. As ATP binding is completed
and P hydrolysis occurs, the ATP pocket closes and the
myosin head changes curvature, C, to move 5 nm
along the actin chains, to bring it into alignment
with the next actin monomer. As the P leaves, D, the
cleft closes and the head attaches to the next actin
monomer. As ADP is released, E, the pocket opens, the
myosin head straightens forcing the actin chain up by
5 nm, the puwer stroke. Adapted from Rayment et ai,
Science 261:50-65, 1993.
along the actin chain (B>C), head reattachment
(D) and finally the power stroke as ADP dissoci-
ates (D>E).
Length - Tension: Relations. Tension pro-
duction, then, should be related to the number
of bridges connected to thin filaments, to the
degree of overlap of actin and myosin filaments,
and 2 to the sarcomere spacing. When resting
muscle is fixed at various sarcomere spacing, the
length of each set of filaments remains constant,
as does their diameter (Fig. 6-10). The amount
of overlap between the thick and thin filaments
varies in direct proportion to sarcomere length,
Figure 6-7. A view of the central region of the band but the A bandwidth remains constant during
at 600,000 x magnification. The projections from the contraction. Experiments with contracting isolat-
thick filaments, the bridges, are the site of interaction ed fibrils also show the bandwidth with the I
between the thick and thin filaments. (From Huxley, band decreases in width with decreasing sarcom-
HE.:] Biophys. Biochem. Cytol., 3:631, 1957. ere spacing. When the sarcomere spacing is just
greater than the sum of the lengths of the and I overlap, no bridge interaction, and consequently
band filaments (3.6 Jllll) there should be no no tension production, Figure 6-9B. As the sar-
6
~
5
~
4
~ f
,":p,
2
~
-(l~_
l
1100
.§ ,1 I
::13 80 1
1
I
I
...
0 60 I
I
I
I
I
L
I
~ 1 I
I
40 1
g I
I
1 I
!
I 1
20 I I I
1 1 I
11.67
0 2·0 12.25
1·0 2·0 2·5 J·o 4·0
Striation 1pIICiJl8 (P)
A
I I
. ,
:••- -- - b - - -_ .:
,
. . 1-------
. l65J1 (0+10) - - - - - _ + _
~ -+I: ;;; "".; :;" ;:; ;::;;: ~F====

_ 220-225.. (b+c) _
~ fI::::;:::::;:~ii1:;;:::-:j::::lt m
I "I:::::::::.::::::
.. lOSJI (1)) •
:::::::::::::::::+ ~
I iI:.': ::"""""
_ 18S-1 90.. (II-c) _
....... "",,,,,,,,1111* ~
_ 1 6 5J1 (0+%) _~
s __====~~~:5;::~:::S:;:~;::;:;;~;:::~r:~:::;;::~;:;~:t==
~======
.1 OS.. 1(1.+.)...
6-====---~~=:~;::~:;:~:~;~:~~;::~:~I========
Figure 6-9. The length tension curve (A) and elem-on micrographs (B,C, and D) ofskeletal muscle showing the
O1'erlap of the sliding filaments. When the filaments barely O1'erlap (B), tension is low. When all bridges are
attlu:hed (C), tension is mRXimum. When the thin filaments O1'erlap (D), tension declines. (Dam from AL
Gordon, AF, Huxley and F.] Julian.] Physiol. 184:170-192, 1966. Elem-on micrographs courtesy of Brenda
Eisenberg, Ph.D., University of Illinois College of Medicine, Chicago, IL)
6-8 CHAPTER 6
comere spacing decreases, the number of bridges

increases and so does the tension. The number
of bridges and the tension increase until all of the
bridges are attached. There are no bridges in the
"""- center of the band, as can be seen in Figure 6-8.
='--'-~---"":"';"-""'~--------"=--- Further shortening gives no increase in ten-
sion since there is no more bridges to interact. In
fact, further shortening leads to decreased ten-
sion since one thin filament must force its way
past its opposite filament, probably disturbing
the bridge filament interaction. Further shorten-
T""'_ ""'- ing also requires compression of the band fila-
Figure 6-10. Calculated values for bridge tension, ments and most of the tension that is produced
length ofseries elastic component, and tension. Note goes to compress the thick filaments.
especially that a second stimulus can capitalize upon
Force-velocity Relation.
extension of the series elastic element and thereby
increase the tension at the tendon. FJ. Julian, We have concentrated so far on the genera-
Harvard Medical School, kindly supplied (these tion of tension at constant length; to do useful
records. For further daails of the computation, see work the muscle must shorten. When a muscle
Julian, F.].: Biophysical]. 9:547, 1969.) shortens against a very light load it shortens very
quickly. As the load increases, the velocity
c
." . . ..
····r·. 'n
. ~ .... ';. .
'.
. .--=---
' : ;.~ ..:'.
. '. . '. :
. ~: . '.' ~
..:.... ... : .. :!
::..
.
. '..
.
.', ,'. . .., ' .'.
:.
...... ~...
.' . . . I··· .
. . . ll!l~~~~~
.........
"
~
Figure 6-11. Schematic representations of the motor end plate as seen by light and electron microscopy. A, End
plate as seen in histological sections in the long axis of the muscle fiber. B, As seen in surface view with the light
microscope. C, As seen in an electron micrograph of an area such as that in the rectangle on A (After R.
Couteaux. From Bloom and Fawcett: A Textbook of Histology. Philadelphia, W.B. Saunders, 1968.)
decreases. A force-velocity curve is shown in sion produced on the tendon is much greater
Figure 6-10. A human forearm was pulling during a tetanus (Fig. 6-1 On) than during a
against increasingly heavy weights. The same twitch.
curve can be obtained with an isolated muscle·,
maximum tension and maximum speed will vary, NERVE-MUSCLE JUNCTION
however, from muscle to muscle. The Endplate
The force-velocity curve is described by the To return to the control of skeletal muscle
equation contraction, the motor nerve enters the muscle ,
(P+a)(V+b)=(Po+a)b, where P is the force, branches, and forms a very close junction, a
Po is the isometric tetanic force, V is the velocity synapse, with the center of each muscle fiber.
of shortening, and a and b are constants. The The axon (presynaptic element) and muscle
constants, a and b, can be fitted uniquely and are (postsynaptic element) remain two distinctly sep-
a major goal for theoretical models of muscle arate cells. The structure of the region is shown
function. in Figure 6-11. Transmission between the axon
Active State. and muscle is by means of the chemical, acetyl-
choline (ACh).
When the bridges from the thick filaments
Acetylcholine. To be considered a transmit-
interact with the thin filaments, they develop ten-
ter, a substance must meet four criteria: (a) it
sion 3 to 5 rnsec after the action potential runs
~ust be effective at the postsynaptic surface, (b)
along the surface. Tension cannot, however, be
It must be liberated by the presynaptic surface in
measured in the tendon for 10 to 20 rnsec fol-
response to and in proportion to nerve stimula-
lowing stimulation. What causes the delay?
tion, (c) there must be an enzyme system for
There is a great deal of elastic material in series
destroying or reabsorbing liberated transmitter,
with the tension-generating element, some
and (d) there must be an enzyme system for syn-
indeed in the bridges themselves. The tension
thesizing the transmitter.
produced by the bridges must first stretch the
Each of these criteria has been met byacetyl-
elastic material before it can be transmitted to the
choline at the nerve-muscle junction. The idea
tendon and the load. Consider for a moment a
of a chemical transmitter between nerve and
person pulling a stretchy nylon rope that is
muscle came from experiments by Otto Loewi in
attached to a large rock. At first the rope stretch-
1921 that demonstrated the slowing of the heart
es only after a delay does it transmit the full force
of his pull. Remember that a pull of a given force when the vagus nerve was stimulated. He
noticed that Ringer's solution that had dripped
will extend the rope to a characteristic length and
no further, but the stretching will take time. over a slowed heart caused a second heart to slow
Let us return to the case of the muscle. as well. The only link between the two hearts
was the Ringer's solution. Vagal stimulation lib-
Following a single stimulus, the bridges generate
their maximum tension for a very short time erated acetylcholine into the solution that affect-
(Fig. 6-10). This short phase corresponds to the
ed the second heart. Acetylcholine can be col-
active state in of A.V. Hills model. The tension lected in from small veins in stimulated muscles.
is mainly expended in stretching the series elas-
Acetylcholine is effective in stimulating con-
ticity; about one-half of the bridge tension traction if it is injected very close to the muscle.
When acetylcholine is microinjected onto an
appears as tendon tension. If a second stimulus
excised muscle, it elicits contraction only when
follows soon after the first, the renewed bridge
injected at the end-plate region. The rest of a
tension pulls on partially extended elastic ele-
normal muscle does not have ACh receptors.
ments and consequently must do less work on
Both biochemical and histochemical studies
them to transmit tension to the tendon; more of
show the presence of a cleaving enzyme, acetyl-
the bridge tension is applied to the tendon. If a
third stimulus follows the first two, the work the choline esterase at the myoneuronal junction. It
is present in both the postsynaptic surfaces in the
bridges do on the series elastic elements is further
subneural folds and on the presynaptic side. It is
reduced; consequently, the work done and ten-
6-10 CHAPTER 6
also present in fairly high concentration in the cal sodium channels that must be repolarized
blood that explains the general ineffectiveness of before it can fire again.
acetylcholine when injected intra-arterially. Acetylcholine Activated Channels. The
Another enzyme, choline acetylase, reconsti- receptor and channel are contained in a single
tutes the acetylcholine, into the synaptic vesicles. transmembrane protein aggregate (Fig 6-12)
The enzymes that produce the vesicles are pro- made up of 5 subunits each of which is thought
duced in the nerve cell body; the number of vesi- to contain three alpha helical columns with a 0.7
cles decreases rapidly after section of the motor om channel down the center. The receptors on
nerve. When an action potential enters the presy- the alpha subunits are some 6 om from the gated
naptic terminal, the accompanying depolariza- ionic channel that is on the cytoplasmic end of
tion opens voltage gated Ca channels. Increasing the channel.
intracellular Ca++ is essential for neurotransmit- Single channel recordings (Fig. 6-13) show
ter release, catalyzing the fusion of synaptic vesi- the channel to be either open or closed. ACh
cles with the surface membrane to release ACh concentration alters the % time the channel is
into the synaptic cleft (Fig 6-12). open. When a microelectrode is inserted into the
Acetylcholine acts on the postsynaptic mem- end-plate region, the usual resting membrane
brane and destroys its selective permeability to all potential is recorded. When the motor nerve is
small ions. The membrane has an equilibrium
voltage of zero millivolts. This voltage is, of
course, never reached, but would be if acetyl-
~-
choline were continuously applied to the end
plate. The high concentration of acetylcholine
esterase prevents such an event. The depolariza- 10, OnTOC, bU IN
tion brought about by the usual amount of
acetylcholine causes a current to flow to the sur-
rounding muscle fiber surface. As the current
flows through the peripheral membrane, it depo-
larizes that membrane and sets up a propagated
action potential. The end-plate region itself is
not electrically excitable; current must flow to
the surrounding area which area contains classi-
--------. 10"".
Figure 6-13. Intracellular electrical e1Iena at the

end-plate region (A), and (B), 2 mm away. The
upper traces are at high gain (3.6 mp) and slow time
scale, (47 msec). In (Aj the miniature end-plate
potentials (minis) are clearly shown, whereas in (B)
they are almost nonexistent. The two bottom traces are
Figure 6-12. A cartoon of a single acetylcholine acti- at low gain, (50mp) andfasttime scale, (2 msec).
pated channel. Each channel has two ACh binding Note the end-plate potential at the leading edge of the
sites; one on the cytoplasmic side ofeach alpha subunit. action potential in A. (From Fatt, P., and Kntz, G.:
Miles, K. and R.L Huganir, Molecular Neurobiology J. Physiol., 117:109, 1952.)
2: 91-124, 1988.
stimulated, the microelectrode records an action depolarization block. Nerve-muscle block and
potential as shown in the lower traces of Figure muscle relaxation should be achieved by infusing
6-13. Careful examination of the left hand action large quantities of acetylcholine but this method
potential will reveal a hump on the leading edge is very inefficient because the acetylcholine is
of the action potential. This hump is the part of broken down rapidly. Succinylcholine binds to
the end-plate potential caused by the release of the postsynaptic surface and causes a permeabili-
acetylcholine. It is a local change in the end-plate ty change. Since it is only slowly broken down, it
region; no end-plate potential is seen 2-mm away produces a long-lasting depolarization. It depo-
(B). The end-plate potential can be seen more larizes the muscle membrane, which e contracts
clearly when curarine is applied to reduce the once and then relaxes. Decamethonium also acts
effectiveness of the acetylcholine and to produce in this manner.
a subthreshold depolarization. Drugs that block the nerve-muscle junction
Small depolarizations are recorded at times are often used in conjunction with anesthetics to
when the motor nerve is quiet. They originate achieve muscle relaxation during surgery. It
in the end-plate region and can be recorded only should always be borne in mind that the respira-
very close to it. These miniature end-plate tory muscle would be blocked so that the patient
potentials ("minis") are quantized (Fig 6-13). must be artificially ventilated.
They represent the release of several vesicles of Drugs that prolong the action of acetyl-
ACh. The amplitude of these potentials increas- choline. Blocking the esterase activity 0 that the
es as more vesicles are released. Each pocket or action of the released acetylcholine is prolonged
vesicle releases some 10-17 moles of acetylcholine can also block the end plate. The anti-
that results in a depolarization of 0.4 mV. An cholinesterase, such as neostigmine, edrophoni-
action potential arriving at the presynaptic termi- um (Tensilon), eserine, and diisopropyl tluo-
nal causes an increase in the rate of vesicle release rophosphate (DFP), all combine with acetyl-
so that about 100 vesicles discharge their acetylcholine esterase and prevent it from cleaving
choline over a very short interval; this amount of acetylcholine, so ACh continues to depolarize
acetylcholine is sufficient to initiate an action the end-plate region and to block transmission.
potential on the muscle surface. Many insecticides block acetylcholinesterase.
MEC~SMSOFDRUGSACTING Agents that block the release of acetylcholine
ON NERVE-MUSCLE JUNCTION from the presynaptic terminal will be discussed
Drugs that Compete for Receptor Site. D- below. The various disorders affecting the neu-
tubocurarine competes for the same postsynaptic romuscular junction are discussed in great detail
site, as does acetylcholine; it binds more strongly below.
to the site but does not cause a permeability EFFECTS OF MOTOR NERVE ON
change. Neuromuscular transmission is blocked SKELETAL MUSCLE
because the acetylcholine cannot get to the sites. From the discussion so far, one might con-
Gallamine (Flaxedil) is a synthetic d-tubocu- clude that the motor nerve supplies only the
rarine. Several snake neurotoxins, including stimulus to contract; this is far from the case.
bungarotoxin, also bind very strongly and block When the motor nerve is cut, the muscle rapidly
the receptor. Hexamethonium and tetramethy- atrophies. Its volume and strength of contraction
lammonium (TEA) also block by competitive decrease - and all of the fibers decrease in size, as
antagonism. These drugs are slowly broken does the total muscle bulk. After three months,
down and paralysis wears off. the muscle bulk may have decreased to as little as
Continued application of acetylcholine, and 25 %of its original bulk. This atrophy is not due
continued depolarization, does not result in con- to muscle disuse alone since disuse, such as that
tinued skeletal muscle activity because the action caused by immobilization, will cause muscle to
potential mechanism must be reset after the first atrophy to 3/4 of its original size in the same 3-
action potential. Any drug that produces a con- month period. An intact motor nerve is neces-
tinual depolarization at the end plate produces a sary for continued survival of the muscle fiber. It
6-12 CHAPTER 6
would appear that the continued release of lism cause the red color. Type II fibers found in
acetylcholine, or possibly some other transmitter, white muscles have a very active myosin ATPase
from the nerve, is the agent responsible for this activity and are relatively lacking in mitochon-
trophic influence. dria. Type II fibers which are responsive for
Denervation Sensitivity. When the muscle quick, phasic contractions depend upon an
is denervated, the entire surface of the muscle anaerobic, glycolytic metabolism; they produce
fiber slowly becomes sensitive to acetylcholine. large amounts of lactic acid.
After several weeks, application of ACh anywhere Red muscle is characterized by a long twitch
on the surface results in an action potential and time, and concomitantly a low frequency of stim-
contraction. Patients who have had a motor ulation will result in tetanus. These muscles are
nerve severed show great sensitivity to injected primarily antigravity or postural muscles; their
ACh for this reason. movements are characterized by long-sustained
Reinnervation. If the cut ends of a motor contractions. The white muscles, on the other
nerve are rejoined, sprouts from the central end hand, have short twitch times and are used for
will grow down the tube left by the degenerated quick phasic movements.
axon. If the distance between the cut and the The speed of contraction is determined by
muscle is short and the cut ends are well aligned, the pattern of activity in the motor nerve. When
the nerve will make contact with the muscle. A nerves from fast and slow muscles are crossed,
new end plate will form, and muscle function will the fast muscle slows down and the slow muscle
be restored. Passive exercise of the muscle dur- speeds up (Fig 6-14). When a limb is immobi-
ing regrowth is helpful to prevent disuse atrophy lized, the activity in motor nerves to a slow mus-
and contractures. cle, which is usually intense, decreases. After sev-
eral weeks the speed of contraction has increased
Slow and Fast Muscles.
markedly. It is not clear how the pattern of activ-
There are two sorts of skeletal muscle: red
ity alters the biochemical control mechanisms
and white. The best known example of this dif-
and the contractile properties of a muscle. Some
ference is the white and dark meat of a chicken;
authors suggest a second transmitter released in
the same qualitative differences appear in mam- very small quantities from motor nerves is
mals.
responsible for modulating which proteins are
Most muscles, particularly in mammals, are
expressed from the muscle genome.
not pure red or white muscle but are made up of
a mixture offibers (Fig 6-14). The fibers in red DISEASES OF MUSCLE
muscles are called Type 1. They are rich in mito- Most classifications divide these disorders
chondria but have a relatively low myosin into two groups: inherited and acquired
ATPase activity. They generate ATP from glu- (Morgan & Hughes 1992).
cose as it is used. Enzymes of oxidative metabo-
Muscular Dystrophies
The major inherited disease is the muscular
dystrophies that are characterized by a primary
degeneration of skeletal muscle. The slow but
progressive destruction of muscle results in a
progressive weakness initially affecting the proxi-
mal muscles.
Duchenne's Muscular Dystrophy. The
I 100ms69 most common varieties of muscular dystrophy
are X linked almost all cases occur in males (rarely
Figure 6-14. Twitch time in a fast, extensor digito-
females with Turner's syndrome or X-chromo-
rum longus (EDL) and a slow, soleus (SOL) muscle.
At birth (left) the difference in twitch time is not some translocation may be affected). Duchenne
striking, yet 5 weeks later (right) the difference is pery originally described the most common type with-
pronounced. (From Close, R.: J. Physiol., 180:542, in this group in 1868. The typical patient with
1965.)
Duchenne's muscular dystrophy (DMD) is a boy only slightly reduced. Creatine Kinase levels are
who has delayed walking. At some point markedly increased. The EMG demonstrates
between the ages of 2 and 5 years, the patient is myopathic features. The muscle biopsy indicates
noted to be clumsy and slow in exercises and features that are similar but less marked than
games. It is soon evident that proximal pelvic those noted above.
girdle lower extremity weakness is present. In Recent major advances have been made in
rising from the floor the patient uses his upper our understanding of the genetics and molecular
extremities and hands placed on the thighs to biology of these disorders (Arahata et al, 1989,
force the body in to an erect position (Gower's Hoffman et al. 1988, see also review of Rowland
sign). Thus counteracting the weakness at hips 1988). The precise locus has been identified: the
and pelvis. At this point, marked enlargement of short arm of the X chromosome at the region
the calf muscles is present (pseudo hypertrophy). designated as Xp 21. The specific affected gene
With progression of the disease, increasing atro- has been isolated and characterized. DNA analy-
phy of muscle and increasing weakness occurs. sis has shown that both DMD and BMD affect
By age 12, the patient is confined to a wheel the same gene (allelic). Portions of the coding
chair. Death occurs late in the teens or early sequence of the gene have been used to produce
twenties from respiratory complications and/or polyclonal antisera directed against the normal
cardiac failure (heart muscle is involved). The muscle protein produce of the normal gene. The
blood creatine kinase level while the patient is still specific protein, dystrophin, is a normal compo-
ambulatory is at least 40 times the upper limit of nent of the plasma membrane, transverse tubule
normal. Levels may be 300-400 times normal. system of the normal muscle fiber. In patients
Electromyogram (EMG) demonstrates myo- with Duchenne's muscular dystrophy, the muscle
pathic features. The muscle biopsy taken early in contained less than <3% of the amounts of this
the course of the disease before severe atrophy is protein found in control patients. In patients
present demonstrates characteristic myopathic with Becker's muscular dystrophy, the dys-
features including: 1) wide spread necrosis and trophin was normal but the size of the protein
phagocytosis of muscle fibers 2) regeneration of (molecular weight) was abnormal. Patients with
muscle fibers, 3) marked variation in fiber size an intermediate clinical course had results bridg-
and 4) large rounded "hypercontracted hyalin- ing these two disorders. Patients with other
ized" fibers. (Fig. 6-15). In late stages replace- types of neuromuscular disorders had normal
ment of muscle by proliferation of endomysial dystrophin.
connective tissue and fat occurs. Thus a defective gene at this specific site may
DMD is the most common lethal, X linked result in a total defect in a failure to produce this
disease with an estimated incidence of 1 in 4000 muscle protein (DMD) in the production of a
live male births (see Moser 1984). The maternal
carrier can be identified based on family history
and an elevated creatine kinase level in the carri-
er. A small % of carriers also has mild weakness
or EMG or muscle biopsy changes. There is
however a high frequency of isolated cases, 30-
50% suggesting a high incidence of new mutants
or mutant maternal carriers.
In families at risk, prenatal diagnosis is possi-
ble (Darras et al. 1987, and see below).
Becker's muscular dystrophy. Becker's mus-
cular dystrophy described in 1955 is a less com- Figure 6-15. Muscle histopathology I: Duchenne's
mon (1 in 20,000 male births) and less severe Muscular dystrophy Marked variation in fiber size is
form of x-linked disorders. Age of onset is later; present with a large dense hypercontrRCted hyaJinized
and the rate of progression is slower. The patient fiber (Compare to 6-21 and 8-21). H&E x 63-
is still ambulatory at age 15. Life expectancy is Courtesy of Dr. Tom Smith, u'Mass Medical Center.
6-14 CHAPTER 6
muscle protein of abnormal size (BMD) or in est runner in the class and could not keep up
various combinations of these deficits. Specific with his peers. In high school he first noted
therapy has not yet been achieved. minor weakness in climbing stairs. By college he
Corticosteroids may produce minor improve- had trouble in climbing one flight. By his senior
ment (Brown 1989). year, he had difficulty descending stairs.
The non X-linked muscular dystrophies are Past History and Family History not remark-
less common. able.
Facioscapulohumeral (FSH) dystrophy is an General Physical Examination:
autosomal dominant with the gene linked to Unremarkable
chromosome 40. The incidence is 0.5- Neurological Examination: The relevant
5.0/100,000 persons. The phenotypic expres- findings included an absence of deep tendon
sion is variable. Some cases begin in childhood, reflexes at triceps and radial periosteal and trace
and have a poor prognosis. Most begin in the late reflexes at biceps. Proximal weakness was present
teens, or early twenties with a slow rate of pro- with intact distal strength and normal muscle
gression. Often the specific age of onset is diffi- bulk..
cult to identifY. The name of the disease reflects Motor system:
the prominent early features of bilateral facial At hipl strength was 3/5; at shoulders, 4/5.
weakness and proximal upper extremity involve- Gower's sign was present in attempting to stand
ment with weakness of shoulder abduction and from a recumbent position.
winging of the scapula. Subsequently lower Gaitwas waddling - consistent with proximal
extremities are involved. In most cases little dis- weakness at hips.
ability of significant degree occurs before the Deep tendon reJlexes2 were absent at triceps
thirties or forties. Life span is relatively well pre- and radial periosteal and trace at biceps.
served. Serum creatine kinase is borderline or Quadriceps and Achilles reflexes were normal.
only mildly elevated reflecting the slow rate of b. Plantar responses were flexor.
muscle breakdown. The EMG and muscle biop- 5) Sensation: All modalities were normal.
sy reflects the myopathic features. Lab:
Limb girdle dystrophies. The limb girdle 1) Erythrocyte sedimentation rate (ESR), thy-
dystrophies are heterogenous autosomal reces- roid studies, and electrolytes were all normal.
sive disorders and some are autosomal domi-
nants. Some begin in the upper extremities at
shoulder and scapula, some in the lower lIbe primarygrading system for strength is that
extremes at pelvic girdle and knees. Progression suggested by the Medical Research Council
is slow and severe disability usually not present (MRC) during HVrld War II' O=no contrac-
until the thirties or even the fifties. Serum crea- tions; 1= flicker or trace of contraction; 2=active
tine kinase is moderately elevated. EMG demon- movement with gravity eliminated; 3=active
strates myopathic features; muscle biopsy movement against gravity; 4=active movement
demonstrates dystrophic features. From a clinical againstgravity and resistance; 5=normal power.
standpoint, there is considerable overlap with Ibe scale is not a linear function- and because of
cases ofindolent polymyositis, motor neuron dis- the wide range included in grades 4 and 5
ease (spinal muscular atrophy), endocrine many examiners willgrade 4(-), 4, 4(+) and
myopathies, and carriers of the DMD gene with 5(-).
minor clinical manifestations.
The following case history illustrates this type 2Deep tendon reflexes are graded as folloWS:
of case: O=absent; trace=minimally present; 1=hyperac-
Case History # 6-1. tive; 2=normal; 3= hyperactive-brisk; 4=hyper-
This 21-year-old white male college graduate
active-unsustained clonus; 4+ sustained clonus.
was referred for evaluation of bilateral leg weak-
As above minor gradations maybe superim-
ness. The patient was delayed in walking until
posed such as 2+, or 3+.
age 2. During grammar school, he was the slow-
2) Muscle enzymes, CK, SGOT, LDH and death. Although cases can present in the neona-
aldolase were all mildly elevated. tal period, the most common ages of onset are
3) Motor and sensory nerve conduction veloci- late adolescence or early adult life.
ties were all normal. The early symptoms relate to complaints of
4) EMG - demonstrated myopathic features gait difficulty and clumsiness. At this point, the
with decreased amplitude and duration of motor more specific diagnosis may not be apparent to
units with a full interference pattern on volition- the non-neurological observer. (The author
al effort. once saw 6 patients in a 8-month period at an
5) Muscle biopsy (left deltoid) reported signif- Army Basic Training base with this diagnosis,
icant dystrophic features: referred with the more general complaints).
a. Marked variation in muscle fiber size in a Examination however will demonstrate a distal
random distribution. limb weakness. Percussion of the thenar hand
b. Central position of subsarcolemmal nuclei. muscles or of the tongue will often demonstrate
c. Significant increase in endomysial connec- a myotonic reaction. (prolonged contraction
tive tissue. delayed relaxation). Myotonia can also be
Subsequent Course. demonstrated by asking the patient to squeeze
Follow Up one year late indicated no pro- the examiner fingers and to then rapidly open the
gression. Two years later, minor progression was hands. Myotonia of the eyelids may be noted in
noted with a minor decrease in hand strength. the continued retraction of eyelids and a lid lag
Over the years slow progression occurred. The after prolonged upgaze. With progression of the
patient reported 17 years after his initial evalua- disease, a significant weakness and atrophy of
tion that he was still able to walk without assis- muscles occur in muscles innervated by the facial,
tance. Climbing stairs was a problem. Face and mandibular supplied muscles, and the accessory
hands were not involved. Additional discussion nerve to the sternocleidomastoid muscles occurs
of these less common dystrophies van be found with the development of characteristic "myo-
in Padberg 1993. pathic facies." Most patients are disabled and
Muscular dystrophies with predominant unable to walk by the thirties or forties. Life
involvement of cranial nerves. Cranial nerves expectancy is reduced because of cardiac and pul-
may be affected during the course of the more monary complications.
common muscular dystrophies. There have The creatine kinase level is usually normal.
however been several families described with The EMG demonstrates myopathic features plus
adult onset. Diseases beginning with predomi- the prolonged myotonic discharges. When
nant and relative selective involvement of cranial audio amplified the EMG myotonic discharge
nerves - usually with autosomal dominant pat- sounds like a "dive bomber". The muscle biop-
tern of inheritance: chronic progressive ophthal- sy shows characteristic features of chains of cen-
moplegia and oculopharyngeal dystrophy. tral nuclei, ringed fibers and selective atrophy of
Myotonic Dystrophy: This is the most com- type 1 fibers.
mon inherited form of muscular dystrophy Myotonic dystrophy should be easily distin-
affecting adults. It is an autosomal dominant dis- guished from syndromes in which myotonic
order with an estimated incidence of 1:8000 in occurs in relative isolation: Myotonic congenita
which cranial nerve and distal limb involvement Thomsen's disease and an autosomal recessive
are prominent3. Multiple organ systems are
involved with variable expression. The non mus- 3Recent studies have demonstrated that the dis-
cular striated manifestations include cataracts, order is related to an increased number of cyto-
baldness, mental subnormality, gonadal atrophy, sine-thymidine-guanine trinucleotide repeats
other endocrine disturbances, low plasma IgG, in the region of the protein kinase gene located
glucose intolerance, smooth muscle autonomic on the long arm of chromosome 19. A DNA
involvement and cardiac conduction defects. probe that detects directly the mutation is avail-
The latter may lead to syncope and sudden able (Shelbourne et a11993, Ptacek et aI1993).
6-16 CHAPTER 6
form (Becker). The myotonic syndromes are triphosphate) which is converted from ADP
characterized by an abnormal increase in mem- (Adenosine diphosphate) by the action of CK
brane excitability with persistent runs of action (Creatine kinase).
potential in the surface membrane. Abnormal Moderate exercise is fueled by aerobic condi-
low chloride conductance has been implicated in tions with glycogen as the main fuel source.
some types of myotonia: myotonia congenita in After 5-10 minutes blood glucose is utilized.
humans, congenital myotonia of the goat (due to Subsequently fatty acids are utilized. After 4
mutagens) and myotonia following ingestion of hours of exercise lipids and amino acids are uti-
aromatic carboxylic acids. lized.
Subsequent K+ accumulation in the trans- In high intensity exercise anaerobic glycogen
verse tubular lumen leads to excessive depolar- breakdown and glycolysis generate additional
ization and the persistent firing of action poten- fuel. At rest lipids are the predominant energy
tials. Similar result occur when normal muscle source.
fiber are placed in a chloride free solution The student is already aware that multiple
However, this mechanism is apparently not enzymes are involved in the events of aerobic and
the explanation for the myotonia of myotonic anaerobic carbohydrate metabolism and in lipid
dystrophy, where intracellular sodium concentra- fatty acid metabolism. The metabolic myopathies
tion is elevated apparently because of abnormali- are relatively rare inborn errors of metabolism,
ties in the regulation of sodium channels. The which involve these enzymes. The specific defect
underlying molecular basis of myotonic dystro- may involve the lysosomal and cytosolic
phy has recently been discovered. An unstable enzymes: The glycogen storage diseases - or the
DNA fragment occurs on chromosome 19q 13 enzymes related to the mitochondrial respiratory
related to an expanded CAG trinucleotide repeat chain for aerobic energy production: The mito-
at the end of a region encoding a protein kinase. chondrial myopathies.
The greater the number of repeats, the more Depending on the specific deficit - a) there
sever the disease (Wang et. al 1994). Ptacek et may be multiple system involvement with persis-
provides a more complete review of the physiol- tent weakness, b) selective muscle involvement
ogy of the myotonic disorders. al (1993). with persistent weakness or c) exercise intoler-
Congenital myopathies. ance with easy fatigue and muscle cramps but
(Refer to Fardeau 1982). These are relative- with little persistent weakness.
ly rare disorders of muscle which primarily pre- The first hereditary myopathy in which a spe-
sents with hypotonic weakness in childhood: cific enzyme defects was identified McArdle's
"The floppy infant" and delay in motor develop- Disease falls into this last category. The enzyme
mental milestones. The specific name assigned muscle phosphorylase is absent as demonstrated
to each of these syndromes is based on the on special stains for this enzyme applied to the
unique features on muscle biopsy and the special muscle biopsy. When the patient exercise glyco-
histochemical stains. The first type described by gen can not be broken down to pyruvate and lac-
Shy and Magee in 1956 is so named because type tic acid and the expected rise in blood lactic acid
I fibers lack mitochondria in the central core in ischemic limb exercise fails to occur. As exer-
which instead contains disorganized tightly cise continues, fatigue and painful cramps occur.
packed myofilaments. In nemaline myopathy If the patient persists, muscle breakdown will
there are peripheral collections of rod shaped occur with a significant rise in blood and urine
bodies - possibly derived from the Z bands. In levels of myoglobin. Significant acute renal
centronuclearmyopathy there are chains of cen- tubular impairment is a complication of any
tral muscles - surrounded by a zone devoid of acute condition in which rapid breakdown of
myofibrillar - ATPase activity. muscle occurs producing myoglobinuria.
Metabolic Myopathies: (Refer to Rowland
et al1986 and DiMauro 1985)
Muscle contraction utilizes ATP (adenosome
Periodic Disorders of Muscles: Past History: - Negative
Familial Periodic Paralysis4 Family History :- Negative
Other rare inherited (autosomal dominant) General Physical Examination: - Negative
disorder of muscle that may also produce acute Neurological examination:.
transient weakness. These are not related to 1) Mental status - Normal
energy metabolism but are characterized instead 2) Cranial Nerves Normal
by episodic failure of muscle membrane excitabil- 3) Motor system
ity. The attacks are often associated with marked a) No atrophy
alterations of serum potassium. There are b) Strength: Intact except: Hip flexors 4/5,
hypokalemic and hyperkalemia (and possibly Triceps 4/5
normokalenic forms). In the hypokalemic form, Deep tendon reflexes: present but relatively
at the onset of the attack a significant movement quiet at quadriceps and Achilles
of potassium and sodium ions into skeletal mus- 5) Plantar responses flexor
cle occurs with a decrease in serum potassium. 6) Sensation: Normal
Attacks may be induced by the administration of Laboratory data:
insulin and glucose or of sodium chloride, by 1) Sed. rate and thyroid functiom normal
alcohol, stress, cold exposure, or by rest after 2) Serum potassium on admission 3.9
exercise. In the hyperkalemic form attacks may mEq/liter (normal 3.9-5.0 mEq/liter)
be precipitated by fasting, cold, stress or by rest 3) Creatine phosphokinase 12.8/12.0
after exercise. In all types mild persistent proxi- 4) EMG - Normal
mal weakness may develop later in the disease 5) Nerve conduction studies normal.
course. Muscle biopsy may demonstrate vascular Additional studies
changes and tubular aggregates. With a baseline potassium of 4.7 mEq/liters,
In both forms the changes in serum levels of the patient was given 38 grams of glucose solu-
potassium are of such magnitude as to produce tion by mouth plus 5% dextrose in water intra-
EKG changes. In the hypokalemic form serum venously plus 15 units of regular insulin. Within
K may be depressed to 2-3 mEg/Liter. In the 15 minutes after insulin administration, the
hyperkalemic form the lead may be as high as 7- patient had increased weakness in all four
8 mEgl/Liter. (Normal 3.9-5.0 mEg/liter). extremities. By 30 minutes, the potassium level
The following case history illustrates many of had fallen to 2.1 mEqjliter. At 60 minutes, the
these points. Case History 6-2. Patient of Dr. patient had total paralysis of all four limbs.
Thomas Twitchell. (Quadriplegia). and no deep tendon reflexes
This 3D-yr. old white housewife had the could be obtained. She was flaccid unable to lift
onset of episodes of night paralysis at age 9 years. her head from the bed. However, she was con-
These occurred several times the month but with scious she could speak, and breath and all cranial
the administration of potassium supplementa- nerves were intact. EKG did show the typical
tion, attacks decreased to 1-2 times per year. At features oflow serum potassium (flat T. waves).
age 32, she remarried and was under increased She was given oral potassium and within 2 hours
stress. One year later she began to have frequent had returned to her baseline state. She was sub-
episodes of nighttime paralysis again. She could sequently treated with potassium supplements
relate her attacks to high carbohydrate meals and plus acetazolamide a drug which affects sodium
cold water exposure as well as stress. potassium transport. Studies by Tacek and asso-
Shortly before the onset of these attacks she ciates 1994 have demonstrated a dihydropyridine
had noted a mild persistent proximal lower receptor mutation produces a calcium channel
extremity weakness which was non-progressive disorder resulting in hypokalemias. A mutation
but did result in difficulty in climbing steps. in the sodium channel produces the hyper-
4The relationship of the periodic paralysis disor-
kalemic form of periodic paralysis.
These cases of primary periodic paralysis
ders to the myotonic disorders and the more spe-
must be distinguished from the more common
cific genetics and physiology are discussed in
secondary varieties which occur in relationship to
Ptacek et a11993.
6-18 CHAPTER 6
the electrolyte alterations of renal disease, adren-

al cortical disease, effects of diuretics, cathartics
and in gastrointestinal disorders with severe diar-
rhea.
Acquired Disorders of Muscle
The major categories are as follows:
1) metabolic: hypokalemic/hyperkalemic
myoglobinuria and alcoholic. (see above). Drugs
such as colchicine used in the treatment of gout
may also produce a myopathy.
2) Endocrine: Hyperthyroid (Thyrotoxic
myopathy) hypothyroid (Myxedema Myopathy) Figure 6-16. Muscle hiswpathology II: Polymyositis
and corticosteroid. The corticosteroid myopathy wide spread necrosis of muscle fibers is present with
occurs not only in patients with Cushing's dis- extensive infiltration by mononuclear inflammatory
ease but also in many patients receiving long cells H&Ex25. (Compare to 6-15). Courtesy of Dr.
term corticosteroid therapy. Typically the weak- Tom Smith, Neuropathology, U. Mass. Medical
Center.
ness begin in the pelvic girdle and proximal mus-
cles of the lower extremities. faces of the limbs, Sedimentation rate and mus-
3) Trauma: Closed muscle compartment cle enzymes are significantly increased. Muscle
compression due to trauma or a deep uncon- biopsy indicates segmental muscle necrosis,
scious state produced by drugs and alcohol may regeneration and inflammatory infiltrates, Figs 6-
produce considerable rhabdomyolysis of an acute 16. EMG indicates not only myopathic features
nature (see Owen et al1979). but also the presence of fibrillations.
4) Inflammatory. (Referto Dalakas 1991). There is an increased incidence of underlying
Inflammation of muscle may occur in a) viral neoplasm in adults with dermatomyositis and
disease such as influenza on Coxsackie, b) bacte- polymyositis (particularly in older adults) .
rial infections by staphylococcus aureus or c) in Common sites are lung and ovary. Overall inci-
parasitic infections due to toxoplasmosis, cys- dence in all cases of dermatomyositis and
ticercosis, and trichinosis that are of the major polymyositis -is 9% (Sigurgeirsson et al1992).
importance in some areas of the world. The term overlap polymyositis refers to
The major considerations in this section are patients who develop polymyositis within the
those cases where the polymyositis occurs on context of already existing autoimmune connec-
autoimmune bases. tive tissue diseases: systemic lupus erythematosus
In some cases, (idiopathic, polymyositis and (SLE), rheumatoid arthritis, periarteritis nodosa,
dermatomyositis) the autoimmune disease is systemic sclerosis and Sjogren's syndrome. It has
restricted to muscle (and skin). The cases cover been estimated that 5-15% of all patients with
a wide age range. The onset and source may be these diseases will manifest polymyositis
acute, subacute or chronic. The chronic gradu- (Isenberg, 1984).
ally progressive pattern is the most common. Most patients (60-70%) with polymyositis
Cranial nerves are usually not involved although and dermatomyositis have a significant response
difficulty in swallowing may be present due to to corticosteroid therapy. Non responders may
posterior pharyngeal striated muscle involve- require more definitive immunosuppressive ther-
ment. Proximal muscles are involved predomi- apy. Approximately one third of non-responders
nantly in dermatomyositis. There is more diffuse have another variety of myositis inclusion body
involvement in polymyositis but with a proximal myositis. Such cases have a male predominate rel-
predominance (limb girdle and neck flexors). In atively normal CPK and greater distal involve-
dermatomyositis there is edema and bluish ment (see discussion Dalakas 1991). Case 6-3
(heliotrope) discoloration of the eyelids, with a demonstrates dermatomyositis complicating
scaly red rash on the face (in a butterfly pattern), ovarian malignancy.
shoulders, upper chest, back and extensor sur-
Case History 6-3. changes reflect - a) paraneoplastic effect of malig-
This 69-yr. old white female had partial nancy or b) the effects of chemotherapy.
resection of ovarian carcinoma in Dec. 1973 and The continued progression of the weakness
received radiotherapy and chemotherapy in in this patient is not unusual. The paraneoplastic
January and February 1974. Two weeks prior to polymyositis syndrome does not have the favor-
admission she had developed progressive weak.- able response to corticosteroids found in the
ness of all four extremities with proximal more idiopathic syndrome.
than distal involvement. Because of difficulty DISEASE OF THE NEUROMUSCULAR
swallowing, she had been on a liquid diet for two JUNCTION
weeks prior to admission. General Physical Diseases affecting the neuromuscular junc-
Examination: 1) There was superficial redness; tion may be classified as to location: postsynaptic
swelling involving the skin of both upper extrem- or presynaptic (see Newsome-Davis 1992, Engel
ities 2) Liver was enlarged. 1984,Drachman 1986).
Neurological examination Postsynaptic Disorders-Myasthenia Gravis
1) Mental Status: Intact The major primary disease due to neuromus-
2) Cranial Nerves: Intact except absent cular junction pathology in this country and
gag reflex western Europe is myasthenia gravis. The preva-
3) Motor System: Weakness of all four extrem- lence is 5-7.5 per 100,000. This is a disease char-
ities proximal greater than distal. acterized by fluctuating weakness of voluntary
4) Reflexes: Deep tendon reflexes were muscle worse on exercise, improved by rest and
depressed in the upper extremities and absent in by administration of anticholinesterase drugs.
the lower extremities This is primarily a disease of adults with onset
5) Sensory System: Intact. between ages 10 and 70. However neonatal and
Laboratory Data congenital cases are recognized. The peak. age of
1) Erythrocyte sedimentation rate increased to onset is between ages 20 and 30. Under age 40,
50 mm per hour. females are affected more often than men in a
2) Muscle enzymes (SGOT LDH, CPK) all ratio of70:30. After age 50, there is a male pre-
significantly increased with creatine phosphoki- dominance of 60:40. Ten %of patients have an
nase elevated to 201/12 units. associated tumor of the thymus gland (thymo-
3) Antinuclear antibody titer was not signifi- ma). These patients tend to be older with a male
cantly elevated (test for SLE) predominance.
4) EMG: Abnormal - consistent with The symptoms usually first appear in the
polymyositis. muscles supplied by the cranial nerves. The
Hospital Course: extraocular muscles for control of eye and eyelid
movement are first affected in 60% of cases and
The patient was treated with high dosage
are affected at some stage in 90% of patients. In
corticosteroids. - (Prednisone). Despite a signif-
some cases, with a relatively benign course, the
icant improvement in muscle enzymes (CPK
symptoms may remain confined to the eye mus-
201>9.9, SGOT.295>102 LDH 320 > 102), the
cles, ocular myasthenia. The patient has a ptosis
weakness continued to progress. During the last
(closure or droop) of one or both eye lids, often
week of life, she had three episodes of aspiration
most apparent on sustained upward gaze.
and increasing respiratory distress expiring 3-29-
Double vision (diplopia) results from a weakness
74.
of one or more extraocular muscles. The early
Comment. This patient received.a diagnosis
occurrence of diplopia may be a reflection of the
of dermatomyositis complicating ovarian malig-
precise synchronization required between the
nancy. In such patients deep tendon reflexes may
two eyes in movement under normal conditions.
be totally absent. Changes may be present on
A minimal weakness of one medial or lateral rec-
sensory or cranial nerve examination, suggesting
tus muscle would disrupt such a precise synchro-
a peripheral neuropathy. Peripheral nerve
nization. In the extensive series of Grob et al
6-20 CHAPTER 6
with 1487 patients followed 1940-1985) 14% of blocks acetylcholine esterase, is then adminis-
patients continued to have localized ocular myas- tered (edrophonium or neostigmine). This
thenia. increases the duration of available acetylcholine
Generalized myasthenia refers to progression at the neuromuscular junction (edrophonium or
to involve other cranial nerves and the extremity neostigmine) and the decremental response is
and trunk muscles. The patient will have diffi- reversed.
culty swallowing (dysphagia), speaking The edrophonium (Tensilon) test can be car-
(dysarthrias ) and chewing (mandibular nerve ried out in the outpatient office. This agent
supplied muscles). In addition a bilateral weak- administered intravenously will often transiently
ness of facial muscles may provide a suggestive reverse or reduce the signs of weakness. Clinical
myasthenic faces. The patient may support head effect occurs in 30-60 seconds and lasts 4-5 min.
or jaw with the hand to compensate for weak- Since related cholinergic agents (anti-
ness. As the disease progresses, more generalized cholinesterases) play a major role in therapy the
involvement of proximal limb muscles develop. test can also be performed to determine whether
In some patients there is significant involve- the patient is receiving too little on too much of
ment of the muscles of respiration. In the series the therapeutic agent.
of Grob maximum level of weakness was reached A very specific test is the measurement of the
during first year in 55% first 3 years in 70% and blood level of the acetylcholine receptor anti-
first 5 years in 85%. After 3-5 years, the disease body positive in 85-90% (see below).
stabilizes. Recently major advances have been made in
The prognosis depends on the age of the our understanding of the underlying pathogene-
patient, the duration of the localized form of the sis and pathophysiology of this disorder. This
disease and on the associated diseases: constitutes a major accomplishment for neurobi-
(thymoma, thyroid disorders other autoimmune ology that has been translated into improved
disorders) . results as regards therapy of the disease.
Myasthenia was once associated with a signif- The role of the thymus appears critical from
icant mortality due to respiratory insufficiency several standpoints. 1) The thymus has a central
and infection but this mortality has now been role in immunology. 2) The thymic hyperplasia
markedly reduced. In the series of Gob, et al. for involves the presence in the medulla of many ger-
patients with maximum weakness in the 1940- minal centers and surrounding T cell areas. Such
1957 era - mortality was 31%, rate of remission germinal centers are rare in non-myasthenic thy-
10%. In 1958-1966 era, the mortality was 15% mus. 3) The thymus contains muscle like cells,
rate of remission 10%. In the 1966-1985 era, and ACH receptors can be demonstrated when
mortality was 7% remission rate was 11 %. these cells are placed in tissue culture. Drachman
The diagnosis is readily apparent from a clin- 1978 has suggested that this receptor bearing
ical standpoint: Fluctuating weakness a) no sen- muscle cells may be particularly vulnerable to
sory finding b) Intact reflexes and no long tract immune attack. Some alteration of these cells by
findings. However there are several confirmato- lymphocytes (perhaps triggered by viral infection
ry diagnostic tests. Jolly in 1895 first described of thymus etc.) could initiate any acute immune
the electrical test that carries his name. Repetitive response directed against ACH receptors.
stimulation of a motor nerve result in a rapid The essentials of therapy in myasthenia gravis
decrease in the amplitude of muscle contraction follow from the neurobiology of the disease.
"decremental response". Jolly demonstrated 1) Initial therapy consists of anti-
that the apparently fatigued muscle would still cholinesterase drugs. The main drug used is
respond to direct galvanic stimulation. pyridostigmine (Mestinon) which has a some-
In modern clinical neurophysiology the what longer duration of action than neostigmine.
motor nerve is stimulated at a rate of 3-5 per sec- For some patients this will suffice particularly if
ond and the reduction in amplitude of the mus- only local ocular myasthenia is present and if this
cle action potential is measured. (Abnormal is responds well.
greater than 10% reduction). An agent which 2) Generalized myasthenia will almost always
require more definitive therapy directed at the Myasthenia Gravis
immune systems. Adams and Victor (1989) have summarized
a} The most definitive procedure is total the major historical landmarks in the study of
thymectomy. As discussed by Rowland, (1987) myasthenia. Welch in 1877 and Erb in 1875 rec-
there is now a consensus that all adults with gen- ognized the lack of any pathology in brain stem
eralized myasthenia should have this procedure to explain the cranial nerve motor findings. The
relatively early in the course of the disease. In the electrical studies of Jolly in 1895 suggested what
"maximum thymectomy" series of 72 non-thy- has come to be recognized subsequently as the
moma patients previously with moderate to location of pathology: the neuromuscular junc-
severe generalized myasthenia reported by tion. The term's pseudoparalysis as well as myas-
Younger et al. (1987), 46% of patients were in thenia gravis was originated by Jolly since no
complete remission (on no medication). 33% pathology was present at autopsy. He also rec-
were asymptomatic on 60-240 mg ofpyridostig- ommended the use of an anticholinesterase
mine daily and 10% were asymptomatic on physostigmine. Walker in 1934 noted the simi-
steroids. Approximately 90% then were in com- larity of some of the signs to those produced by
plete remission or asymptomatic. An additional the poison curare and began the use of
6% were improved. At least 1-4 years were physostigmine. Buzzard in 1905 in a detailed
required to see the maximum response to thera- clinical pathological analysis of 5 cases described
py. There was in significant decline in the titre of the lesions in thymus; (Thymic hyperplasia
acetylcholine receptor antibody. Although this which now has been noted in over 80% of
was not a matched control series, the results are patients) and the minor lymphocytic collections
in striking contrast to the contemporary results in muscle. Buzzard proposed that an autotoxic
of non surgical treatment of moderate to severe agent could produce all of these findings. He
generalized myasthenia (see Grob. 1987). Other also noted the association of the disease with thy-
major centers have confirmed these results. rotoxic cases. Simpson in 1960 proposed an
Schumm et al. (1985) has also recommended the autoimmune basis for the disease because of the
procedure in patients with pure ocular myasthe- increased incidence of other putative autoim-
nia, if no spontaneous remission and no satisfac- mune disease: thyroiditis, lupus erythematosus
tory response to cholinesterase inhibitors occurs and rheumatoid arthritis.
in a 6-month period. In their series, thymecto- Electron microscopic studies by Zack et al.
my prevented the subsequent development of 1962 and by Engel and Sarta 1971, Engel et al
generalized myasthenia; none of 18 patients pro- 1976 had demonstrated significant changes in
gressed over two years from ocular to generalized the postsynaptic region with shallow postsynap-
myasthenia. tic folds, a widened synaptic cleft. In contrast the
Thymectomy was originally performed pri- presynaptic area was normal as regards the num-
marily to remove thymomas in patients who ber and size of presynaptic vesicles. Fambrough,
coincidentally also had myasthenia gravis; some Drachman and Satyamurt; (1973) then demon-
improvement in the myasthenia also occurred strated a marked (3 fold) reduction in acetyl-
(Blalock et al. 1939). Considerable experience in choline receptors per neuromuscular junction in
subsequent years has demonstrated a poorer motor point nerve biopsies of myasthenic
response of the myasthenia in such cases of thy- patients. Compared to control subjects, there
moma to thymectomy. were a decreased number of binding sites for a
b} Other types of immunosuppression may radioactive labeled snake poison, alpha bungaro-
also be employed in the pre or postoperative toxin which can be purified from the venom of
period or in those patients unable to tolerate the cobra and krait. This toxin binds in an irre-
thymectomy. These include corticosteroids, versible manner to the acetylcholine receptor. In
plasmapheresis (plasma exchange) and cytotoxic 1973, Patrick and lindstrom demonstrated that
drugs (azathioprine). repeated immunization of rabbits with acetyl-
choline receptor protein derived from the electric
organs of eels reproduced the disease. These ani-
6-22 CHAPTER 6
mals develop all of the clinical and electrical fea- operator for several years had noted a general
tures of myasthenia gravis. Antibodies to the sensation of fatigue in his arms and legs at the
ACH receptor protein could be identified end of a day. Approximately 6 to 7 weeks prior
attached to the ACH receptor. Moreover, nor- to admission, on Dec 7, 1975 the patient began
mal animals receiving these antibodies also devel- to have more significant difficulty with a marked
oped myasthenia. increase in the degree of weakness of the arms
Subsequently Lindstrom et al (1976) and and legs. At the same time, the patient noted
several other groups reported a radioimmunoas- significant slurring of words, difficulty in swal-
say for acetylcholine receptor antibody. This is lowing, and drooping of the lids. All of these
now a standard laboratory test for myasthenia symptoms were transient; they were not present
gravis with a 90% detection rate in the serum of in the morning; they were clearly precipitated by
myasthenic patients. (The serum level does not exercise. For example, although the patient
correspond to the severity of the disease). Engel would initially have strong chewing movements,
(1984) were able to demonstrate immune com- as soon as he began to chew for a short period
plexes at the postsynaptic junction in biopsies he would develop fatigue of jaw muscles. The
from myasthenic patients. When the degree of ptosis was sufficient to result in diffi-
immunoglobulin derived from serum of myas- culty in driving.
thenic patients is administered to mice, the char- The patient had been receiving neostigmine
acteristic myasthenic syndrome develops in the 15 mg every 6 hours. He reported that 30 mg
recipient animal (Toyka, et al. 1974). The syn- every 6 hours produced significant diarrhea and
drome of neonatal myasthenia also suggests a hypersalivation. In addition this dose exacerbat-
serum or plasma transmissible factor. 15% of ed swallowing and chewing problems.
children born to myasthenic mothers will mani- Past history: The patient had a long-stand-
fest clinical signs of weakness lasting several ing problem of marked obesity.
weeks due to passive transfer of anti ACH recep- Neurological examination: Four hours
tor antibodies across the placenta. Circulating after neostigmine 15 mg.
ACH receptor antibodies and electrophysiologi- 1. Mental status: intact
cal findings can be demonstrated in these infants 2. Cranial nerves:
and even in additional neonates who do not a. A significant bilateral ptosis of the eyelids
manifest clinical weakness. was present. The degree of ptosis was markedly
Subsequent studies reviewed by Drachman increased by exercise when complete closure of
(1986) suggest several mechanisms for antibody the left eyelid occurred.
action: 1) there is a significant increase in the rate b. On repetitive upward gaze, a bilateral
of degradation of ACh receptors, 2) the anti- weakness of superior rectus developed.
body actually blocks the binding sites of the c. There was a bilateral facial weakness, worse
acetyl choline receptor and, 3) there is a comple- on exercise, more marked on the right than on
ment mediated damage to and subsequent the left.
change in the geometry of the junction with a d. Jaw movements (opening, closing, and
reduction in efficiency of transmission. lateral movements) were weak. The degree of
Cells cultured from patients with myasthenia weakness was increased by exercise.
gravis but not from control subjects can synthe- e. Lateral tongue movements, particularly on
size acetylcholine receptor antibody in vitro. sustained pressure, became weak.
The highest levels of production are obtained 3. Motor system:
from thymic cells of patients with medullary a. There was a significant weakness in shoul-
thymic hyperplasia. Peripheral blood lympho- der abductors, elbows flexor and extensors, and
cyte lymph nodes and bone marrow also pro- handgrip. The degree of weakness was marked-
duce the ACH receptor antibody. ly increased by repetitive exercise.
Case History 6-4. NEeR. 4. Reflexes:
This 44-year-old, white, married, machine a. Deep tendon reflexes were symmetrical.
b. Plantar responses were flexor.
5. Sensory system: All modalities were intact. action of acetylcholine esterase at the neuromus-
Laboratory data: cular junction is to rapidly terminate the action
1. Chest x-rays and tomogram studies of thy- of ACH. This allows high rates of transmission
roid function were normal. Subsequent tests for across the synapse. If acetylcholine esterase is
lupus erythematosus were negative. inhibited, acetylcholine remains on the receptor
2. A tensilon edrophonium test was per- and in the synaptic space.
formed. This demonstrated an almost immedi- There are two classes of acetylcholine
ate eye-opening effect with the disappearance of esterase inhibitors:
the bilateral ptosis. The ptosis, however, had a) reversible: (carbamates), and
reappeared 3 to 4 minutes after injection of 10 b) relatively "irreversible" (organophos-
mg of the agent. phates)
Subsequent course: The patient was treated a) The reversible agents include those anti
with pyridostigmine and stabilized on a dosage ACH esterase drugs used in the treatment of
of 90 mg 5 times per day (approximately every myasthenia gravis. An increased availability of
four hours). On the dosage his ocular bulbar acetylcholine is of value in counteracting the
and generalized weakness stabilized until June weakness due to decreased numbers of receptors
1973 when increasing generalized weakness in this syndrome. Excess amounts of such drugs
developed. The patient had gradually increased produce excessive amounts of acetylcholine at
his dosage to 180 mg every three hours. the receptors as noted in the above case history
Respiratory distress increased and the patient resulting in increased weakness referred to as
was readmitted in extreme distress in the superi- "cholinergic crisis" The dose of the drug must
or position. Tidal volume was zero. He had be reduced. In the management of such patients
marked bilateral ptosis and diffuse skeletal mus- the edrophonium ("Tensilon") test is of value.
cle weakness. Analysis suggested the patient was b) The relatively irreversible agents
in "cholinergic crisis." He was intubated, venti- (organophosphates) constitute a much more
lated and received no medication for 60 hours. serious problem - not only does a significant
Repeat tensilon test now demonstrated marked acute cholinergic effect occur but there is dam-
improvement in respiratory effort and in skeletal age to the postsynaptic membrane and delayed
weakness. Pyridostigmine was reinstituted and effects on peripheral nerve. Senanagake and
based on edrophonium tests, the patient was sta- Karolliedde 1987 distinguished three syn-
bilized on 90 mg every 3 hours. A tracheosto- dromes. 1) The acute cholinergic syndrome is
my was performed and thoracic surgery consult- accompanied by autonomic effects fascicuiations,
ed regarding thymectomy. The surgeons con- and at times central effects (coma) 2) The inter-
sidered that the marked obesity constituted too mediate syndrome occurring in 10% of patients
great an operative risk for surgical thymectomy. after recovery from the acute syndrome 24-96
The patient instead received radiation of the hours after the poisoning - identical to an acute
anterior mediastinum, 3000 rads over one myasthenic syndrome with respiratory cranial
month. At the time of discharge tidal volume nerve and proximal limb muscle involvement. If
was now 3000 cc. The patient did well with no the patient survives the respiratory problems,
additional problems over the next three years. recovery may occur in 5-18 days. 3) A delayed
An exacerbation occurred in 1976. distal motor neuropathy occurs in some patients
He was subsequently treated with long term at 2-5 weeks after exposure.
prednisone therapy eventually being maintained The organophosphates are the neurotoxic
an alternate day therapy. On March 26 1983, he agents of chemical warfare. They are also exten-
had a respiratory arrest followed by cardiac sively employed as pesticides. As discussed by
arrest. Despite resuscitation he died after a one- Davis (1987) this is a major problem in the
month period of anoxic encephalopathy. developing countries where the sale of such
Other post synaptic syndromes: pharmaco- chemicals is often unregulated, the chemicals are
logic and toxic: (see also discussion above) often repackaged in unlabeled containers. The
1) Acetylcholinesterase inhibitors: The usual original containers are often reused. The storage
6-24 CHAPTER 6
and use are often unsupervised and the popula- drome however may precede the appearance of
tion is often unable to read any warning label. the tumor by months or years. In some patients
The magnitude of the problem is staggering. (1/3) a malignancy may not be identified, but
In Sri Lanka alone between 1978 and 1980, there may be other evidence of autoimmune dis-
there were 80,000 patients admitted with pesti- ease.
cide poisoning and 6083 of these patients died. The underlying pathophysiology relates to a
Seventy five % of all cases were due to decrease in the release of acetylcholine quanta
organophosphorous. In Sri Lanka, the majority from the nerve terminal (Not only at the neuro-
of complex cases were the result ofingestion with muscular junction but also at cholinergic nerve
suicidal intent. endings in the autonomic nervous system). As
2) Agents that bind to the acetylcholine discussed by Newsom-Davis (1992), this defect
receptor and thus block access of acetylcholine to in release relates to immunoglobulin g antibody
the receptor. that binds to presynaptic Ca channels and pre-
a) d-tubocurarine - competes for the receptor vents their voltage gated opening. As the action
in a reversible manner. Initially a South potential enters the presynaptic region, fewer Ca
American Indian arrow poison - now used in channels open, less Ca++ enters to catalyze the
anesthesia. binding of vesicles to the surface membrane.
b) Repolarizing agents: biquartenary ammo- Hence less ACH is released. The disorder may
nium salts. These resemble acetylcholine. They be transferred passively (via plasma from
are agonists that initially produce depolarization patients) to mice. The patients are improved by
and then block the site. They are utilized to pro- plasma exchange or by drugs that increase
duce muscle relaxation during general anesthesia acetylcholine release. Treatment of the underly-
and during mechanical respiration. ing malignancy may produce some improve-
c) Snake toxins: derived from the venom of ment.
the cobra and krait. These snakes are common 2) Botulism: The toxin of the bacteria
in India, Sri Lanka, Southeast Asia and Taiwan. Clostridium Botulinum produces an acute syn-
The neurotoxic effect produced is often an acute drome of paralysis involving extraocular muscles,
myasthenic syndrome with respiratory paralysis. cranial nerves muscles of respiration and then
As discussed by Watt et al. (1986) and by progressively descending to involve limbs.
Drachman (1986) for some of the toxins, - alpha Cholinergic autonomic junction is also involved.
cobra toxin, the binding is reversible and can be Thus the pupil which is spared in myasthenia
treated with anticholinesterase. For other toxins often is involved (dilated). Anaerobic bacteria
in the group, alpha bungarotoxin from the that may contaminate improperly canned food
Taiwan Krait, the binding is less reversible and or preserved meat produce the neurotoxin.
the effects of anticholinesterase less consistent. Clusters of cases bring this problem to alteration
Some snake venoms also contain toxic agents the attention of public health officials. Many
that act at the presynaptic region (B. bungaro- cases are fatal. In infants and some adults, the
toxin of the krait). bacteria itself may be present in the gastroin-
1) Eaton-Lambert (or Lambert-Eaton) testinal tract or in a wound producing the toxin.
Syndrome: The patient usually an adult has pre- (See Bartlett 1986). The toxin binds rapidly to
dominantly proximal limb weakness which may cholinergics nerve endings and blocks the quan-
be progressive but which fluctuates. In contrast tal release of acetylcholine. Once the toxin
to myasthenia, a) bulbar ocular and respiratory enters the nerve ending, the available therapeu-
muscle involvement is not common. b) Exercise tic antitoxin if administered has little action. The
improves the weakness. c) Repetitive stimulation flaccid paralysis then is often long lasting (see
of the motor nerve produces an incremental Chia et al. 1986).
response in the muscle action potential. 3) Antibiotics: The aminoglycoside antibi-
Most patients with this disorder have an otics: neomycin, streptomycin, and kanamycin
underlying malignancy, most often a small cell act to interfere with the quantal release of acetyl-
carcinoma of the lung. The neuromuscular syn- choline. In most patients this presents no signif-
icant clinical problem. When blood levels are
high due to high dosage or renal failure and
when the patient has myasthenia or a subclinical
myasthenia. There may be the presentation of
an acute paralysis. Most often there is an associ-
ated factor of anesthesia and the patient fails to
regain normal ventilation after anesthesia has
been discontinued. The effects may also be seen
with another type of antibiotics.
4) Spider venom: Black widow. This toxin
produces rapid release of quanta of acetylcholine
storage vesicles. The clinical syndrome is char-
acterized by severe muscle contraction followed
by paralysis.
CHAPTER 7
Spinal Cord: Structure and Function
Since the spinal cord is the best-understood speak, then, of gray matter, which contains cell
and least complex of the major elements of the bodies and synapses relating to the sensory and
central nervous system, it is appropriate to begin motor activities of the segment, and of white
the discussion of the eNS with it. The spinal matter, which contains axons running to and
cord has two fairly distinct functions. It conducts from the brain.
action potentials to and from the brain and it Each spinal cord segment has four nerve
relates to "its" segment. roots attached to it (Fig. 7-1). Each root is made
The spinal cord is segmented, one segment up of many nerve bundles entering the body of
per vertebra, and in the less complex nervous sys- the cord almost continuously. The two anterior
tem of fish, the region of the body relating to roots, which carry axons out of the spinal cord to
each segment is a cylindrical band the width of innervate muscles, are known as motor roots.
the vertebra. Into this spinal cord segment flows The two posterior roots carry sensory informa-
all of the sensory information from the body seg- tion into the spinal cord. Since man stands ver-
ment: information on pain, temperature, and tically, we refer to posterior and anterior; in ani-
position of the muscles, touch, and vibration. mals, dorsal and ventral. The cell bodies of all of
The axons that innervate the muscles of that the sensory fibers are in the posterior root gan-
body segment have their nuclei in the spinal cord glion. Damage to the right anterior root will
segment. paralyze motor units on the right side of the
In the human there is only a general rela- body. Damage to the left posterior root will
tionship between the sensory segments and mus- interrupt all modalities of sensation from a small
cles innervated by the same segment of the cord. region on the left side of the body. The roots
The size and shape of the regions vary consider- join just before they leave the spinal canal,
ably, but the principle remains the same - that of through the intravertebral foramen, and form a
relating, in sensory reception and motor control, single spinal nerve.
to a delimited region of the body. At each seg-
mental level, incoming sensory information con- GROSS ANATOMY
nects, in a stereotyped manner, to motor out- The gross anatomy of the spinal cord is illus-
flow. The knee jerk reflex and the reflexive with- trated in Figure 7-2. The cord runs through the
drawal from pain are examples of segmental spinal canal of each vertebra, as is shown in
spinal cord activity.
In addition to relating these functions to spe- Posterior fun culus
IS~"i' g,"gl~"
Posterior root
cific regions, the spinal cord processes incoming
sensory information and sends some of it on to
the brain. This is a second and basically distinct
function of the spinal cord: conduction to and
from the brain. These two functions are anatom-
ically separated. Inspection of a cross section of
spinal cord shows white columns surrounding a
butterfly-shaped interior gray column (Fig. 7-1).
The myelin sheaths of the thousands ofaxons
running up and down in the white matter, the
dorsal, lateral and ventral funiculi, produce the
white color. The thousands of cell bodies in the Figure 7-1. The posterior and anterior roots in rela-
center give that region a gray appearance. We tion to the gray and white matter of the spinal cord.
7-2 CHAPTER 7
ura Arachnoid
Pia
Figure 7-3. The relationships of the vertebral column,

the meninges and spinal cord.
thoracic, 5 lumbar, and 5 sacral spinal cord seg-

ments. They are shown in relation to the verte-
bral column in Figure 7-2. There are 7 cervical
vertebrae; the C8 in Figure 7-2 is the eighth cer-
vical spinal nerve that arises from the anterior and
posterior roots of the eighth cervical spinal cord
segment. The eighth cervical nerve emerges
below the seventh cervical vertebrae and above
the first thoracic vertebrae. The spinal nerves are
always named for the spinal cord segment of ori-
gin. The intervertebral disk and foramen (Fig 7-
5) are normally named by the vertebrae above
and below, i.e., L4, 5 disk; L5, Sl foramen.
Figure 7-2. The lateral aspect of the spinal cord During development and growth, particular-
exposed within the vertebral canal. The spinous ly intrauterine growth, the vertebral column
processes and the laminae of the vertebrae have been grows faster than the spinal cord it contains so
removed and the dura mater has been opened longitu- that, in the adult, the spinal cord does not extend
dinally. (From Clemente, C. (Ed) Gray's Anatomy,
the length of the vertebral column (Fig 7-2). As
Philadelphia, Lea & Febiger,198S.)
a result, the spinal roots run interiorly before
Figure 7-3, and is protected by a number oflay- they leave the spinal canal. The spinal cord ends
ers of meninges. The pia mater is closely adher- at the first or second lumbar vertebra, and below
ent to the cord. Cerebrospinal fluid occupies the this level the spinal canal contains only spinal
subarachnoid space. The arachnoid lies snugly roots. This mass of roots reminded early
against the thick, tough dura. The spinal dura anatomists of a horse's tail, so it was named
forms a protective tube beginning at the dura of cauda equina. The nerve roots run through the
the skull and tapering to a point in the region of subarachnoid space, which is filled with cere-
the sacral vertebrae. Between the dura and the brospinal fluid. When a needle is inserted
vertebrae lies the epidural space, usually filled through the space between the fourth and fifth
with fat. The denticulate ligaments anchor the lumbar vertebra (Fig 7-4), the point penetrates
spinal cord to the dura. the dura and pushes aside the spinal roots. If the
The spinal cord and, more importantly, the needle were inserted above L2 there would be
spinal roots, are named in relation to the verte- danger of damaging the spinal cord. Samples of
bral column. In humans there are 8 cervical, 12 cerebrospinal fluid can be taken through this
SPINAL CORD: STRUCTURE AND FUNCTION 7-3
~~:-- Subarachnoid space
First lumbar
vertebra
A 8
Figure 7-4. The technique of lumbar puncture. (From House and Pansky: A FUnaWnal Approach to
Neuroanatomy. New York, McGraw-Hil~ 1960.
needle; pressure can be measured or anesthetic tion, also form the white matter.
agents or radio-opaque dyes (as in Fig 7-4) A section of the cervical cord contains senso-
injected. ry fibers running up to the brain from the tho-
The anterior and posterior roots join to form racic, lumbar, and sacral sections. It also contains
a spinal nerve (Fig 7-1) just before leaving the motor fibers running down to innervate motor
vertebral canal through a recess in the posterior axons of the thoracic, lumbar, and sacral sections.
process of each vertebra as shown in Figure 7-5. The white matter of a section of the lumbar cord,
The canal, the intervertebral neural foramina, is however, only contains fibers to and from the
only a little larger than the nerve so that any
swelling of the nerve or diminution of the diam-
eter of the canal will pinch the nerve. It is not
uncommon for the intervertebral disc to rupture
posteriorly or laterally and press on a spinal nerve
as it exits. The very intense pain this pressing
causes is referred to the area of the skin where the
nerve began. Frequent sites where the nerve
roots are pinched are the intervertebral foramina
between 12 and S1, which give rise to the sciat-
ic nerve. The pinched nerve gives the patient the
impression that a hot knife is being dragged
along the posterior aspect of his calf
Cross-sections.
The relative amounts of white and gray mat-
ter vary with the spinal cord level (Fig 7-6).
White matter decreases in bulk as the sections are
further from the brain. Motor tracts from the
brain leave the white matter to enter the gray
matter and synapse with motor neurons. Figure 7-5. An MRI of a normal spinal cord in the
Sensory fibers entering the cord, section by sec- spinal canal. Sagittal section.
7 -4 CHAPTER 7
lumbar segments inferior to it and the sacral seg-

ments. The white matter columns have the
shape of thin pyramids with their bases at the C.l. Th.8.
foramen magnum and their tips at the last sacral
section.
,:·"
The situation in the gray matter is quite dif- Th.l!.
G
ferent. Since the gray matter innervates a seg- C.~.
ment, the size of the gray matter (the number of
cells it contains) is related to the complexity of '~" ...~-..
. ' , L.S.
the segment. The hand, for example, is inner-
••
'/ '
vated by cervical segments 6, 7 and 8 (C6, C7 0.5.
and C8) and the first thoracic segment (Tl).
S~.
The hand has the highest concentration of sen-
sory receptors of any region of the body. All of
C.B.
these receptors send their axons into C6 to TI Coe.
where they synapse, thus increasing the girth of
the posterior gray matter. The muscles of the
hand can carry out very fine and intricate move- Th.£.
ments. They are innervated by nerves having
their cell bodies in the gray matter of C6-Tl.
Such movements require many motor nerves Figure 7-6. Typical spinal cord cross sections. (From
and many cell bodies in the anterior gray matter. Gross, G.M. (ed.); Gray's Anatomy. Philadelphia, Lea
Consequently, the cord is enlarged at C6-Tl. and Febiger.
The situation is much the same in the lumbar served by the cord segments. The muscles
region. Sensory input from and motor output to underlying these areas have essentially the same
the leg is complex and the gray matter is large. innervation. More detailed areas are shown in
The thoracic and sacral segments, on the other chapter 8.
hand, have very small gray matter areas since they
SEGMENTAL FUNCTION
innervate only a few muscles and receive relative-
ly uncomplicated sensory messages. Anterior hom Cells
Segments can be recognized, then, by the The final effector cell of the spinal cord, the
amount of gray and white matter relative to the anterior hom cell (Fig. 7-8) is probably the best
whole cross section. In the lower cervical seg- place to begin a discussion of the segmental func-
ments the section is large, oval, and white matter tion of spinal cord segments. The extensive den-
and gray matter are nearly equal. The thoracic dritic tree allows upwards of 20-50,000 individ-
segments have much more white matter than ual synaptic areas or knobs while the large cell
gray matter and the shape of the gray matter, a body may have another 1-2,000 synaptic knobs.
thin H, is very characteristic. The lumbar seg- Incoming axons may have more than one synap-
ments have more gray matter than white matter, tic connection and hence exert greater control.
and the sacral segments are very small and have Each anterior hom cell gives rise to one large (8
much more gray matter than white matter. The to 12 _m) axon, called an alpha motor neuron,
segments can also be recognized by the shapes of which innervates a motor group or unit made up
the gray matter. A careful review of Figure 7-6 of 10 to 200 individual muscle fibers. There is
and Spinal cord Figures 1-4 in descriptive atlas only one motor end plate on each muscle.
should provide a basis for recognizing the seg- Therefore, for a motor group to contract, the
mental levels of spinal cord sections. The area anterior hom cell on the proximal end of the
of the body which sends sensory fibers into a axon must fire an action potential. The muscle
given spinal cord segment is called a dermatome. group is chained to its anterior hom cell. This
These have varying shapes and sizes. Figure 7-7 anatomical relationship is often called the final
may help you to remember the general area common pathway. Activation of a specific ante-
rior hom cell precedes activity of a motor group.
There are many ways to activate this anterior
hom cell, many thousand axons synapse upon it
and its extensive dendritic tree.
A
Figure 7-8. A moror neuron from the cervical spinal
cord of a human with prominent Nissl
substance(rough endoplasmic reticulum), AAThionin
Stain <X 75>.
Neurons in the anterior hom can be divided
into medial, and lateral groups (Fig. 7-9).
1. The medial nuclear division is divided into
posterior medial and anterior medial groups.
The posterior medial nucleus is most prominent
in the cervical and lumbar enlargement. The
medial nucleus innervates the muscles of the axial
skeleton.
2. The lateral nuclear division innervates the
appendicular musculature. In the thoracic
region the intercostal and associated muscles are
innervated by this region. In the cervical and
lumbar enlargement, these nuclei become espe-
cially prominent and are divided into individual
columns of nuclei (Fig. 7-9) and these nuclei
columns include anterior, anterior lateral, acces-
sory lateral, posterior lateral and retroposterior
lateral. These nuclei are represented functionally
so that from medial to lateral one passes from
midline spine, to trunk, upper and lower limb
girdle, upper leg and arm and lower leg and arm
to hand and foot. The most lateral nuclear
groups innervate the muscles in the hand and
foot.
3. The preganglionic autonomic nuclei lie in
B c L5
the intermediolateral column, a prominent later-
al triangle in the gray matter (Fig 7-6; Th.2).
Figure 7-7. Key dermatome boundaries in man. A.. There are two distinct groupings. The interme-
Anatomical Position. B-anterUJr surface and c-poste- diolateral nucleus from C8 to L2 is the origin of
nor surface. From Zimmerman J and JlUObson S, the preganglionic sympathetic neurons which
Gross Anatomy, Little BrllWn 1990. synapse again either in the sympathetic trunks or
7-6 CHAPTER 7
in remote ganglia. The sacral nucleus in S2 to S4 in the posterior root ganglion. The axons can be
is the origin of preganglionic parasympathetic divided into many classes by the sensory modal-
fibers that run to several ganglions in the walls of ity they carry. As far as we know, each axon car-
the pelvic organs. ries information about only one modality, such
REFLEXES OF A SINGLE MUSCLE as pain. The intensity of the pain or other sensa-
All of the sensory axons entering the posteri- tion is coded as action potential frequency. Later
or roots are bipolar cells having their cell bodies in this chapter, the various modalities will be dis-
Posteromedial column
II Anteromedial column
I Central column
Retroposterolateral
~-+---- column
ni
lii
1il
01:
lii E
-:;,
Ul_
00
0.0
Retroposterolateral
column
I I
I I
I I
I I Central column
I
I I .
Anteromedlal column
posteromedial column
Figure 7-9. Functional localization within the anterior horns. (From Bossy: Atlas of Neuroanaromy.
Philadelphia, W.B. Saunders, 1970.)
SPINAL CORD: STRUCTURE AND FUNCTION 7 -7
cussed in detail. For the present, two modalities one stretched. The reflex continues for as long as
will suffice for examples: muscle stretch and pain. the muscle is stretched (Fig. 7-12).
Pain is carried by very small axons, many of them There are stretch reflexes in all muscles, but
unmyelinated, which have high thresholds and they are much stronger in the antigravity muscles,
slow conduction velocities. The stretching of particularly the leg extensors. In addition to the
muscles, on the other hand, leads to a barrage of familiar knee jerk from the quadriceps group,
action potentials in large, heavily myelinated brisk stretch reflexes can be elicited from the
nerve fibers. These axons have low thresholds ankle (the Achilles tendon), the jaw, and the
and rapid conduction velocities. biceps and triceps muscles in the arm.
Stretch Reflexes. The classic stretch reflex is Although the reflex loop is completed within
the knee jerk, produced by tapping the patellar a few segments of spinal cord, the magnitude of
tendon. This simple involuntary response is such the response can be drastically altered by input
a familiar part of the physical examination and from other levels. For example, grasping the
has been used so frequendy in medical humor hands together and pulling will gready enhance
that precise description seems unnecessary. This the knee-jerk response (reinforcement). As will
simple test can give the astute examiner many be discussed later, the magnitude or briskness of
clues to the function and dysfunction of the ner- the response can give many clues to pathological
vous system. processes.
The knee jerk is described quantitatively by
Figure 7-10, which is taken from the early work of AXON
the great English physiologist Sir Charles LATERAL
Sherrington. As the figure indicates, after a brief

stretch, the muscle contracts with a delay of
about 10 msec. It can readily be shown that this
is a response mediated by the spinal cord. When
the nerve to the muscle is cut, the response is
abolished. When the spinal cord is severed from
the rest of the nervous system, the response
remains.
Figure 7-11. The pathway for the monosynaptic
stretch reflex.
Reflexive Response to Pain. The majority of

spinal cord responses have more flexibility than
the monosynaptic response, as can be seen in the
Figure 7-10. A brief stretch reflex recorded from the
quadriceps tendon. The initial smal4 sharp response
reflex withdrawal from pain. This is one of the
is the quick stretch which initiated the large response. most important of the protective reflexes of the
The time marks are 20 msec apart. (From Balli!, et spinal cord. The flexors are activated and the
al.: Proc. Roy. Soc., B98, 589, 1925.) injured limb withdrawn. Figure 7-12 shows the
responses of the ankle flexor muscle, the tibialis
anterior, to stimulation of the nerve branches
The pathway of this response is very simple leading to the skin - branches which contain pre-
(Fig. 7-ll) . The axon from the stretch receptor dominandy pain fibers. It can immediately be
runs into the posterior hom, and while it branch- seen that the combined response is considerably
es many times in the gray matter, it eventually greater than the sum of the two. This augmen-
synapses direcdy on the cell body of the anterior tation of response is known as facilitation and is
hom cells of the muscle stretched. The stretch one of the most basic integrative responses of the
reflex is often referred to as a monosynaptic nervous system. The reaction is graded in
reflex. The only muscle which contract is the response to the intensity of the stimulus and the
7 -8 CHAPTER 7
area stimulated. (Fig. 7-/4). The tension is maintained until the

The mechanism of facilitation is shown in biceps tendon is stretched; then the tension
Figure 7-13. Stimulation of nerve A excites two abruptly drops. This diminution or abolition is
anterior horn cells to threshold. Two more are called inhibition. Inhibition is, together with
excited in a subthreshold manner; they do not facilitation, the keystone of the integrative action
fire an action potential. Nerve B stimulates two of the spinal cord and probably the entire ner-
totally different anterior horn cells to threshold vous system.
and the same two to just below threshold. The pathway for the inhibitory response is
Simultaneous activation of nerves A and B brings shown in Figure 7-15. A collateral (branch) of the
all six cells to threshold and elicits a greater ten- stretch receptor nerve from the biceps muscle
sion from the muscle. runs to an interneuron, which in turn synapses
on the anterior horn cells of the quadriceps. As
far as we know, all inhibitory responses are car-
ried out through at least one interneuron. The
endings of one nerve, such as the stretch recep-
tor nerve, all have the same effect, either facilita-
tion or inhibition. For the nerve pathway to
B exhibit the other type of function, an interneu-
ron must intercede.
The pathway for the inhibition shown in
Figure 7-14. Trains of action potentials from the
stretch receptors of biceps enters the anterior
root and stimulate biceps anterior horn cells and
Figure 7-13. A mechanism ofsummation.
via an interneuron, inhibits the quadriceps mus-
Stimulation of nerve A fires the solid anterior horn
cells and excites the clear cells. Stimulation of nerve cle.
B excites the lined cells to fire and excites the clear
cells. Stimulation of both nerves fires all of the cells. I
RECIPROCAL INNERVATION OF A
JOINT
l'
When the biceps femoralis muscle contracts, S::':-~-iB----i-----;----------:;--
the opposing muscle, the quadriceps, is stretched
because both muscles are connected to the tibia.
Figure 7-14. Inhibition of a streteh reflex (M) in an
The quadriceps group has a strong stretch reflex
extensor muscle, quadriceps, by streteh, at B, of a flexor
which is not elicited when the biceps femoralis muscle, biceps. T is the applied streteh to the extensor
contracts. When the quadriceps tendon is tentUJn that initiated the streteh reflex. (From Liddell
stretched, stretch reflex tension develops and Sherrington: Proc. Roy. Soc., B97, 267, 1925.)
Figure 7-12. Tension response in the tibialis anterior to stimulation of the skin of (A) the ipsilateral foot, (B)
ipsilateral calf, or (C) both. Stimulation of both sites results in a tension response greater than the sum of the indi-
vidual responses: summation. Spinal rabbit. (From unpublished experiments ofBoA. Curtis, M.e. Fleming, and
E.M. Marcus.)
SPINAL CORD: STRUCTURE AND FUNCTION 7 -9
ed, the record in Figure 7-16 is obtained by stim-

ulating a cutaneous nerve to mimic pain. When
the nerve is stimulated at high voltage, many
small pain fibers are stimulated. The response in
the anterior horn cell can be the firing of an
action potential, as in the lowest record. This
response is the electrically recorded counterpart
of the reflexive withdrawal from a painful stimu-
lus, as shown in Figure 7-13. When the stimulus
intensity is reduced, upper records; intensity is
reached when no action potential is produced,
yet the cell body still responds. The response is
Figure 7-15. The pathwayfor the inhibition shown in a subthreshold depolarization of the anterior
Figure 7-14. Trains of action potentials from the stretch horn cell called an excitatory postsynaptic poten-
receptor of biceps enters the anterior root and stimulate tial, abbreviated EPSP. This response brings the
biceps anterior horn cells and, pia an interneuron, anterior horn cell closer to threshold, that is,
inhibits the quadriceps anterior horn cells. closer to firing an action potential that would
MEMBRANE BASIS OF INTEGRATION cause contraction of a motor group. The EPSP is
When a microelectrode is inserted into the localized to the cell body and dendrites. The
anterior horn of the spinal cord, the tip, with axon is unaffected. In contrast to the action
luck, eventually penetrates an anterior horn cell. potential, it is a graded response.
This penetration is signaled by the abrupt jump The EPSPs can add up until threshold is
of voltage between the tip and the extracellular reached and an action potential is fired as is
fluid from 0 to -70 mV. This intracellular work shown in Figure 7-17. Note that the second
was pioneered by Sir John Eccles and his collab- EPSP in A is larger (greater depolarization) than
orators and is discussed at length in his book, The the first. The effect of the first had not yet ''worn
Synapse. In this experiment the anterior roots are off" and the second could add on top of it. In B
cut to prevent action potentials, generated by the the second EPSP follows sooner and adds up to
stimulator, from traveling up the motor axons a threshold depolarization, initiating an action
antidromatically (backwards). Stimulation, then, potential.
mimics only sensory input. Low voltage stimu- This is the basic mechanism of facilitation.
lation activates only the larger, stretch receptor The two classic types of facilitation, temporal and
axons. The extracellular recording from the pos- spatial, are the same in terms of a membrane
terior root gives a signal proportional to the response: the EPSP's add up. Spatial response
number ofaxons stimulated. After the cell is refers to the EPSP's generated as a result of the
penetrated it must be identified; it is almost cer- activation of two different nerves as Figure 7-13.
tain to be an anterior horn cell because of their Temporal summation, as illustrated in Figure 7-
large size. Other cell bodies and glia cells are so 20, means summation in time; its membrane
small that penetration is very unlikely. The des- basis depends upon the time course of the EPSP.
tination of its axon is determined by using the The membrane repolarizes slowly following the
stretch reflex pathway. Each muscle nerve is initial rapid depolarization of an EPSP and a sec-
stimulated in turn until a short latency, all or ond EPSP can add upon the first. Frequently
nothing; spike (action potential) response is this "added boost" will bring the cell membrane
obtained. This is the equivalent of a monosy- to the threshold for firing an action potential in
naptic stretch reflex. A spike response recorded the axon.
from an anterior horn cell is the counterpart of Delay.
muscle tension. There is a delay of approximately 0.8 msec
Excitatory Postsynaptic Potential, EPSP. between the arrival of an action potential from a
When a flexor anterior horn cell has been locat- stretch receptor axon and response of an anterior
7-10 CHAPTER 7
horn cell. This delay and other features strongly

support chemical transmission at the synapses on
the anterior horn cell. The identity of the trans-
mitter is still not entirely clear although there is a
great deal of evidence to suggest that L-gluta-
mate and L-aspartate are the transmitters for
many of the excitatory synapses in the spinal
cord.
These transmitters destroy the selective per-
meability of the postsynaptic membrane, just as
acetylcholine does at the myoneural junction.
The equilibrium potential is then zero millivolts.
The membrane never reaches zero under the
influence of excitatory transmitters since they are
rapidly removed. At the anterior horn cell mem-
brane, however, unlike the myoneural junction,
the amount of excitatory transmitter released is
not always sufficient to depolarize the cell body
to threshold.
Inhibitory Postsynaptic Potential, IPSP.
When the nerve leading to the quadriceps mus-
cle is stimulated, the membrane of a flexor (an
antagonist) anterior horn cell hyperpolarizes, as
shown in the recordings in Figure 7-l8. This
hyperpolarizing response called an inhibitory
postsynaptic potential (IPSP), moves the mem-
brane further from threshold, making it more
Figure 7-16. EPSP's: The upper trace ofeach pair is

an intracellular record from a biceps anterior horn B
cell. The lower trace ofeach pair is the action current
from the posterior root and is proportional to the
number ofsensory axon! firing. As the number of
axon! firing increases, the depolarization (an EPSP)
increases until threshold for the anterior horn cell is
reached and an action potential fires. The bottom Figure 7-17. The summation of two EPSP's to fire an
pair of records is the intracellular version of a stretch action potential. In B the second EPSP followed soon-
reflex. The rest of the action potential of the lower er and added upon the first to achieve a threshold
record is off the scale. The average resting potential is depolarization, initiating an action potential.
- 70 m V. (From Brock, Coombs, and Eccles: J. Physiol., (From Brock, Coombs, and Eccles: J. Physiol., 117, 431,
117, 431, 1952.) 1952.)
...
A A B
iEZ: '" .
Figure 7-18. The response (an IPSP) of a biceps ante-

rior horn cell to stimulation of the quadriceps nerve.
The upper trace of each pair is the action current from
the posterior root; the lower is the intracellular record.
The greater the number ofsensory RXOns firing the
more negative and longer lasting is the IPSP. (From
Coombs, Eccles, and Fatt: ]. Physiol., 130, 396, 1955.)
difficult to fire an action potential and is a post-
synaptic inhibition. The IPSP is the membrane Figure 7-19. Summation of an IPSP and an EPSP.
equivalent of inhibition. As noted earlier, inhibi- The lower trace of each pair is an intracellular
recording from a biceps anterior horn cell. The upper
tion is effected through an interneuron (Fig. 7-
trace is the action current in the posterior root. In A
14). the nerve to the biceps was stimulated and an action
The transmitters substances responsible for potential ef/oked; this is the intracellular equivalent of
the IPSP include GABA and glycine. They a stretch reflex. In B the nerve to quadriceps was
specifically increase the chloride conductance of stimulated and an IPSP was ef/oked. In C the two
the anterior horn cell, typically for hundreds of were stimulated 45 msec apart and a spike resulted.
msec. The membrane potential at rest is -74 mV In D the two were stimulated 2.2 msec apart and no
indicating there is considerable sodium conduc~ action potential resulted; the IPSP generated by the
tance in relationship to potassium and chloride quadriceps stimulus inhibited the biceps anterior horn
cell. In C the hyperpolarization effict of the IPSP had
conductances. The calculated values for potassi-
declined by the time the second nerve was stimulated.
um, chloride, and sodium equilibrium voltages (From Coombs, Eccles, and Fatt: ]. Physiol., 130 396
are: VK = -90 mY, VCl = -80 mV and VNa = 1955.) , ,
+45 mV. A large increase in chloride conduc-
marized in Figure 7-19 along with some of the
tance will result in a membrane potential of -80
neurotransmitters implicated in their activation.
mV and this is the equilibrium potential at the
All of these ionic channels act on a time scale of
height of the IPSP.
milliseconds to seconds.
Summation of IPSP's and EPSP's can occur
The fast EPSP channel (A) is very similar to
as shown in Figure 7-19. The microelectrode is
the ACh channel at the myoneuronal endplate.
recording from an anterior horn cell innervating
It opens to all small ions and depolarizes rapidly
biceps (a flexor). When the stretch receptor
and decisively. The somewhat slower IPSP Cl-
nerve ~om the biceps is stimulated (Fig. 7-19A),
channel (B) is equally important. Selective
an actton potential fires; this is the stretch reflex.
increase in PK (C) usually occurs after action
When the nerve to the quadriceps (an opposing
potential firing in the axon and is thought to be
extensor) is stimulated (Fig. 7 -19B), a large IPSP
me~ated by increasing Cai, possibly Ca entering
is recorded; this is the inhibition of a stretch
dunng the very positive voltages of the action
reflex of an opposing muscle. When the two are
potential. All of these mechanisms depend on
stimulated 45 msec apart (Fig. 7 -19C), the cell
inc:easing ionic permeability (decreasing cell
fires. When the delay was reduced, the mem-
resIstance) and to rapidly changing intracellular
brane depolarizes but does not reach threshold
ionic concentrations which must be restored by
(Fig.7-19D).
energy expenditure.
SYNAPTIC MECHANISMS The next two mechanisms (D,E) rely on
decreases in permeability and are more energy
The dendritic tree and cell bodies of spinal
efficient.
cord neurons contain a varied collection of
The active transport of unequal numbers of
receptor mediated ionic channels that are sum-
7-12 CHAPTER 7
ionic changes can result in changes in membrane cell body of an anterior horn cell are expressed
voltage; 3Na/2K and 3Na/Ca are examples. within the anterior horn cell as depolarizations
The relative importance of this electrogenic (EPSP's, a very few of which will, by themselves,
mechanism is not clear. fire the cell) and hyperpolarization (IPSP's,
Intermediate term changes in neuron base- which inhibit firing). The membrane potential
line characteristics (more or less excitable) are of the cell is constantly changing under the influ-
produced by altering the number of active chan- ence of these two types of input. Whenever the
nels on the cell surface. For example, in response membrane potential reaches the firing level of
to noxious stimuli 5 HT is co-released from sen- the axon (-55 mY), action potentials are gener-
sory a nerve which increases the C-AMP level of ated with a frequency proportional to the depo-
the interneuron causing rapid inactivation by larization past threshold. For the purposes of
dephosphorylation of potassium channels. transmission, depolarization, more positive than
Whenever an action potential enters the presy- threshold, is coded as frequency. When these
naptic region, the depolarization is prolonged action potentials bombard another cell they are
because the normal increase in PK that hastens once again decoded into changes in the mem-
repolarization is lacking. Consequently, the volt- brane potential of that cell body.
age gated Ca channels remain open longer allow- It is not clear why the EPSP's and IPSP's
ing greater Ca entry and hence greater transmit- recorded from the cell body are of different
ter release. This augmented response may last amplitude. This may be due to differences in the
for several hours after 5 HT liberation. The key amount of transmitter released or may be due to
to specificity is both the type of receptor and the the location of the synapse on the cell. Since the
enzyme chain-second messenger system linked dendrites, like the cell body, conduct potential
to it. Receptors for Epinephrine & disturbances in a decremental, cable fashion,
Norepinephrine increase the number of phos- synapses close to the cell body will have a greater
phorylated, hence active, Ca channels. influence on the membrane potential.
Enhancement of synaptic transmission lasting It is possible to show inhibition of firing of
one or more days occurs by increasing the anterior horn cells without any change in the
amount of neurotransmitter released from each resting membrane potential; no IPSP precedes
synaptic vesicle. Increase in synaptic vesicle con- the inhibition. The inhibition is thought to take
tent presumably reflects changes in gene expres- place presynaptically, either at a nearby unidenti-
sion that could last a very long time and might be fied interneuron or more probably, in the junc-
the synaptic basis of long-term memory. This tion region between the axon and the dendrite.
mechanism alters the importance of existing We will discuss this type of inhibition later in this
synapses. A synaptic junction that previously chapter.
needed the cooperative effort of 10 other synap-
STRETCH RECEPTORS
tic junctions to depolarize the cell body to
threshold can now do so alone. The Muscle Spindle. In the previous discus-
The only other major variants seen when sion of spinal reflexes, reference to stretch recep-
recording from anterior horn cells are long-last- tors was very general. The major dynamic
ing (30 to 40 msec) responses. These are stretch receptor is the muscle spindle. This is a
thought to involve many interneurons possibly bundle of modified muscle fibers that lie parallel
arranged in a circular path so that an action to the rest of the muscle fibers. Its structure is
potential "chases its tail" around the circuit for shown in Figure 7-20; it is composed basically of
several revolutions, stimulating the anterior horn three to five small muscle fibers each containing
cells on each revolution. They may also be pro- a specialized, nonstriated region in their center.
duced by long acting neurotransmitters co- The striated ends of the muscle fibers can con-
released from the same axons that release the tract and are innervated by small, gamma motor
shorter acting neurotransmitters. neurons. These gamma motor neurons have cell
Slow Potentials. Action potentials in axons bodies in the anterior horn, just as do the large
making synaptic contact with the dendrites or alpha fibers that innervate the bulk of the muscle.
flower-spray endings on either side of the annu-
lospiral ending. These axons rise to the ipsilater-
al cerebellum, carrying information on "uncon-
scious position sense". They apparently play no
part in the stretch reflex.
Gt-oup I ++++Ganvno lor
The basic function of the stretch receptor is
crfferonl ---f--H to fire when the muscle is stretched. The
Gt-oup II response of the annulospiral ending is of short
crfferonl
latency. The frequency of firing is at first high; it
I )o;o..{;d-\----"'::' Secondory endings then slows down, but never adapts completely.
molor
Nuclear chain fiber The Gamma System. The function of the
~.r1'o~- Nud_ bag fiber
intrafusal muscle fibers is more difficult to under-
~-- Primary endings stand. The first function is to keep the muscle
spindle tight as the extrafusal fibers contract·
.
FIgure 7-26 shows this. At the rest length (A)
'
the spindle is tight. Any further stretch will set
up a volley of action potentials in the la sensory
nerve that will lead to a stretch reflex; contraction
Skel.lal muscl. of the extrafusal fibers. When the extrafusal
fiber
fibers contract because of firing in the alpha
motor neuron alone, the spindle goes slack (B)
and is no longer responsive to stretch. Indeed
the muscle would have to be pulled out slightly
further than the rest position for the spindle to
react. To rectifY this situation, the gamma motor
Figure 7-20. A muscle spindle. (From Gardner:
Fundamentals of Neurology. Philatklphia, W.B. neuron fires, thus contracting the intrafusal fiber,
Sautukn, 1968.) and the spindle is tight again (C). Through the
mechanism of the gamma motor neurons the
The small muscle fibers in the spindle are called
sensitivity of the stretch reflex is maintained
intrafusal fibers, and the large muscle fibers that
throughout the entire range of the limb move-
make up the bulk of the muscle are referred to as
ment. For example, the knee-jerk reflex can be
extrafusal fibers. The extrafusal fibers are primar-
elicited in many positions of the lower leg.
ily innervated by large (8-12 }l) axons. The pat-
Another function of the intrafusal fibers is to
tern is not exclusive and there is some dual inner-
ch:mge the sensitivity of the annulospiral ending
vation; alpha motor fibers to both intra and
(FIg. 7-21). It can easily be seen, in the last col-
extrafusal fibers.
umn, that the response to 20 gm tension or an
There are two sensory nerves which take ori-
equivalent stretch can be drastically altered by
gin from the unstriated center region of the mus-
activity of the intrafusal fiber. Apparently the
cle spindle. The largest, (12 }l) classified la, comes
annulospiral ending reacts to stretch or deforma-
from the center of the sensory region. The
tion whether it is from without, as in stretch, or
unmyelinated ends of the nerve wrap around
from within, as in intrafusal muscle fiber activity.
each of the muscle fibers and are called primary
Probably the most important function of the
or annulospiral endings. From these endings
intrafusal fibers is to modulate contraction of the
arise the action potentials that stimulate the
extrafusal fibers via the stretch reflex. It is clear
stretch reflexes. This axon gives off many types
from Figure 7-21 that activation of the gamma
of collateral within the gray matter of the cord
fibers and subsequent contraction of the intra-
that then travel up and down the cord for sever-
fusal fibers sets up a response in the la sensory
al segments.
fibers which is indistinguishable from the
The second ending gives off a smaller nerve
classified IIa, from specialized, secondary 0; response to stretch (compare response in the
upper right and lower left in Figure 7-22. This
7-14 CHAPTER 7
a: MOTOR NEURON STlt.lII.ATED 'MOTOR NEURON

EXTRAF\JSA1. FlB£RS CONTRACT STIMULATED ALSO
INTRAFUSAL fiBERS
CONTRACT
EXTRAfUSAL
fiBERS
A B c
Figure 7-21. The effect ofgamma activation of intrafusal muscle fibers upon maintenance of "tone" in the muscle
spindle. When just the extrafusal fibers contract (B) the spindle becomes slack and unresponsive to small stretehes.
When both alpha and gamma systems are activated, the spindle is once again taut and responsive to small stretehes.
activation of the Ia sensory fiber leads to con- ing increases its rate of firing and causes reflexive
traction of the extrafusal fibers. This is probably shortening of the extrafusal fibers and shortening
best shown by the accompanying sketches (Figs. of the muscle as a whole, as is happening in C.
7-22). This process continues in D until point E is
The length of A is the equilibrium point for reached. At E the muscle as a whole has con-
the stretch reflex when there is no gamma activ- tracted sufficiently to decrease the stress on the
ity; stretch of this muscle would lead to extrafusal center region of the muscle spindle and reduce
contraction. At A the gamma fiber is suddenly the rate of firing of the Ia fiber to threshold for
activated. During the period B, the intrafusal the stretch reflex.
fibers are contracting, stretching the annulospiral The shortening and subsequent maintenance
ending and altering the sensitivity of the primary of muscle length and, consequently, of the joint
stretch receptor to the dashed line. The Ia end- angle was brought about by a constant gamma
activation (Fig 7-24). The rate of firing of the
gamma system, initiated by the brain, has not
o Qm. • 5Qm 20Qm.
changed during the entire time. The new posi-
~
i::: 0 , I
tion (E) is not affected by the load the muscle
..
.'
II)
Q: 4-6 dI" had to move. If the load was light, the new posi-
e !
tion was reached quickly; if the load was heavy

~ 9-11 .1.1,1 *tlil" MlII~1!
the new position was reached slowly. In any
! !
<Ii
~ 14·16 .Ilt~HU I .td 11111111 WIIN'IIII'I! ! event, the new position was reached and main-
tained without further judgment from the motor
Figure 7-22. The response of an Ia fiber from an centers of the brain.
annulospiral ending to streteh and gamma activity.
This loop will provide good length control if
Notice that the number ofaction potentials fired
increases with streteh (weight) and gamma activa- movement is very slow. If movement is faster,
tion. The downward deflections are stimulus artifacts this simple type of loop will begin oscillating
ofgamma stimulation. (From KujJler, et al.: J. because of nerve conduction and synaptic delays.
Neurophysiol, 14,29,1951. As the muscle is contracting, its length at t=O is
23A
ACTION
r:::'=\, 1-#----~-----'TMRESJjOUl
I. tII~"" fOll
STRETCH RUUlC
IIISClE LENGTM
Figure 7-24. The effect ofgamma activation upon

maintenance of "tone" in the muscle spindle.
sent up the sensory nerve and arrives at the spinal
cord at t+15 msec. After a 5 msec delay the rate
of firing of the anterior horn cell varies. This
variation arrives via the motor nerve at the mus-
cle in another 15 msec. Thirty-five msec have
elapsed, the muscle is no longer at its original
23B length and the "correction" is no longer correct.
@ This will lead to a cycle of over corrections
..-I! Astlerotlofft.oof[odecr~'H, around the intended length: oscillations.
I. IMIt "COIII"".. ofll"
,JIJo,,,lh,"""' .. The oscillations can be rectified if the control
-I system is given information on the rate of change
of position, velocity. With this information the
control system in the spinal cord can figure out
where the muscle will be at the end of the delay
l time and make corrections accordingly. Careful
® M' ,J;\r bn ....d..t.dI inspection of Figure 7-21, particularly the right
~.~ Iltlrlll,of. of llitlo I 8 i,
I..... lilrHh04 r" "flo ••• hand column, will show that the firing rate at the
COI!I."I .. oflbcul" oaIflbtn
beginning of movement is faster: there is veloci-
~ ty information in the signal from the stretch
receptor.
The difficulty with the pure gamma stimula-
... tion of muscle activity theory is that recordings
•
® .... "~11"11'. ~ "'I. 'd such as are shown in Figure 7-21 show that the
~.r-- alpha fibers are activated at about the same time

AII~M ~"IC oiIl "I " 11111
"".IIMI r.... "" ...... 1
.'1.1..... ""'1 "flUN'lJ as the gamma fibers, not 30-40 msec later as the
~ ~ theory predicts. Other evidence suggests that
---------------T----------------· muscle movement probably gets started by direct
alpha stimulation and is later reinforced by reflex-
ive gamma stimulation. The termination point
Figure 7-23A. & 23B The role of the gamma system may well be found and maintained mainly
in setting a new muscle length. (Refer to textfor dis-
through the gamma system.
cussion.)
7-16 CHAPTER 7
Let us digress a moment and consider the INTERNEURONS

simplest type of muscle movement - opposing Only a very small portions of the cells of the
the thumb to the palm. Cells in the anterior gray matter of the spinal cord are anterior hom
hom are activated by fibers from the large cells; the vast majority are interneurons - small
descending corticospinal tract, a direct pathway, cells with short dendrites and axons. These cells
of which more will be said later. The intensity of interconnect incoming sensory axons and
stimulation and the number of motor groups descending spinal cord tracts with each other and
activated are determined by the motor cortex. with anterior hom cells.
The motor cortex basically sets the tension that is One such interneuron is the Renshaw cell
to be developed. The distance moved is a func- that must be studied in a somewhat roundabout
tion of the resistance to movement and the dura- fashion. After the posterior (sensory) roots have
tion of the stimulus. The extent of movement is been cut, stimulation of a muscle nerve (for
visually controlled; when the thumb reaches the example, to the gastrocnemius) will result in
desired position, the motor cortex stops stimu- action potentials traveling back up the motor
lating the anterior hom cells. nerve (antidromic) and entering the spinal cord.
In contrast to this type of movement, which An extracellular electrode records a burst of high
requires constant attention if the desired position frequency action potentials from the Renshaw
is to be achieved, many of our movements, such cell in response to a single volley of action poten-
as walking, require little attention beyond the tials (Fig. 7-26). Electrophoresing dye from a
decision to walk along the sidewalk. Most of us recording electrode has localized these cells.
can even chew gum at the same time! These After a Renshaw cell has been characterized phys-
movements are probably carried out through iologically by its response to antidromic stimula-
mediation of the gamma system, which allows tion, dye is deposited at the tip of the electrode
the brain to set a desired position and then for- by passing current through the microelectrode.
get about it. Compare, then a corticospinal sys- An example of this widely used technique is
tem, which produces a force, and a second sys- shown in Figure 7-27. When many such dots are
tem, the gamma system, which produces a new placed together on a spinal cord cross section
position. Although it is not completely clear at (Fig. 7-27) they all appear in the most anterior
this time, it would appear that the gamma ante- portion of the anterior hom. This is the same
rior hom cells are innervated by descending region in which the axons from the anterior hom
motor tracts other than the corticospinal. This cells branch.
system is controlled by neurons in the brain The firing of anterior hom cells activates the
stem; the reticular formation, the vestibular Renshaw cell with acetylcholine as the neuro-
nucleus and the red nucleus. transmitter. Studies of a Renshaw cell show it to
Golgi Tendon Organs. Golgi tendon
organs are a second type of stretch receptor
found in the tendinous insertion of muscles. It
contains no muscle fiber system. This receptor is I SUPRASPINAL
in series with the muscle fibers and signals ten-
sion via Ib sensory fibers. It is much more sensi-
tive to tension generated by the muscle than to
stretch of the muscle. Activation of the sensory
fibers from the tendon organ causes an inhibition
of the contraction of the muscle. Among the
functions of the tendon organ is to protect the
insertion of the muscle from too great a stress
which might tear the insertion from the bone.
Tension information from the tendon organ is
transmitted to higher centers via both dorsal and
ventral spinocerebellar tracts. Figure 7-25. Major classes of input to Renshaw cell.
remove inhibition from the anterior horn cell 2
in Figures 7-26, 27, 28. The effect of inhibition
of an inhibitory cell is called disinhibition. This
doesn't mean that anterior horn cell 2 will fire,
since that requires a facilitatory stimulus, but it
Figure 7-26. Renshaw cell activity, left hand responses does mean that no inhibition is being applied via
are produced by stimuli to ventral roots conducted that particular Renshaw circuit. This phenome-
antidromically. This activity can be inhibited (rigllt non of disinhibition is quite common in the ner-
hand responses) by (A) a squeeze of the ipsilateral toe vous system.
and (B) by stimulus to the contralateral biceps-semi-
tendinous nerpe. (From Wilson, Talbot and Kato: J. POSTERIOR HORN
Neurophysiol., 27, 1063, 1964.)
Laminar Organization. The posterior horn
be activated by antidromic stimulation of any of contains the entry of the sensory fibers and their
a great many motor nerve fibers; even from dif- rich synaptic connections. Many names have
ferent muscles. These muscles, however, usually been proposed for the regions of the posterior
belong to a single functional grouping, such as and intermediate horns to describe their anatom-
knee flexors or ankle extensors. The effect of ical and physiological variations. In order to clear
Renshaw cell activation upon other anterior horn up this confusion about the terminology of the
cells is inhibitory; it depresses or totally inhibits organization of the gray matter of the cord,
firing. This is shown diagrammatically in Figure Rexed proposed a laminar organization of the cat
7-25. Activity in anterior horn celli will inhibit, spinal cord which has since been extended to all
via the Renshaw cell, anterior horn cell 2. This primates. The gray matter is divided into nine
inhibition is usually to opposing muscle groups. layers with a thin tenth region surrounding the
The Renshaw cell itself can be inhibited by a vari- central canal, Figure 7-28.
ety of pathways, such as squeezing the ipsilateral Lamina I forms the cap of the dorsal horn
toes and stimulating the muscle nerve on the and is penetrated by many fibers. It includes the
contralateral side (Fig. 7-26). Note that in each nucleus posterior marginalis. Many interseg-
case the response to the antidromic stimulation is mental pathways arise from this layer.
much reduced. Lamina 2 corresponds to the substantia
Since the Renshaw cell is inhibitory to ante- gelatinosa. This nucleus extends the entire
rior horn cells, inhibiting the Renshaw cell will length of the cord and is most prominent in the
cervical and lumbar levels. Cells in this lamina
also form intersegmental connections.
Lamina 3 is the broad zone containing many
myelinated axons and receives many synapses
from the dorsal root fibers.
Lamina 4is the largest zone and consists pri-
marily of the nucleus proprius of the dorsal horn.
This nucleus is conspicuous in all levels.
Lamina 5 extends across the neck of the dor-
sal horn and in all but the thoracic region is
divided into medial and lateral portions. The lat-
eral portion consists of the reticular nucleus that
Figure 7-27. Localization of the Renshaw cells by the is most conspicuous in the cervical levels.
method of dye electrophoresis from the recording elec-
Corticospinal and posterior root synapses have
trode. A, The dye spot among the anterior horn cells.
The dye spot, arruw, is an azure blue while the cells are been identified in this lamina.
purple. B, The location of a number of dye spots super- Lamina 6 is a wide zone most prominent in
imposed upon a tracing of a lumbar spinal cord seg- the cervical and lumbar enlargements. In these
ment. (From Thomas and Wilson: Nature, 206:211, levels, it is divided into medial and lateral zones.
1965.) Terminals from the posterior roots end in the
7-18 CHAPTER 7
Motor Neurons to Neck & Trunk
Figure 7-28. Rexed's lamination pattern of the spinal gray matter on the right and the location of ventral horn
cells on the left, Lumbar Section. Myelin Stain,
medial region while descending fiber tracts pro- these cells (alpha motor neurons) form much of
ject to the lateral zone. the ventral rootlets that supply the extrafusal
Lamina 7 includes most of the intermediate muscle fibers. The medial group innervates the
region of the gray matter in the spinal cord. In muscles of the axial skeleton while the lateral
this lamina are found the intermediolateral and group innervates the muscles of the appendicular
intermediomedial nuclei. The nucleus dorsalis or skeleton.
nucleus spinal cerebellar of Clark is obvious in Lamina 10 includes the commissural axons.
C8 through L2 levels. The axons arising from Posterior root fibers. Sensory nerve fibers
this nucleus form the posterior spinocerebellar enter the spinal cord gray matter (Figure 7-28)
tract. In the cervical and lumbar enlargements, by a medial bundle of large, heavily myelinated
this lamina includes many of the internuncials fibers and a lateral bundle consisting of thinly
and the cell bodies of gamma efferent neurons. myelinated and unmyelinated axons. The heavi-
Axons from posterior roots, cerebral cortex and ly myelinated medial bundles convey information
other systems end in lamina 7. Cells in lamina 7 from the large dorsal root ganglion cells subserv-
form tracts that project to higher levels including ing encapsulated somatic receptors (muscle spin-
cerebellum and thalamus. In the thoracic and dles, pacinian corpuscles, Meissner's corpuscles),
sacral regions axons also leave this lamina to form carrying information on touch, position and
preganglionic autonomic connections. vibratory senses. Upon entering the spinal cord,
Lamina 8 in the cervical and lumbar enlarge- the axons divide into ascending and descending
ment is confined to the medial part of the ante- processes, both giving off collaterals. Many of
rior horn. Many of the axons from these nerve these collaterals end in the segments above or
cells form commissural fibers in the anterior below the level of entry. Branches from the larg-
white column. Axons from descending pathways er fibers enter the ipsilateral posterior funiculus
originating in the brain stem terminate here. and ascend to the medulla. The large myelinat-
Lamina 9 includes the largest cell bodies in ed axons also have numerous terminals in Clark's
the spinal cord, the horn cells. The axons of nucleus in lamina 7. Collaterals from posterior
I
Anterior white
commissure •
Anterior
•
~pil'Wll ~rtl'r)'
Figure 7-29. Diagram illustrating a chordotomy. The cross section of the spinal cord shows the lamination of the
spinothalamic tract, the position of the pyramidal tract in relation to it, and the presence of other tram in the
luwer quadrant. A piece of bone wax is mounted 4.5 mm. from the tip of the knife as a depth gauge. Heavy
cUY1Jed lines in the ventral quadrant indicate the sweep of the knife. Note that a desire to spare the lateral corti-
cospinal tract would result in sparing the sacral dermatomes. (From Kahn and RJJnd: ]. Neurosurg. 9:611-619,
1952.)
root fibers also enter Lamina 7 and 9 ending on and cerebral cortex should we talk about pain.
intemtmcial neurons and anterior hom cells for Pain perception by these higher centers triggers
reflex activity. affective responses and suffering behaviors. The
The smaller, lateral btmdle of thin axons (A pain experience varies enormously from person
delta & C fibers) conveys information from free to person and the circumstances may alter the
nerve endings, tactile receptors and other tmen- response. Contrast the pain of your thumb
capsulated receptors. These fibers, conveying being hit with a hammer when you are: fixing
impulses of tissue damage, temperature and light your sail boat, doing a "chore" arotmd the house
touch sensation, enter Lissauer's tract (fasciculus or holding the nail for someone else.
dorsal lateralis) (Figures 7-28, 7-34). Axons As a gross oversimplification we perceive pain
from Lissauer's tract enter laminas I, II and III. in two ways. As pricking, itching or sharp and
Axons from this lamina ascend and descend in easily localizable, such as a razor blade cut or a
Lissauer's tract to reenter the same lamina, mosquito bite. This type of pain is usually short
lasting, up to a day or so, and is usually tolerated.
NOCICEPTION AND PAIN In contrast, pain may be described as dull,
Any stimulus, such as heat, trauma or pres- aching or burning and is poorly localized. This
sure, which produces tissue damage or irritation, type of pain is longer lasting (rheumatoid arthri-
is a nociceptive stimulus. Nociceptive stimuli are tis) or repetitive (menstrual cramps) and is often
the afferent arm of many reflexes; locally, a red poorly tolerated, frequently coloring the persons
wheal develops arotmd a cut, withdrawal of a entire view of life.
limb from a hot pipe is a spinal cord reflex, while Receptors. Tissue damage releases a variety
tachycardia from an electric shock to the finger is of typical intracellular substances including K+,
a brain stem autonomic reflex. Only when this H+, bradykinin, as well as specialized com-
nociceptive information reaches the thalamus potmds such as: serotonin from blood platelets,
7-20 CHAPTER 7
a member of the transient receptor potential fam-

ily of ion channels with VRl and VRL-l also
members of this family.
These nerve fibers carrying nociceptive infor-
mation join peripheral nerves, segregate into
spinal nerves and once inside the spinal dura, join
posterior roots. Their cell bodies are in the pos-
terior root ganglia while the axon continues and
enters the spinal cord in the lateral bundle.
Nociceptive information entering on one poste-
rior root projects for 2-3 segments up and down
the cord in lamina I-III. From centuries old clin-
ical observation we know all nociceptive infor-
Figure 7-30. The lamination pattern of the major mation reaching consciousness, had hence caus-
tracts of the spinal cord. (From Walker: Arch Neural. ing pain, crosses the neuro-axis close to the seg-
Psychiat. (Chicago), 43:284, 1940.) ment of entry and rises in the contralateral white
substance P from nerve terminals and histamine column.
from mast cells. All of these substances direcdy Modulation of Pain Transmission.
stimulate the free endings of small, myelinated A Transmission of pain information through the
delta fibers (l-S Jl diameter) and smaller, non- chain of neurons in the posterior root is influ-
myelinated C fibers (O.2S-1.S Jl diameter). A enced by many factors, some of them originating
second group of released substances including within the segment, some from higher centers.
prostaglandin precursors and leukotrienes act as Most of us, after cutting or bruising ourselves,
sensitizes. Many of these small fibers have collat- rub the surrounding area and obtain relief of the
erals ending in regions containing neurotrans- pain for as long as we rub. An animal that has
mitter vesicles that apparendy amplifY nocicep- been hurt will lick the wound, presumably to
tive stimuli by releasing substance P when the obtain relief of pain. This subjective phenome-
free nerve ending is stimulated. non is frequendy spoken of as counter irritation;
In addition to these relatively non-specific stimulation of the large, myelinated touch fibers
receptors, the upper end of the range of stimuli reduces the magnitude of transmission of pain
to temperature and pressure receptors generates sensation through the posterior horn. This mod-
nociceptive responses. For example, heating a ulation takes place in the substantia gelatinosa,
patch of skin to 40°C with a heat lamp gives a lamina II, within the "Gate" proposed by Wall
comfortable, warm sensation. Heating to 47°C and Melzak.
generates a painful, but tolerable experience. Several clinical observations point to the
Higher temperatures are perceived as unbearable importance of large fiber inhibition of nocicep-
pain. tive transmission, even in the absence of apparent
Cold is a divers sensation and recendy a cold nociceptive stimulation. Perhaps the most
channel has been identified (McKeeney, painful of these condition is avulsion, traumatic
Neuhauser & Julius 2002). Cold and warmth are tearing out, of posterior roots. Surgical severing
sensed by thermoreceptor proteins on the free of posterior roots, instead of giving pain relief,
nerve endings of the somatosensory neurons; often results in intolerable pain. In both cases
one channel, vanilloid receptor subtype 1 (VRl) large fiber input is lost. In contrast, destruction
os activated by temperatures above 43° C, and by by a laser beam of the lateral dorsal root entry
vanilloid compounds including capsaicin the zone (for small fibers) is often highly successful in
component of hot chili peppers. The other vanil- blocking the flow of nociceptive information up
loid receptor type 1 (VRL-l) is sensitive to tem- the neuro-axis. The large fiber input is largely
peratures above SO°C. The cation channel that is spared because they enter in the medial zone.
methanol activated (CMRl-cold methanol type Severed peripheral nerves often generate
1) is activated by temperatures of 8-30°C and is itching or burning sensations, causalgia, which
and II. The mechanism of postsynaptic action is
a reduction in potassium permeability leading to
depolarization. The major inhibitory trans-
mitters in the pain pathway are the
enkephalinjendorphin series of peptides released
from cells entirely within the posterior horn,
mostly lamina II. Their action is closely mimic-
ked by the opioid peptides. At least three modes
of action have been shown, although all studies
are complicated by the very small size of the cell
bodies in the substantia gelatinosa (lamina II).
An increase in potassium permeability has been
shown which hyperpolarizes the cell and acts as
an IPSP. Many studies suggest these compounds
also compete with the excitatory transmitters of
the region, substance P and glycine, for postsy-
naptic sites. Other studies suggest reduction of
Figure 7-31. (A) The location of the corticospinal
tracts as shown by degeneration caused by a lesion in Ca++ influx into the presynaptic terminal in
the internal capsule. (From Wechsler: Clinical response to incoming depolarization and conse-
Neurology. Philadelphia, W.B. Saunders, 1963.) (B) quent reduction of the amount of excitatory
The collateral branches of a corticospinal axon origi- transmitter released. Other studies implicate
nating in the monkey moror cortex and innervating presynaptic inhibition (below).
ulnar nerve moror neurons. The collaterals extend up Injection of opioids into the lumbar CSF
and duwn the spinal cord for 2-3 mm (/ segment). often reduces nociceptive transmission and
From FutRmi, Brain Res. 164:279-284, 1979.
reduces the pain experience. The effect is
can be alleviated by stimulating the large diame- blocked by the universal narcotic blocker, nalox-
ter axons central to the cut. The large diameter one. Successful acupuncture increases endor-
axons have low thresholds so can be stimulated phins in the lumbar CSF.
without stimulating the smaller, high threshold Descending axons in both the anterolateral
nociceptive fibers. Activity in the large fibers sup- and posterior white columns influence transmis-
presses background nociceptive inflow. TENS, sion across this chain of synapses.
Trans Epithelial Nerve Stimulation, is often Supraspinal control of these enkephalinjendor-
effective in preventing, or reducing, peripherally phin neurons is from the brain stem, particular-
generated nociception from becoming pain; ly from the locus ceruleus (Norepinephrine) and
effective in closing the gate. Raphe nuclei (5HT), both in the medulla. These
As mentioned earlier, branches of many areas in turn are modulated by the periaqueduc-
incoming large axons enter the posterior column. tal gray of the midbrain that also contains an
Stimulation of the posterior column sends inhibitory endorphinjenkephalin system.
antidromically-conducted action potentials into Stimulation of these structures results in pro-
the posterior horn and often reduces the pain found anesthesia (electroanesthesia).
experience. While the descending pathways are not clear,
Damaged small axons are prone to develop- we can suppress the flow of nociceptive informa-
ing alpha2 adrenergic receptors, so the axon tion through the posterior horn by positive
becomes sensitive to norepinephrine liberated by thinking, for example, all "pain" studies are
the peripheral sympathetic nerves. bedeviled by a 40% placebo effect. Yes, the third,
Pharmacological blocking or surgical severing post surgical morphine injection can be replaced
sympathetic outflow often reduces pain. with saline and still "work" half the time.
The major excitatory neurotransmitter in the Presynaptic Inhibition. In contrast to the
pain system is substance P that is found in abun- cells in the anterior horn, the major mechanism
dance in the posterior horn, particularly lamina I of inhibition in the posterior horn is presynaptic.
7-22 CHAPTER 7
larization. The reduced amount of transmitter

released by cell II causes a smaller EPSP in cell
III (panel C); in this example cell III does not
reach threshold. Presynaptic inhibition appears
to be particularly useful in the sensory system
because specific inputs to cell III can be blocked;
)~
while other inputs (such as cell N) have not lost
their influence.
Projection fibers. After the extensive pro-
cessing just described, large diameter, myelinat-
/7)
ed axons with cell bodies in lamina I and V cross
the neuro-axis near the central canal (Fig 7-28)
to join the anterior-lateral white matter. These
fibers are described later in this chapter as the
Spinothalamic tract as they project to the brain-
stem and ultimately the cerebral cortex.
TRACfS
The white matter of the cord contains axons
Figure 7-32. The Babinski response. Upper, The nor- which run up and down the spinal cord con-
mal adult response to stimulation of the lateral plan- necting segment to segment and the segments to
tar surface of the foot. Lower, The normal infant and the brain. (The white matter is divided into three
abnormal adult response. regions that are delimited by the presence of the
After a volley of action potentials enter the pos- dorsal roots that separate the posterior from the
terior root, prolonged depolarization can be lateral funiculi and the ventral roots that sepa-
measured in that and adjoining posterior root rates the lateral from the anterior funiculi Fig. 7-
axons as well as in the substantia gelatinosa. All 28).
available evidence suggests that the next cell in The posterior funiculus consists primarily of
the transmission pathway is not depolarized. If the posterior columns. The lateral funiculus is a
an action potential( s) enters the endplate region solid mass of myelinated nerve fibers containing
of cell II, a reduced amount of excitatory trans- many tracts with the ascending fibers on the out-
mitter is released because of the existing depo- side and the descending fibers closer to the gray
LATERAL CORTICO-
SPINAL TRACT
ANTERIOR CORTICOSPINAL TRACT
Figure 7-33. The major descending tram in man.

ascending and descending tracts. The location
of the tracts must be determined by observing
any degeneration caused by discrete lesions.
In this section we will provide an overview of
the pathways in the spinal cord. A detailed dis-
cussion of the individual sensory and motor
pathways are included in the diencephalic chap-
ter 17. The discussion in this section will focus
on topics relevant to only the spinal cord.
DESCENDING TRACTS IN the spinal
LATERAL SPINOTHAlAMIC TRACT cord.
Corticospinal Tracts. Commands for vol-
untary movement travel from the brain and
through the spinal cord in the corticospinal tract.
This tract has its origin in the cerebral cortex,
most prominently from the motor and premotor
cortex of the frontallobe(see Chapter 17). At
the junction between the medulla and the spinal
cord (the level of the foramen magnum) most of
the fibers cross the neuroaxis, decussate, and
move laterally and posteriorly to form the lateral
corticospinal tract (Fig. 7-36).
The location of this pathway in the human is
determined by analyzing cord sections obtained
at autopsy from cases where cortical destruction
has occurred in the motor areas of the precentral
gyrus or in the internal capsule and axons degen-
erated following death of the cell body (Fig 7-
31).
The Lateral Corticospinal Tract is the major
tract for voluntary control of skeletal muscle.
Figure 7-34. The spinothalamic tract/anterolateral
Destruction of this tract leads to paralysis of
system. Incoming fibers that are activated by tissue
damaging stimuli may rise ipsilaterally for up to 3 skeletal muscle and the loss of voluntary move-
spinal cord segments (as the fiber entering on the left) ment. This paralysis is usually total distally, in the
before synapsing and crossing the neuro-axis and hand, and somewhat less severe in the trunk
entering the spinothalamic tract. The fiber entering musculature. If the right tract is severed at Cl, a
on the right synapses at the lePel ofentry, one IlXOn paralysis of both the right arm and leg will result,
crosses the neuro-axis and rises, the other IlXOn enters Hemiplegia, a paralysis of the arm and leg on the
the anterior horn to participate in local reflexes, such same side. Monoplegia is the paralysis of a sin-
as withdrawal from a hot surface. The major projec- gle limb.
tions of the spinothalamic tract are: midline medulla
(0), perilUJueducml grey of the midbrain, and two ASCENDING SENSORY TRACfS
nuclear groups of the thalamus, the ventral posterior
lateral nucleus which projects in turn to the post cen- All ascending sensory systems have three
tral gyrus, as well as the interlaminar nucleus which types of neurons;
projects widely. 1) Primary sensory neuron in dorsal root
ganglion attached to each segment of the spinal
matter. The only way that the location of indi-
cord
vidual tracts can be determined is to examine
2) Second order neuron in dorsal horn of
sections after an injury in the nervous system.
spinal cord or gracile and cuneate nuclei of
The anterior funiculus likewise carries many
medulla.
7-24 CHAPTER 7
The axons of the second order sensory neu- Ascending fibers from lower levels (sacral lev-
ron cross the neuro-axis, become contralateral, els) lie medially while those from upper levels lie
and form ascending pathways within the spinal laterally. In uppermost thoracic and all cervical
cord and brainstem that terminate on third order levels, the posterior column is divided into the
neurons. medially placed fasciculus gracilis that includes
3) Third order neurons in the thalamus. fibers from the lower extremity and lower thorax
Third order neurons project to the ipsilateral sen- and the laterally placed fasciculus cuneatus which
sory area of the cerebral cortex. include fibers from the neck, upper extremity and
Tactile Discrimination-Posterior columns. upper thorax. The axons in the dorsal column
Fibers in the posterior fasciculus, also known as are primary uncrossed axons and continue with-
the dorsal column, (Fig. 7- 35), are the major, if
not exclusive, pathway for signals conveying joint
position sense, tactile localization, 2 point dis-
crimination, and vibratory sensation. Fibers con-
veying touch sensation rise both in the posterior
column and several other fasciculi. The fibers in
this region consist primarily of heavily myelinat-
ed dorsal root ganglion fibers. Upon entering
the posterior fasciculus via the medial entry root
zone, these fibers divide into ascending and
descending branches.
posrclI/olI COL liMNS
Figure 7-35. The posterior columns

Figure 7-36. The corticospinal tram.
out a synapse ipsilaterally up to the lower medul- the internal capsule onto the postcentral gyrus of
la where the secondary neurons begin. The axon the cortex.
of the secondary neuron crosses to the contralat- Lesions in this pathway usually diminish tac-
eral side and forms the medial lemniscus that tile localization, 2-point discrimination and
ascends through pons and midbrain to the ven- vibratory sensation. There is also loss of ability to
tral posterior lateral nucleus of the thalamus. appreciate weight differences. Position and
The third order neuron in the thalamus sends movement sense is also affected. These deficits
their axons ipsilaterally by the posterior limb of are most pronounced in the fingers and extrem-
ities than in the thorax or abdomen. These
TABLE 7·1: MAJOR PATHWAYS IN THE SPINAL CORD
Pathwa}' Origin Termination Function

Corticospinal Motor Cortex Lamina 7 and 9 Voluntary movement of limbs
Contralateral in spinal cord
Rubrospinal magnocellular portion of lamina 7 and 9 Involuntary Support of movement.

Contralateral red nucleusin midbrain Facilitates flexor and inhibits
extensor motor neurons,
particularly arm nexors
Tectospinal Deep layers of Lamina 7 & 9 of Support corticospinal pathway

Contralateral superior colliculus cervical spinal cord
Vestibulospinal Lateral vestibular nucleus All levels of cord CoordinaHon of eye

Uncrossed of Cranial nerve VIII lamina 7&8 and neck movements
Reticulospinal Nucleus reticularis Lamina 7 & 8 of all levels nnuence gamma motor system
gigantiocellularis in the of cord but especially cervical Facilitory to extensor motor
medulla and from nucleus and lumbar enlargements neurons.
reticularis pontus caudalis
and oralis of the pons
MLF Cranial nerves iii, Cervical cord Coordination of eye

v, vi, vii & VIII, XI and neck movements
Descending Autonomic Hypothalamus and Sympathetic to lamina 7

Pathways Bilateral brain stem in C8·l2 Parasympathetic
to Sacral nucleus of S2-S4
Spino-spinal System. All spinal cord levels lamina involved in intersegmental

intersegmental and connections or taking part in
dorsal root fibers the 2-neuron reflex arch.
Posterior spinal Clark's nucleus in IpSilateral vermis of unconscious tacHle and

cerebellar some of lamina 7 from C2·l2 cerebellum proprioceptor information.
largest myelinated Encapsulated(Golgi tendon
axons origin of group organs, stretch receptors and
IA and IB afferent fibers. muscle spindles
IpSilateral
Anterior lamina 5, 6 & 7 Contralateral vermis unconscious tactile

spinocerebellar from most levels of cerebellum proprioception
Contralateral
Cuneocerebellar accessory cuneate anterior lobe and also go unconscious tacHle and
IpSilateral nucleus in low medulla into the pyramis and uvula proprioceptive information for
of the cerebellum. upper extremity and neck
7-26 CHAPTER 7
deficits also produce poorly coordinated move- many types of stimuli of both high and low
ments; posterior column ataxia. intensity with response graded by intensity.
The Anterolateral pathway. Fibers carrying 3) high threshold units, activated only by
information on pain and temperature sense from nociceptive stimuli.
the body all rise in the contralateral spinothalam- 4) thermosensitive units, with high action
ic tract (Fig.7-34). Compression, intrinsic dis- potential frequency signaling nociception.
ease or deliberate section all result in anesthesia All of these units have small receptive fields
of the contralateral body beginning 3 segments peripherally and larger fields toward the midline.
below the level of disruption. The posterior horn seems to tease apart what
Pain and Temperature. Primary Cell stimulus from what part of the body. Recording
Bodies-Cutaneous receptors for pain and tem- from the thalamic endings of these fibers also
perature send axons to small and medium sized shows this separation of function as well as
dorsal root ganglion cells. These axons enter the adding a wake up function- ouch! A unilateral
spinal cord via the lateral aspects of the dorsal section of this tract (Fig. 7-29) for relief of pain
root entry zone. Most of these fibers enter produces a complete absence of pain and tem-
Lissauer's tract and branch extensively (over 2 or perature from the opposite side of the body last-
3 segments on either side of the segment of ing for 6-9 months, but pain sensation slowly
entry) before entering the posterior horn, lamina returns. Nociceptive information probably rises
I, II and III (Fig. 7-28). in Lissauer's tract until it is above the cut and
The secondary neurons arise primarily from then crosses.
cell bodies in lamina I and V that give origin to There are several "pain" responses to noci-
large axons which cross in the anterior white ceptive stimuli. A direct spinothalamic pathway
commissure and ascend in the contralateral ante- to the contralateral ventral posterior medial
rior-lateral funiculus. As discussed earlier in the nucleus of the thalamus with third order projec-
chapter (Nociception and Pain) many factors tion to the postcentral gyrus probably mediates
modulate information transfer across the posteri- sharp, localizable pain. Stimulation of the post
or horn; between incoming nociceptive fibers central gyrus, however, rarely generates the sen-
and outgoing spinothalamic fibers. sation of pain. Pain is rarely reported by patients
There is a somatotopic arrangement in the during epileptic (cortical) seizures. Apparently
spinothalamic tract (Fig. 7-34) with the most lat- the thalamus tells us what (pain) and the post
eral and external fibers representing sacral levels central gyrus tells us where. We test this pathway
while the most intermediate and anterior fibers with the light prick of a pin and expect the
representing cervical levels. Pain fibers are locat- patient can tell us, or point to, the location of the
ed anteriorly to the more posteriorly placed tem- pin prick.
perature fibers. The dull throbbing quality of the pain prob-
Perhaps as many as half the fibers in the tract, ably ascends by a multi-synaptic pathway via
often called the spinoreticular tract, end in the brain stem synapses to the midbrain and then to
brainstem, while many of the rest send collaterals interlaminar thalamic nuclei with much wider
into the brainstem on their way to the thalamus cortical projection including the limbic system.
(Chapter 15). There are endings in two major The limbic system (Chapter 22) has much to do
nuclei of the thalamus: the ventral posterior with our outlook upon life. The thalamus alone
medial nucleus and the intralaminar nuclei. (see can signal poorly localized pain to consciousness.
Chapter 15) In addition to the spinal thalamic and spinal
Recordings from individual spinothalamic reticular pathways, there are other pathways that
neurons reveal four major functional categories, may convey pain and thermal information to the
all contralateral. thalamus. The cervicothalamic pathway origi-
1) low threshold units, activated only by gen- nates from the lateral cervical nucleus in the lat-
tle stimuli, for example, by stroking hairs on the eral column at level CI and C2 and projects to
arm. the brain stem and thalamus. Another is the
2) wide dynamic range units, activated by spinotectal tract running from the spinal cord to
deep relate to the loss of the anterior hom cell or the
Upper and Lower Motor Neurons. motor axon. The loss of reflexes and the flaccid
Causes of muscle weakness or paralysis can be tone of the muscles relate to the loss of the motor
grouped functionally into two categories. If the side of the stretch reflex pathway. Often, it is
difficulty is located in the corticospinal or other possible to observe spontaneous twitching of the
descending motor tract the problem is called an muscle, fasciculayers of the superior colliculus. It
upper motor neuron lesion. If the problem is in also conveys pain and thermal information with
the anterior hom cell, its axon, or its motor some synaptic interruption before reaching the
group, the problem is called a lower motor neu- thalamus.
ron lesion. Other Spinal Pathways. We have just listed
Weakness, hyperreflexia, the Babinski sign, the major ascending pathways. There are also
and a type of increased resistance to passive pathways from the spinal cord to reticular forma-
movement at a joint, spasticity, characterize the tion of the brain stem to the vestibular nuclei of
upper motor neuron syndrome. Passively mov- the medulla and pons, the inferior olive of the
ing or rotating the ankle, knee, hip, shoulder, medulla and to nuclei and pons and midbrain.
elbow, or wrist joints easily demonstrates the (See Chapter on functional localization in the
increased tone. In the normal individual, the Brain Stem and the Major Pathways -Chapter
joints all move easily. When spasticity is present, 15).
the joint is easy to move for a short interval, then
resistance to movement increases rapidly; upon
further pressure, the resistance suddenly gives
way. This latter phenomenon is often referred to
as a clasp-knife reflex. In the leg, spasticity is
greatest in the extensors, whereas in the arm the
flexors are more affected.
Upper Motor Lower Motor
Neuron Dysfunction vs Neuron Dysfunction
Spasticity Flaccidity
Hyyperreflexla Hyporeflexia
Babinski Sign Fasciculation
Very little atrophy Severe muscle atrophy
Descending motor tracts normally exert an

inhibitory effect on spinal cord reflexes.
Hyperreflexia is a sure sign of decreased corti-
cospinal function. Decreased function of the
corticospinal tract also effects a curious reflex of
the foot, Babinski's sign. If a moderately sharp
object such as a key, is drawn over the lateral
boundary of the sole of the foot, the toes of an
adult flex (curl). In very young children and in
adults with corticospinal tract destruction, the
toes extend and fan out as shown in Figure 7-22.
Weaknesses, loss of reflexes, extreme muscle
wasting, and a flaccid tone, hyporeflexia, to the
muscles, characterize the lower motor neuron
syndrome. The reasons for the weakness and
muscle wasting are discussed in Chapter 6 and
CHAPTER 8
A Survey of Diseases of
Peripheral Nerve, and Nerve Root
INTRODUCTION: in the distribution of the involved peripheral

nerves. Damage to the sympathetic fibers, tra-
In chapter 2, we have already considered,
the differential features of disease of muscle versing the peripheral nerves, may result in
compared to disease of peripheral nerve com- alterations in sweating and skin temperatures.
Nerve conduction studies demonstrate reduc-
pared to disease of the nerve root compared to
tion in velocity (if the basic process involves
central nervous system disease. Diseases of
loss of myelin, demyelination) or in the ampli-
peripheral nerve and nerve root both repre-
tude of the motor or sensory action potential
sent, lower motor neuron disorders. In con-
trast to disorders of muscle, both involve,
(if the basic process involves predominately a
loss ofaxons). In mononeuropathies the spe-
motor and sensory features. As we will discuss
cific site of damage (conduction block) may be
in greater degree, peripheral nerve disorders,
may involve specific nerves in a local manner demonstrated. The EMG will demonstrate
abnormal spontaneous activity: fibrillations
(mononeuropathies) or peripheral nerve in a
(onset 10-25 days after the axonal damage)
more generalized manner (polyneuropathies).
Mononeuropathies must be distinguished positive sharp waves and fasciculations.
As will be discussed later in greater
from radiculopathies. This distinction can be
made based on the pattern of motor deficit, the detail, diseases of peripheral nerves are
pattern of deep tendon stretch reflex deficit, essentially of two types: (a) localized
the pattern of sensory deficit and the distribu- mononeuropathies involving a single
tion of pain. Figure 8-1 compares radicular peripheral nerve, often due to trauma or
(dermatomal or segmental) sensory innerva- compression or less often, occlusion of
tions to the superficial sensory innervations of blood supply. (b) Symmetrical polyneu-
peripheral nerve. ropathies - usually distal and usually due to
a metabolic disturbance involving many
nerves. The polyneuropathies reflect many of
PERIPHERAL NERVE DISEASE.
the systemic, toxic and metabolic disease con-
Diseases involving the peripheral nerves sidered in pathology. As a general rule any
have a combination of motor and sensory patient with diabetes mellitus or with chronic
symptoms and signs. Lower motor neuron alcoholism or receiving chemotherapy is likely
findings are present with a flaccid type weak- to present symptoms or signs (often subclini-
ness and atrophy. Sensory symptoms and find- cal) of a polyneuropathy. In many cases we are
ings (involving to a variable degree all modali- not able to establish a specific cause for the
ties of sensation) are present within the same polyneuropathy. We may not have sufficient
distribution as the motor findings. These information about environmental or industrial
patients, however, do not show evidence of exposure. In some cases we have insufficient
damage to the long fiber systems involved in information regarding the family history.
transmitting sensory and motor information In a mononeuropathy, the weakness and
within the central nervous system. sensory signs and symptoms are clearly within
In general, mental status is intact. Deep the distribution of a specific plexus peripheral
tendon reflexes and superficial reflexes nerve, e.g., sciatic, radial, median, or ulnar.
(response to plantar stimulation) are absent (Fig. 8-1). Common sites of compression
within the distribution of the involved periph- include the radial nerve at the radial (or spiral)
eral nerves. Fasciculations may be present with- groove of the humerus, the ulnar nerve at the
8-2 CHAPTER 8
PERIPHERAL NERVES SPINAL (RADICULAR)

DERMATOMES
TIUIiIEMINAL -f 0I'HTHALMIC
MAXILLARY 8R.
MANDIBULAR BR.
CERVICAL CUTANEOUS
lNTEACOSTOBRACitIAL
MEDIAL BRACHIAL C;Ul:_--f--"i+1l
POST. BRACHIAL CUT. --~
ANTERIOR FEMOIlAL CU1:---+-
COIIIMON PERONEAL
SAPHENOUS
SUPERFICIAL PERONEAL-~\-
DEEP ....._IUII.'-""'I:I~~
A SURVEY OF DISEASES OF PERIPHERAL NERVE, AND NERVE ROOT 8-3
$~ (RADICULAR) PERIPHERAL NERVES

IERYATOMES
ST. SUPRACLAVICULAR N.
......_+-_tNTUCO$108RACt11AL CUT.
LATERAL THORACIC R.....

.......--II--IIED. 8RACHIAL CUT.
POST. BRACHIAl. CUT.

l8R.OF RADIAL.)
\...:..........-+-_ MED.ANTEBRACHIAL CUT.

POST. ANTEBRACHIAL CUT.
(8R. Of' RADIAL J
USCULOOUTJI,NEOUS
(LAT. ANTEBRACHIAL CUT.)
SUPERFICIAL. RADIAL
MEDIAN
~-i--I--.AHT FEMORAL CUT. N.
~p--V--OBTURATOR
OIltlON PERONEAL N.
PERONEAL N.
8-4 CHAPTERS
NERVES CORDS OIVISIONS TRUNKS ROOTS 2A

from 4th c:ervical
5th cervical
Nerve to subclaVIUS
ana ac:cessory cnr.nic:
6th cervical
7th cervical
~--- Long Ihoracic
~I
,\1edlln
Ulnar MeCll1 pectora! 1 SI In oraclc
Med antebrachial ~ Llterll "eclotal

from 2nd thoraCIC
cutaneous
Medii' br,ch", S:Joerlor subscapullr
cutaneous ThorleOdorSiI
Inferior subscapular
Figure 8-2. A) Plan of the ~rlUhial Plexus: Note origin of median nerve from both medial and lateral cord, of
ulnar nerve only from med,al cord with radicular origin, from C8, T1, of radial nerve from posterior cord only.
(From Clemente, C. Gray's Anatomy. Philadelphia. Lea and Femger. 30th Ed. 1985, p. 1205).
olecranon process of the elbow, the median MONONEUROPATHIES:

nerve in the carpal tunnel, the brachial plexus UPPER EXTREMITY
at the thoracic outlet, and the peroneal nerve as
BRACIllAL PLEXUS -[C5, 6, 7, 8 Tl-
it leaves the popliteal fossa and curves around
(Fig.8-2,8-3)J
the head of the fibula.
Patients frequently present with a com-
A specialized form of mononeuropathy:
plaint of transient distal sensory symptoms and
mononeuropathy multiplex reflects multifocal
weakness involving the upper extremity occur-
involvement of peripheral nerve for example in
ring in relationship to sleeping posture or posi-
inflammatory diseases of blood vessels.
tion of the arm. The symptoms are often bilat-
In addition, in neurofibromatosis (Von
eral. Rarely the symptoms are persistent rather
Recklinghausen's disease), multiple peripheral
than intermittent. These symptoms are
nerves and nerve roots may be involved by
referred to as the thoracic outlet syndrome or
tumors arising from the Schwann cell and
the neurovascular syndrome of the thoracic
mesodermal components. This disorder will be
outlet. Both the brachial plexus and the sub-
discussed in relation to the spinal cord.
clavian artery pass through a relatively narrow
A SURVEY OF DISEASES OF PERIPHERAL NERVE, AND NERVE ROOT 8 -5
suprascapular .n. mlddl(' trunk 2B

sup. tnmk
....-':-"'----",--- C6
/·""O::::~----C7
.......-:::;;...;;~----CH
---<~~~--:-:~- T I
~/-~:""':----:~~-- Inf. trunk
lllt'cI ia I cord
ftrst rib
post. corcl
i
radial n. )
ulnar n.
Figure 8-2 B) Braehial plexus. Relationship to the MUM foramina the first rib and the clal1iele. (From
Zimmerman]. and Jacobson S. Anatom, Boston. Little Brown 1989 p.176.
area with clavicle anteriorly and the first rib ology. The specifics are often unclear. Brachial
posteriorly (Fig.8-2). Alterations in posture neuritis is often associated with considerable
may produce compression of the brachial pain in the arm. Radiotherapy to the axilla for
artery - producing a tingling pins and nee- breast carcinoma may also involve the upper
dles sensations ("paresthesias") involving all plexus in a relatively nonpainful syndrome.
fingers and a distal weakness. Often specific Lower Plexus: Malignant infiltration of
maneuvers will demonstrate the intermittent the plexus from tumors at the apex or upper
compression of the brachial artery. Neural lobe of the lung ("Pancoast tumor") often
syndromes of the outlet tend to involve pri- involves the lower (C7, 8,Tl) half of the plexus
marily the ulnar nerve, or the lower roots producing severe pain. The related sympathet-
(C8-Tl). At times a cervical rib or tight band ic plexus is often involved producing a
may further compress the narrow outlet. Horner's syndrome. Upward traction on the
Upper Plexus: In addition to the relatively plexus may occur at birth (Klumpke's) or in
benign thoracic outlet syndrome, often trau- children who suddenly are pulled up by the
ma, traction downwards as in birth injuries arm producing damage to the lower half of the
(Erb's) or brachial neuritis may involve the plexus.
upper plexus roots C5-6 (Fig.8-2) resulting in Case 8-1 provides an example of a brachial
weakness of muscles about shoulder and flexors plexopathyand Horner's syndrome in a patient
at elbow. Brachial neuritis presumably has a subsequently found to have an apical carcino-
post infectious or immunologic or familial eti- ma of the lung.
8-6 CHAPTER 8
lowed by a decrease in sweating on the left side

of face and body. Three months prior to
admission the patient had the onset of weak-
ness of the left arm. The patient soon noted.
Physical examination demonstrated
swelling, redness, change in temperature and
sweating and limitation of motion of the left
arm, plus distension and firmness of the left
supraclavicular space. Orthostatic hypotension
was present
Neurological examination: Symphabetic
System: Seen as a full Horner's syndrome on
the left. Motor System: atrophy in the median
(thenar eminence) and ulnar (first interosseus)
distribution, weakness in left arm most marked
in the median and radial distribution. Reflexes:
Decreased deep tendon reflexes left arm
Sensory System: Decreased pain in the left C7, C
8 dermatomes.
Clinical diagnosis: Brachial plexopathy
and Horner's syndrome due to apical lung
tumor (Pancoast tumor).
Laboratory data: Computerized tomogra-
phy of the lower neck and upper chest after
venous injection of the contrast material into
the left arm indicated: near occlusion of the left
subclavian vein at the level of the first rib and a
necrotic mass in the left lower neck posterior to
the thymus and carotid sheath and invading
Figure 8-3. Dissection of Nerves of the Left Upper the muscular structures of the prevertebral
Extremity from anteriorly. Note exposed position of the region and arising from or extending to the left
ulnar nerve in the olecranon groove at the elbow, posi- apex of the lung. Nerve conduction and EMG
tion of median nerve at the carpal tunnel at the wrist studies indicated a severe axonal lesion of the
and relationship of the brachial artery to the brachial lower half of the brachial plexus with a marked
plexus and clal1icle. &e also fig 8-4. (From Clemente,
C. Gray's Anatomy 30th Ed. Philadelphia. Lea and
involvement of median and ulnar nerves and
Femger 1985, p. 1214). less of the radial nerve. Biopsy of the left supra-
clavicular mass revealed adenocarcinoma pre-
Case 8-1 This 57 yr. old right-handed sumably of pulmonary origin.
white male with a 30-year history of heavy cig- Subsequent course: The patient received
arette smoking (2 packs per day) had a 2-year radiotherapy (3000 rads) to the left lung apex
history of progressive pain in the left upper and the left supraclavicular area with a decrease
extremity beginning with mild pain at the left of pain and of swelling in the arm. The patient
elbow, then a lack of sensation in the left ulnar expired 1.5 years after radiotherapy and 3.5
distribution. Eight months prior to admission, years after onset of symptoms.
the left hand had become swollen and painful. Often a brachial neuritis involves only a lim-
Severe pain on motion at the shoulder also ited portion of the brachial plexus. Limited
developed. Six months prior to evaluation involvement of the long thoracic nerve (C5, 6,
drooping of the left eyelid was first noted fol- 7) is relatively frequent.
Case 8-2 presented on CD ROM pro-
vides an example of a neuropathy of the
long thoracic nerve occurring in a woman 1
day after delivery.
Ulnar nerve (C8, T1): This nerve is often
exposed to trauma as it passes through the
groove behind the medial epicondyle at the
elbow (Fig. 8-3). Each of us has struck our
"funny bone" at some time and we are all
acquainted with the ulnar distribution of posi-
tive sensory symptoms, ring and 5th finger.
Repeated trauma to the nerve or fractures at
the elbow may produce more persistent symp-
toms including atrophy of the hypothenar and
interossei muscle and weakness of digiti quinti
abductor, ring and fifth finger flexors, the
interossei, and the thumb adductor.
Median nerve (C5, C6, C7, C8, T1): The
major syndrome of the median nerve relates to
compression at the carpal tunnel by the overly-
ing transverse carpal connective tissue. (Fig. 8-
3, 8-4). Pain and paresthesia extend into the
Figure 8-4 Disseaion of Nerves and Muscles of the
median nerve supplied fingers predominantly palm of the right hand. ( From Clemente, C: Gray's
index and middle, with less invovement of Ana.romy 30th Ed. 1985,p. 1219 after Testut).
thumb and median side ring finger when
severe. There is significant weakness and atro- Physical examination demonstrated mild
phy involving the median supplied thenar mus- inflammatory synovitis in the hands, with mild
cles of the hand:-abductor pollices brevis, soft tissue swelling in the wrists, ankles, proxi-
opponens and the finger flexors. A positive mal interphalangeal joints, and metacarpal pha-
Tinel's sign is present on percussion over the langeal joints.
carpal tunnel. Carpal tunnel syndrome may Neurological examination demonstrated
complicate any process where edema or a minor weakness in left hand grip and left
swelling occurs at wrist or hand: rheumatoid thumb opponens and a marked tenderness
arthritis (as in case 8-3), trauma, myxedema over the left carpal tunnel area with a positive
(hypothyroid state) or acromegaly (a state asso- Tinel's sign on palpation or percussion of the
ciated with excessive production of pituitary median nerve in the carpal tunnel (tingling
growth hormone-see Chapter 16). paresthesias extending from the carpal tunnel
into the median nerve supplied fingers).
Case 8-3 This 83 yr. old right-handed Clinical diagnosis: Compression of medi-
white widow and retired shoe factory worker an nerve at carpal tunnel.
with a 20-30 year history of rheumatoid arthri- Laboratory data:Nerve conduction stud-
tis, in relationship to an exacerbation of her ies indicated severe delays in both sensory and
joint symptoms, had the onset of tingling motor conduction for median nerve at carpal
paresthesia in the left median distribution of tunnel on the left with mild findings on the
hand and fingers most prominent in the mid- right.
dle finger, less in index and ring and minor in Subsequent course: Despite the use of
thumb. There was pain in the hand particular- nonsteroidal anti-inflammatory agents, re-eval-
ly or making a fist. uation 2 weeks later indicated additional pro-
8-8 CHAPTER 8
Radial nerve (C6, 7, 8): The major syn-

drome of this nerve relates to injury at the spi-
ral groove of the humerus (Fig.8-S) related to
fractures or to so called "Saturday Night Palsy"
(pressure effects on arm draped over a hard
surface are noted due to excessive alcohol
intake so that the paresthesias fail to awaken
the patient and the compression therefore con-
tinues). The characteristic weakness involves
the wrist and finger extensor as well as the long
abductor of the thumb.
The brachioradialis muscle is usually
involved. Lesions at this level however usually
spare the triceps muscle also supplied by radial
nerve. A wrist drop is characteristic. A cock up
wrist splint is utilized to maintain the hand in a
physiological position. With time recovery will
occur.
MONONEUROPATHIES :
LOWER EXTREMITY
LUMrnARSACRALPLEXUS
[Ll-S3 (FIG.8-6, 8-7)].
The lumbar plexus is composed of nerve

roots Ll - lA, and the sacral plexus of nerve
roots lA-S3. Both may be involved by malig-
nancies within the pelvis. Both may also be
commonly involved in the painful diabetic
mononeuropathy that occurs on a vascular
basis.
Neuropathies may commonly involve the
Figure 8-5 Dissection of the nerves of the right upper following branches of the lumbar plexus.
extremity -from posteriorly. Note the radial course of the
1. Lateral femoral cutaneous nerve of
radial nerve prwiding innervation to the triceps muscle,
and to the extensors of wrist and finger (From Clemente, the thigh (L2, L3). This nerve supplies the
c.: Gray's Anatomy. 30th Ed. 1986, p. 1220.) anterior-lateral aspect of the thigh. It enters
the thigh by passing between the two points of
gression: greater weakness in grip and pain and attachment of the lateral aspect of the inguinal
touch sensation now decreased bilaterally in ligament to the anterior superior iliac spine
the median nerve distribution. Despite the use (Fig.8-8). There is sensitivity of the supplied
of local steroid injections, reevaluation one cutaneous area to contact from any clothing or
month later indicated persistence of symptoms, repetitive tactile stimulation. Tingling pares-
with atrophy present in the thenar eminence thetica are present. At times burning painful
on the left. Carpal tunnel surgery on the left paresthesia is present; thus, the name "meralgia
hand was performed with improvement of paresthesia". The common causes are weight
symptoms. When symptoms developed in the gain or weight loss. The following underlying
right hand, similar surgery was performed with diseases are frequent: obesity, pregnancy, dia-
relief.
-From 12th thoracic
Iliohypogastric
Lat. femoral cutaneous
lumbar
Accessory obturator
Obturator
Lumbosacral trunk
Figure 8-6. Pum of the Lumllllr Plexus. The ",nterior di"isions ofL2, 1.3, L4 unite to form. the oinurlJtor nert1e.
The posterior diPisions ofL2, 1.3, L4 (shtuled) unite to form. the fttnowd nerpe. TIPigs from L2, ",nd 1.3forms the
IIItmdfttnowd cuttJneOfU nerpe. (From Clemente, c.: Gray's Anatomy, 30th Edit.. 1985 p. 1226).
betes and infrequently pelvic malignancy. SCIATIC NERVE AND DIVISIONS

2. Obturator nerve (L3, lA), (Fig.8-8, 8- Neuropathies may commonly involve the
9,8-10) this nerve supplies the adductors of sciatic nerve, (the major trunk originating from
the thigh. The major causes of injury relate to the sacral plexus) or the two major divisions of
difficult deliveries: pressure from fetal head or the sciatic nerve: the common peroneal and
forceps. the posterior tibial nerves. The two divisions
3. Femoral nerve (U, 3,4), (Fig-8-8, 8- are bound together from the plexus to just
10). This nerve supplies the quadriceps muscle above the popliteal fossa. They are separate
necessary for extension at the knee and the ili- nerves below that point. The other branches
acus and psoas muscles necessary for hip flex- of the sacral plexus are a) the gluteal nerves to
ion. Diabetic mononeuropathy on a vascular the gluteus medius and gluteus maximus; b)
basis is the most common cause of this neu- the pudendal nerve (S2, 3,4) to the perineal
ropathy. Hematomas into the iliac muscle may muscle of the anal sphincter.
compress the nerve. Pelvic malignancies and Sciatic nerve: (lA, LS, Sl, S2), (Fig. 8-11).
pelvic surgery may injure the nerve. This nerve supplies the hamstring muscles and
8-10 CHAPTERS
SI.Jp!),ior glul981 n -Jdllliil....__
Inferior gluleal n.-iG~-~
To piriformis - - - . ,
To qu adratua temo ris ,nd

intefior gemellu8
To obturator Intertlus
BUpeI'oor gemellus
Post. fem . Cutlltl&oU8 n.
f'erfoTatjr"l9 cutan~us n .
Pudenda f
To levator ani. coccygeu, and

sphincter ani e.temus
Figure 8-7 Plan of the Sacral Plexus and Coccygeal Plexus: Posterior diJlisions are depicted as striated. Anterior
diJlisions are unshaded. Note origin ofcommon peroneal nerJle from posterior diJlisions JA-S2 and of tibial nerTIe
from anterior diJlisions (JA-S3). The two nerJles are joined together to form the sciatic nerTIe (From Clemente, C:
Gray's Anatomy, 30th Ed. 1985, p. 1235).
all muscles below the knee. Common causes Peroneal Nerve: (lA, LS, SI), (Fig. 8-1 0,
of injury are a) fractures of pelvis or femur, b) 8-11): This nerve has a) superficial branch:
gunshot wounds of the buttock; c) Injections cutaneous and muscular supply to the everter
of medications into the buttock - e.g. peni- of the foot (peroneal muscles) and b) deep per-
cillin. d) Diabetes mellitus mononeuropathy. oneal or anterior tibial branch supplying the
8A
ilioInguinal n.
ilioinguinal n.
il1ohypogastr1c n.
genitofemoral n. --~
lateral femoral culaneous n. - __- . : I

genitofemoral n.
femoral n. - _ _...:!
i-"";';';'-- lateral femoral

scIatic n. cutaneous n.
obturator n. --""'"""'~::--~~~~
adduC'lor brevi m. ----'o;:---if-
Figure 8-8. A) Dissection of the lumbar and sacral plexuses. tkmonstrating their relationship to the vertebral
foramina and the inguinal ligament and the sciatic nott;h. (From Zimmerman, J.and Jacobson, S. Anatomy
1989p.108.
ankle and toe dorsi flexor muscles and sensa- This nerve supplies the posterior calf mus-
tion to the dorsum of foot and lateral aspect of cles. The gastrocnemius and soleus muscles,
the cal£ This nerve passes around the head of (the plantar flexor and then continues as the
the tibula from the popliteal fossa to the ante- posterior tibial nerve to supply intrinsic foot
rior aspect of the leg. In this location, the nerve muscles. It also supplies sensation to the plan-
is relatively superficial and very subject to pres- tar surface. The posterior tibial nerve passes
sure from leg crossing (when seated in tight behind the medial malleolus in a relatively
coats or tight boots) or operating or obstetrical superficial location and enters the tarsal tunnel.
room stirrups. The major manifestation of In this location, the nerve may be palpated and
compression is a foot drop or unstable ankle is subject to compression. Entrapment also
(due to weakness of ankle dorsiflexors and occurs due to disease in the tendon sheaths
everter). that accompany the nerve in the tunnel.
The following case 8-4 provides an example
Tibial Nerve: (lA, L5, SI, S2): (Fig.8-11)
of a mononeuropathy involving the lumbar -
8-12 CHAPTER 8
lumba, porttUfi
8B
of sympathetIc
FirS! IU(llloir n
Nttl.vCI lu .... uadra-
lU::f IUlllbOrum
IhuhypogaSlroc "
' homYUlnal n
Ihohypogastnc n -,.~'t;jjii:
Genllofemorlll n
Th,rd lumbar n - +filiiii':
lilac branch of Ramus commu ~
iliohypogastric _ LL!!O= nleans

Abdominal branch
of Iliohypo
FOUrlh lumbar n .
cutaneous n
fIfth lumbar n -H:~p;.w'-i

Ilioinguinal n .
External spermatic
branch of genlto-
temoral n .
lumboInguinal branch
01 genitofemoral ·n
POSIeroor branch of
lateral femoral
cutaneous n.
Anteroor branch of -!-;;;""'-I/...U
lateral femoral
cutanoous n.
Aponeurosis of ex- Dorsal nerve

tornal obliQue of penos
Deep and superficial dissection of the lumbar plexus. (Testut.)
Figure 8-8. B) Dissection of the Lumbar Plexus. Note relationship of the plexus to the psoas muscle (dissected
away on right silk of abtWmen) iliacus muscle and pelvic structures. Note the course of the lateral femoral cuta-
neous, femoral and obturator nerJIes and possible sites of compression. (From Clemente, c: Grais Anatomy 30th
Ed. 1985 p.1228).
sacral plexus in a diabetic patient who also had the onset of a severe toothache like pain in the
a peripheral neuropathy. lateral and anterior surface of the right leg from
hip to knee. No other symptoms were present.
Case 8-4: This 75 yr. old right-handed
Neurological examination: Motor System:
white widow with a one-year history of non-
Weakness was present in the proximal muscles
insulin dependent diabetes mellitus had the
of the right lower extremity. Reflexes: Deep
sudden onset of weakness in the right leg, most
tendon stretch reflex was absent at the right
prominent at hip and knee, three weeks prior
Achilles and patellar compared to left. Sensory
to evaluation. Shortly thereafter, she had
Figure 8-9. Dissection of the Slur/dana Pudendal Plexuses. Sagittal View. Note the relationship of the plexus to
the visceral struaures. Note also the course of the obturator nerve (from the lumbar plexus) as it passes forward
to enter the obturator canRlana foramen. &e also Fig. 8-6B (From Clemente, G.: Gray's Anatomy, 30th Ed.
1985,p.1233).
System: Pain sensation was decreased in a sym- Laboratory data: nerve conduction studies
metrical manner over the toes and feet and two indicated slowed conduction over the left sural
thirds of the distance up the calves. However nerve, absence of conduction right sural nerve
there was also a focal deficit in pain sensation and both peroneal nerves - leg to ankle. The
over the right third lumbar dermatome. EMG studies demonstrated acute denervation
Vibration was decreased at toes compared to in sampled muscles supplied by the right
ankles compared to knees in a bilateral man- femoral nerve: rectus femoris, vastus medial
ner.. Significant tenderness was present over and iliopsoas plus muscles supplied by major
both the sciatic nerve at the sciatic notch and components of the sciatic nerve gastrocnemius
the femoral nerve in the femoral canal of the and peroneus longus. Myelogram and CT scan
anterior thigh. of the pelvis were normal.
Clinical diagnosis: 1. Acute diabetic Subsequent Course: The patient
mononeuropathy: lumbar and to a lesser improved but then 9 months later has an acute
degree sacral plexopathy; 2. Diabetic distal exacerbation in the right leg and one year later
peripheral neuropathy. had a similar process involving the left leg.
8-14 CHAPTERS
l.elerBI
femoral
CutaneoUi n
Nef\1i to
o1)hJ'llOl' Int.,TUI'I
Pool ......
cute -... ----:~~ic:III_. lI'''Ii''.'lI~
AnI.
c;utaneou'li
Amerior diVISIon P",·nell -..:=ftM!
branch brol\dl
at obturtHOr n
Me<! br of Inl
cutaneous n.
Saphenou. n .
,1U~~- CommOn
peIOM •• 1
SVII\f.ltelal
JlU11\J11th.1 n
Deep
paroneal n --
Figure 8-11. Nerves of the Right Lower Extremity

Posterior Vuw: The medial and lateral sural cuta-
neous nerves have been shifted in position by the dissec-
Figure 8-10. Ne1'1les of the Right Lower Limb tion. Note a) The relationship of the sciatic ne1'1le to
Anterior Vuw: Note the emergence of the femora~ possible sites of intramuscular injection into the but-
obturator and lateral femoral cutaneous nerPes into tock. b) The relationship of the tibial and peroneal
the upper anterior thigh. The relatively superficial nerves to the popliteal fossa, c) The relatively exposed
course of the common peroneal nerve as it passes position of the peroneal ne1'1le in relationship to lateral
around the head of the fibula from posterior - calf head offibula (not fully dissected), d) Relatively
(popliteal) location to anterior calf is best seen in Fig. superficial position of the tibial nerPe behind medial
8-11. (From Clemente, G.: Gray's Anatomy, 30th Ed. malleolus of ankle. (From Clemente, G.: Gray's
1985,p.1231). Anatomy, 30th Ed. 1985, p. 1238)
Over the subsequent 9 months significant most common example of an acute rapidly pro-
improvement occurred so that she was able to gressive polyneuropathy. (Acute idiopathic
ambulate with a cane. polyneuritis, acute inflammatory demyelinat-
ing poly infectious polyneuropathy, Landry-
POLYNEUROPATHIES: Guillain-Barre Disease).
Polyneuropathies may be classified from This is a rapidly progressive predominantly
several standpoints: motor peripheral neuropathy that evolves over
1. Predominantly motor vs. predominantly 10-14 days and affects legs, arms and in many
sensory vs. predominantly autonomic vs cases cranial nerves. In some cases there is pro-
mixed. gression to involve the muscles of respiration.
2. Acute vs. subacute vs chronic Sensory symptoms are present but in most
3. The site of pathology: a) axonal- "dying cases sensory findings are minor compared to
back phenomena" -distal degeneration as in the motor findings. In severe cases, tracheoto-
metabolic diseases or arsenic intoxication. b) my and mechanical respiratory assistance may
Segmental demyelination with the preservation be required. Prior to the era of modern respi-
ofaxons - as in the immunological post infec- ratory assistance, the death rate was as high as
tious polyneuropathy or some connective tis- 25%.
sue disorders or chronic lead poisoning. The essential pathology consists of perivas-
4. Etiology: Major categories. cular lymphocytic infiltrates, perivenous seg-
a) Infection - leprosy. mental demyelination. Nerve roots as well as
b) Inflammation: Vasculitis - periarteritis. peripheral and cranial nerves are involved. In
c) Immune disorders. more severe cases, axons as well as myelin are
d) Intoxications: Arsenic, lead, anti neo- involved with secondary Wallerian degenera-
plastic agents, industrial chemical exposures) tion. In very severe cases, with involvement of
e) Metabolic disorders: nutritional deficien- the proximal nerve or nerve root, the motor
cies of B vitamins, diabetes mellitus, and ure- neuron may also be damaged and destroyed.
mia, critical care unit neuropathies The cerebrospinal fluid is usually without a cel-
f) Degenerations: hereditary. lular reaction but does shown an increase in
g) Tumors: neurofibrobromas, protein that peaks several weeks after onset. In
schwannomas. most cases, slowing of motor nerve conduction
From a practical standpoint, the usual will be demonstrated, consistent with a
approach is to combine the several types of demyelinating peripheral neuropathy. Acute
classification. motor axonal neuropathy is a variant in which
1. First classifY as to acute, subacute or motor axonal degeneration occurs with only
chronic. minimal demyelination and inflammation. In
2. Then classifY as to predominantly motor the Miller Fisher variant or syndrome, a gait
or sensory or autonomic. The majority are ataxia, areflexia, and ophthalmoplegia are pre-
mixed. sent but limb weakness is absent and nerve
3. If possible classifY as to axonal, or conductions are normal, although CSF protein
demyelinating based on EMG /nerve studies is increased. There are also sensory and auto-
and in some cases; on nerve biopsy. (A survey nomic variants.
of peripheral nerve histopathology is presented The underlying pathogenesis of the syn-
in Fig.8-12--8-16) drome is now apparent. In 60-70% ofpatients,
4. Then classifY as to etiology. a viral respiratory or gastrointestinal inftction
has occurred 1-2 weeks prior to the onset of the
Acute progressive motor neuropathy with neurological symptoms. Other patients have
variable sensory features. experienced infectious mononucleosis, viral
The Guillain Barre Syndrome provides the hepatitis, other viral illnesses, surgical proce-
8-16 CHAPTER 8
Figure 8-12. Histopathology of Peripheral Nerve I Figure 8-13. Histopathology of Peripheral Nerve II.
Wallerian Degeneration. Considerable necrosis and Chronic Axonal neuropathy. A marked loss of myeli-
degeneration ofaxons, myelin, and Schwann cells has nated fibers has occurred. However these are clusters
occurred. The field is dominated by large macrophages ofaxons surrounded by a thin myelin sheaths suggest-
containing remnant ofaxons, myelin, fat globules etc. ing that regeneration ofaxons has occurred.
("Digestion Chambers"). Toluidine Blue x 100 Toluidine Blue X 100. Courtesy of Dr. Tom Smith,
(approx.). Courtesy of Dr. Tom Smith, Neuropathology,
U. Mass. Medical School. Ropper 1992). Glucocorticoid steroids usually
have no significant effect although massive
dures or immunizations - (old type of serum intravenous therapy (1 OOOmg / day of methyl-
antibodies vaccine, swine influenza vaccine of prednisolone) in uncontrolled trials has been
1976). The acute motor axonal neuropathy reported to have a possible effect.
variant appears to follow infection with.the gas- The following case history 8-5 provides an
trointestinal agent: Campylobacter jejuni. example of a mild case of this syndrome.
The pathological and clinical manifestations
of the disease are considered to reflect an Case 8-5: Approximately two weeks after
immunological reaction directed at peripheral influenza infection, this 7l-year-old right-
nerves. A similar syndrome - experimental handed male awoke with tingling of the plan-
allergic neuritis has been produced in rabbits tar surfaces of his feet, unsteadiness and weak-
and other laboratory animals 2 weeks after ness at the knees. Over the next 10 days, he
immunization with homogenized peripheral experienced a gradual decrease in lower
nerve (Waksman and Adams 1955). Sera from extremity power but no progression of the sen-
patients with the syndrome react with multiple sory symptoms. He denied low back pain,
antigens in peripheral nerve. The levels ofIgM bowel or bladder symptoms.
antibodies against peripheral nerve-myelin cor- Neurological examination: Motor Systems:
relate with the disease course. Sera from some Weakness was present in the lower extremities
patients with Guillain Barre Syndrome will both proximal and distal slightly greater on
produce demyelination in neuronal tissue cul- right than left. Reflexes: A minimal dysmetria
ture (McFarlin in Asbury and Gibbs 1990; was present in the upper extremities. All deep
Keski in Dyck 1993). tendon stretch reflexes were absent in upper
In more severe cases, plasmapheresis is now and lower limbs except for a trace triceps.
employed. In the cases treated by the Guillain Plantars demonstrated no response to stimula-
Barre Study Group (1985) within two weeks tion. Sensory System: There was a mild decrease
of onset, there was a definite reduction in the in pain and temperature sensation over toes.
length of time for hospitalization, for mechan- Perianal sensation was normal. To a greater
ical respiration and for resumption of walking. degree, position and vibratory sensation were
More recent studies have suggested that intra- decreased in the toes.
venous immune globulin-G maybe even more Clinical diagnosis: Guillain Barre syn-
effective (for a review of current concepts see drome: acute post infectious polyneuropathy.
Laboratory data: CBC, glucose, renal bolic producing a distal symmetrical sensory,
functions, liver functions, electrolytes, protein motor neuropathy often with painful feet
immunoelectrophoresis and ESR (40mmjhr) (dysesthesia and hyperesthesia)
and MRI of the spine were all normal. CSF: 1) Nutritional deficiencies of B vitamins:
protein was increased to 206 m~A" with 0 thiamine, pyridoxal phosphate, and folic acid,
white blood cells and a glucose of 76m~A,. B12, (often multiple) are frequently encoun-
Serological tests and cultures were negative. tered. a) In association with alcoholism b) in
EMG/nerve conduction studies demonstrated chronic elderly intensive care patients -"critical
slowing of motor nerve conduction velocity. - illness polyneuropathy of Bolton et. al., 1993
consistent with a demyelinating neuropathy. c) in the "dry" or neuropathic form ofberi beri
Course: the patient's condition stabilized seen in prisoner of war camps, in famine, or in
and he was transferred to a rehabilitation fa.ci1- underdeveloped parts of the world.
ity. 2) Heavy metal intoxication) Arsenic - dis-
Other causes of the syndrome of acute pro- tal sensory motor. A more acute form associat-
gressive motor neuropathy: ed with acute arsenic intoxication also occurs
1) The exotoxin produced by the bacillus, c. .b) Lead - predominantly motor with greater
Diphtheria: pharyngeal and laryngeal muscles involvement of the upper extremities (wrist
are affected 1-2 weeks after the pharyngeal drops due to radial nerve involvement).
infection followed by a general polyneuropa- 3) Hexacarbon industrial solvents used in
thy: arms then legs after 4-5 weeks. glues and plastic production n-hexane and
2) Acute intermittent porphyria is inherited methyl-n-butyl ketone (see Spenser et al
as an autosomal dominant trait. A metabolic 1975).
defect in the liver results in increased produc- 4) Other industrial agents: acrylamide,
tion of and high urine levels of porphobilino- trichloroethylene.
gen and its precursor delta aminolevulinic acid 5) Medication induced: a) Isoniazid (INH)
(involved in hemoglobin metabolism). The for treatment of tuberculosis -produces a pyri-
severe motor neuropathy may be accompanied doxine deficiency. b) Nitrofuradontins used for
by abdominal pain or psychosis or convulsions. the treatment of bladder infection) Anti-neo-
Anticonvulsants, barbiturates, sulfa drugs and plastic agents including: cis-platinum and vin-
estrogens may trigger attacks. cristine d) Thalidomide no longer available
3) Toxic polyneuropathies: once marketed as a tranquilizer e) Drugs used
a) Triorthocresylphosphate :the so-called to prevent seizures (anticonvulsants )-pheny-
Jamaican Ginger polyneuropathy seen during toin is the most prominent in this group - usu-
the prohibition era reflected contamination of ally the syndrome is subclinical.
bootleg alcohol by this agent). b) Thallium 6) Uremic polyneuropathy occurs in 60-70%
salts. patients with chronic renal failure. The syn-
All of these acute polyneuropathies as well drome clears slowly with renal transplantation.
as many subacute and chronic polyneu- Chronic polyneuropathy: Common caus-
ropathies are characterized by an acellular cere- es are as follows:
brospinal fluid that often has an increased pro- 1) Diabetes mellitus: distal symmetrical pre-
tein content. dominantly sensory - axonal - peripheral neu-
Acute polyneuropathies are distinguished ropathy (see case 4 above) etiology is not clear
from subacute and chronic polyneuropathies. but may involve accumulation of glucose, fruc-
There is no clear-cut distinction, subacute may tose and sorbitol in nerves). Autonomic neu-
evolve into chronic over years. ropathies or painful distal neuropathies may
occur. Successful pancreatic transplantation
Subacute Polyneuropathies: may halt progression of the disease (Kennedy
The common causes are toxic and meta- et al1993).
8-18 CHAPTER 8
2) Remote effects of malignancy: carcinoma 3) Bassen Kornsweig Syndrome - a rare auto-

of lung, ovary, and breast. Mixed sensory somal recessive syndrome which begins in
motor or motor or selective sensory. infancy - the metabolic defect is a deficiency of
3) Complications of connective tissue disor- beta lipoprotein and of cholesterol. As above,
der: periarteritis, rheumatoid arthritis. In some peripheral nerve, cerebellum, heart, and retina
cases this is a complication ofHIV infection. are all affected. In addition - fatty stools,
4) Leprosy: the most common world wide (steatorrhea) retarded growth and an abnormal
infectious cause of peripheral neuropathy appearance of red blood cells (acanthocytosis)
5) Chronic inflammatory demyelinating is present.
polyneuropathy (CIDP) Subacute-chronic 4) Familial dysautonomia (Riley-Day
"Guillain Barre Syndrome" progressive or Disease). A deficiency of serum dopamine B
relapsing remitting form of the more common hydroxylase, the enzyme that converts
acute idiopathic polyneuropathy. These disor- dopamine to norepinephrine results in severe
ders occur on an immunological basis; compo- abnormalities of the sympathetic autonomic
nents of peripheral nerve are the targets of the nervous system. In addition, small myelinated
immune system. These neuropathies are often and unmyelinated fibers are involved produc-
very responsive to the administration of ing a selective loss of pain and temperature sen-
steroids such as prednisone or drugs that mod- sibilities.
ifY the immune system (immunoglobulin G) or 5) Porphyria in contrast to the previous
to plasmapheresis. (Refer to Dyck, et al1981, processes produces an acute syndrome (see
and Dalakas et al. 1981). Some of these cases above).
are associated with HN infection. (See B. Mixed sensory motor inherited polyneu-
Cornblatt, 1981). ropathies without a clearly defined metabolic
6) Abnormalities ofplasma proteins usually abnormality. In the series of 205 patients
a monoclonal abnormality of immunoglobulins referred to the Mayo Clinic (Dyck et al1981)
(multiple myeloma, macroglobulinemia, cryo- with chronic polyneuropathies of unknown
globulinemia and benign monoclonal gam- cause, 86 or 42% were found to have an inher-
mopathy). ited disorder of this type.
7) Hereditary peripheral neuropathies. The most common disorder in this group is
A. Those disorders in which a specific metabol- peroneal muscular atrophy -Charcot Marie
ic defect has been identified. Several may be Tooth Disease (CMT). This disease is inherit-
cited. ed as an autosomal dominant. Distal motor
1) Familial amyloid polyneuropathy autoso- involvement is prominent. Sensory fibers are
mal dominant (Andrade type). Amyloid accu- less involved. There are often associated mal-
mulates in blood vessel walls and in the formations of the feet pes cavus (high arches).
endoneurium. An often-painful syndrome Relatives may manifest minimal, minor or par-
begins in the adult with sensory and autonom- tial forms of the diseases which are sometimes
ic symptoms and slowly progresses to a full asymptomatic - so called "forms fruste". The
polyneuropathy over 10-15 years. age of onset is usually in the second or third
2) Reftum Disease. Hereditary ataxic decade, occasionally later. More recent studies
polyneuritis (Autosomal recessive). Phytanic have suggested at least two major forms of the
acid (a fatty acid) accumulates in blood and disease referred to as hereditary motor sensory
nerves. The symptoms begin in late childhood neuropathy I & II, (HMSN I & II) and sever-
or adolescence. In addition to a peripheral al minor forms (HMSN III-VII). (Refer to
neuropathy, cerebellar ataxia, a degeneration of Asbury 1992, and Harding and Thomas
the retina (Retinitis pigmentosa) neurogenic 1980).
deafuess and a degeneration of cardiac muscle HMSN Type I is characterized by
(cardiomyopathy) are present in most patients. demyelination with the hypertrophic onion
bulb changes that are seen when demyelination previously cited, 24% of patients remained in
and remyelination has occurred (Fig. 8-14). the unknown etiology category.
The nerves may also be grossly enlarged. A
marked reduction occurs in nerve conduction DISORDERS OF THE NERVE ROOT:
velocity. Three subtypes have been identified: RADICULOPATHY:
CMT lA,CMT 1B and CMT 1 C. All of these
The major problem affecting the nerve
subtypes are transmitted as an autosomal dom-
root is compression by a ruptured disk or by
inant and have slow conduction implying a
osteophytes projecting into the neural foramen
demyelinating disorder. Type CMT lA
from the degenerative process affecting the
accounts for 60% of all hereditary peripheral
disks (spondylosis).
neuropathies and is linked to a point mutation
These processes primarily involve the cervi-
occurring on chromosome 17 at the PMP 22
cal and lumbar areas. These problems are
gene segment. This gene encodes myelin pro-
among the most frequently encountered in the
tein and appears to be duplicated (Roa et al
neurological office. In the cervical area the C
1993). Type CMT IB has been linked to chro-
5-C 6 and the C6-C7 interspaces are most fre-
mosome l.
quently involved with compression of the C6
HMSN Type II (CMT 2) has a somewhat
or C 7 nerve roots nerve roots Less often the
later age of onset. Nerve conduction velocity is
C5 or C 8 nerve roots are involved. The rela-
normal; there is no histologic evidence of
tionship of the disc space to the nerve root and
demyelination. The underlying pathology is
to the spinal cord is demonstrated in Figure 8-
considered neuronal. Most subtypes 2A-2D
17.
have autosomal dominant inheritance
In the lumbar area the L 4--5 (L5 nerve
HMSN Type III -Dejerine Sotta)s neuropa-
root) and L5-S1 (Sl or L5 nerve root) inter-
thy - (CMT-3) is a less common but more
spaces are most frequently involved. Less often
severe recessive or autosomal dominant disor-
the L3-4 or L2-3 disc interspaces are involved
der beginning in the first decade of life with
with involvement of the L4 or L3 nerve roots.
both sensory and motor features. The disorder
In the diagnostic analysis of a radiculopathy
may map to lq or 17 p or to other sites. The
the following features should be considered:
essential pathologic change is demyelination
1) The acute onset of pain in the limb in a
with subsequent remyelination to produce the
radicular distribution (Fig.8-1) with associated
hypertrophic onion bulb formations (Fig 8-
pain in the neck or lumbar spine.
15). Nerves are grossly enlawed to palpation;
2) In general the radicular pain is out of the
progression is more rapid and disability greater.
proportion to the neck or back pain.
Case 8-6 presented on CD ROM provides
3) The radicular pain is described a sharp,
an example of a patient with autosomal domi-
shooting, burning, or electric shock or tooth
nant Charcot Marie Tooth disease and slow
ache like pain. The pain is exacerbated by
nerve conduction consistent with type lA.
maneuvers that suddenly increase pressure
8) Unknown Cause: Even when the patient
within the CSF space, for example coughing,
has been fully investigated in a specialized cen-
sneezing or straining at stool.
ter, a specific etiology may still not be found.
4) Radicular sensory symptoms plus or
In the Mayo Clinic series (Dyck et al 1981)
minus radicular sensory findings may be pre-
Figure 8-14. Histopathology of Peripheral Nerve III Segmental demyelination: Teased nerv~ fiber preparation.
This 7411: old man had a peripheral neuropathy associated with aJmor~liPy ofplt:uma protem (monoclonal.
cryoglobulinemia). Courtesy of the authors, Lippa, G.F., Chad, D.A, Smtth, T.w" Kaplan, M., Hammor, K..
Muscle and Nerve: 626-631,1986 (Wiley).
8-20 CHAPTERS
Figure 8-15. Histopathology of Peripheral Nerve IV

Hypertrophic "onion bulb" neuropathy. Repeated
episodes ofsegmental demyelination and remyelina-
tion may result in finely myelinated axons surround-
ed by whorls of uverlapping intertwined processes of
&hwann cells. In addition, this microscopic field
demonstrates a significant decrease in total numbers
offibers and a significant increase in connective tis-
sue. Toluidine Blue X63 (Approx.). Courtesy ofDr.
Tom Smith.
Figure 8-16. Histopathology of Muscle III Neurogenic
sent Atrophy in a patient with Charcot Marie Tooth
5) Selective weakness of muscles supplied Disease, Grouped atrophy is evident. H&E X 63
by a specific cervical or lumbar nerve root may (Approx.) Courtesy ofDr. Tom Smith.
be present. In considering sensory symptoms as com-
6) Selective depression of a deep tendon pared to sensory findings, when there is
stretch reflex supplied by a specific cervical or involvement of a single nerve root, it is impor-
lumbar nerve root may be present. tant to note that sensory symptoms (radicular
7) In restricted lateral disk herniations in pain and paresthesias) may be present although
the cervical area, no long tract sensory or the examination demonstrates no actual senso-
motor or reflex findings should be present that ry deficit as regard pain or touch sensation.
is there is no evidence for an upper motor neu- This is a reflection of the fact that there is an
ron lesion. In restricted lateral disk herniations overlap of radicular sensory fields. Thus one
in the lumbar area no bladder symptoms half of the dermatome of C-7 is also supplied
should be present. by C-6 and the other one half by C-8 (Fig.8-
8) With midline herniations in the cervical 19a). The total sensory field then for a single
area, signs of spinal cord compression may be nerve root is therefore more extensive than
present and are considered below in chapter 9. demonstrated in the standard sensory diagrams
9) With midline herniations in the lumbar (Fig.8-19b).
area, urinary retention and a disturbance of The following case history (8-7) provides
sexual functions may be present due to involve- an example of lumbar root compression sec-
ment of the cauda equina. ondary to a herniated disk.
The usual distribution of hypalgesia and of
radicular pain in the upper extremity is demon- Case 8-7: This 37 year old right-handed
strated in figure 8-18. See also figure 2-1 for white female day care worker in relationship to
the lower extremity heavy lifting had the acute onset of persistent
pain in the lumbosacral area shooting as a sharp
+-~--------SPINOUS PROCESS
A--~;==="-"-----PIA
NA.--~ EPIDURAL SPACE
, ~~~!5"-!t-~------- ~URA
~ ARACHNOIO
I!(-~------
~E:""~~;:::::--- SUBARACHNOIO SPACE
~L~~mi:1!tT>,. -~+---ARTICULAR FACET

~~~=-'~ __ POSTERIOR ROOT
.....~.....- - DORSAL ROOT GANGLION
".Aa;t:a.·,. I,.~~;;;,.....--VERTEBRAL
" ..nalv.r .... ARTERY
~...Joo!I---INTER"ERTEBRAL. FORAMEN
-~l....Ioo:------ __ INTERVERTEBRAL OISC
Figure 8-17. Anatomic Relationships of the Cervical Spinal Cord and the Cervical Intervertebral Discs. lAteml
and midline disc protrusions are indicated. (Modified after Frykholm, Aaa. Chir. &and. 101:345, 1951).
pain into the left buttock.. One month later, she toe extensors, ankle dorsiflexors, everter and
developed numbness left posterior thigh and inverters with mIDor atrophy in the calf.
left posterior calf to the ankle. Three months Reflexes: The Achilles deep tendon stretch
later, she had the acute onset of severe pain in reflex was absent on the left compared to active
the lumbar area now extending to the posteri- ( 3) right Achilles and both patellar reflexes.
or thigh and subsequently to the posterior calf Sensory System: Pain sensation was markedly
as a shooting pain. Tingling paresthesias now decreased on the left side over the L5 and Sl
extended into the small toes. The pain in the dermatomes and to a considerable degree over
leg was triggered by coughing or straining at S2-5. On straight leg rising, pain was present in
stool. Despite a prolonged period of bed rest, both leg and back at 45-50 degrees on the left.
pain medication and non-steroidal anti-inflam- Maneuvers: On palpation, there was marked
matory agents, no improvement occurred. tenderness over the left sacroiliac area and over
Neurological Examination (6 months the left sciatic nerve at the sciatic notch and
after onset of symptoms): Motor System: over the left posterior tibial nerve behind the
Significant weakness was present on the left at medial malleolus of the ankle. The patient was
8-22 CHAPTERS
in severe pain sitting, standing or recumbent.

Clinical Diagnosis: Rupture of disk with
involvement of nerve roots L5, Sl and proba-
bly cauda equina.
Laboratory data: MRI, (Fig.S-20)
demonstrated a massive rupture of the disk on
the left at the IA-L5 level with inferior exten-
sion and marked compression of the cauda
equina.
Subsequent course: The patient eventual-
ly agreed to removal of the ruptured disk, 5
weeks after the initial neurological evaluation.
She had some relief of pain but over the next 3
years she continued to have a foot drop with
significant weakness at left ankle and toes, an Figure 8-18 Dermatome charts of the upper extremity
in man outlined by the pattern of hypalgesia, following
absent left Achilles reflex, and sensory deficits
rupture of an intervertebral disk. From Keegan, IJ.,
over the left L 5 distribution. and Garrett, RD.: Anat. Bec., 102: 417, 1948 (Wiley).
Most patients (75%) with a more limited
lumbar radicu10pathy respond to a period of steroidal anti-inflammatory agents, modifica-
strict bed rest for 3 to 5 days on a firm mattress tion of posture, heat or cold and weight loss if
and bed board, nonsteroidal anti inflammatory indicated are appropriate measures. Activities at
agents, heat or cold and possibly the temporary work may have to be temporarily modified, use
use subsequently of a back support. Those who of a support belt or corset may be indicated.
fail this therapy may require local steroid injec- For cervical radicu1opathy, at home cervical
tion or surgical therapy. Only if surgical thera- traction, a cervical collar, cervical, pillow and,
py is a consideration should MRI studies be nonsteroidal anti-inflammatory agents are usu-
obtained. ally effective. Most (75%) patients will usually
Benign non-malignant back pain alone, respond to these measures. When these mea-
either acute or chronic is an extremely com- sures fail and radicular symptoms and findings
mon complaint Usually it is benign in nature. persist, surgical therapy may be considered. At
However a complete history and general phys- such a time MRI scans is appropriate.
ical examination is indicated to identifY imme- The following case history 8-8 demon-
diate precipitating events. In addition, the his- strates the effect of a ruptured cervical disk
tory should survey for, any past history of producing compression of a cervical nerve
malignancy, or change in bowel habits, urinary root.
pattern or menses etc. A rectal and or pelvic
Case 8-8: This 45 year-old right-handed
examination is indicated particularly when
married white female educational coordinator
there is no clear-cut history of trauma. In the
2 weeks prior to evaluation had the acute onset
middle aged or older male patient, appropriate
pain in the neck radiating into left arm with
laboratory studies to rule out prostatic malig-
pain and tingling in the index and middle fin-
nancy are indicated (prostatic specific anti-
ger of the left hand. The pain would shoot
gen/antibody-PSA). If such a survey is nega-
into the arm is she coughed or sneezed or
tive and no neurological symptoms or signs are
strained to move her bowels. 4 months previ-
present, then neurological consultation and
ously the patient had experienced pain in the
lumbar MRI scan are not indicated. Plain films
neck extending to the left shoulder area but
of the lumbar spine will usually suffice to rule
that symptom had cleared. In the last several
out orthopedic disease. Such benign back pain
days prior to consultation the patient had
does not require a course of bed rest. Non
developed twitching of biceps and triceps mus-
cles. She had no leg or bladder symptoms.
Neurological examination: The left tri-
ceps deep tendon stretch reflex was absent or
reversed. Pain sensation was decreased over the
left index and middle fingers. Neck motion was
limited for extension and rotation and there
was tenderness over the spinous processes of C
7 and Tland over the left supraclavicular area.
Clinical diagnoses: Cervical 7 radiculopa-
thy secondary to lateral rupture of disk.
Treatment: The use of cervical traction,
cervical collar, nonsteroidal anti inflammatory
agents, various pain and anti muscle spasm
agents, epidural injection and various measures
in physical at therapy for 4 weeks failed to pro-
duce any relie£ Pain was now predominantly in
the arm and her examination now demonstrat-
ed additionally significant weakness at the left
triceps muscle. MRI (fig 8- 21) demonstrated a
lateral disk rupture at the C 6 -7 interspace.
The patient underwent a left sided laminecto-
my at that level with removal of ruptured disk
material. She had a resolution of symptoms
except for a minor residual tingling, a decrease
in pain sensation over the index finger, and a
mild decrease of the left triceps deep tendon
stretch reflex.
Schwannomas arising from the nerve root:
These tumors arise from Schwann cells of the
peripheral nerve or nerve root. When the
nerve root is involved the tumor may be pre-
sent within the bony canal and/or external to
the bony canal. The tumor may enlarge the
neural foramen. Depending on the size and
location of the tumor the nerve root alone may
be involved (Fig.8-22) or the spinal cord may
also be involved (refer to chapter 9). When the
Figure 8-19 A) Method of mntIining sensibility tv tumor arises from a nerve root within the
demonstmte the sensory skin field of II nerve root. cauda equina, multiple nerve roots may be
Shemngtvn seaioned three roots lIbwe lind three below involved. (Fig.8-23).
the intllet root tv be studied. In this dilJ81'lIm the fIVer- Tabes Dorsalis: this late complication of
IIIp of the third lind fifth thorllCic spi1UJl roots is
syphilis involving the nervous system is a result
demonstmted. (From RRnsom, s., lind ClRrk, s.: The
Anlltvmy of the NerT101U System, 10th Edition. of the infectious agent, the spirochete involv-
PhiltuielphitJ, W. B. SIIuntiers, 1959, p.129). ing the posterior (dorsal) root and to some
B) 1JermIItomes in mIIn tiemonstrllted by the method extent the dorsal root ganglion producing sec-
of mntIining sensibility. (From Lewis, T.: Pllin. New ondary degeneration in the posterior columns.
York, MlICmilllln, 1942, p. 20, lifter Foerster). Disease of the dorsal root ganglion: The
8-24 CHAPTERS
lancinating pain in a radicular distribution.

Within 3 or 4 days, the involved dermatome
demonstrates a vesicular eruption. The tho-
racic derma tomes are most frequently
involved. In approximately 20% of cases, cra-
nial nerve root sensory ganglion are involved
most often cranial nerves 5 (primarily the oph-
thalmic division) and 7. Although the dorsal
root ganglion is primarily involved, occasional-
ly the anterior root or horns are involved pro-
ducing atrophy and weakness. Rarely, the
spinal cord is involved, producing a clinical
myelitis. The anti viral agent, acyclovir is effec-
tive in reducing the course of disease. Post her-
petic neuralgia is the term applied to the per-
sistent severe pain occurring in 20% of patients
one month after the rash has healed. The
occurrence of this chronic pain syndrome is
more frequent in elderly patients; 75% of
patients with H.Zoster who are over the age of
70 years continue to have severe pain one
month after healing of the cutaneous lesions.
Treatment with lidocaine skin patches, the tri-
cyclic antidepressant nortriptyline or the anti-
convulsant gabapentin or oral opioids may pro-
duce a moderate reduction in pain in some of
these patients. A recent study has demonstrat-
ed the effect of intrathecal methylprednisolone
in patients who were still refractory at one year
(Kotani et al2000).
The herpes simplex virus may also remain
dormant in the sensory root ganglion and may
Figure 8-20: Laural protrusion of a Lumbar disc:
Case 8-7: lumbar radiculopathy MRI A) sagittal sec- be activated to produce radicular pain. With
tions B) transverse section. the type 2 virus (vaginalis), the sacral segments
are often involved, and urinary retention may
major disease involving the dorsal rootganglia is
occur.
infection by the herpes zoster/varicella virus. In
actuality this is a reactivation of a virus remain-
ing dormant in the dorsal root ganglion after
previous varicella (chickenpox) infection.
Diseases that alter the immune system such as
infection, e.g. HN, or lymphomas may activate
the virus and in some cases generalized zoster
may occur. Ten-25% of patients with general-
ized lymphoma will develop H.Zoster. In addi-
tion local irritation of a nerve root or a prima-
ry neoplastic process arising in organs closely
related to the dermatome may activate the
virus. The clinical disorder begins with sharp
Figure 8-22: Schwannoma of nerve root at L2level.

MRI. This 53-year-old female had an 18-month histo-
ry ofprogressive low back pain that began to radiate to
the right foot with numbness of the lateral aspect of the
right foot and numbness of left thigh. Examination
demonstrated only decreased pain sensation of the left
anterior thigh and lateral aspect of the right foot. An
MRI of the lumbar spine demonstrated a circum-
scribed Schwannoma at the lumbar-2 level, subse-
quently removed by Dr. Alex Danylevich.
Figure 8-23. This 23-year old ftmale had multiple

Figure 8-21: Lateral protrusion of a Cervical disc: neurofibromas. In this cr scan a Schwannoma at the
Case 8-8: Cervical radiculopathy. MRI A) sagittal sec- lumbar level is demonstrated.
tion B) transverse section.
CHAPTER 9
Spinal Cord:
Clinical Considerations
Disease affecting the spinal cord is a fre- TABLE 9-1. CONSEQUENCES OF EXTRINSIC COMPRESSION
quent cause of chronic neurological disability. OF SPINAL CORD
Often, young adults are involved as in injuries
due to war, motor vehicle accidents, motorcy- Symptoms Anatomical correlation
cle accidents, diving and skiing accident. and signs
Special units have been developed for the care,
1. Radicular pain Posterior root and ganglion
and rehabilitation of the unfortunate victims of at level of
these injuries. Early recognition and manage- compression.
ment of a potential spinal cord compromise is
essential. 2. Radicular sensory Posterior root and/or
symptoms at posterior hom
It is important to differentiate extrinsic
level of
(compressive) and intrinsic diseases of the compression
spinal cord.
Continued spinal cord compression will 3. Segmental Segmental lower motor neuron
produce irreversible damage. For extrinsic dis- atrophy, findings due to Involvement of
weakness and the anterior hom cells and
eases, surgical therapy is then indicated as early fasclculatlons, at anterior roots.
as possible. level of
In general, extrinsic compressive lesions compression
(Table 9-1) manifest a number of local seg-
mental features at the level of the lesion as well 4. Segmental Involvement of the anterior root and
depression of anterior hom or of posterior root and
as long tract findings below the level of the deep tendon or hom. The monosynaptic reflex
lesion. stretch reB exes arc has been interrupted as regards
.Acute spinal cord compressions or transits afferent or elferent component
actions: The phenomena of spinal shock
5. Long tract a. Spastic (UMN) weakness,
and the pattern of reflex recovery: After the
findings below increased deep tendon reflexes &
acute and sudden loss of supra segmental con- the level of the Babinski sign (extensor plantar
trol, a temporary depression of segmental lesion: response) due to damage to
reflex activities occurs. Deep tendon stretch descending pyramidal tracts.
reflexes are depressed. Cutaneous and auto- b. Spastic neurogenic bladder due to
nomic reflexes may also be affected. The bilateral involvement of UMN control
with release of the segmental
excitability of alpha and gamma motor neurons bladder stretch reflexes.
and of interneurons is depressed. This is more C. Deficits in position, vibration,
prominent in man than in species such as the and other proprioceptive and light
cat or dog related to the progressive encephal- touch sensation due to posterior
ization of function that has occurred in the pri- column damage.
d. Deficits In pain and temperature
mates. In the frog, the duration is fleeting; in
sensation due to lateral
the cat, spinal shock lasts a matter of minutes or spinothalamic pathway damage.
hours. In the monkey duration is a matter of
days or weeks. In humans, the duration is usu-
ally of several weeks. In the cat or dog spinal cortical spinal tracts. It is important to note
that the depth and duration of spinal shock
shock follows damage to the vestibulospinal
and ventral reticular spinal tracts. In primates, depends on the rapidity (acuity) and complete-
spinal shock depends more on damage to the ness of spinal cord section. Slowly evolving
chronic spinal cord compressions are not char-
9-2 CHAPTER 9
acterized by spinal shock. Fever or infection capabilities may consist of crossed extension,
will prolong the duration of spinal shock or (the contralateral lower limb extends when the
may result in a recurrence of spinal shock once ipsilateral will lower limb is responding to a
recovery has occurred. Immediately after an painful stimulus by flexion). Sweating below
acute transection, the patient will demonstrate the level of transection may not return for 3-4
a depression of all the deep tendon stretch months. In the cat and dog-alternate flex-
reflexes and to a lesser degree the flexion reflex- ion/extension, alternate stepping and in high
es. The limbs will be flaccid and paralyzed. The cervical preparations inter limb reflexes may
bladder will be flaccid that is hypotonic or occur (the upper limb movements are appro-
atonic due to depression of the bladder stretch priately triggered by lower limb responses).
reflex. Within a short period of time (1 - 5 With marked extensor tone, a partial capacity
weeks), the flexion reflexes including the sign for brief periods of standing may return.
of Babinski will recover and remain prepotent. Clearly there is a phylogenetic factor; such
The flexion reflex, (the withdrawal of the foot extensor capabilities are more limited in the
and leg on painful stimulation) is a polysynap- spinal human. In comparison the capabilities of
tic reflex. The afferent component of the reflex the frog or chicken with a high cervical tran-
arc is mediated by group II and III myelinated section are well described in common
fibers and group IV unmyelinated fibers, from terminology.
a variety of receptors in skin, muscle, and The Brown Sequard hemisection syn-
joints. Initially in the human, the flexion reflex drome (Table 9-2): Transactions of the lat-
may be manifested as a mass reflex. When fully eral one-half of the spinal cord or lateral com-
developed, this mass reflex may consist of gen- pressions of the spinal cord for example by
eralized reflex flexor spasms of the muscles of tumors such as Schwannomas, meningiomas or
the trunk and lower extremities accompanied metastases will produce a classical syndrome
by sweating, emptying of the bladder and in which reflects the anatomy of the spinal cord
males penile erection and ejaculation. Initially, and of the spinal cord pathways.
the receptive field for triggering this response is The progressive subacute or chronic
quite extensive, involving any tactile or noci- anterior midline compression syndrome:
ceptive stimulus to the foot, leg, abdomen or The spinal cord is gradually compressed back-
thorax. With the passage of time, the mass wards against the bony canal elements. Based
reflex becomes less prominent and local sign on the clinical and experimental studies of
develops. The more specific reflex movement Tarlov, the following sequence is often noted.
then depends on the more specific location of Initially the symptoms and signs will be rel-
the stimulus. For example, a painful stimulus to evant to posterior columns followed by symp-
the outer border results in flexion, inversion, toms and signs of lateral column involvement
and adduction as opposed to a similar stimulus and finally by symptoms and signs relevant to
to the inner border of the foot that results in the lateral spinothalamic system. From a clini-
flexion, eversion, and abduction. The mass cal standpoint, the initial symptoms may con-
reflex may return if fever or infection occurs. sist of a numbness of the lower extremities and
Over a number of weeks to months depending a sensory ataxia. An ascending spastic weak-
on the completeness of transection (longer if ness of the lower extremities will then develop
complete), stretch reflexes with other extensor followed by an ascending deficit in pain and
reflexes and postures will return. The deep ten- temperature sensation. Such a pain and tem-
don stretch reflexes will then become hyperac- perature deficit will initially involve the sacral
tive. There will be a spastic rather than a flaccid segments then lumbar segments followed by
weakness. Bladder emptying and bowel evacu- the thoracic segments and finally the lower cer-
ations return 3 to 4 weeks after injury. The vical segments. This sequence reflects the lam-
bladder will subsequently become hypertonic ination pattern of the lateral spinal thalamic sys-
that is spastic with small capacity. The extensor tem in which sacral segments are most extrin-
SPINAL CORD: CLINICAL CONSIDERATIONS 9-3
TABLE 9-2 CLINICAL SIGNS IN BROWN SEQUARD course of spinal cord compression the apparent
SYNDROME level of sensory deficit will be considerably lower
than the actualleve! of compression.
Deficit Cause of Clinical Deftcit It is important to recognize that slowly
evolving extrinsic lesions (such as intradural
Aspastic weakness below and Injury to the lateral
ipsilateral to the side of column/cortical spinal meningiomas and neurofibromas) despite con-
transection/damage system. siderable distortion of spinal cord may produce
only minimal symptoms and have a good
Deep tendon renexes increased Injury to lateral column/ response to surgical therapy. In contrast, rapid-
below and ipsilateral to the cortical spinal system.
side of transection/damage ly evolving lesions such as metastatic epidural
tumors, more often present a relatively acute or
The sign of Babinski will also Injury to pyramidal tract subacute course and often have a poor
be present ipsilateral to the in the lateral column. response to therapy. At times such metastatic
side of transection/damage
----------------------- lesions are complicated by vascular compro-
IpSilateral loss of vibration, Injury to posterior column mise.
position sense and all other SPECIFIC EXTRINSIC LESIONS
proprioceptive sensory OF THE SPINAL CORD.
modalities below the level
Fracture dislocations: (Fig.9-1) In civilian
of transection/compression
life, most injuries to the cord do not represent
A contralateral loss of pain Involvement of the lateral actual lacerations of the spinal cord but are a
and temperature sensation spinothalamic tract. result of crush injuries caused by fracture dislo-
beginning 1 or 2 segments cations in the cervical or thoracic area. Vascular
below the level of the
transection/compression effects often complicate such crush injuries.
Infarction (related to compression of anterior
An ipsilateral band of Damage to the anterior spinal artery and of veins) and hemorrhage
weakness atrophy and root and or the anterior may occur often in a central cord location (the
fasciculations may be present horn.
latter is referred to as hematomyelia). After
at the level of transection
resorption of a hemorrhage, a cystic cavity may
IpSilateral depression of Damage to the afferent remain. Falls transmit force to the thoracic
deep tendon stretch reflexes or efferent components vertebrae; the resulting compression fractures
at the level of transection/ involved in the may collapse the vertebrae and caused a sharp
compression monosynaptic
angulation of the axis of bony support. A sim-
stretch reflex arc.
ilar compression and collapse; may also occur
An ipsilateral band of loss Damage to the posterior from other non-traumatic causes such a tuber-
of pain, temperature and root and posterior horn culosis of the spine (Pott's disease), metastatic
touch sensation may be carcinoma and osteoporosis. Injuries to the
present at the level of transection
cervical spine resulting from fracture disloca-
tion are common in auto accident, and in div-
sic and cervical segments most intrinsic. As a
ing accidents. In rheumatoid arthritis, the
general rule then, extrinsic lesions do not have
odontoid is commonly fractured and dislocat-
sacral sparing. The earlier involvement of pos-
ed. It is important to note that fractures of the
terior and lateral columns may reflect the
vertebrae may occur without a marked degree
sequence of structural compression or the
of dislocation. In such cases great care must be
greater vulnerability of the heavily myelinated
taken in moving these patients. Thus, in frac-
fibers.
tures of the cervical spine, the patient should
It is important then to realize that the
remain supine with the neck immobilized to
apparent upper level ofsensory level for pain and
avoid flexion and extension during transporta-
temperature may not be the actual level of com-
tion. (Utilize a makeshift collar or sandbags.)
pression. When the patient is seen early in the
Once the patient arrives at a treatment center,
9-4 CHAPTER 9
IB
Figure 9-1. Traumatic lesions of the spinal cord: A) Fracture dislocation of thoracic vertebra has crushed and
almost transected the thoracic spinal cord. B) Afracture dislocation of the cervical spine (due to an auto accident
2 weeks prior to death) has produced an almost complete transection of the spinal cord at the C7 level. (From
Blackwood, w., Dodds, T. c., and Somerville, J. c.: Atlas of Neuropathology, 2nd Edition, Baltimore, Williams
and Wilkins, 1964,p.147).
additional measures such as traction or spinal that no compromise of the spinal cord occurs.
fusion must be considered. The use of very In other patients, the bony canal in relatively
high dosage corticosteroids may have some narrow (spinal stenosis) and compromise
value in reducing the edema of the spinal cord. occurs. The pattern of ascending and descend-
Cervical disk disease: Acute ruptures ing degeneration found at autopsy following
and chronic cervical spondylosis with cervi- spinal cord compression in a patient with cervi-
cal spinal cord compression: This is probably cal spondylosis is demonstrated in Figure 9-2.
the most common cause of cervical spinal cord This 64 year old male had a 6 year history of
compression. Acute lateral or midline rupture progressive spastic paraparesis with atrophy and
of disk material may occur in the cervical area fasciculations at C4-CB, bilateral corticospinal
related to trauma or sudden coughing or and posterior column findings in the lower
straining. The term cervical spondylosis refers extremities and a deficit in pain sensation
to a more chronic process. The disk degener- below the T 10 level. Softening of the spinal
ates with increasing age, the disk material cord was present at the cervical 7 levels. The
begins to bulge, the disk space narrows, and following case illustrates the syndrome of spinal
the secondary formation of osteophytes (bony cord compression secondary to cervical disk
spurs) occur. The osteophytes may project lat- disease.
erally into the neural foramina producing nerve Case 9-1: This 34-year-old female after 2
root compression and/or may be located in a weeks of prolonged hyperextension of her neck
midline location producing spinal cord com- while painting walls and ceilings developed a
pression (Fig. 8-17). Not all bulging disks and transient 6-hour period of weakness in both
osteophytes compress the spinal cord. In some her legs. She then developed pain in the right
patients, the vertebral canal is sufficiently wide side of her neck, her right shoulder and right
upper arm, followed by weakness in the right decreased in the left lower extremity from the
leg. Shortly thereafter she noted intermittent toes to the groin. The entire buttock and the
prickly sensations (paresthesias) in both lower perianal area were also involved in this deficit.
extremities. And she was unable to walk.. Clinical diagnosis: Partial Brown-Sequard
Neurologic exam: Motor: weakness was syndrome due to acute ruptured cervical disk
present in the right upper extremity most involving the right side of cervical cord.
prominent at the triceps and wrist extensors Laboratory data: CT myelogram demon-
(4/5) with a lesser degree of weakness at del- strated a probable extruded disk at the C5-C6
toid, pectorals, wrist flexors and finger abduc- level to the right of the midline displacing the
tors plus a minor degree of weakness at right spinal cord posteriorly and to the left (Fig.9-3).
ankle dorsiflexion (4.5/5). Gait was ataxic. Cerebral spinal fluid protein was signifi-
Reflexes: Bilateral ankle clonus was present with cantly elevated to 141 mg % (normal is less
bilateral Babinski signs. Sensation: Vibratory than 45mg %), consistent with a spinal cord
sensation was decreased in the right lower block.
extremity at toes ankle and knee with associat- Subsequent course: She was unwilling to
ed proprioceptive deficits. Pain sensation was have an MRI or any neurosurgical procedure
undertaken to remove the disc. With the use of
a cervical collar, she had had rapid resolution of
her symptoms and continued to do well over
the next 8 years. Refer to CD ROM for addi-
tional details.
The MRI scan remains the study of choice
in patients with cervical spine pathology as
demonstrated in Figure 9-4. This 31-year-old
male jumped off a truck carrying an 80-pound
bag on his shoulder. The following morning,
he awoke with severe pain throughout the
spine on coughing. And intermittent tingling
of both hands for approximately 4 months
2B Nine months later, he still had an equivocal
• plantar response and MRI demonstrated a rup-
tured disc at the C5-6 interspace.
Metastatic carcinoma: May involve the
vertebrae without producing spinal cord or
nerve root compression. However continued
growth of the tumor or vertebral collapse may
lead to spinal cord compression. The tumor
may spread to the epidural space from the ver-
tebral involvement producing spinal cord com-
8 pression. Vertebral collapse may also produce
spinal cord compression from bony elements
Figure 9-2. Ascending and Descending Degeneration: of the vertebrae. A metastatic tumor may also
Cervical Spondylosis with Spinal Cord Compression appear in the epidural space without direct
Myelin smins. A) Upper cervical spinal cord ab01le
involvement of the vertebrae. In such cases,
level ofcompression: ascending degeneration predomi-
nantly in posterior columns. B. Lower cervical cord tumor within the thoracic or abdominal cavity
just below area of softening: descending degeneration may have spread through the neural foramina
predominantly in lateral columns. (Courtesy of Dr. into the epidural space. Lymphomas in the
Jose Segarra, Boston Veterans Administration thoracic or abdominal cavity in a paravertebral
Hospital).
9-6 C~TER9
Figure 9-3. Cervical Disc Rupture: Bruwn Sequard

Syndrome, Cnse Hisrory # 9-1: cr Scan of cervical
cord post metrizamide myelography. Refer to text.
location often spread in this manner. Spread of

metastatic rumor may also occur via the venous
plexus or via other hematogenous routes. The
majority of metastatic rumors involve the tho-
racic and lumbar areas. The majority of cases
originate from primary disease in the lung,
breast, prostate and kidney. Based on the
autopsy studies of Barron in 1959, 5% of all
systemic cancers will eventually develop spinal
epidural spread. A significant proportion of
patents presenting with epidural spinal cord
compression secondary to metastatic disease
may not have been previously known to have a Figure 9-4 Acute Rupture ofcervical disc midline
malignancy. In a series from a large general and right lateral at CS-C6. A) MRI Tl weighted
hospital (The London Hospital) in 1982,47% sagittal section ofcervical spinal cord slightly to right
of the patients were in this category. 14% of of midline demonstrating a ruptured intervertebral
disc at CS-C6 interspace. B) Transverse sections at
patients never had the primary location deter- CS-C6 interspace refer to B for correlation of levels-
mined. Case 9 - 2 demonstrates the conse- slice- 9 and 10. Cross-section at approximately CS, C6
quences of metastatic carcinoma producing demonstrating an extra dural mass to the right of the
spinal cord compression. midline displacing the spinal cord posteriorly and to
Case 9-2: This 55 year-old white house- the left.
wife first noted pain in the thoracic-right with the control of bowel movements and uri-
scapular area, 5 months prior to admission nation. At age 40, 15 years prior to this admis-
Three months prior to admission, a progressive sion, she had undergone a left radical mastec-
weakness in both lower extremities developed tomy for an infiltrating carcinoma of the breast
resulting in a bed ridden state in which she was with regional lymph node involvement.
unable to move her legs or even to wiggle her Neurological examination: Motor system:
toes .She had also noted a progressive pins and a marked flaccid weakness in both lower
needles sensation involving both lower extrem- extremities with retention of only a flicker of
ities. At the same time she developed difficulty flexion at the left hip. Reflexes: Plantar respons-
es were extensor bilaterally (bilateral sign of spinal cord above and below the area of com-
Babinski). Sensory system: Position sense was pression. Thus other epidural lesions may be
absent at toes, ankles, and knees and impaired identified). The best treatment of metastatic
at the hip bilaterally. Vibratory sensation was spinal cord compression is a high index of sus-
absent below the iliac crests bilaterally. Pain picion and early recognition to prevent the
sensation was absent from the toes through the results seen in this case.
T 6-T 7-dermatome level bilaterally with no Acute epidural abscess: The dura mater
evidence of sacral sparing. Tenderness to per- of the spinal cord is separated from the perios-
cussion was present over the midthoracic ver- teum of the surrounding bony canal by a nar-
tebrae (T4 and T5 spinous processes) row space containing fatty tissue (the epidural
Clinical diagnoses: Spinal cord compres- space). This space may be infected by an infec-
sion at T4-T5 vertebral level most likely section in adjacent tissues for example skin (furun-
ondary to metastatic epidural tumor. cles) or bone (osteomyelitis involving the ver-
Laboratory data: XRay Studies: The tebrae). Alternatively, hematogenous spread of
patient had multiple metastatic lesions in lungs, infection from distant sources may occur. The
T4, T5 vertebrae and head of femur. An emer- usual organism is staphylococcus aureus .The
gency myelogram demonstrated a complete usual site is midthoracic. The epidural abscess is
block to the flow of contrast agent at the T5 rare compared to the epidural tumors just con-
level due to an extradural lesion displacing the sidered and rare compared to meningitis and
spinal cord to the left. brain abscess. Nevertheless early recognition is
Subsequent Course: An emergency tho- necessary. Prompt drainage, decompressive
racic T3-T4 laminectomy demonstrated ade- laminectomy and antibiotic therapy are essen-
nocarcinoma presumably metastatic from tial to avoid the poor prognosis of continued
breast in the vertebral processes, laminae and spinal cord compression.
epidural space displacing the spinal cord. The early symptoms of severe back pain and
Following removal of tumor from epidural fever are followed by radicular pain or weakness
space and subsequent radiotherapy, movement and then the acute or subacute development of
in the lower extremities had returned to 30% of the signs of spinal cord compression.
normal and pain sensation had returned to the Approximately half the cases evolve over days
lower extremities to a moderate degree. to 2 weeks; half evolve over a period greater
In this case, a myelogram was performed, at than 2 weeks. These latter cases are usually sec-
the present time; the most appropriate diag- ondary to vertebral osteomyelitis. If treatment
nostic procedure would be an MRI scan. is delayed, functional transection of the spinal
However in circumstances where that study cord is the usual outcome related both to the
cannot be performed, on an emergency basis direct effects of compression and the indirect
then an emergency myelogram (or myelo- effects of compression on the blood supply and
gram-CT) is appropriate. The presence of per- the involvement of the blood vessel walls by
sistent mid thoracic - scapular back pain in a the infectious process. The diagnosis is estab-
patient with a past history of breast malignan- lished by the appropriate clinical history, an
cy should always prompt a search for metastat- MRI study or myelogram-demonstrating
ic lesions in vertebrae. In any case, the earliest blockage of the subarachnoid space by an
development of motor or sensory symptoms in epidural mass and subsequent aspiration of pus
a patient with a past history of malignancy and from the epidural space.
back pain should lead to prompt neurological Tuberculous involvement of the verte-
evaluation and investigation. (The present brae with secondary spinal cord compres-
standard of investigation would include appro- sion: Tuberculosis was once a common dis-
priate MRI study of the spine, which has the ease in urban centers of the United States and
advantage of allowing studies not only of the Europe. In other parts of the world for exam-
specific area of compression but also of the ple, India, tuberculosis remains a common dis-
9-8 CHAPTER 9
ease. Tuberculous involvement of joints, tuber- the arachnoidal cell clusters. Since the more
culous arthritis, is a complication of untreated common location is the cerebral hemisphere a
tuberculosis in children. A very common site more complete discussion of histologic types
of involvement is the dorsal spine. The process will be found in a later chapter. The typical
often appears to begin in the disc space and gross appearance of this tumor in relation to
then involves the adjacent vertebrae. The dis- the spinal cord is shown in Figure 9-5.
ease process, tuberculous spondylitis (or Pott's These tumors occur most frequently in
disease), results in destruction of the body of middle-aged females (many meningiomas have
the vertebrae and of the intervertebral disc. estrogen receptors). The most frequent loca-
Collapse of the vertebrae and severe angulation tion is the thoracic portion of the spinal cord,
of the bony canal occurs. In addition the
chronic infection may spread into the epidural
space as a local mass of infection or may accu-
mulate as a mass under the ligament posterior
to the vertebral bodies. All of these factors may
contribute to spinal cord compression.
Diagnosis can now be established by MRI
scan. Treatment consists of drainage of any
mass pockets of infection compressing the
spinal cord, anti tuberculous chemotherapy,
immobilization and possibly fusion of the
spine.
Intradural - extra medullary spinal cord
tumors (meningiomas and Schwannomas):
In many earlier operative series this category of
extrinsic tumor internal to the dura but exter-
nal to the substance of the spinal cord,
accounted for the largest percentage of spinal
cord tumors. Such series accumulated prior to
the advent of the MRI tended to underesti-
mate epidural metastatic tumors because such
patients were usually not admitted to special-
ized neurological-neurosurgical units. For
example among 567 cases of spinal cord
tumors collected from the literature by Merritt, Figure 9-5. Gross appearance of meningioma com-
in 1967, 59% were intradural extra medullary, pressing the ventrolateral aspect of thoracic spinal cord.
25% were extradural and 11% were (From Russell, D.S., and Rubinstein, LJ.: Pathology
intramedullary. The extradural tumors have of Tumors of the Nervous System, 2nd Edition.
Baltimore, Williams and Wilkins, 1963, p. 45).
already been considered in relationship to
metastatic spread of carcinoma and lymphoma. in part because the thoracic segments consti-
The intramedullary tumors will be considered tute the longest extent of the spinal cord.
later under intrinsic lesions: gliomas and Other areas however are not immune. In the
ependymomas. Essentially 2 types of tumor upper cervical area these tumors may arise in
constitute in a relatively equal proportion all of relation to the foramen magnum producing
the intradural lesions: meningiomas and both lower brain stem and upper cervical cord
Schwannomas (neuromas). Both types are symptoms. The symptomatology of a typical
benign in the sense that they are not locally meningioma arising in the thoracic spinal cord
invasive and do not spread to distant sites. area might include thoracic back pain that radi-
Meningiomas: These tumors arise from ated around to the interior chest in coughing
and strammg at stool. Ascending sensory
upper motor neuro symptoms in the lower
extremities might evolve slowly over 6 to 12
months. Examination might demonstrate the
findings of the bilateral transverse or Brown
Sequard hemisection discussed above. In addi-
tion local tenderness would be present over the
spinous processes at the level of involvement.
Note that local tenderness over the spinous
processes is common in extradural and
intradural extra medullary tumors. MRI scan
(or CT- myelogram if MRI is not available)
would reveal an intradural extramedullary
tumor with partial or complete block to the
flow of CSF. CSF protein would be increased.
These tumors require early neurosurgical inter-
vention to avoid progression to a chronic para-
plegic state. With the slow growth of the
tumor, the capacity for recovery of function
despite considerable distortion of the spinal
cord is usually quite surprising once the com-
pression has been relieved.
Schwannomas: These benign tumors arise
from the cells of the nerve sheath. These
tumors as noted above may arise in relationship
to peripheral nerve, cranial nerves or nerve
root. As discussed above those that arise in rela-
tion to nerve root with in the bony canal may
compress nerve root and/or the spinal cord
depending on location and size of the tumor.
The symptoms and signs may be very similar to
those of a meningioma. Because these tumors
arise from the nerve root radicular pain is often
more conunon than in meningiomas. The use
ofMRI to image Schwannomas is demonstrat-
ed in Figure 9-6. This 43 year old male had
several months of pain in the cervical area that
radiated into the anterior chest on coughing
plus tingling from this area to the sacral area on
sneezing. He had a marked decrease in all deep
tendon reflexes in the right upper extremity. Figure 9-6. &hwannoma with compression of spinal
cord. MRI with contrast enhancement. A) Sagitt41
and percussion tenderness over the C6-7 spin-
seaion-midline. B) Coronal seaion between posterior
ous processes. All symptoms resolve following arches and dorsal surface ofspinal cord. C) Transverse
removal of the tumor. Note that the tumors seaion-Tl-vertebrallevel.
may attain considerable size and produce only
minimal spinal cord symptoms. As with all Case history 9-3 presented on the CD
spinal cord lesions, the preferred neuroimaging ROM demonstrates the course of an
technique is the MRI scan. Schwannoma compressing spinal cord.
Neurofibromatosis Type I (von
9-10 CHAPTER 9
Recklinghausen's disease): This is an autoso- nervous system are affected. At any given level,
mal dominant inherited disease characterized a specific lesion is not restricted to a specific
by multiple peripheral neurofibromas (tumors neuronal or fiber system: a) multiple sclerosis,
composed of Schwann cells, collagen and reti- b) other demyelinating disorders c) collagen-
culin fibers). There are also various anomalies vascular disease lupus erythematosus and vas-
of the skin (multiple > 6 cafe au lait spots and culitis.
cutaneous neurofibromas), iris (Lisch nodules
-pigmented hamartomas) and skeletal system. SPECIFIC INTRINSIC SYNDROMES
Large plexiform neurofibromas may produce WCAL DISORDERS:
marked facial deformities. Patients may also Vascular disease: anterior spinal artery
manifest meningiomas or intrinsic gliomas occlusion: Primary vascular disease affecting
involving the optic nerve, brain or spinal cord the spinal cord is not common although a sec-
but such central lesions are less common than ondary vascular component may be present in
in type II neurofibromatosis considered below. many of the spinal cord compression syndrome
This form of neurofibromatosis is also referred discussed above. Any understanding of the
to as peripheral neurofibromatosis; and occurs clinical syndrome found in vascular disease of
once in 3,000 live births. The mutated NFl the spinal cord is dependent on knowledge of
gene has been localized to chromosome 17q. the anatomy of the arterial supply of the spinal
The CT scan and MRI appearance of cord (Fig. 9-7). The major artery of the spinal
Schwannomas involving nerve roots has been cord is the anterior spinal artery that is located
presented in chapter 8. in a midline position at the anterior median fis-
Neurofibromatosis Type IT: This type sure. This single thin midline vessel has a bilat-
also known as central neurofibromatosis is also eral origin from the intracranial portions of
an autosomal dominant but is rare compared each vertebral artery. The arterial flow as this
to neurofibromatosis type 1 occurring 1 in vessel descends is dependent on additional sup-
50,000 births. The mutated NF 2 gene has ply from the radicular arteries. These radicular
been localized to chromosome 22. In contrast arteries are derived from the cervical portion of
to type 1, peripheral manifestations are uncom- the vertebral artery particularly at C3 and C 5
mon. Skin and bone lesions do not occur. levels and the inferior thyroid artery at the C6
Instead the patients have multiple types of level. Additional radicular arteries originate
tumors of the central nervous system. Most from the aorta as the intercostal thoracic lum-
patients eventually develop bilateral acoustic bar and sacral arteries. Most of the radicular
neuromas (actually vestibular Schwannomas). arteries of the thoracic area do not contribute a
This problem will be discussed in greater detail significant supply. However, the middle tho-
in the brain stem chapter. racic artery usually at T 7 and the artery of the
INTRINSIC DISORDERS OF THE lumbar enlargement, (the artery of
SPINAL CORD Adamkiewicz) which usually arises between
Three general categories of intrinsic disease TI0 and L2 are of particular importance.
must be distinguished: There are then border zones of blood supply in
1. UJcal disease affecting one or more adja- the rostral-caudal axis between the cervical and
cent segments: a). Infarcts produced by occlu- lumbar segments of major supply. The actual
sion of the anterior spinal artery b) transverse border zones of circulation are at segments T4
myelitis c) intramedullary spinal cord tumors: andLl.
gliomas and ependymomas d) syringomyelia When the transverse anatomy is considered:
2. System diseases affecting one or more neu- 1. Anterior spinal artery: This midline ves-
ronal or fiber rystems: a) motor neuron disease, sel supplies the anterior and lateral columns
b) tabes dorsalis c) combined system disease d) and almost all of the gray matter except for the
spinal cerebellar degeneration posterior horns.
3. Multifocal disorders: various levels of the
arteries.
&-_ _ ""'''"'' artery Since the largest area of the spinal cord is
supplied by a single anterior spinal artery, it is
not surprising that most vascular disease involv-
ing the spinal cord presents as the syndrome of
the anterior spinal artery that is infarction of
the territory supplied by this vessel (Fig. 9-8).
This 71-year-old male had the acute onset of a
flaccid paraplegia with an absence of deep ten-
don reflexes in the lower extremities and a pain
trunk
sensory level at T7-S.No recovery occurred.
Actual occlusion of this vessel is rare. The
5th Intercostal
;::::t !1~......S;i1M---~n'.ry. (Spinal usual cause of the syndrome relates to diseases
branch)
of the aorta or to surgical procedures involving
the heart, aorta, or related vessels. Clamping of
the upper aorta for the surgical treatment of an
aneurysm of the aorta may result in a decrease
in blood flow in the critical intercostal branch-
es supplying the spinal cord. A dissecting
aneurysm of the aorta (a tear within the wall of
the vessel with blood under high pressure dis-
secting down the media of the wall of the
blood vessel) often results in the occlusion of
intercostal and other vessels arising from the
aorta. Other arteries arising from the arch of
aorta such as vertebral and carotids may also be
occluded. In other instances, the occlusion of
Figure 9-7. Vascular Anatomy of the spinal cord.
intercostal branches particularly at T 10 may
Anterior spinal artery: the major radicular (segmen-
tal) blood supply is diagrammed. From Clemente, c., occur during surgical procedures on the kidney
Gray's Anatomy, 30th Ed, Philtulelphia , Lea and
Febiger, 1988.
2. Posterior spinal arteries: These paired
vessels supply the posterior horns and the pos-
terior columns, each derived from the intracra-
nial segment of a vertebral artery. These poste-
rior spinal arteries also receive contributions
from the posterior branches of the radicular
arteries.
3. Anastomotic Vessels. At each level, coro-
nal arteries at the periphery of the spinal cord
connect the anterior spinal artery and the pos-
terior spinal arteries. These anastomotic vessels
at the periphery also serve to interconnect the
blood supply of adjacent segments. A trans-
verse border zone or watershed must also exist
in the central gray matter where penetrating
Figure 9-8. Infarction of spinal cord in distribution
branches of the anterior spinal artery meet the of anterior spinal artery secondary to occlusion of
penetrating branches of the posterior spinal radicular artery at T6. Courtesy ofDr. Jose Segarra
9-12 CHAPTER 9
or lumbar sympathetic ganglia. 1978 series of Ropper and Poskanzer, (in

The resultant neurological syndrome is which all patients had myelography, since this
manifested by the acute onset of a paraplegia was prior to the modern era of neuroimaging)
which is usually flaccid due to spinal shock and 138 patients presented from 1955 to 1975
a bilateral deficit in pain and temperature with an acute myelopathy or myelitis. In this
below the level of lesion with preservation of overall group, 82 (59%) had an anatomical
vibratory and position sense. If the area of mass lesion usually an epidural metastatic
infarction involves the lumbar sacral area the tumor, four (3%) had a dissecting aortic
anterior horn cells will also be destroyed. The aneurysm and presumably an anterior spinal
legs will then remain flaccid, muscle atrophy artery syndrome, and 52( 38%) remained in the
will develop, deep tendon stretch reflexes will transverse myelitis category.
never recover and spasticity will never develop. Of the 52 patients in this residual transverse
The prognosis then for a significant degree of myelitis category, 33% had a prior viral illness
recovery is usually poor. Theoretically, if the and presumably could have had a post infec-
thoracic spinal cord were infarcted, with tious myelitis. 6% had cancer of the lung, ovary,
preservation of the lumbar and sacral seg- or prostate but without spinal cord compres-
ments, deep tendon reflexes could recover and sion and presumably had a remote effect of
spasticity without atrophy in the lower extrem- malignancy. 13% of patients eventually devel-
ities could develop after several days. oped multiple sclerosis with the transverse
In distinguishing other acute processes pro- myelitis as the presenting syndrome.
ducing paraplegia, the rapidity of onset and the The remaining 48% had no specific possible
anatomical pattern of infarction seen in occlu- etiology.
sion of the anterior spinal artery should be con- In 21% of these patients the appearance of
sidered. Other processes such as trauma or symptoms was acute with mid thoracic back
hemorrhage into the spinal cord (hemato- pain, weakness of legs, sensory deficit below
myelia) from rupture of a malformed blood the level of lesion and urinary retention evolv-
vessel may produce an acute syndrome. The ing over less than 1 to 12 hours. In 69% of
history, and findings as well as the MRI scan patient's the symptoms progressed in an
and the CSF examination would be distin- ascending manner over 14 days and then stabi-
guishing factors. Spinal arteriovenous malfor- lized with the findings of a spastic paralysis and
mations may also produce a progressive syn- spastic bladder. In 10% of patients, the course
drome with episodes of acute exacerbation was a stuttering progression over 10- 28 days.
related to infarction and hemorrhage, but the The progressive patients had a better prognosis
anatomical pattern will differ from the acute than those with the acute onset. In the era
anterior spinal artery syndrome. Multiple scle- prior to MRI scans, myelograms were usually
rosis may also produce a relatively acute onset normal but occasional patients were found to
of symptoms but the anatomical pattern will have mild swelling of the spinal cord.
differ and lesions will usually be present else- In cases of transverse myelitis, pathological
where in the nervous system. Acute transverse examination of the spinal cord reveals an acute
myelitis and the spinal cord compressions dis- or subacute necrotic process involving a num-
cussed above do not produce the anatomical ber of segments. In other cases, areas of
pattern of the anterior spinal artery syndrome. demyelination are present.
The syndrome of acute or subacute The MRI is able in most cases to image
transverse myelitis: When all other causes of these pathologic changes. In mild cases, the
an acute or subacute myelopathy have been MRI may be normal.
excluded, there remain a group of patients Case 9-4 presented on the CD ROM and
without evidence of an extrinsic compressive or in Figure 9-9A illustrates the diagnostic dilem-
intrinsic vascular lesion. Usually the upper or ma provided by such cases of transverse
mid thoracic spinal cord is involved. In the
variant of transverse myelitis in which a rela-
tively acute transverse myelitis is associated
with an acute unilateral or bilateral optic neuri-
tis. Some of these cases represent a variant of
multiple sclerosis; others a variant of a post
infectious .myelitis, or rarely a paraneoplastic
syndrome.
Subacute -chronic HTL V associated progres-
sive myelopathy HAMI tropical spastic para-
paresis: This is a myelopathy produced by the
retrovirus HTLV that causes human T cell
leukemia. A chronic meningoen-
cephalomyelitis is associated with demyelinat-
ing lesions in posterior and lateral columns. A
sensory level may be present in the thoracic
area. In tropical areas, the incidence may be as
high as 128/100,000. The risk factors for
transmission of the disease include many of the
factors found with HIV infection: sexual trans-
mission, intravenous drug use and blood trans-
fusions. The CSF and MRI findings are similar
to multiple sclerosis (which actually has a lower
incidence in tropical as opposed to temperate
areas). Differentiation may be made by a deter-
mination of antibody levels in serum and CSF.
Intrinsic spinal cord tumors: Rarely
metastatic tumors may be found within the
substance of the spinal cord. However most
intramedullary tumors are intrinsic arising from
the glial (astrocytic or ependymal) compo-
nents. The glioma arising from the astrocytic
Figure 9-9. Transverse myelitis: A) Case 9-4 MRI
(Tl) (CASE ON CD ROM) This 42 year old female series of cells is the most frequent intrinsic
had the sudden onset of back pain at T6-8, followed by tumor of the spinal cord found in the cervical-
tingling and weakness in the lower extremities plus thoracic spinal cord. Most spinal cord ependy-
urinary retention evolving over 12 hours and then momas arise at the lower end of the spinal cord
improving. B) This 54 year old female with a prior in the filum terminale. Intrinsic tumors of the
history of non Hodgkin,s lymphoma developed a pro- spinal cord are rare compared to intrinsic
gressive quadriparesis over 6 days ,and then rapidly
tumors of the cerebral hemispheres and com-
improved possibly related to high dosage corticosteroids.
pared to extrinsic tumors of the spinal cord.
myelitis A 42 year old woman had the relative- Ependymomas are often relatively localized
ly sudden onset of back pain at T6-T8 and a and are to some extent discrete tumors.
tingling in the lower extremities. Over the next Astrocytomas on the other hand often tend to
12 hours, she developed weakness in the lower infiltrate the surrounding tissue without any
extremities and urinary retention. She then had particular limiting border. Several or many
improvement over the next 24 hours. A CT adjacent segments may be thus involved by the
myelogram indicated a widened spinal cord at tumor. In some children, the tumor does
T7-8. Eventually clinical and MRI improve- appear to have limiting borders and thus may
ment occurred over several months. be shelled out at surgery. A cystic component
Devic's syndrome (neuro myelitis optica) is a is often present and the cyst may be drained at
9-14 CHAPTER 9
surgery. The overall diameter of the spinal cord trallocation (Fig. 9-1 0). The cavity is surround-
is increased and this may be visualized at myel- ed by a border of gliosis, (an area of prolifera-
ography or on MRI scans. The increased mass tion of astrocytes with the production of glial
of the spinal cord produces pressure on the fibers. The cavity is usually ventral to and dis-
pedicles of the vertebrae. Plain x-ray films of tinct from the central canal that is lined by
the spine may demonstrate the resultant ependymal cells .As the disease progresses, the
increased interpeduncular distance. From a his- syrinx may however extend into the central
tological standpoint the spinal cord astrocy- canal. The location of the syrinx is critical for
toma is usually of a uniform appearance with a understanding the early symptoms and signs
relatively low to moderate grade of malignancy that develop. The syrinx initially involves those
(grade 1-2). This is reflected in the usual clini- pain and temperature fibers crossing the mid-
cal course that extends over a period of several line in the anterior white, commissure. Thus
years with a 5-year survival after surgery of up the initial symptoms and signs relate to a selec-
to 90% of patients. Contrast this to the astro- tive loss of pain and temperature sensation in
cytoma that infiltrates the cerebral hemispheres the cervical segments producing a cape like
which has a much more malignant histological deficit (Fig. 9-11). Since, initially touch, vibra-
grade of 3-4, and a much shorter survival. tory and proprioceptive sensation are pre-
A typical case is that of a young adult or served, this is referred to as a dissociated senso-
child who presents with a several year history of ry deficit. The patient often reports painless
a slowly progressive lower motor neuron weak- burns and painless trauma to the hands and
ness and atrophy of 1 extremity involving mul- arms. Although these symptoms and findings
tiple segments. Sensory symptoms in that are usually bilateral, occasionally because of the
extremity might develop at the same time or irregular shape of the syrinx the symptoms and
subsequently with or without radicular pain. As signs may be predominantly unilateral. The
the process continues upper motor neuron subsequent course of syringomyelia is variable
weakness of the ipsilateral leg might be fol- since the syrinx often varies in its shape and pat-
lowed by a similar involvement of the opposite tern of expansion. The anterior horns however
leg. Subsequently a slowly progressive lower are often subsequently involved resulting in
motor neuron weakness might develop in the local atrophy fasciculations and local flaccid
opposite upper extremity. Depending on the paralysis of hand or upper extremity muscles
pattern of infiltration, long tract sensory find- with a segmental loss of deep tendon stretch
ings might be present or absent. Bladder func- reflexes. As the syrinx continues to expand, lat-
tion would usually be well preserved. Very literal and at times posterior columns may be
tle local tenderness would be present over the involved with resultant long tract motor and
vertebrae in contrast to extrinsic tumors. The sensory findings. Although the process is most
changes in plain spine x-rays, myelographyJCT
and MRl scan have been noted above. The
patient would improve following laminectomy,
drainage of any cystic component and in some
cases removal of tumor in cases (usually pedi-
atric) where the tumor could be discreetly sep-
arated from the surrounding tissue.
Radiotherapy would also produce considerable
improvement.
Syringomyelia: this disease usually affects
Figure 9-10. Syringomyelia producing enlargement
the cervical portion of the spinal cord but may of the cervical spinal cord, destroying the anterior
extend into thoracic and lumbar segments. The white commissure and the anterior horn. A dense bor-
basic pathology involves the formation of an der ofgliosis is evident around the cavity. (Holzer
irregular cavity (syrinx) in a central or paracen- stain for glia). (Courtesy ofDr. E. Ross).
malformations, the cerebellar tonsils extend
down through the foramen magnum com-
pressing the cervical medullary junction. In
type II Chiari malformations, there is caudal
displacement of the lower end of the medulla
and 4th ventricle as well as of the cerebellar
tonsils through the foramen magnum .As a
result, the brain stem is elongated and distort-
ed with an abnormal bend. Other abnormali-
ties at this junction may include the Dandy
Walker malformation in which the 4th ventri-
cle is markedly dilated due to a closure or fail-
ure of development of the foramina of
Magendie and Luschka. In other cases a
meningioma may be present at the junction or
inflammation of the meninges (arachnoiditis)
may have occurred. In all of these abnormali-
ties at this junction, a dilatation of the central
Figure 9-11. Syringomyelia with dissociated sensory canal (hydromyelia) usually occurs, and the
loss. The cape-like distribution of a selective pain and syrinx appears to develop from this dilated cen-
temperature deficit with intact touch sensation Oller tral canal. In some of these cases hydrocephalus
the upper extremities is demonstrated. is also present.
prominent in the cervical spinal cord, the syrinx In type II syringomyelia, no specific etiology
may extend into the thoracic and lumbar spinal is present. These cases referred to as idiopathic
cord. In addition, the process may extend into constitute approximately 60% of all cases.
the medulla as syringobulbia. In such cases, the In type III syringomyelia, the syrinx appears
syrinx is usually present as a slit like cavity to relate to other disease of the cervical spinal
extending in a ventral lateral direction from the cord.
floor of the 4th ventricle (the continuation of In approximately 8 - 16% of patients with
the central canal) into the dorsal lateral syringomyelia, there is an associated
medullary tegmentum. In this location, many intramedullary tumor.
of the symptoms and signs relevant to the Syringomyelia may also follow severe spinal
medulla will be similar to those of the lateral cord trauma or following spinal cord compres-
medullary infarct to be discussed in the brain sion, developing late after the event from areas
stem chapter. The symptoms and signs of of necrosis (myelomalacia).
syringobulbia are often predominately unilater- Diagnosis can be made based on the clini-
al although bilateral lesions may occur with cal findings with confirmation by MRI studies
involvement of the nucleus ambiguous. The of the spine and brain.
slit like cavity may be difficult to visualize on The following case 9-5 provides an example
MRI scans of the brain. of syringomyelia.
The precise etiology of syringomyelia is Case 9 - 5: This 33 year-old female credit
variable, and the underlying pathophysiology is union manager had a 3-year history of inter-
often not clear. mittent pain and paresthesias extending from
In type I syringomyelia, there is an abnor- the left cervical area to the left arm and hand
mality, usually developmental at the cervi- predominandy involving the middle finger. In
comedullary junction. The Chiari or Arnold the last 3 months, weakness of the left arm and
Chiari malformation is a frequent association. had developed and paresthesias of the left arm
Two types of the Chiari Malformation are rec- had become more continuous.
ognized: type I and type II. In type I Chiari Neurological examination: Motor system:
9-16 CHAPTER 9
A mild weakness was present at the left triceps

muscle. Reflexes: There was depression of all
deep tendon stretch reflexes in the left upper
extremity. Sensory system: There was a selective
cape like decrease of pain and temperature sen-
sation in the left upper extremity (shoulder and
arm) . In addition, there was a selective decrease
in pain sensation over the T 3-T5 dermatomes
on the right.
Clinical Diagnosis: syringomyelia
Laboratory data: MRI scan of the spinal
cord demonstrated an extensive irregular cavi-
ty extending from C2 to T 9 with a major
enlargement of the spinal cord at the T 4 ver-
tebrallevel (Fig.9-12).
MRI scan of the head demonstrated a type
1 Arnold Chiari malformation with displace-
ment of the cerebellum below the foramen
magnum (Fig.9-13).
Subsequent course: Dr. Alex Danylevich
performed a laminectomy at T4 and shunted
the large cavity into the subarachnoid space.
Figure 9-14 and Case 9-6 (presented on
the CD ROM) represent a more complex and
more advanced example of syringomyelia and
syringobulbia.
SYSTEM DISEASES OF
THE SPINAL CORD:
Figure 9-12. Syringomyelia. Case 9-5 MRI Scan.
These are diseases in which there is a rela- A) Cervical 2-Thoracic 5: Sagittal Section lOmm to
tively selective involvement of particular neu- left of midline-the arruw is on the cervical 7 verte-
ronal cell groups and/or their fibers. At times, bral body. B) Cervical 6- Thoracic 9: Sagittal sec-
several related cell or fiber systems are involved. tion 10 mm right of the midline. The point of widest
System diseases are not of a uniform etiology. enlargement of the spinal cord is opposite the T4 ver-
Nutritional deficiencies, infections and degen- tebral body.
erative disorders are found in this category.
SPECIFIC SYSTEM DISEASES:
Disorders of the anterior hom cell:
Acute anterior poliomyelitis: This disease
is caused by a filterable virus that invades the
central nervous system. The virus spreads from
the gastrointestinal tract by means of a viremia
or by spreading up the axis cylinders of the
autonomic nerve fibers. On reaching the cen-
tral nervous system, the virus then involves
preferentially the large motor neuron of the
spinal cord and brain stem resulting in damage, Figure 9-13: Arnold Chiari malformation associated
degeneration, or death of these neurons and with syringomyelia Case 9-5 MRI (See text)
Figure 9-15. Acuw anwnor poliomyelitis. Lumbar

spinal cord, with a loss of large anwrior horn motvr
neurons and replacement by clusters of mononuclear
cells. Cresyl piolet stain (X100) (Courtesy ofDr. Jose
Segarra).
intercostal muscles or from damage to the res-

piratory centers in the medulla. The spinal fluid
Figure 9-14 Syringomyelia. Case History #9-6. findings are typical of aseptic meningitis with a
(CASE ON CD ROM). MRI Scan. This 60 year old predominantly lymphocytic response; however
male had clinical findings ofsyringomyelia and
very early in the disease polymorphonuclear
syringobulbia. A) Midline Sagittal Section demon-
strating a central capity beginning at the cerPical two cells may predominate. The majority of
segment and extending well intv the upper thoracic patients with anterior poliomyelitis make a
segments. B) Transverse Sections demonstrating the complete or significant recovery. A significant
irregular nature of the central capity. 1) CerPical1- proportion may actually be labeled as nonpara-
/epe~ no definiw capity. 2) CerPical2 mel-capity is lytic cases because a paralysis fails to develop
predominawly right sided extending intv right pom- even in the acute state. However an estimated
rior column, 3) CerPical4 me/-bilawra/ capities. 20 -30% of all cases have a significant residual
deficit or disability: a flaccid paralysis with atro-
inflammatory changes in the surrounding tis-
phy, fasciculations, and loss of deep tendon
sue (Fig.9-15). Neurons in the posterior horn
stretch reflexes. In many cases, one limb, often
and interneurons of the spinal cord are to a
a lower extremity is predominantly involved. In
lesser degree often involved in the acute stage.
bulbar cases, many patients remain respirator
The correlated clinical phenomena consist
dependent. We may presume that in the major-
of a prodromal period of fever, malaise,
ity of cases many neurons invaded by the virus
headache plus gastrointestinal and upper res-
manifest a transient dysfunction but are not
piratory symptoms. This is followed in some
destroyed.
patients, by a stage of meningeal irritation and
Recent interest has centered on the devel-
then in some patients, by the development of a
opment of additional weakness and atrophy
flaccid paralysis. This involves in an irregular
many years after the acute episode called the
manner, many of the muscles of the extremities
post polio syndrome. The underlying patho-
and trunk (the spinal form) or the muscles sup-
logical basis for this progression is not entirely
plied by the bulbar motor nuclei (the bulbar
clear. The muscles involved however appear to
form). Muscles affected in the bulbar form
be those previously affected in a clinical or sub-
include the facial, palatal, pharyngeal and
clinical manner with or without residual paral-
tongue. In the acute phase cramps are often a
ysis. Electromyography in many patients after
significant symptom. Respiratory paralysis may
the acute phase of poliomyelitis demonstrates
occur in severe cases because of the involve-
changes in many muscles that were not clini-
ment of the motor nuclei of the diaphragm and
cally affected by the acute disease.
9-18 CHAPTER 9
With the development of the Salk vaccine proximal limb weakness. Note overlap with
(formalin inactivated virulent strains) and the progressive muscular atrophy form of amy-
Sabin (attenuated live virus) vaccine, infections otrophic lateral sclerosis discussed below.
with the poliomyelitis virus are now extremely Underlying molecular basis: types I, II, ill
rare in the United States and other developed have all been mapped to chromosome 5 at
countries. Worldwide eradication is now possi- region 5qll.2--5q13.3 where a survival motor
ble but economic factors and warfare has pre- neuron (SMN) gene is located. Deletions in
vented such eradication in many parts ofAfrica, exons on this gene occur in these patients. The
and Asia. In countries where the natural disease genetic defect responsible for the type IV, adult
(due to the ''wild,'' naturally occurring virus) onset cases is unknown.
has been eliminated rare cases are still encoun- X-Linked Recessive Bulbospinal
tered as a result of infection from immuniza- Neuronopathy (Kennedy's Disease): This
tion with the live attenuated virus. In addition, adult onset disease affects males over the age of
adults who have not been immunized may be 30 years. Degeneration of motor neurons in
infected by exposure to infants or children who spinal cord and brain stem occurs. There are
have just been immunized with the live atten- minor sensory findings. The disease is rare
uated virus. compared to the progressive muscle atrophy
Case 9-7 presented on the CD ROM pre- form of amyotrophic lateral sclerosis to be con-
sents an example of poliomyelitis in an adult sidered below but somewhat more common
who had not been immunized. than the adult onset type of spinal muscular
Spinal muscular atrophies: This is a atrophy. The importance of this disorder
group of genetic disorders that involve the relates to the underlying molecular basis: an
anterior hom cell, without involvement of the abnormal increase in the trinucleotide cytosine
corticospinal or sensory systems. All are auto- -adenine-guanine (CAG) repeats in the region
somal recessive. Four types are identified based of the androgen receptor gene on the X chro-
on age of onset. The later the age of onset, the mosome. Many of these patients will have
slower the progression. The earlier the age of gynecomastia; some will have testicular atro-
onset, the more likely that bulbar motor neu- phy. In normal individuals, there are 17-26
ron involvement and respiratory fuilure will be repeats. In the patients, there are 40-65
present in addition to the findings of anterior repeats. A similar expansion in the number of
hom cell involvement. The incidence of the CAG trinucleotide repeats occurs in other dis-
infantile and juvenile forms of the disease is eases involving different aspects of motor func-
estimated as 1 in 6,000 - 20,000 births. The tion and affecting different chromosomes:
major disease to be differentiated is usually a Huntington's disease and the spinocerebellar
disease of muscle i.e. a myopathic process. degenerations. The CAG trinucleotide repeats
EMG studies, muscle biopsy and genetic stud- encodes poly glutamine. With excessive func-
ies are useful in establishing the diagnosis. tion, protein aggregation occurs in the motor
Types are based on age of onset. neuron nucleus resulting in degeneration. As in
Type I, infantile form (Werdnig-Hoffinan these other disorder,s the higher the number of
Disease): onset: last trimester of pregnancy-6 repeats, the earlier the age of onset.
months: floppy.
Type II (Intermediate/arrested form of Disorders of the motor system affecting
spinal muscular atrophy):onset <18 months: both the lower motor neuron and the
delayed motor dates. upper motor neuron
Type III Juvenile form (Kugelberg- Amyotrophic lateral sclerosis (motor
Welander Disease):onset 5-15 years: proximal neuron or motor system disease, ALS): this
limb weakness. is a relatively common degenerative disease of
Type IV, Adult onset spinal muscular atro- unknown etiology affecting predominantly
phy: onset>20years:very slowly progressing adults of 40 to 60 years of age. Prevalence is
estimated at 4- 10 per 100,000. Approximately neurons of the spinal cord have low activity of
10% of cases are inherited usually as an autoso- these calcium-binding proteins. In contrast,
mal dominant rarely as an autosomal recessive. those neurons which are not affected in ALS;
In 15-20 % of the autosomal dominant fami- the oculomotor nuclei, the sensory neurons,
lies, a mutation has been mapped to the gene the cerebellar Purkinje cells and the nucleus
locus for superoxide dismutase on chromo- relevant for the bladder (Onuf's nucleus) have
some 21. This enzyme is involved in the detox- a high level of immunoreactivity for calcium
ification of the free radical superoxide to binding proteins.
hydrogen peroxide. Whether injury from free An additional hypothesis as to etiology,
radicals is responsible for the neuronal degen- concerns possible failure of action of nerve
eration in sporadic cases is uncertain. growth factors. Table 9-3 outlines the clinical
Clustering of cases of ALS has been noted features and the neuropatholic correlation in
among the Chamorros on Guam, on the Kii ALS.
peninsula of Japan and in western New The majority of cases referred to as classical
Guinea. In these clusters, there is an overlap ALS eventually have involvement of all of the
with cases of Parkinson - dementia complex. In systems listed in Table 9-3. However the dis-
these areas, the prevalence of ALS was former- ease may begin with involvement of the bulbar
ly 100 times that of sporadic cases in other motor neuron or the spinal cord lower motor
parts of the world when studied in the 1950's. neuron or the upper motor neuron. The onset
With improvement in nutrition and in water may be very asymmetrical and limited to one
supplies, the incidence has decreased. Thus limb. The terms applied to those cases with
possible toxic factors have been suggested, only one of the systems involved are presented
although a possible predisposition may also be in table 9-3.
present in these populations. As regards the eti- The diagnosis in those cases with a classical
ology in most sporadic cases of ALS, the ALS syndrome can be established on the basis
hypothesis of glutamate excitotoxicity has of the clinical symptoms and signs. Those cases
gained prominence in recent years. Glutamate with a progressive bulbar symptomatology may
serves as the major excitatory transmitter in the require MRI studies to exclude other brain
central nervous system. Excessive long-term stem pathology such as a brain stem glioma.
ingestion of the chick pea (Lathyrus sativus) Those cases with a progressive cortical spinal
that contains a neurotoxin, a glutamate recep- syndrome will require MRI study of brain and
tor agonist may produce a neurological syn- cervical spinal cord to exclude other treatable
drome (lathyrism) in which selective damage to conditions such as parasagittal or foramen
upper motor neurons in the motor cortex magnum meningioma. Those cases with a pro-
occurs. As we will discuss later in relationship gressive spinal muscular atrophy syndrome will
to dementia, an epidemic of food poisoning require nerve conduction studies and elec-
related to contaminated mussels occurred in tromyography to exclude motor neuropathies.
the Canadian Maritime Provinces in the early These latter patients may also require studies
1980s with manifestations of motor neuron for immunological and toxic causes.
disease and dementia. Domoic acid, a potent Electromyography in anterior horn cell dis-
glutamate receptor agonist was found to be the ease will show evidence of both denervation
specific neurotoxin. Related to glutamate exci- and reinnervation. Some of the muscle fibers of
totoxicity is the role of the subsequent influx of a motor unit that have lost their innervation
excessive amounts of intracellular calcium. may be reinnervated by axonal sprouting from
Intracellular calcium binding proteins protect surviving anterior horn cells. Muscle biopsy
against the effects of excessive intracellular cal- will demonstrate grouped motor unit atrophy
cium. Those neurons that degenerate in ALS (as in figure 8-16) Thus a group of muscle
such as the large cortical pyramidal cells the fibers all innervated by the same anterior horn
bulbar motor neurons and the alpha motor cell will be atrophic where as a neighboring
9-20 CHAPTER 9
group of muscle fibers innervated by an intact ties developed. There had been no sensory
anterior horn cell will be well preserved. MRI symptoms, no urinary symptoms, and no
studies of the brain particularly in patients with change in mental status. There had been a
prominent upper motor symptoms and signs weight loss of 30 lb.
will demonstrate atrophy in the motor and pre- Neurological examination: Cranial
motor areas. nerves: V: the jaw jerk was hyperactive (deep
Overall median duration of disease ranges tendon stretch reflex). VII: A bilateral periph-
from 23 - 52 months. 20 to 25% of all patients eral paralysis was present involving the upper
live longer than 5 years and 8 -16% of patients and lower face with a paucity of facial expres-
survive beyond 10 years. The prognosis of sion. IX, X: Although a gag reflex was present,
patients with ALS depends on the type of dis- elevation of the uvula was poor. The voice was
ease and on the initial manifestations as indi- hoarse and speech was of low volume. XII.
cated in Table 9-4. Ridges of atrophy and fasciculations were pre-
Note that questions have been raised been sent along the lateral borders of the tongue.
raised as to whether cases of primary lateral Motor system: Widespread muscular atrophy,
sclerosis and progressive muscular atrophy rep- fasciculations and weakness were present in all
resent diseases that are distinct from classical four extremities. Reflexes: The deep tendon
ALS. Cases that remain as pure anterior horn stretch reflexes at the biceps, triceps, and patel-
cell involvement longer than 36 months are lar were hyperactive at 3 +. However the right
usually classified as PMA. The age of onset is Achilles reflex was 2 + and left was decreased at
usually younger as well. Overall younger oto 1. The plantar responses were both exten-
patients have a better prognosis. sor (bilateral sign of Babinski). Sensory fYstem:
The following case history 9-8 demon- Intact.
strates the full clinical extent of a classical case Clinical Diagnosis: amyotrophic lateral
ofALS. sclerosis (fully developed-classical type).
Case 9-8: This 66 year-old married white Laboratory data: The EMG studies muscle
male merchant, 9 months prior to evaluation and biopsy were consistent with the diagnosis.
had the insidious onset of a progressive weak- Subsequent course: The patient experi-
ness and atrophy involving the lower extremi- enced additional difficulty in swallowing. He
ties and subsequently a similar but lesser expired 3 months after the above evaluation,
involvement of the upper extremities. Three- approximately 1 year after the onset of his dis-
month prior to evaluation, the patient had the ease.
onset of thickness of speech, a difficulty in swal- Other diseases with selective involvement
lowing solids and to a lesser degree liquids. At of the cortical spinal tracts:
the same time stiffuess in both lower extremi-
TABLE 9-3. CORRELATION OF CLINICAL SIGNS AND NEUROPATHOLOGY IN ALS AND RELATED DISORDERS
Clinical Sign Location of Neuropathology If this system only is involved

1. atrophy, fasclculaHons, Alpha motor neurons of anterior horn Progressive muscular atrophy
flaccid weakness and loss of (PMA)
deep tendon stretch reflexes (DTR's)
2. bulbar palsy (ON 5,7,9,10,11,12) Bulbar motor neurons of medulla and pons Progressive bulbar palsy
3. upper motor neuron findings of Degeneration of corHcospinal tracts Primary lateral sclerosis
spastic weakness, increased DTR's secondary to loss of large/giant (PLS)
and sign of Babinski pyramidal cells In motor cortex (Fig.9-1S)
4. Pseudobulbar findings of Bilateral degeneration of cortlcobulbar Progressive pseudobulbar palsy

increased Jaw Jerk and gag tracts secondary to loss of large/giant
plus pseudobulbar speech. pyramidal cells in motor cortex
TABLE 9-4: SURVIVAL RELATED TO ONSET OR TYPE
(DERIVED FROM MATSUMOTO ET At, 1998
AND MACKAY, 1963)
Classical Duration Relatively Duration

ALS (mean) Pure forms
OVERALL 36 months
Bulbar onset 17 months' Pogressive 17 months

bulbar palsy
Corticobulbar 24 months
onset
Spinal motor 33 months Progressive 159 months

neuron onset muscular (13 years)
atrophy (PMA)
Corticospinal 36months Primary lateral 224 months

onset sclerosis (PLS) (19 years)·'
• Worst prognosis ··Best prognosis

ical examination of the nervous system demon-
strates a minor degeneration of the posterior
columns in addition to the marked degenera-
Figure 9-16. Amyotrophic Lateral Sclerosis. tion of the corticospinal tracts.
Degeneration of the corticospinal tracts is demonstrat-
ed in this myelin stain. (Courtesy of Dr. Emanuel R. Degeneration of the posterior columns sec-
Ross). ondary to disease of the posterior root:
In addition to primary lateral sclerosis, Tabes dorsalis (Fig. 9-17): this is a late
another very slowly progressive disorder has complication of the sexually transmitted disease
been identified: hereditary (or familial) spastic syphilis caused by the spirochete, Treponema
paraplegia. The prevalence of this disease may pallidum. Three stages of the disease are rec-
be as high as 1 in 10,000. In 70-85% of cases ognized: Primary, secondary, and tertiary. A
the transmission of the disease occurs as an lesion of abraded skin and or mucous mem-
autosomal dominant. Genetic studies have branes that begin as a painless papule, which
indicated linkage to different chromosomes for then subsequently ulcerates to form the chan-
different families: 14q or 15q or 2 p. Less often cre, characterizes the primary stage. The chan-
an autosomal recessive pattern is present. In
most cases, onset of disease occurs in child-
hood or adolescence, less often, after age 35.
Initially the lower extremities are primarily
involved, with delays in motor development or
clumsiness in walking or athletic activity. As the
disease progresses the spastic paraparesis
becomes evident. As in many of these degener-
ative disorders a deformity of the feet, pes cavus
Figure 9-17. Tabes Dorsalis. Ascending degeneration
may occur. Later in the disease, the upper
of the posterior columns in a 67-year-old white male
extremities may be involved. In addition a with tabes Mrsalis, abMminal crises, luetic aortitis,
minor decrease in vibratory sensation in the and luetic optic neuritis. Myelin stain (Courtesy of
lower extremities may be noted, and patholog- Dr. Jose Segarra).
9-22 CHAPTER 9
cre may involve the genitalia or lips or oral cav- determine where his feet were placed. He
ity or anus. The primary lesion develops after would often go 18-20 hours without voiding.
an incubation period of approximately 20 days, Neurological examination: Cranial
and may persist for an additional 14 -40 days. nerves: pupils were small, did not respond to
There is an associated painless lymphadenopa- light but did respond to accommodation.
thy. Primary lesions involving the vagina or Motor system: A gross ataxia of gait and stance
cervix or anus may go unrecognized and in was present worse with eyes dosed (positive
other locations may be mistaken for other tran- Romberg sign). Reflexes: Deep tendon reflexes
sient diseases. In approximately a one-third of were absent in the lower extremities. Sensory
these patients asymptomatic spread to the ner- system: Position and vibratory sensation was
vous system may be documented by a cerebral absent at toes and ankles. Pain sensation was
spinal fluid examination. The secondary stage of decreased over the nose and nipples.
disease begins at a variable interval of 2 - 12
TABLE 9-5:THE SYNDROMES OF TERTIARY NEUROSYPHILIS
weeks after contact. It is characterized by a (DERIVED FROM MERRITT, ADAMS &SOLOMON, 1946)
generalized maculopapular rash which may be
confused with other infectious exanthems and
Type and % Location of Pathology Delay In onset
constitutional symptoms such as fever fatigue of all tertiary after infection
and generalized lymphadenopathy. The symp- neurosyphilis
toms may be so mild that the patient has little (predominant
awareness of this stage of the disease. Again syndrome)
approximately one-third of patients would Acute Meninges plus cranial 2 months to
demonstrate a meningeal infection were spinal meningitis neuropathies 26 years
fluid examination to be performed. However usually
only 1 to 2% of patients in the secondary stage <1 year
actually have symptoms of meningitis. After a Meningo- Meninges and arteries Several months
variable period following infection of months vascular (16%) in subarachnoid space to 20 years,
to 30 years, the late or tertiary manifestations (arteritis with infarcts in average of
involving the nervous system and the cardio- brain and spinal cord) 7 years
vascular system appeared in 28% of all patients General paresis Invasion of cerebral 20 years
in the pre antibiotic era. Symptomatic neu- (12%) cortex by the spirochete
rosyphilis developed in 7-9% of all patients in with dementia and
that era. Prior to the antibiotic era, tertiary personality changes
neurosyphilis constituted a major neurological (see chapter 30)
problem. A resurgence of the disease may Tabes dorsalis Inflammation and 10-25 years.
occur in the future. The various types of ter- (30%) infeelion of posterior
tiary neurosyphilis are listed in Table 9-5.Note rools and secondary
that the primary process in almost all these syn- degeneration of
dromes relates to the late effects of meningeal posterior columns plus
(see table 9-6 below)
infection and inflammation.
The Clinical Symptoms and Signs of Tabes Mixed usually Combined cerebral 10-25 years
Dorsalis are listed in table 9-6. general paresis cortex and posterior
Case 9-9 provides an example of tabes and tabes rools plus
(see table 9-6 below
dorsalis.
Case 9-9: This 40 year old male had a 4- Chronic Skin, bones, CNS
year history of severe lancinating type pains in granulomas
either leg worsened by exposure to cold weath- (gummas) Rare
er or hot water. This was accompanied by a
Asymptomatic Asymptomatic Usually 1year
progressive deterioration of gait, which was (31 %) meningitis
particularly impaired in the dark. He could not
Clinical diagnosis: Tabes dorsalis TABLE 9-6: TABES DORSALIS: CORRELATION OF CLINICAL
Laboratory data: The diagnosis was con- FINDINGS AND LOCATION OF NEUROPATHOLOGY
firmed by positive serological tests for syphilis
in serum and CSF. Clinical Sign Location of Pathology
The diagnosis of tabes dorsalis is dependent 1. loss of conscious Degeneration of heavily
on the recognition of the clinical pattern of dis- proprioception: Involving myelinated floors entering
the lower extremHies the posterior columns
ease. It may not be possible to obtain a reliable
history of the primary or secondary lesions. 2. loss of unconscious loss of medium diameter
The clinical diagnosis is confirmed by serolog- proprioceptive fibers, In the posterior root
ical tests of the serum and by cerebrospinal information. and possibly posterior hom
fluid examination demonstrating a positive on their way fo neurons in
the nucleus dorsalis
serological test, some mild increase in (Clarke's column)
mononuclear cells, a mild elevation of protein
and an increase in gamma globulin. The sero- 3. Unsteadiness of stance loss of proprioceptive
logical test are of 2 types: 1) the nonspecific and galt: sensory ataxia. information in posterior
reagin antibody tests such as the RPR and the Positive Romberg sign columns from lower
extremities fo cerebellum
VDRL. 2) The specific treponemal antibody and cerebrum
test such as the fluorescent treponemal anti-
body absorption test (FTA ABS). As regards 4. loss of the deep tendon loss of the heavily
the nonspecific antibody tests, a positive serum stretch reflexes myelinated la fibers in
manifested as an the posterior rool.
test alone indicates only previous infection
absence of Ihe patellar
without necessarily indicating neurosyphilis. and Achilles reflexes.
Moreover a false positive test may occur in
other febrile illnesses and other immunological 5. Bladder dysfunction - loss of the afferent flbers In
disorders. A false negative nonspecific test in hypotonic flaccid the posterior roots of 52, 53
dilated bladder occurs, and 54 conveying stretch
the serum may occur in up to 30% of patients
atonic neurogenic information from detrusor
with chronic neurosyphilis. The specific anti- bladder muscle of the bladder
body tests on serum are positive in almost all (Interferes with reflex
cases of neurosyphilis. The positive nonspecific contractions of the detrusor
test of the spinal fluid when contamination of muscle and subsequent
the spinal fluid by blood has been ruled out is emplyingof the bladder)
diagnostic of neurosyphilis. 6. Fleeting sharp pains in the Damage to small diameter
Penicillin is the treatment of choice of neu- legs the back, the body or flbers conveying pain
rosyphilis. The current recommendations of face so-called ightenlng sensation, in the posterior
the u.s. public health service are that the Ipalns. AI times the viscera rools
may also be involved.
patient receive 24,000,000 units a day intra-
venously for at least 14 days. This should elim- 7. loss of sensation In the Damage 10 sensory fibers
inate the activity of the organism. However teet and subsequent from the leg with degenerative
many of these symptoms and signs will persist trauma may result in changes In the joints
since the chronic damage to nerve roots and trophic ulcers (Charcofs joinls)
nervous system from the meningeal or the 8. Abnormalities of the lesion in pretectal region of
meningoencephalitic inflammation or vascular pupillary response to light upper midbrain or possibly
components has already occurred. A reexami- (the Argyll Robertson in ciliary ganglion
nation of the spinal fluid at 6 months may con- pupil). Pupil is small
tinue to show a weakly positive serological test (miotic), Irregular, fails fo
respond to light and to
for syphilis but all other abnormalities should sympathetic stimulation.
clear. The serum nonspecific serological tests Pupil does accommodate.
may continue to remain weakly positive.
9-24 CHAPTER 9
Combined degeneration of the posterior result, abnormal fatty acids may be synthesized
and lateral columns: and incorporated into neuronal lipids.
Subacute combined degeneration: Although the precise metabolic defect respon-
sible for the neurological syndromes is not
Combined system disease due to vitamin B12
deficiency: The combination of posterior and entirely clear, the first reaction is considered to
lateral column degeneration may be seen in be the more likely explanation.
several diseases involving the spinal cord. Of Approximately 30 to 70% of all patients
with pernicious anemia develop neurological
these various causes, the most important char-
acteristic syndrome is that of subacute com- symptoms and signs. Even when severe anemia
bined degeneration secondary to vitamin B12 is present the neurological state may be rela-
(cobalamine) deficiency. In most cases the basic tively normal and the explanation is unclear.
On the other hand, severe signs of neurologi-
defect is a lack of intrinsic factor, the enzyme
cal involvement may be present in the absence
produced by the parietal cells of the gastric
mucosa, the same cells that produce gastric of anemia. In some instances folic acid may
been present in the absence of vitamin B12.
acid. In most cases, this occurs on a genetic or
Folic acid will correct the anemia but will not
immunological basis or as a result of a previous
affect the progression of the neurological syn-
gastrectomy. Intrinsic factor is necessary for the
absorption of vitamin B12 that occurs in the dromes.
distal ileum. In a few cases, the deficiency of The neurological syndromes relate to the
vitamin B12 does not indicate a deficiency of degeneration of myelin and subsequently of
intrinsic factor but rather reflects an overall
axons.
1. The major site of involvement is the
severe nutritional deficiency (eg. a diet defi-
spinal cord (Fig. 9-18). Initially the process is
cient in this vitamin) or represents a failure of
most severe in the heavily myelinated fibers of
the absorption of vitamin B12. Such a malab-
the posterior columns. This results in paresthe-
sorption syndrome may occur with a tropical
sias in the extremities and a sensory ataxia
or non-tropical sprue. In other instances a
accompanied by a + Romberg sign a
blind loop has occurred and bacterial growth
has resulted in consumption of vitamin B-12. 2. At the same time, the same process
The presence in the small intestine of the fish affecting the heavily myelinated sensory fibers
also affects peripheral nerves resulting in pares-
tapeworm d. Latum may also result in the con-
thesias and a loss of deep tendon reflexes.
sumption of vitamin B12.
3. Subsequently the heavily myelinated
Two active forms of cobalamine have been
fibers of the lateral columns are involved pre-
identified in humans. Methylcobalamin func-
dominantly affecting the lateral cortical spinal
tions as the cofactor for the conversion of
tracts. Bilateral Babinski signs will be found.
homocysteine to methionine. When the reac-
Hyperactive deep tendon reflexes are not likely
tion fails to occur, folate metabolism is
impaired and as a result there is a defect in
DNA synthesis. As a result, megaloblastic mat-
uration fails to occur and the characteristic
megaloblastic picture of pernicious anemia
results. The methionine that results from this
conversion is also utilized for the production of
choline and choline containing phospholipids.
When defective, the formation and mainte-
nance of myelin may be impaired. The second
form of cobalamine, adenosylcobalamin is nec- Figure 9-18 Combined Systems Disease. Degeneration
essary for the conversion of methylmalonyl - ofposterior and lateral columns is Ikmonstrated in this
coenzyme A to succinyl -coenzyme A. As a myelin stain of cervical spinal cord. (Courtesy ofDr.
Emanuel R. Ross).
because of the effects of the peripheral neu- ed with vitamin B12 injections with improve-
ropathy. ment in symptoms.
4. Less often the cerebral hemisphere white Spinal forms of spinal cerebellar
matter may be involved. Rarely for unknown degeneration: Spinocerebellar degenerations
reasons this site predominates producing a pro- represent overlapping groups of degenerative
gressive dementia. diseases that are usually of unknown etiology.
5. Occasionally the optic nerve is involved In some cases and families the predominant
producing an optic neuropathy. pathology involves peripheral nerve; in others
Diagnosis: Clinical syndrome + low B12 the cerebellum, in others, the cerebellum and
level «200pgjml) + Schilling test demonstrat- brain stem, in others, the cerebellum, brain
ing low absorption and subsequent excretion stem and basal ganglia. In the type to be con-
«8%) of labeled vitamin B 12 in urine with sidered in the section, the predominant
improvement after combined B12 and intrinsic involvement is of the spinal cord. However as
factor. will be evident, peripheral nerve is also often
Treatment: Monthly injections (IM) of involved during the course of these cases.
1000mcg of vitamin B12, after loading during Fried.reich's Ataxia: In most series of
the first month, 1000mcg daily X 5 days, then hereditary ataxia, this type accounts for 50% of
weekly X 3 weeks. all cases. It is the most common of the autoso-
Case 9-10 demonstrates the symptoms mal recessive type and is certainly the most
and signs of a typical case of combined system common of the early onset hereditary ataxias.
disease. The prevalence of this disease in Europe and
Case 9-10: This 48 year-old house painter the United States is 1-2 cases per hundred
had a 16-week history of progressive impair- thousand. The initial symptom: an ataxia of
ment of gait mainly unsteadiness and imbal- gait appears in childhood or adolescence
ance worse in the dark than in the light and tin- although rarely symptoms may appear in the
gling paresthesias of all his toes. Twelve weeks young adult years. Subsequently, pyramidal
prior to admission, tingling began in his fin- tract findings and dysarthria may appear.
gers. Weakness had not been a major com- Approximately 50% of the patients have a distal
plaint although he had noted shortly before wasting suggesting a peripheral nerve involve-
admission some sense of heaviness in his legs ment. Most patients have a distal loss of deep
on climbing steps. tendon reflexes and a distal sensory neuropathy
Neurological examination: Motor system: involving large diameter fibers. Deformities of
walking a tandem gait with eyes closed was dif- the foot including pes cavus (Fig.9-19) are
ficult. The Romberg test was positive. Reflexes: common. Deformities of the vertebral spine
Achilles deep tendon stretch reflexes were such as scoliosis (curvature) or kyphoscoliosis
absent. Bilateral Babinski sign was present. are also common. In some cases, blindness due
Sensory system: vibratory sensation was absent at to optic nerve involvement and deafuess due to
toes, ankles and knees. Position sense was 8th cranial nerve involvement is prominent.
decreased at toes. There was a minimal The majority of patients have abnormal elec-
decrease in pain and touch sensation over the trocardiograms. Cardiac arrhythmias and ven-
toes. tricular enlargementjhypertrophy are com-
Clinical diagnoses: Combined system mon due to myocardial muscle and conduction
disease. system involvement. Ten % of patients has
Laboratory data: consistent with the diag- overt diabetes mellitus. The disease slowly pro-
nosis. Serum B12 level: none detected. gresses with a mean age of death in the 30s
Schilling test demonstrated 1% excretion of usually due to the cardiac involvement and to
radioactive B12 in the urine which increased to the bed ridden state.
12% with intrinsic factor. Pathological examination (Fig. 9-20)
Subsequent course: The patient was treat- demonstrates a loss or degeneration ofaxons
9-26 CHAPTER 9
superior vermis of the cerebellum, the termina-

tion of the spinocerebellar pathway. There is
usually a mild loss on neurons in the dentate
nuclei of the cerebellum and of the inferior oli-
vary nuclei of the medulla which projects to the
cerebellum. A more significant loss of neurons
is found in the nuclei for cranial nerves 8, 10
and 12. Mild degenerative changes may be
noted in the optic nerves. In contrast the
peripheral nerves demonstrate a more signifi-
cant distal loss oflarge myelinated axons.
From the standpoint of clinical pathological
correlation, the ataxia is primarily a sensory
ataxia due to the involvement of posterior
columns, dorsal root ganglia, peripheral nerve
and a lesser degree, the spinocerebellar path-
ways. However some cerebellar component is
also present. The dysarthria reflects involve-
ment of cranial nerves 10 and 12 in addition to
some possible cerebellar component.
Figure 9-19. Friedreich's Ataxia: Pes Capus. A simi- The underlying genetic basis of the disease
lar abnormality of the foot may occur in other disease is an unstable expansion of a trinucleotide
states. (From wechsler, 1.: Clinical Neurology, 9th repeat GAA (guanine adenine adenine) which
Edition. Philadelphia, W.B. Saunders, 1963, p. 123).
maps to the chromosome locus 9 q 13 .On
that is most severe in the posterior columns of normal chromosomes, the number of GAA
the cervical spinal cord and is accompanied by repeat ranges from 7 to 22. In contrast, 96% of
a significant loss of cells in the posterior root patients with Friedreich's ataxia have both alle-
ganglion. The corticospinal and spinocerebel- les expanded to 100 to 2,000 repeats. Patients
lar (lower extremities) and cuneocerebellar with a larger number of repeats have an earlier
(upper extremities) pathways also demonstrate age of onset and a more severe form of the dis-
degeneration ofaxons. There is also a loss of ease. They are also more likely to have a car-
neurons in Clark'scolumn, the cells of origin of diomyopathy. The trinucleotide expansion
the spinocerebellar pathway. In some cases, apparently results in a decrease in a protein
there is a minor loss of Purkinje cells in the which has been labeled frataxin and which may
function as a mitochondrial iron transporter.
The buildup of untransported iron could then
result in defects of free radical regulation and
oxidative metabolism.
Case history 9-11 presented on the CD
ROM demonstrates the typical history and
findings in a case ofFriedreich's ataxia followed
over a long period of time.
MULTIFOCAL DISORDERS
Figure 9-20. Friedreich's Ataxia. Degeneration of AFFECTING THE SPINAL CORD:
posterior columns and, to a lesser extent, of lateral
columns is demonstrated in this myelin stain ofcervi- Two categories of pathology produce mul-
cal spinal cord. (From Wechsler, 1.: Clinical tifocal symptoms and signs affecting central
Neurology, 9th Edition, Philadelphia, W.B. Saunders, nervous system disease: demyelinating disease
1963,p.28)
and vascular disease particularly small vessel dis- exacerbations of the disease. Genetic and famil-
ease such as vasculitis. When the spinal cord is ial clustering has also been noted.
considered the first variety occurs frequently; The disease is characterized by the dissemi-
the second is encountered less frequently. nation of the pathological process in time and
Demyelinating diseases: In this category space. Thus there is a diagnostic criterion that
of disease we mean a pathological process in various lesions be acquired at different times.
which there is a primary destruction of nor- At any given moment, the various lesions than
mally formed myelin. We have already indicat- will be at a different stage of development. It is
ed other disorders in which damage to myelin also a diagnostic criterion that multiple levels of
in system disorders is but one step in the the central neural axis are affected. At a given
destruction of the axon. In addition, destruc- level the lesion cuts across various fiber systems;
tion of myelin and axons may occur as a conse- it is not a system disease.
quence of vascular infarction. There is another The pathological picture varies with the
rare group of disorders, the leukodystrophies stage of the disease. The initial areas of involve-
occurring in childhood, adolescence or early ment are perivenous with infiltration of
adult life, in which an extensive diffuse loss of mononuclear cells; plasma cells and lympho-
myelin occurs. The loss however involves the cytes .A slight degeneration of oligodendro-
destruction of defectively formed myelin. cytes may be noted. There is a destruction of
Multiple sclerosis: Among the primary myelin. There is than a stage of infiltration by
demyelinating diseases, the most common vari- macrophages in which the destroyed myelin is
ety is multiple sclerosis also referred to as dis- removed. There is then a stage of astrocytic
seminated sclerosis. This is a relatively common proliferation with the production of glial fibers.
disease of unknown etiology primarily affecting These areas of gliosis result in the firm sclerot-
young or middle-aged adults with most ic gray appearance of old lesions and thus the
patient's first demonstrating symptoms name multiple sclerosis (Fig. 9-21). In some
between the ages of 18 and 50. The frequency early cases, re myelination by oligodendrocytes
of disease varies based on geographical origin. may occur. As the disease progresses actual
Those who reside in the northern temperate destruction of the axons may occur as demon-
zone for the first 18 years of their lives are at strated at pathological examination and by
greatest risk as opposed to those who have MRI scans. Perivascular infiltration of plasma
spent those years in a more tropical climate cells and lymphocytes is the probable source of
Within a given geographic area whites are at production of the increased amounts of
higher risk than blacks. Approximately 1 in immunoglobulin -G in the cerebrospinal fluid
1,000 individuals of northern European origin of most patients with active multiple sclerosis.
who have resided in temperate climates during Among all patients with multiple sclerosis 40 -
those early critical years will develop multiple 60% will have such an elevation. Immuno-elec-
sclerosis at some point during their lifetime. An trophoresis of the CSF will demonstrate a
autoimmune disorder of the central nervous more specific abnormal population of oligo-
system has been suggested and therapy has clonal bands within the IgG in 75 to 85% of
been directed at this suspected etiology. As patients. A moderate increase in the number of
with many autoimmune disorders, frequency is lymphocytes will also be found in the CSF dur-
higher in females than in males, (ratio of ing acute exacerbations These CSF finding
1.6/1.0). As discussed recently by Noseworthy however are not specific for multiple sclerosis,
(1999), while it is unlikely that a viral invasion also being present in neurosyphilis, and post
of the nervous system directly causes the dis- infectious encephalomyelitis.
ease, it is possible that molecular mimicry-the Cases are classified according to the
antigenic similarity between viral organisms anatomical level involved in the initial acute
and neural tissue - may trigger the autoim- stage for example spinal, cerebellar- brain stem,
mune reaction. VIral infections may also trigger optic nerve, cerebral hemisphere. A more
9-28 CHAPTER 9
been employed. When patients of appropriate

age present with the initial findings of syn-
dromes that are seen commonly in multiple
sclerosis such as transverse myelitis, or optic
neuritis, or the brain stem syndrome of inter-
. nuclear ophthalmoplegia or an acute cerebellar
syndrome they are labeled as possible multiple
sclerosis.
The main ancillary technique for diagnosis
is the MRI scans. The MRI scan has simplified
the diagnosis since many cases of possible or
probable now have been shifted into the defi-
nite category at first presentation. The visual
evoked potential may also be of value in pro-
2IB viding evidence of an optic nerve lesion in
patients with involvement of other areas of the
nervous system.
The following case 9-12 is an example of
multiple sclerosis beginning with an episode
affecting spinal cord, but in which the MRI
scans demonstrated not only the suspected
spinal cord lesion but also, cerebral lesions.
Case 9-12: This 32 year old female regis-
tered nurse had a 6 month history of tingling
Figure 9-21. Multiple sclerosis affecting the spinal paresthesias in the lower extremities beginning
cord. A) A 58-year-old male with a long history of
progressive multiple sclerosis. At postmortem exami-
in the toes on the right foot and then the left
nation multiple plaques of variable age were present and gradually spreading to the rib margin on
in the nervous system. (Courtesy of Dr. Jose Segarra). the right and slightly lower on the left. Three
(8-26A) B) This 44-year-old male 20 years previously months later she developed tingling of the ring
had experienced a single acute episotk ofpossible mul- and 5th fingers bilaterally. Six weeks prior to
tiple sclerosis involving spinal cord and was asympto- evaluation, a positive Lhermitte's sign devel-
matic in the interim until his acute tkath from an oped: flexion of the neck produced electric
unrelated cause. (Courtesy ofDr. Jose Segarra).
shock sensations that extended down from the
important classification takes account of the buttocks into lower extremities.
pattern of evolution of the disease for example: Neurological examination confirmed the
relapsing- remitting, primary progressive or positive Lhermitte's sign. There was no local
secondary progressive. Some patients have a cervical tenderness. Reflexes: The left plantar
benign disease with only 1 or 2 episodes with a response was extensor; the right equivocal.
relatively complete remission. Overall 85% of Sensory system: Pain and cold were decreased up
patients began with a relapsing /remitting to the Ll-L2 vertebrae posteriorly (but possi-
course and 15% with a primary progressive bly at times to the rib margin on the right), and
course. anteriorly up to D7 dermatome on the right
Diagnosis of multiple sclerosis is based on and to D9 dermatome on the left. Vibratory
the clinical history and examination. When sensation was bilaterally decreased at toes,
patients have clear-cut evidence of lesions dis- ankles, and knees with a greater defect on left
seminated in time and space they are referred than right.
to as manifesting definite multiple sclerosis. Clinical diagnosis: Cervical myelopathy.
When dissemination in time or in space is pre- While the Lhermitte's sign could be seen in
sent the label of probable multiple sclerosis has multiple sclerosis, this sign also could be pro-
duced by compression of posterior columns. ROM includes several episodes indicating
Laboratory data: MRI ofthe cervical spine clear-cut clinical involvement of the spinal cord
(Fig.9-22) demonstrated a large area of in a patient with multiple sclerosis followed
demyelinating at C2 involving the right lateral over a number of years. In addition several
column and to the lesser degree the left poste- episodes relevant to brain stem are document-
rior column. MRI brain (Fig 9-23) demon- ed. The history of the patient's brother with a
strated multiple demyelinating lesions in both single episode of probable transverse myelitis is
cerebral hemispheres. also presented.
CSF studies were consistent with the diag- Present clinical and MRI studies indicate
nosis in terms of an increased count of 181ym- that most patients with relapsing/remitting
phocytes plus a markedly elevated multiple sclerosis do have an increasing lesion
Immunoglobulin G index). Two oligoclonal load resulting eventually in symptoms or signs
bands were present (normal = 0-1). that do not resolve. The present approach then
Subsequent course: The patient received a 5- is to utilize early in the disease course agents
day course of high dose (1 OOOmg/day) intra- that modifY the immune system. Agents such
venous methylprednisolone with some as the beta interferons decrease relapses and
improvement in the sensory symptoms in the secondary progression. The effects are evident
legs. She had subsequent episodes affecting from both a clinical and MRI standpoint.
spinal cord and brain stem and was treated with Many would now advocate beginning such
beta interferon. therapy after the first episode in a patient who
Case history 9-13 presented on the CD had clear-cut MRI evidence of multiple lesions
such as case 9-12.
Acute exacerbations are usually treated with
high-dose intravenous corticosteroids with the
patient receiving 1,000 mg a day of methyl-
prednisolone for 5-7 days. This shortens the
course of the exacerbation with the possibility
of less residual disability. There is no clear-cut
therapy for primary progressive multiple scle-
rosis although various major immunological
therapies have been investigated.
Figure 9-22: Multiple sclerosis involving the spinal Figure 9-23: Multiple sclerosis involving brain. Case
cord. Case 9-12 see text. MRI A) Sagittal section. 9-12. MRI. See text.
B) transverse section.
CHAPTER 10
Case History Problem Solving: Part I
Spinal Cord, Nerve Root, Perepheral Nerve
and Muscle
LESION DIAGRAMS: For each of the fol-
lowing diagrams, indicate the structures
involved, the clinical symptoms and signs that
would be present and the most likely patholo-
gy. That is name the disease or syndrome.
Diagrams 1-10 follow.
L
Figure 10-3
R L L
Figure 10-1 Figure 10-4
L L
10-2 CHAPTER 10
Figure 10-8
Figure 10-10
CASE mSTORY PROBLEM SOLVING type pain in the above distribution, also
PART I - SPINAL CORD, NERVE extending at times into the index and middle
ROOT, PERIPHERAL NERVE AND fingers. In association with the pain, he expe-
MUSCLE rienced tingling Pins-and-needles paresthesias
Each of the following case histories deals with in the right upper extremity in a distribution
disease at the level of muscle peripheral nerve similar to that noted above. During this peri-
root and spinal cord. For each case relevant to od the patient also noted minor weakness of
spinal cord, be prepared to draw a diagram of the right hand. The lower extremities and
the lesion indicating the appropriate spinal bladder were not involved. When symptoms
cord level, the location of the lesion, and the persisted, neurological consultation was
nature of the pathologic process. If disease of obtained.
the spinal cord is present, decide whether the
NEUROWGIC EXAMINATION
process is intrinsic or extrinsic and whether
it involves a single-level lesion or is a system Mental status: Intact.
disease. Cranial nerves: II-XII intact.
CASE 10-1: A 48-year-old white male, while Motor system:
lifting a heavy object, approximately two a. There was significant weakness of the
months prior to neurological consultation, right triceps (50% of normal) with minimal
had the sudden onset of pain in the posterior weakness of the right wrist extensor and the
cervical area and radiating into the right shoul- finger abductors of the right hand. There
der, down the posterior aspect of the arm into was no weakness of the lower extremities.
the elbow. Coughing or straining at stool b. Gait was intact.
resulted in a shooting, burning electric shock- c. No definite atrophy was present.
Rare fasciculations were noted in the right
CASE HISTORY PROBLEM SOLVING PART I: SPINAL CORD 10-3
triceps muscles. involved in this case.
Reflexes: 8. Why did coughing and straining at stool
a. Deep tendon reflexes produce an exacerbation of the pain?
Biceps: right, 2+; left, 2+ 9. How would you manage this problem?
Triceps: right, 0; left, 2+ IO.Which imaging studies should be obtained
Brachioradials: right,I to 2+; left, 2+ and when should these studies be obtained?
Patellar: right, 2+; left, 2+
SUBSEQUENT COURSE
Achilles: right, 2+; left, 2+
b. Plantar responses: The patient had a reduction in pain and
Right flexor, left flexor. sensory symptoms following the use of cervi-
Sensory System: cal traction. Strength improved and the
Minor decrease in pain sensation was present triceps deep tendon reflex returned.
over the right middle finger. Pain, touch, posi-
tion, and vibratory sensation were otherwise CASE 10-2: This 58-year-old white house-
intact. wife presented with a 7 -month history of
Neck: There was limitation of neck motion in throbbing midthoracic back pain, which at
all directions due to pain. Pressure over the time would radiate to the anterior chest and
lower cervical spinous processes produced a was aggravated by coughing or by straining at
radiation of pain onto the right upper extrem- stool. Two months prior to admission, numb-
ity. There was also local tenderness on ness of the right foot was noted, which
pressure over the right supraclavicular area. gradually spread up the leg so that within a 6-
QUESTIONS week period, a level just below the breast ante-
1. Is the spinal cord directly involved by this riorly and just below the scapula posteriorly
lesion1 If so, indicate the level. If not, cite was involved. Six weeks prior to admission, a
evidence against such involvements. Are similar ascending numbness of the left foot
the anterior roots involved? If so, indicate developed. One month prior to admission,
the level. If not, cite evidence against such weakness of both lower extremities was noted,
involvement. Are the dorsal roots involved? the right being weaker than the left. For 2
If so, indicate the level. If not, cite evidence months, difficulty in control of urination had
against such involvement. been present.
2. What is the localizing significance of the GENERAL PHYSICAL
relatively selective weakness of the right tri- EXAMINATION:
ceps muscle? Normal.
3. What is the explanation for the occasional
NEUROLOGIC EXAMINATION:
fasciculations noted in the right triceps
Mental Status: Intact
muscle?
Cranial Nerves: Intact
4. What is the localizing significance of the
Motor System:
selective depression of the triceps deep
a. Bilateral decrease in strength was pre-
tendon reflex? Review also the segmental
sent at hip, knees and ankles.
levels involved in the biceps, radial, patellar
b. Gait was shuftling, possibly spastic.
and Achilles deep tendon reflexes.
Reflexes:
5. What is the localizing significance of the dis-
a. Deep tendon reflexes were active in
tribution of pain and numbness experienced
the upper extremities, possibly related to a
by the patient?
significant degree of anxiety. The patellar
6. What is the localizing significance of the
reflexes were markedly hyperactive (4+).
restricted pain deficit in the right hand?
b. The plantar response was markedly
7. Speculate concerning the pathology
extensor on the left and borderline on the
10-4 CHAPTER 10
right. Three days prior to admission, she awoke with

Sensory System: numbness of the hands and the plantar sur-
a. Pain and temperature sensation were faces of the feet. On the day prior to admis-
decreased bilaterally below the xiphoid ster- sion, she began to experience diffuse weakness
num anteriorly and the T6 spinous process of all 4 limbs and of her face. This worsened
posteriorly. The degree of impairment was over 24 hours.
greater on the right than the left side.
PAST mSTORY:
b. Position sensation was absent at the
unremarkable, she did smoke S-1O cigarettes
left toes.
per day.
c. Vibratory sensation was absent at the
left toes and decreased at the left ankle and GENERAL PHYSICAL
knee. EXAMINATION:
Vertebral percussion tenderness was present Blood pressure slightly elevated (140/90),
over the T3-TS spinous processes. with elevated pulse of 116.Temperature 97.6
dig. (Oral). Respiration 20.There was mild
LABORATORY DATA:
erythema of the pharynx, but no lym-
X-rays: Thoracic spine X-ray was negative. phadenopathy.
Chest X-ray was negative.
NEUROLOGICAL EXAMINATION:
QUESTIONS
1. What is the significance of this selective Mental status and cranial nerves were normal.
combination of signs and symptoms: 1. Motor system: diffuse weakness: right upper
a. The degree of impairment of pain and extremity 3+-4+/S)eft upper S-/S.
temperature sensation was greater on the Symmetric weakness in lower extremities in
right side than the left. the following muscles: iliopsoas 3/S,ham-
b. Position and vibratory sensation was strings 4/S,gastrocnemius 4/S,anterior tibials
absent at left toes but intact on the right. 4/S,extensor hallucis longus 4/S.
c. The plantar response was markedly 2. Reflexes: Deep tendon stretch reflexes were
extensor on the left but borderline on the everywhere absent. Plantar responses were
right. flexor.
2. Where is the lesion located? Be specific and 3. Sensory system: intact except for a minimal
indicate basis for your conclusions. decrease in pinprick over the soles of the
3. Is the pathology intrinsic or extrinsic? feet.
4. Provide a differential diagnosis as to the LABORATORY DATA:
nature of the pathology and defend your
1. CSF: day of admission: tube #1; 1800
conclusions.
RBC's, S lymphocytes; tube #4: 3 RBC's, 1
S. What diagnostic studies would you request?
lymphocyte. Protein normal: 36 mglltb, glu-
When would you obtain those studies?
cose normal: 70.
6. What therapy would you recommend?
CSF: one week after admission: protein: ele-
What type of consultation would you
vated to 92 mglltb, no significant cells were
request? When would you obtain this con-
present
sultation? What results would you expect
2. WBC: slightly elevated: 12,600
from therapy?
3. ESR, and ANA were normal.
4. Monospot and hepatitis A IgM antibodywere
CASE 10-3: This 16 year old right-handed positive.
white female high school student, 7 days prior QUESTIONS:
to admission awoke with a bilateral sensation 1. Localize the lesion. Is this a problem of
of numbness and tingling of teeth and gums. spinal cord, peripheral nerve or muscle?
2. How do you interpret the absence of deep compared to biceps and radial periosteal (bra-
tendon reflexes? chioradialis), which were active (2 to 3+).
3. How do you interpret the CSF findings? The patellar and Achilles deep tendon reflexes
4. Now be more specific as to the type of were hyperactive (3+ to 4+).
pathology -assign a clinical diagnosis. b. Superficial reflexes: bilateral extensor
5. What would EMG/nerve conduction plantar responses were present (bilateral
studies demonstrate? Babinski signs).
5. What would a nerve biopsy demonstrate? Abdominal reflexes were decreased bilaterally.
6. How would you manage this case in terms Sensory System:
of treatment if clinical findings improved? a. Position sense was defective for gross
Note that findings may already have been movements of the great toes bilaterally.
improving: the bilateral facial weakness of b. Vibratory sensation was markedly
which she had complained was no longer decreased below the level of the T7 spinous
present. process.
7. What measures should be undertaken if c. Pain and light-touch sensation were
weakness was progressing and respiration markedly decreased below the level of the
was compromised? umbilicus. Sacral segments were involved.
CASE 10-4: This 47-year-old white male, There was also a poorly defined band of
inspector of small parts entered the hospital decreased pain sensation over the upper tho-
complaining of weakness and numbness in rax. Pain sensation was somewhat greater on
both legs. Five months prior to admission, the the left than on the right.
patient had noted a burning-type pain extend-
LABORATORY DATA:
ing over the right forearm. Soon thereafter, he
became aware of a gradually increasing numb- 1. Glucose tolerance test revealed a diabetic-
ness, pins-and-needles sensation involving his type curve, with a fasting blood sugar of
legs; first the right and then the left. This was 122, 30 minute sample of 205, 60 minute
followed by a weakness of both lower extrem- sample of 218, and 150 minute sample of
ities, which increased in severity. Urgency of 142 mg/l00 ml.
urination, occasional bowel incontinence, and 2. Lumbar puncture revealed a partial dynam-
increasing impotence were also noted. ic block with the head in extension.
Cerebrospinal fluid protein was elevated to
NEUROLOGIC EXAMINATION: 80 mg/lOO ml (normal 45 mg/l00 ml).
Mental Status: Intact. QUESTIONS
Cranial Nerves: Intact. 1. Indicate the level of the lesion in this case
Motor System: and the structures involved in the patholo-
a. Strength was intact in the upper gy.
extremities but decreased in the lower 2. Assuming that the pain in the upper
extremities to 50% of normal. The involve- extremities early in the course of the disease
ment of the right leg was greater than that of had some localizing significance, why was
the left leg. the sensory level for pain present only up to
b. A mild degree of spasticity was the level of the umbilicus (TI0) (that is,
present at the knees and ankles, with a spastic pain sensation was absent or decreased
gait. below the umbilicus)?
c. No atrophy or fasciculations were 3. Was the pathology in this case intrinsic or
present. extrinsic (compressive) to the spinal cord?
Reflexes: Cite the evidence for your conclusions.
a. Deep tendon stretch reflexes at tri- 4. What diagnostic procedures would you
ceps were decreased bilaterally (0 to 1+) undertake prior to surgery?
10-6 CHAPTER 10
5. Granted that the patient had, among other positive).

findings, posterior and lateral column signs, d. Cerebellar tests, such as bringing the
why is the diagnosis of combined system finger-to-the-nose, when performed with eyes
disease unlikely in this case? open, were not remarkable.
Reflexes:
HOSPITAL COURSE
a. Deep tendon reflexes were every-
Surgery was performed by Doctor Samuel where absent.
Brendler. Examination two weeks after b. Plantar responses were extensor bilat-
surgery revealed some return of pain sensation erally (bilateral Babinski signs).
over the thorax, abdomen and lower extremi- Sensory System:
ties. Walking had improved. Evaluation 2 a. Vibratory sensation was absent at the
months after surgery indicated continued toes and ankles and markedly decreased at
improvement as regards gait. Position sense the knees and iliac crests in a symmetric man-
had returned to the lower extremities, but ner. There was also a significant decrease at
vibration sense was still absent. the fingers, with a lesser decrease at the wrists
and elbows.
CASE 10-5: This 73-year-old retired execu- b. Joint position sense was defective for
tive was referred for evaluation of paresthesias fine-amplitude movements at the toes but
(pins-and-needles sensation and numbness) elsewhere was intact.
involving all four extremities. Approximately c.Pain and light-touch sensation were
8 months previously, while hospitalized for intact.
gallbladder surgery, the patient developed a QUESTIONS
glove-and-stocking distribution of paresthesias 1. This patient presents a common neuro-
involving all four extremities in a symmetric logic syndrome. Indicate the site of pathol-
manner. The level of sensory symptoms grad- ogy. Present a differential diagnosis and
ually ascended over the ensuing weeks and indicate the most likely pathology.
months; in the lower extremities, as far as the 2. Does this patient have a single-level lesion
perineum; in the upper extremities, to the level or a system disease?
of the elbows. In the several months prior to 3. Discuss the diagnostic significance of the
admission, the patient had also noted increas- sensory symptoms and findings.
ing unsteadiness of gait, primarily when 4. Explain the absence of deep tendon reflex-
attempting to walk in the dark. es.
5. What is the significance of a "positive
Family History There were several relatives
Romberg sign"?
with pernicious anemia but no relatives with
6. Indicate the significance of bilateral exten-
neurologic disease.
sor plantar responses (Sign of Babinski).
NEUROLOGIC EXAMINATION: 7. Outline what additional tests you would
Mental Status: Intact. perform to confirm the diagnosis. Indicate
Cranial Nerves: Intact. the normal values for those tests.
Motor System: 8. What treatment would you undertake? (Be
a. Strength was intact. specific)
b. Gait was broad-based, with unsteadi-
ness on the turns. The degree of ataxia was CASE 10-6: This 21-year-old single white
increased by eye closure. female was admitted to the hospital because of
c. The patient with eyes open and progressive difficulty in walking. Nearly four
standing on a narrow base was relatively years before admission, the patient first noted
steady. When his eyes were closed, a signifi- a relatively rapid onset of weakness in the left
cant swaying was apparent (Romberg test
hand. Three months later, she noted a throb- Sensory System:
bing pain in the neck that radiated into the left a. Pain and temperature sensation were
arm and left hand and was accompanied by intact.
some numbness (paresthesias) of the fingers of b. There was a slight distal decrease in
the left hand. Weakness of the left upper vibratory sensation at the toes.
extremity slowly progressed and was accompa- Cranium and Vertebral Column:
nied by atrophy. Four months before admis- No local tenderness or abnormalities were pre-
sion, a more rapid progression of left arm sent.
symptoms was noted, and weakness of both
LABORATORY DATA:
lower extremities began, initially on the left
and to a greater extent than the right. Just 1. Cervical spine X-rays showed bony changes:
before admission, weakness of the right upper widening of the spinal canal n anteroposte-
extremity was noted. Bladder symptoms were rior and lateral diameters was noted.
not present. 2. Thoracic spine X-rays showed that
kyphoscoliosis was present.
NEUROLOGIC EXAMINATION: 3. Cerebrospinal fluid protein was increased to
Mental Status: Intact. 150 mg/l00 mi.
Cranial Nerves: Intact. QUESTIONS
Motor System: 1. Where is the pathology located (be
a. Severe atrophy of all muscles of the specific)?
left upper extremity was present, with flexion 2. Present a differential diagnosis. In this case
(claw-hand deformity) contracture. you will need to consider the radiology
Fasciculations were present in almost all of findings.
the left upper extremity muscle groups. Mild 3. What is the most likely pathology?
atrophy of the intrinsic muscles of the right 4. What is your diagnostic approach to this
hand was also noted. patient?
b. There was weakness of the muscles of 5. Outline your therapeutic approach to this
the left upper extremity, most marked patient.
distally but also involving the shoulder girdle, 6. What therapeutic results are expected?
with a lesser weakness of the muscles of the
right upper extremity. Both lower extremi-
Case 10-7: This 39-year-old white married
ties were weak, the left more so than the
airplane mechanic had the gradual onset of
right.
muscle weakness approximately 18 months
c. Spasticity was present bilaterally on
prior to admission: This involved both arms
passive movement at the knees and ankles.
and legs, with greater involvement of the prox-
Reflexes:
imal muscles than of the distal muscles.
a. Deep tendon reflexes were depressed
Gradual progression occurred so that 14
in the left upper extremity. The biceps reflex
months before admission, significant difficulty
was absent: the triceps and brachial radialis
in walking was experienced. Shortly there-
(radial periosteal) reflexes were hypoactive
after, the patient experienced difficulty in swal-
(1 +). In the right upper extremity the biceps
lowing, but this problem improved following
reflex was depressed (1 +), whereas the triceps
his hospitalization the previous year. Weakness
was 2+. In the lower extremities, the patellar
of extremity musculature also improved fol-
and Achilles were hyperactive to a marked
lowing the use of cortisone. The patient at no
degree (4+).
time had difficulty in voiding. He had no sen-
b. Superficial reflexes: Plantar responses
sory symptoms; he had had no actual pain or
were extensor bilaterally. Abdominal reflexes
tenderness in the muscles.
were absent.
10-8 CHAPTER 10
NEUROLOGICAL EXAMINATION: NEUROLOGIC EXAMINATION:

Mental Status: Intact. 1. Severe flaccid weakness in voluntary move-
Cranial Nerves: Intact. ment in the upper extremities, particularly
Motor System: The patient had severe weakness at the shoulders.
and atrophy of muscles (both proximal and 2. Spasticity was present on passive motion of
distal) of all four extremities but with clearly the lower extremities.
more marked involvement of the proximal 3. The gait was also ataxic.
musculature. The patient was unable to lift his 4. The deep tendon reflexes were absent in the
arms above the shoulder and unable to lift upper extremities but hyperactive in the
his legs oft' the bed. No fasciculations were lower extremities at patella and Achilles.
present. The plantar responses were extensor
Reflexes: bilaterally.
a. Deep tendon stretch reflexes were 5. Sensation for pain and temperature was
everywhere absent except at the ankle where selectively decreased over the shoulder and
normal 2+ reflexes were found. arms .An MRI scan of the cervical spine was
b. Plantar responses were flexor. performed.
Sensory System: No abnormalities were QUESTIONS:
present. 1. What is the significance of the selective
LABORATORY DATA: decrease in pain and temperature over the
1. Erythrocyte sedimentation rate was elevated shoulders and arms?
to 45 mm/hr. 2. What would you expect the MRI to
2. Electromyogram and muscle biopsy were demonstrate?
consistent with the clinical diagnosis. 3. Select the appropriate MRI from the group
of illustrations below that best corresponds
SUBSEQUENT COURSE: to this case.
Following treatment with prednisone in high 4. What therapeutic approaches are possible?
dosage, the patient had a gradual improve-
ment in strength.
QUESTIONS:
1. Does this patient have a problem localized
to spinal cord, nerve root, peripheral nerve
or muscle?
2. Present a differential diagnosis of this prob-
lem and indicate the most likely diagnosis.
3. Outline the expected findings on elec-
tromyography and muscle biopsy.
4. Would any other laboratory data be of help
in establishing the diagnosis?
CASE 10-8: This 37-year-old white male was

evaluated by Doctor Sandra Horowitz for a
diagnosis of upper extremity disability. His
neurologic history had begun, 20 years previ-
ously with weakness in both upper extremities.
An extensive laminectomy had been per-
formed 19 years earlier.
Figure lO-lA Figure lO-2A
Figure lO-3A
Figure 10-4A
CHAPTER 11
Functional Anatomy of the Brain Stem
I. INTRODUCTION cord. Table 11-1 lists the general contents of
This chapter presents an overview of the each region of the brain stem.
anatomy of the brain stem and describes cer- TABLE 11·1. REGIONS IN THE BRAIN STEM
tain functional centers. The brain stem con-
sists of medulla, pons and midbrain (Fig 11-1 REGION CONTENTS
and 11-2). We will first start at the medul- Tegmental-anterior noar Cranial nerve nuclei and
lospinal junction and then discuss several levels of fourth ventricle and all ascending and descending
of the medulla, pons, and midbrain. The dis- cerebral aqueduct Tracts except for tracts in basis
cussion of each level will include the important Basis-anterior surface Corticospinal, corticonuclear,
functions, nuclei and tracts found in that level. of tegmentum And corticopontlne tracts
The medulla, pons, and midbrain are subdi-
Tectum-posterior surface Cerebellum for medulla and
vided by their relationship to the ventricular
of fourth ventricle pons; superior and inferior
system. One division, the tectum, forms the and aqueduct colliculi of midbrain
roof and walls or the posterior surface; the
other division, the tegmentum, forms the floor
or anterior surface. The basis forms the anteri- TEGMENTUM
or surface of the tegmentum. The tegmentum of the brain stem (medul-
la, pons, and midbrain) is continuous (Fig 11-
3), and it can be divided functionally into five
wnes: ventricular, lateral, medial, central and
basilar. This is done to help the student under-
stand the basic plan of the brain stem. Each
half of the brain stem should be considered
organized like an apple with the core being the
Figure 11-1. Gross VIeW of the Brain Stem in

Sagittal Section of the brain.
The tectum in medullary, pontine, and

midbrain levels consist of regions that have
highly specialized functions related to the spe-
cial senses and movement. The tegmentum
contains cranial nerve nuclei, the reticular for-
mation, and tracts that interconnect higher Figure 11-2. The regions of the brain stem. Sagittal
and lower centers as well as tracts that inter- MRJ-T1.
connect the brain stem with other portions of
the central nervous system. The basis consists reticular formation and the pulp formed by the
of the descending fibers from the cerebral cor- four surrounding wnes (Figures 11-3 A,B,C,
tex to the brain stem, cerebellum, and spinal Table 11-2).
11-2 CHAPTERll
TABLE 11-2 THE FIVE ZONES IN THE TEGMENTUM
Zone Gray Malter White Malter

Ventricular medulla:hypoglossal all levels - descending
(Dorsal) & vagal trigones, autonomics
SOlitary nucleus medulla -
vestibular & cochlear solitary tract
nerves & nuclei pons :
LOWER MEDULLA median eminence
with facial colliculus
midbrain: CN II & '"
Lateral inferior olive all levels

medulla & pons - spinothalamlc,&
descending nucleus Rubrospinal. medulla-
of V spinocerebellars
trigeminal afferents
Inferior cerebellar
peduncle pons -
lateral lemniscus
midbrain - lateral
lemniscus &
medial lemniscus
Medial reticular formation all levels - MLF &

raphe nuclei tectospinal. medulla -
medial lemniscus
Central reticular formation ascending &

(Core) central & lateral descending reticular
INFERIOR COLLICULUS nuclei. medulla- tracts,
ambiguous descending
pons - motor nucleus autonomies
Figure 11-3. Regions in the brain stem, Coronal sec- of V, facial nucleus,
tions; A-medulla, B-pons, G-midbrain. para pontine nucleus.
midbrain - red nucleus
ll. FUNCTIONAL & substantia nigra
LOCALIZATION IN
CORONAL SECTIONS OF THE Basilar Medulla; arcuate medulla- pyramid
BRAIN STEM nucleus pons: pons-inferior cerebellar
pontine gray peduncle midbrain-
The previous sections on the brain stem cerebral peduncle
have discussed gross anatomy and cranial
nerves. In this section, we will discuss the
functional anatomy of the brain stem byexam- Although the discussion in this chapter of
ining coronal sections at representative levels each level is confined to the coronal section
through the medulla, pons and midbrain. under examination, it should be noted that
Each level will contain the following illustra- most nuclei and all tracts extend through more
tions: than just one level. Therefore, when reading
A - a myelinated section with the nuclei this section the student should keep in mind
and tracts labeled on the outline below. the origin and destination of structures identi-
B - an MRI at a similar level (Please fied in each of these sections.
remember that the MRI is from a living It is especially important that the student
patient while the brain sections were obtained understand the function and clinical impor-
from postmortem examination) tance of the anatomical structures they are
FUNCTIONAL ANATOMY OF THE BRAIN STEM 11-3
TABLE 11-3. GRAY & WHITE MATTER EQUIVALENTS dent should be aware that the development of
IN SPINAL AND BRAIN STEM STRUCTURES the cerebellum, midbrain, and cerebrum has
greatly affected the neural contents of the
SPINAL CORD EQUIVALENT BRAIN STEM brain stem and has lead to the formation of
REGION REGION
many nuclei and tracts (for example the fol-
Dorsal (sensory) hom Ventricular zone, lateral region
with sensory cranial nerves lowing nuclei - inferior olive of the medulla,
VII, IX, X; pontine gray of the pons, red nucleus and sub-
lateral zone cranial nerve V stantia nigra of the midbrain, and the corti-
conuclear and corticopontine tracts).
Ventral (Motor) Hom Ventricular Zone, medial
Motor Cranial Nerves - MEDULLA
III-VI, X-XII Blood supply-Vertebral arteries
Reticular Formation with and its branches
motor nuclei of Cranial
Nerves V, VII, IX & X The first level we have included is at the
sensory and motor decussation (Fig 11-4).
Intermediate Zone Reticular formation and This section has mostly spinal cord elements,
associated nuclei
the ventral horns and the three white matter
Intermediolateral Cell Parasympathetic Nuclei with columns; however, one can also note brain
Column (Sympathetic) Cranial Nerves III, VII, IX & X. stem elements--the gracile and cuneate nuclei.
Tl-Tll,Ll & L2; This region is the transitional zone and the
Parasympathetlcs S2-54.
region is the size and shape of the spinal cord.
Lateral Column = Basilar Zone= As we move up the brain stem, we come to the
Corticospinal/crossed, corlicospinal/not crossed widened medulla with the opening of the
rubrospinal, Lateral Zone - fourth ventricle.
Spinothalamic spinothalamic &rubrospinal
In the brain stem tegmentum the gray and
Posterior Column = Medial Lemniscus = white matter appear intermingled; however,
uncrossed Gracile & crossed taCllle InformaHon there is a basic organization of the tracts in the
cuneate fasciculi brain stem zones, as shown in Table 11-4.
Anterior Column = MLF, Medial Zone - MLF, TABLE 11-4. MAJOR TRACTS IN TEGMENTAL ZONES
vestibulospinal, teClospinal reticular formation
Reliculosplnal, reticulospinal Ventricular zone - SOlitary tract and autonomic tracts
spinothalamic lateral zone vestibulospinal
Medial zone - MLF, tectospinal, medial lemniscus
studying. The cranial nerve nuclei and many Lateral zone - spinalhalamies, rubrospinal,
pathways (e.g., corticospinal, corticonuclear, cerebellar peduncles, and lateral
lemniscus. Medial lemniscus enters
and spinothalamic) in the brain stem are clini-
this zone In pons and midbrain.
cally important since any functional abnormal-
ity in these systems help to identify where the Central core descending autonomies and
disease process is occurring in the eNS. (reticular formation)- central tegmentaltraCl.
DIFFERENCES BElWEEN THE Basilar zone - corticospinal and corliconuclear.

SPINAL CORD AND BRAIN STEM
The interior gray matter and exterior white MEDULLA
matter of the spinal cord gradually changes to Gross Landmarks en the Medulla. The
a mixture of gray and white matter in the brain tegmentum of the medulla has two distinct
stem. Table 11-3 identifies the nuclei and levels, a narrow lower portion which is similar
tracts in the spinal cord and lists their func- to the spinal cord and an broader upper por-
tional equivalents in the brain stem. The stu- tion which includes the landmarks that are a
11-4 CHAPTER 11
hallmark of this level, the medullary pyramids reached their maximum bulk with the addition
and the inferior olivary prominence. of the last of the fibers from the uppermost
LEVEL: SPINOMEDULLARY cervical levels. The somatotopic arrangement
JUNCTION WITH MOTOR of the tactile fibers in the posterior column are
DECUSSATION (Fig. 11-4) as follows: the most medial fibers are sacral,
then come the lumbar, thoracic, and most lat-
Gross Features. This level resembles the
erally, cervical fibers.
spinal cord as the dorsal columns - the funicu-
Spinothalamics/anterolateral column. Pain
lus gracilis and the funiculus cuneatus are con-
and temperature from the extremities,
spicuous; the trigeminal funiculus is more lat-
abdomen, thorax, pelvis, and neck are carried
erally placed.
by the lateral spinothalamic tract located at the
On the anterior surface of the spinal cord,
lateral surface of the medulla. Light touch
the medullary pyramids (corticospinal tracts)
from the extremities, thorax, abdomen, pelvis,
are evident (Fig 11-4A). Note that this
and neck is carried via the anterior spinothala-
descending pathway on the right side has first
mic tract, which is seen on the surface of the
crossed (decussated) with the fibers, shifting
medulla just posterior to the corticospinal
from the anterior surface of the medulla, then
tract. In the spinothalamic pathways sacral
entered the lateral funiculus of the spinal cord.
fibers are on the outside while cervical fibers
The narrow spinal canal is present in the gray
are on the inside. The dorsal and ventral spin-
matter above the pyramidal decussation ..
ocerebellar tracts are found in the lateral
Motor Cranial Nerve Nuclei (Fig ii-4A).
funiculus.
Only the cranial portion of nerve XI is present
The rubrospinal and tectospinal tracts,
at the lateral margin of the reticular formation.
which are important in supporting voluntary
It innervates the Stemocleidomastoids and
motor movements, are found in the lateral
trapezius muscles that rotate the head and ele-
funiculus and near the midline in the
vate the shoulders, respectively.
medullary and pontine levels).
Sensory Cranial Nerve Nuclei (Fig 11-4A).
The primary axons convey pain and tempera- LEVEL: LOWER MEDULLA AT
ture from the head and neck and are located in SENSORY DECUSSATION (FIG. 11-5)
the spinal tract of the fifth cranial nerve; these Gross Features. At this level the fourth ven-
fibers have descended from the pons. The sec- tricle narrows. The funiculus gracilis and the
ond order axons originate from the underlying funiculus cuneatus are conspicuous on the
descending nucleus and their axons cross and posterior surface of the spinal canal, while the
then ascend contralaterally to the ventral pos- medullary pyramids are prominent on the
terior medial nucleus of the thalamus. The anterior surface Fig ii-SA and B.
nucleus lateral to the pyramidal tract is the Ventricular Zone.
inferior reticular nucleus, a portion of the
Motor Cranial Nerve Nuclei (fig 11-SA).
reticular formation. This section contains the inferior extent of the
White Matter (fig 11-4A). At this level the hypoglossal nerve (XII) and the dorsal motor
tracts are still in the same positions as in the
nucleus of the vagus nerve (X). The hypoglos-
spinal cord. Tactile discrimination (fine touch,
sal nucleus innervates the intrinsic and extrin-
pressure, vibration sensation, and two-point
sic musculature of the tongue, while the dor-
discrimination) and proprioception from the
sal motor nucleus of the vagus nerve provides
extremities, thorax, abdomen, pelvis, and neck
parasympathetic preganglionic innervation of
are carried via the dorsal columns. The nuclei
the viscera. This level marks the superior
can now be seen that are the 2° neurons in
extent of the cranial portion of the eleventh
this pathway, the gracile and cuneate nuclei.
cranial nerve in the ambiguous nucleus.
The gracile and cuneate tracts (fasciculi) have
4A
FASCICULUS GRACILIS
NUCL. CUNEATUS
DORSAL
SP INOCEREBELLAR
~-+-DESCENDING NUCL. 1Z:
VENTRAL
SPINOCEREBELLAR
SENSORY DECUSSATION
RUBROSPINAL TR.
SPINOTHALAMICS OF PYRAMID
MEDU LLARY PYRAMID
Figure 11-4. Brain Smn at transition level between

&er1Iical spinal cord and medullar-Sensory
Decussation. Coronal
Lateral Zone.
Sensory Cranial Nerve Nuclei (Fig ll-SA).
Pain and temperature from the head are con-
veyed by the descending nucleus and tract of
nerve V that is prominent anterior to the
cuneate nucleus. Note that myelinated ipsilat-
eral primary axons are on the outside of the
second order neurons while the second order
11-6 CHAPTER 11
SA
DORSAL MOTOR NUCL:x.
GRACILIS
FASCICULUS NUCL
CUNEATUS
SPINOCEREBELLAR
TRACTS: -+-+-+- NUCL CUNEATUS
ESCENDING NUCL 1Z
TRACT :JZ:
RUBROSPINAL TRACT
SENSORY DECUSSATION
INFERIOR OLIVARY NUCL
ARCUATE NUCL.
Figure 11-5. Brain Stem at lower medullary /evel.

Coronal
neurons are leaving the inner surface of the

nucleus, crossing and entering the medial
lemniscus, forming the trigeminothalamic
(quintothalamic) tract.
White Matter (Fig ll-SA).Pain and tem-
perature from the extremItleS, thorax,
abdomen, pelvis, and neck are carried via the
lateral spinothalamic tract. The spinothalamics
are located in the lateral fimiculus throughout
the spinal cord and brain stem! The anterior conspicuous in this section. Internal arcuate
spinothalamic tract is adjacent to the lateral fibers are seen leaving the inner surface of the
spinothalamic tract. gracile and cuneate nuclei, curving around the
The tract carrying unconscious proprio- ventricular gray, crossing the midline (sensory
ception from the upper extremity originates decussation), and accumulating behind the
from the external cuneate nucleus and its fibers pyramid and beginning the formation of one
enter the cerebellum through the posterior of the major ascending highways, the medial
spinocerebellar tract. The function of this lemniscus. The serotonin containing raphe
nucleus is similar to that of Clark's column in nucleus of the reticular formation is found in
the spinal cord. this zone throughout the brain stem.
The vestibulospinal tract is found internal The medial longitudinal fasciculus is locat-
to the spinothalamic tracts. The dorsal and ed in the midline of the tegmentum just below
ventral spinocerebellar tracts are seen on the the hypoglossal nucleus and above the tec-
surface of the medulla covering the spinal tract tospinal and mediallemniscal pathways. In all
of nerve V and the spinothalamic tracts. levels of the brain stem it will be in this sub-
The rubrospinal tract is an important affer- ventricular position.
ent relay to the alpha and gamma neurons in Central Zone
the spinal cord. It originates from the red
The central core of the medulla, pons, and
nucleus in the tegmentum of the midbrain,
midbrain consists of the reticular formation,
crosses the midline, and descends. It is found
which is important for many vital reflex activi-
in the lateral funiculus of the medulla internal
ties and for the level of attentiveness.
to the spinocerebellar tract and anterior to
spinal nerve V throughout the pons and Basilar Zone
medulla. It is important in postural reflexes. This level contains the corticospinal fibers
The tectospinal tract is phylogenetically an old just before they cross in the medullospinal
tract, being the equivalent of the corticospinal junction. Note that the pyramidal system is
tract in non-mammalian vertebrates. It origi- named for the passage of the corticospinal
nates from the deep layers of the superior col- fibers through this pyramidal shaped region
liculus and to some extent from the inferior respectively (Fig 11-5 A-B). One of the impor-
colliculus. It is seen anterior to the medial lon- tant concepts from this section is that axons
gitudinal fasciculus throughout the medulla, that form the volitional motor pathway, pyra-
pons, and midbrain and is important in coor- midal system, originate in the cerebral cortex.
dinating eye movements and body position. These tracts are located in the basis of the
brain stem and include the corticospinal and
Medial Zone.
corticonuclear fibers that run in the medullary
The medial lemniscus is the largest path-
pyramid. Motor system fibers that do not run
way in the medial zone. However, as we
in the medullary pyramid are considered
progress superiorly in the brain stem these
extrapyramidal (e.g., cerebellar peduncles,
fibers migrate laterally to finally enter the later-
rubrospinal tectospinal, etc.) The location of
al zone in the midbrain. This migration is nec-
the major structures in the tegmentum of the
essary for the medial lemniscus to be correctly
medulla is listed below in Table ll-S.
positioned as it enters the thalamus.
Tactile discrimination and proprioception LEVEL: INFERIOR OLIVE OF THE
are conveyed from the extremities, thorax, MEDULLA (FIG. 11-6)
abdomen, pelvis, and neck by the axons in the Gross Features. At this level the medullary
fasciculus gracilis and cuneatus. The nucleus tegmentum expands laterally with the promi-
gracilis and the nucleus cuneatus form the sec- nent inferior olive located behind the pyra-
ond order neurons in this pathway and are mids. The floor of the fourth ventricle con-
11-8 CHAPTER 11
TABLE 11·5. MAJOR TRACTS AND NUCLEI IN MEDULLARY V are nearly obliterated by the olivocerebellar
TEGMENTAL ZONES fibers.
b. Solitary Tract & Nucleus. Taste and vis-
Ventricular Zone· Cranial nerve nuclei of VIII, X& XII ceral sensations are found in the solitary nucle-
(motor nuclei medial; sensory lateral) solitary nucleus us and tract in the tegmental gray below the
and tract.
medial vestibular nucleus. Fibers from cranial
Lateral Zone· Cranial nerve roonelS exit in relation to the nerves VII, IX, and X ascend and descend in
inferior olive with the XII nerve anterior to the olive this tract carrying general sensations from the
and the rootlelS of IX, Xand XI posterior to the olive. viscera (nerve X) and gustatory sensations
RoonelS for VIII exit in the cerebellopontlne angle.
from the taste buds in the tongue (nerves VII
Tracts: Inferior cerebellar peduncle, spinothalamic, and IX) and epiglottis (nerve X).
rubrospinal; nuclei: external cuneate, descending c. Vestibular. The medial and descending
nuclei and tract of V. vestibular nuclei are present with first order
Medial Zone· Nuclei· raphe or medial reticular. axons (Fig. 11-6B) found in the descending
Tracts = MLF, tectospinal, medial lemniscus root of cranial nerve VIII, interstitial to the
descending nucleus. Fibers may be seen run-
Central Zone· Nuclei of reticular formanon, ambiguous ning from the vestibular nuclei into the medi-
nuclei of IX·XI, inferior olivary complex,
allongitudinal fasciculus.
Tract: central tegmental tract , the major ascending
reticular pathway d. Auditory. The dorsal and ventral cochlear
nuclei are second order nuclei in the auditory
Medullary Basis - Tracts contains corncospinal and pathway and receive many terminals from the
cornconuclear tracts In medullary pyramid.
cochlear portion of nerve VIII seen within its
borders.
tains the median eminence and the vestibular Cerebellar. The conspicuous inferior oli-
and cochlear tubercles. The median eminence vary nucleus in the anterior portion of the
consists of aqueductal gray, while the vestibu- medullary tegmentum consists of the large
lar tubercle is formed by the medial vestibular main nucleus and the medial and dorsal acces-
nucleus and the descending root and nucleus sory nuclei. The entire complex is important
of cranial nerve VIII. The dorsal cochlear in supplying information to the cerebellum.
nucleus forms the cochlear tubercle. The ven- Removal of the olive in animals produces con-
tricle at this level is at its widest extent. (Fig. tralateral increase in tone and rigidity in the
6A and 6B) The sulcus limitans in the ventric- extremities, with concomitant uncoordinated
ular floor separates the medially placed motor movements. The olive connects to the con-
cranial nuclei from the laterally placed sensory tralateral cerebellar hemispheres via the inferi-
cranial nuclei. or cerebellar peduncle. The climbing fibers
found on the dendrites of Purkinje's cells in
Ventricular Zone
the cerebellum originate in the inferior olive.
Motor Cranial Nerve Nuclei (Fig 11-6A).
The olive also has strong connections with the
This level marks the superior extent of nerve
red nucleus and receives input from the spinal
XII and the dorsal motor nucleus of nerve X.
cord, cerebellum, red nucleus, intralaminar
The ambiguous nucleus in the lateral margin
nuclei, and basal ganglia. The central core of
of the reticular formation contains cell bodies
this section, as in other levels, consists of neu-
innervating the pharynx and larynx (nerve X).
rons of the reticular formation.
Lateral Zone Medial Zone (Fig 11-6 A). The serotiner-
Sensory Cranial Nerve Nuclei. gic raphe nuclei of the reticular formation are
a. Trigeminal. Pain and temperature are found in this zone. The position of the MLF,
conveyed from the face by nerve V. The tectospinal and medial lemniscus corresponds
descending nucleus and tract of cranial nerve to that in the previous level.
6A
SUPERIOR \;~'"~.'~LIC"~ llMITANS
SUPERIOR
"-;~::;""'--':'--I- VESTIBULAR
NUCL.
DESCENDING
NUCL \'Ill
INFERIOR CEFIEBIEll.JI.R-;-=:;
PEDUNCLE
DESCENDING TR. ]l
VENTRAL SP I NOICERIEBIELl.AR
PYRAM IDAL
MLF
Figure 11-6. Brain Stem at mid-medullary /erJel. Coronal

11-10 CHAPTERll
Figure 11-6. Brain Stem at mid-medullary level. Coronal
Basilar Zone (11-6A&B). The medullary COLLICULUS (FIG. 11-7)

pyramids are prominent at this level. The VENTRICLE EQUIVALENT
rootlets of cranial nerve XII exit lateral to the LEVELMRI.
pyramid. Gross Features. The bulk of this section
PONS consists of the middle cerebellar peduncle
Blood Supply - Basilar Artery (brachium pontis) and the cerebellum. In
and its branches Figure 11-7 the bulk of the cerebellum has
Gross Landmarks. The hallmark of pontine been removed. The fourth ventricle narrows
levels is the prominent basis ponti that is pre- as it nears the cerebral aqueduct. The
sent on the anterior surface. The cerebellum medullary pyramids are present at the anterior
forms the posterior surface. The tegmentum surface. Note that the inferior olive is no
takes up much less of these levels due to the longer present.
massive enlarlement of the pontine basis. With VENTRICULAR ZONE
the cerebellum removed the posterior surface Motor Cranial Nerve Nuclei
of the tegmentum demonstrates the three- (Fig 11-7B).
cerebellar peduncles (see Fig. 1-15) inferior 1. The nucleus of nerve VII is conspicuous
cerebellar peduncle, middle cerebellar pedun- at the lateral margin of the tegmentum. This
cle, and superior cerebellar peduncle - posteri- nucleus innervates the muscles of facial expres-
or surface and the fourth ventricle is now sion. In the pons, in close proximity to the
opened. ventricular floor, the rootlet of this nucleus
LEVEL: LOWER PONS AT LEVEL swings around the medial side of the nucleus
OF FACIAL NERVE AND FACIAL of nerve VI forming the internal genu of nerve
VII. These fibers then pass lateral to the way. The auditory fibers are seen accumulat-
nucleus of nerve VII and exit from the sub- ing inferior to the superior olive and cutting
stance of the pons on the anterior surface in through the medial lemniscus to form the lat-
the cerebellopontine angle. erallemniscus.
2. The nucleus of nerve VI innervates the White Matter (fig 11-7B). At this pontine
lateral rectus muscle of the eye. The rootlet level, some of the ascending tracts are starting
leaves the anterior surface of the nucleus and to move more laterally. The medial lemniscus
has the longest intracerebral path of any nerve will shift laterally and approach the rubrospinal
root. The fibers finally exit on the anterior sur- and spinothalamic tracts.
face of the brain stem near the midline at the Tactile discrimination and proprioception
pontomedullary junction. The close proximi- from the limbs, thorax, pelvis, abdomen, and
ty of the nucleus of nerve VI to the rootlets of neck are conveyed by fibers in the mediallem-
nerve VII demonstrates why any involvement niscus, which is seen posterior to the corti-
of the nucleus of nerve VI usually produces a cospinal tract.
concomitant alteration in function of nerve Pain and temperature from the head are
VII. The nucleus of nerve VI and the internal conveyed by the secondary trigeminothalamic
genu of the rootlets of nerve VII form the tracts, which are found in the medial lemniscus
prominent facial colliculus on the floor of the and ascend to the nucleus ventralis posterome-
fourth ventricle. dialis in the thalamus.
Cerebellar Pathways (fig 11-7 B). At this Pain and temperature from the extremities,
level the middle and inferior cerebellar pedun- thorax, abdomen, pelvis, and neck are carried
cles form the lateral walls of the ventricle as in the lateral spinothalamic tract, which is near
well as the bulk of the cerebellar medullary the anterior surface of the pons, close to the
center. The ventral spinocerebellar tract is medial lemniscus.
seen lateral to the superior cerebellar peduncle The anterior spinothalamic tract that is
that it enters and then follows back into the mixed in with the lateral spinothalamic tract
cerebellum. The superior cerebellar peduncle carries light touch.
consists primarily ofaxons carrying impulses The gustatory fibers from the tongue are
from the dentate nucleus of the cerebellum to found in the solitary tract. The secondary
the red nucleus and the ventral lateral nucleus fibers ascend bilaterally in the medial lemnis-
in the thalamus. This tract is also called the cus. Fibers carrying visceral sensations also
dentatorubrothalamic tract. The tractus unci- synapse in the solitary nucleus.
natus connects the deep cerebellar nuclei with Medial Zone.
the vestibular nuclei and reticular formation
The raphe or the medial reticular nuclei are
bilaterally.
present in this level. The medial lemniscus at
Lateral Zone this level contains secondary fibers from the
Sensory Cranial Nerve Nuclei (fig 11-7B). dorsal columns and the spinothalamic,
Pain and temperature are conveyed from the trigeminothalamic, and solitary tracts. The
head. At pontine levels the descending nucle- medial longitudinal fasciculus and tectospinal
us of nerve V is small, while the tract is large. tracts are still present near the midline in the
The superior vestibular nucleus is seen at the floor of the fourth ventricle with the medial
lateral margin of the ventricle with primary longitudinal fasciculus conspicuous under the
vestibular fibers present in its substance. floor and the tectospinal tract below it.
Auditory sensation at this level is related to the Central Zone (Fig 11-7 A&B). In the cen-
superior olive that is seen inferior to the motor ter of the pontine tegmentum, the main effer-
nucleus of nerve VII. The superior olive is one ent ascending tract of the reticular system, the
of the secondary nuclei in the auditory path- central tegmental tract, occupies the bulk of
11-12 CHAPTERll
7A
CEREBELLAR CORTEX GENU E

7B
SUPERIOR CENTER-CEREBELLUM
MLF DLF
SUPERIOR VESTIBULAR
NUCL
ROOTLETS3rr--~----~~~~_____ t -:.J-~~---":::""--!------+-M OTOR NUCL E:
DESCENDING TR :'l
NUCL Y
SUPERIOR OLIVARY NUCL

TRAPEZOID BODY
Figure 11-7. Brain stem at pontine level of Cranial Nerve VII. Coronal
the reticular formation. V is conspicuous bilaterally in the reticular for-
Internal to the nucleus of VI is the para- mation, medial to the sensory nucleus and the
pontine reticular nucleus that coordinates eye entrance of the root of nerve V. Each of these
movements. Fibers descend the opposite nuclei provides innervation to the ipsilateral
TABLE 11-6. MAJOR CONTENTS OF TEGMENTAL ZONES OF muscles of mastication.
THE PONS Sensory Cranial Nerve Nuclei (fig ll-BA).
Tactile discrimination from the face is carried
Ventricular Zone: Nuclei = Median eminence with facial by the trigeminal root into the main sensory
colliculus (nucleus of VI), superior vestibular nucleus nucleus of nerve V, seen lateral to the
of VIII. intrapontine root of nerve V. The secondary
fibers originate from this nucleus and ascend
Lateral Zone: Nuclei-main sensory of V, descending of V;
Tracts - spinal of V. crossed and uncrossed. The crossed fibers run
Tracts = spinothalamic and rubrospinal. adjacent to the medial lemniscus (ventral
trigeminothalarnic), while the uncrossed fibers
Central Zone: Nuclei =reticular formation, facial nucleus, run in the dorsal margin of the reticular for-
paraponline reticular nucleus, superior olive
and lateral lemniscus. Tracts = crossing of mation (dorsal trigeminothalarnic). Both fiber
lateral lemnlscal nucleus of cochlea. pathways terminate in the ventral posterior
medial nucleus of the thalamus.
Medial Zone: Nuclei = Raphe nuclei of the reticular Proprioception from the majority of the
formation. Tracts = MLF, tectospinal,
crossing auditory fibers, medial lemniscus. muscles in the head is carried in by the mesen-
cephalic root and ends in the mesencephalic
Basilar Zone: Middle cerebellar peduncle with pontine nucleus of nerve V, located lateral to the walls
gray that forms the bulk of the pons at these levels. of the fourth ventricle in the upper pontine
Tracts = Corticospinal and corlicobulbar.
------ and midbrain levels. Note cranial nerves V &
VII in the MRI 11-SB. These neurons are the
frontal eye fields, synapse here and then con- only primary cell bodies (dorsal root ganglion
nect via the MLF to the nuclei ofN and III . equivalent) in the CNS. These axons synapse
Basilar Zone (fig 11-7 B). The descending on the Chief Nucleus of V. The jaw jerk is a
corticospinal and corticonuclear pathways are monosynaptic stretch reflex. The receptor is
nearly obscured by the fibers of the middle the mesencephalic nucleus of nerve V and the
cerebellar peduncle and the pontine gray. effector is the motor nucleus of nerve V.
Table 11-6 reviews the contents of the pontine The superior olive is one of the nuclei in
tegmentum. the auditory system. Auditory fibers are seen
LEVEL: UPPER PONS AT THE running through the superior olive or inferior
MOTOR AND MAIN SENSORY to it cutting through the medial lemniscus and
NUCLEI OF NERVE V (Fig. 11-8) crossing the midline, forming the trapezoid
body. The fibers are then found lateral to the
Gross Landmarks. The bulk of this section
medial lemniscus and are known as the lateral
consists of the middle cerebellar peduncle and
lemniscus. The pontine nuclei are conspicu-
cerebellar cortex. The fourth ventricle begins
ous in the basilar portion of the pons.
to narrow as it nears the cerebral aqueduct.
White Matter (Fig ii-BA). At this level the
Ventricular Zone. In this level there are no
medial lemniscus has moved from the midline
motor cranial nerve nuclei on the floor of the
to a more lateral position, and many of the
ventricle. With the nuclei in the ventricular
ascending sensory systems are now either in
floor being for visceral functions.
the medial lemniscus or adjacent to it.
Lateral Zone Medial Zone. The raphe nuclei of the retic-
Motor Cranial Nerve Nuclei (Fig ll-BA). ular formation are evident in this level. The
The rootlet ofCN Vand motor nucleus ofnerve medial longitudinal fasciculus is larger in this
11-14 CHAPTERll
MEDULLARY CENTER-CEREBELLUM CEREBELLAR CORTEX

NUCL JZ:
NUCL
CENTRAL TEGMENTAL TR.
PYRAMIDAL TR.
Figure 11-8. Brain stem at pontine level of Cranial Nerve V. Coronal

In this section the midbrain forms the roof
and floor of the narrow cerebral aqueduct,
while the pons makes up the basilar portion.
The roofis the inferior colliculus, an important
nucleus in the auditory pathway.
TECTUM
Inferior colliculus (Fig 11-9 A&B). The
gray matter of the inferior colliculus forms the
tectum at this level. The inferior colliculus is
divided into three nuclei, a large central nucle-
us, and a thin dorsal nucleus the paracentral or
cortical nucleus, and an external nucleus. The
central and cortical nucleus functions as a relay
Figure 11-8. Brain stem at pontine level of Cranial center for the cochlea. The external nucleus
Nerve V. Coronal
functions for the acusticomotor reflexes
section between the motor nuclei of cranial through the tectospinal pathway. The brachi-
nerves III and VI because it contains many um of the inferior colliculus carries auditory
vestibular and cerebellar fibers necessary for information onto the medial geniculate nucle-
accurate eye movements. The tectospinal us of the diencephalon. The tectospinal path-
fibers always lie below the MLF. way descends from this region and terminates
Central Zone. In the reticular formation on motor nuclei of the lower cranial nerves
the central tegmental tract is conspicuous. and upper cervical ventral horn cells.
Basilar Zone. The corticospinal tract is
found in the pontine gray and white matter. TEGMENTUM
Ventricular Zone (Fig 11-9 A&B). The
MIDBRAIN
periaqueductal gray is conspicuous in midbrain
Blood Supply-Basilar Artery and
levels. Descending and ascending tracts asso-
Posterior Cerebral Arteries
ciated with the visceral brain are found here.
Gross Landmarks. On the anterior surface In the midbrain, the lower half of the peri-
of the midbrain we find the principal landmark aqueductal gray and some other nuclei in the
of this level, the cerebral peduncles with the tegmentum are part of the midbrain limbic
third cranial nerve exiting from the medial sur- area. This zone is important in our level of
face of the cerebral peduncles in the interpe- attentiveness. Bilateral lesions to the periaque-
duncular fossa. On the posterior surface of the ductal gray and midbrain tegmentum usually
midbrain we find the corpora quadragemini, produce comatose patients.
the superior and inferior colliculi. The fourth Motor Cranial Nerve Nuclei (fig 11-9
cranial nerve exits from the posterior surface of A). The nucleus of cranial nerve IV is seen
the midbrain and the junction with the pons .. indenting the medial longitudinal fasciculus in
In a coronal section through the midbrain lower regions of the midbrain. The axons of
one finds the red nucleus in the tegmentum of this nucleus pass posteriorly (unique for a cra-
the midbrain. (Fig. 11-9B). Also in the inferi- nial nerve) and exit the brain at the midbrain-
or levels in the tegmentum just before the red pontine junction where the fibers then pro-
nucleus one finds the crossing of the superior ceed anteriorly to reach the superior oblique
cerebellar peduncle. muscle through the superior orbital fissure.
LEVEL: INFERIOR COLLICULUS Sensory Cranial Nerve Nuclei (fig 11-
AND 9A). Proprioception is conveyed from the
PONTINE BASIS (Fig. 11-9) muscles in the head and neck. The mesen-
cephalic nucleus of nerve V is located at the
11-16 CHAPTERll
9A
CEREBRAL AQUEDUCt PERIAQUEDUCTAL GRAY
INFERIOR COLLICULUS
SUPERIOR
LEMNISCUS
MEDIAL
CORTICOPONTINE DECUSSATING
FIBERS PONTINE FIBERS
CORTICOSPINAL TRACT ===~~~~I-:;-e';iJ1PONTINE NUCLEI
Figure 11-9 Brain stem at inferior collicular level. OJronal

9B
Inferior
Cerebral "AQlaa&l(~t_-.!
ial
Temporal
Lobe
Red
Figure 11-9 Brain sUm at inferior collicular level. Coronal
lateral margin of the periaqueductal gray. lemniscus is seen superior to the mediallem-
Remember these are the only primary sensory niscus. These secondary auditory fibers are
neurons in the eNS; their axons join the now entering the inferior colliculus. Many of
medial lemniscus and ascend to the ventral these fibers synapse and then continue up into
posterior medial nucleus in the thalamus. This the medial geniculate as the brachium of the
nucleus controls the superior oblique muscle inferior colliculus.
of the eye. Medial Zone (fig 11- 9 A). The raphe
Lateral Zone (Fig 11-9A). At this level nuclei of the reticular formation are very con-
the medial lemniscus and the other major spicuous in these levels. The mediallongitudi-
ascending tracts are stretched over the lateral nal fasciculus is prominent in the floor of the
surface of the tegmentum of the midbrain. ventricle as it nears cranial nerve III; the fibers
The spinothalamic and trigeminothalarnic located within it are important in coordinating
fibers are found lateral to the medial lemniscus ocular movements.
while the auditory fibers are located above Central Zone (fig 11- 9 A). This zone in
them. Thus the following sensory modalities the lower tegmentum of the midbrain is near-
for the entire body are located here: tactile dis- ly completely filled with the crossing fibers of
crimination, proprioception, pain and temper- the superior cerebellar peduncle. Ultimately,
ature, gustatory and visceral sensations. all these fibers decussate and continue up to
Auditory Fibers (fig 11-9A). The lateral the red nucleus where some fibers synapse, but
11-18 CHAPTER 11
the majorities of these axons bypass the red is a laminated structure important in relating
nucleus and terminate on the ventral lateral eye movements and body position. The tec-
thalamic nuclei. tospinal tract originates from its deepest layer
Basilar Zone (fig 11-9-A). The bulk of this and provides connections onto certain cranial
region is taken up by the pontine gray and and spinal neurons.
descending fibers from the cerebrum to the
Ventricular Zone
pontine gray, the corticopontine system. The
Sensory Cranial Nerve Nuclei (fig 11-10
corticospinal and corticobulbar fibers are also
A). Proprioception is conveyed from the mus-
present here.
cles in the head and neck by the mesencephal-
LEVEL: SUPERIOR COLLICULUS ic nucleus of nerve V, located at the lateral
AND PONTINE BASIS (Fig. 11-10) margin of the periaqueductal gray in the supe-
rior collicular levels as well as in the upper pon-
TECTUM
tine and inferior collicular levels.
Superior Colliculus (Fig 11-10). The Motor Cranial Nerve Nuclei (fig 11-10
superior colliculi form the rostral portion of a). Cranial nerve III is visible in the floor of
the midbrain tectum. The parenchyma of the the cerebral aqueduct, adjacent to the medial
superior colliculus is organized in layers. There longitudinal fasciculus. This nerve supplies the
are four layers containing gray and white mat- medial, inferior, and superior rectus muscles
ter from inside out: stratum zonale, stratum and the inferior oblique and superior levator
cinereum, and stratum opticum and stratum muscles of the eyelid. The Edinger-Westphal
lemnisci. The superficial layers of the superior nucleus of nerve III is also present; it provides
colliculus receive their input from the retina preganglionic parasympathetic innervation to
and visual cortex with the contralateral upper the constrictor muscle of the pupil via the cil-
quadrant medially and the contralateral lower iary ganglion.
quadrants laterally. In contrast the deeper lay-
Lateral Zone.
ers receive their input from polysensory
sources including the cerebellum, inferior col- White Matter (Fig 11-10A). Medial
liculus, spinal cord, reticular formation gracile, Lemniscus. At this level in close proximity to
cuneate, trigeminal nuclei, and visual regions. the medial lemniscus includes most of the
A portion of the tectospinal pathway originates ascending sensory fibers (Table 11-7). This
at this level and descends in the lower brain tract is stretched out over the inferior and lat-
stem to terminate on the lower cranial nerves eral surface of the tegmentum, with the fibers
and ventral horn cells of the spinal cord. that mediate pain and temperature from the
(Remember the tectospinal and tectobulbar extremities, thorax, abdomen, and pelvis locat-
fibers terminate on the same motor nuclei as ed at its superior extent. The trigeminal fibers
the corticonuclear and corticospinal path- form its middle portion, and the fibers that
ways). The zone of the tectum just above the mediate tactile, proprioceptive, and visceral
superior colliculus, the pretectal zone is impor- sensations are placed medially.
tant in light reflexes. Anterolateral Colunm.
TEGMENTUM Lateral Spinothalamic. Pain and temper-
ature from the limbs, thorax, and pelvis are
Gross Features. In this section the roof and
found in this pathway.
floor are formed by the midbrain, while the
Anterior spinothalamic. Light touch
basilar portion is made up of peduncles and the
fibers from the limbs, abdomen, and neck are
pons. The roof is the superior colliculus, an
seen in close proximity to the lateral spinothal-
important station in the visual pathway. The
amic pathway.
cerebral aqueduct forms the narrow ventricular
Auditory Pathway. The fibers from the
lumen. (Fig. 11-10B). The superior colliculus
lOA
SUPERIOR AQUEDUCT
GENICULATE
CENTRAL TEGMENTAL TR
NUCL ]I[
I' -:'-----+-t-SUBSTANT1A NIGRA
1---:::;~:7L_-I-- INTERPEDUNCULAR
UCL
INTERPEDUNCULAR
FOSSA
CORTICOSPINAL TR
OECUSSATING PONTINE FIBERS
Figure 11-10. Brain stem at superior colticular level. Coronal

11-20 CHAPTER 11
nucleus has minimal if any projections in the

human onto the thalamus, although it most
likely influences the cerebellar input onto the
thalamus.
The substantia nigra is also located in this
level just behind the cerebral peduncle. Its
functions are discussed in the relationship
between the basal ganglia and movement (see
Chapter 18).
Medial Zone (fig 11-10 A).
The serotinergic raphe nuclei of the reticu-
lar formation are present in this level. The
medial longitudinal fasciculus in the floor of
the cerebral aqueduct is conspicuous and con-
Figure 11-10. Brain stem at superior collicular level. nected across the midline. The oculomotor
Coronal complex indents the MLF and receives ascend-
inferior colliculus (called at this level the ing fibers from cranial nerves VI and VIII
brachium of the inferior colliculus) are seen at through the MLF.
the inferior surface of the superior colliculus. The tectospinal fibers at this level are pri-
On the left side they enter the medial genicu- marily from the superior colliculus.
late nucleus of the metathalamus at which Basilar Zone (Fig 11-10A&B)
point they reach their final subcortical center. Cerebral Peduncles. At this level, the fron-
There is a complete discussion of the auditory topontine fibers, which occupy the most medi-
and vestibular pathways in the Special Sensory al part of the cerebral peduncles, enter the
Section found on the CD ROM. pons. Figure 11-11 is a stained section through
Cerebellar Fibers. The superior cerebellar the cerebral peduncles demonstrating the rela-
peduncle continues to cross in the tegmentum tionship between the peduncles, and the III
of the midbrain; just above this level many of cranial nerve. The corticospinal fibers and
these fibers synapse in the red nucleus, while many of the corticobulbar fibers are still in the
others will continue to the ventral lateral peduncle. In Figure II-lOB, a coronal section
nucleus in the thalamus. through the brain, the relationship of the cere-
Central Zone (fig 11-10A). The central bral peduncle to the medial temporal lobe
tegmental tract is conspicuous in the midbrain demonstrates that the cerebral peduncles are
tegmentum in the reticular formation. The adjacent to the medial temporal lobe. This
red nucleus is found in the medial edge of the may be significant if herniation of the tempo-
reticular formation. In the human it consists of rallobe produces compression of the cerebral
a small magnocellular region and a large par- peduncle and cranial nerve III with the accom-
vocellular region. Fibers from all cerebellar panying cranial nerve and upper motor neuron
nuclei, but especially the dentate, synapse here. signs. Table 11-7 lists the significant struc-
Corticorubral fibers run bilaterally from tures in the tegmental zones of the midbrain.
the motor cortex synapse here also terminate
III. FUNCTIONAL CENTERS IN
here in a somatotopic relationship. Fibers
THE BRAIN STEM
from the red nucleus terminate directly or
indirectly in the cerebellum and on many of Now that the anatomical features of the
brain stem have been discussed, it is appropri-
the motor nuclei in the brain stem and spinal
cord, which also receive input from the corti- ate to identifY some important functional cen-
cospinal and corticonuclear pathways. The red ters located in the brain stem and dien-
cephalon. During this discussion, it will
become evident that the cranial nerves are the TABLE 11-7. MAJOR CONTENTS OF TEGMENTAL ZONES
pivotal point for many of these activities. IN MIDBRAIN
A. RETICULAR FORMATION
Ventricular Zone: Cranial nerve nuclei are
The central core of the medulla, pons, and Nuclei: IV (Inferior collicular level), and III
midbrain tegmentum consists of the reticular (Superior Collicular Level).
formation. Upon microscopic examination,
this region is seen to consist of groupings of The parasympathetic nucleus of Edinger-Westphal, asso-
ciated with cranial nerve III, to the pupillary constrictor is
neurons separated by a meshwork of medullat- also present. The interstitial nucleus of Caja!, and the
ed fibers. With a Golgi neuronal stain the nucleus of DarscheWfiz important pupillary renexes are
Golgi Type I cells with long axons, neurons also found here.
are shown with their dendrites extending
Tracts: MLF and descending autonomics and ascending
reticular fibers.
Lateral Zone: Tracts: Medial lemniscus, lateral lemnis-

cus, spinothalamlcs and brachium of inferior colliculus,
with a conftuens of the major ascending tracts.
Central Zone: Nuclei : Reticular formation with red nucle-

us and origin of rubrospinal tract. Substantia nigra present
just posterior to the cerebral peduncle.
Tracts: central tegmental and origin of rubrospinal
Medial Zone: Nuclei: Raphe nuclei which forms the

serotinergic pathway.
Figure 11-11. Brain stem at level of cerebral Tracts - MLF, with tectospinal and decussation of superior
peduncles and III cranial nerve. Weil stain. cerebellar peduncle and rubrospinal tract. The tectospinal
Coronal section and rubrospinal tracts originate in the midbrain.
Basilar Zone. Tracts: Cerebral peduncle containing from

transversely and the axons bifurcating into
medial to lateral frontopontine, cortlconuclear, corti-
ascending and descending branches, which cospinal, parietopontine, temperopontine, and occipito-
run throughout the system. Each neuron ponlines.
receives input from at least 1000 neurons, and
each neuron connects to as many as 10,000 central, and lateral groupings. Most of the
neurons in the reticular formation. nuclei in the reticular formation consist of
The reticular formation of the brain stem large cells with ascending and descending
blends inferiorly into lamina VII of the cord axons. Functionally, the reticular formation in
and while superiorly it is continuous with the the medulla is especially important since the
hypothalamus and dorsal thalamus of the dien- descending reticulospinal fibers and much of
cephalon. Many nuclei have been identified in the ascending reticular system originate there.
the reticular formation. Descending Reticu10spinal System. The
Functionally, the nuclei can be divided into nucleus reticularis gigantocellularis is found at
cerebellar and noncerebellar nuclei. (Table 11-
TABLE 11- 8 : FUNCTIONAL GROUPINGS OF NUCLEI IN
8). The cerebellar portion of the reticular for- THE RETICULAR FORMATION
mation includes primarily the lateral and para-
median nuclei of the medulla, and the tegmen- Non-Cerebellar Cerebellar Related
tal nucleus of the pons. Raphe, central, and lateral and paramedian
The noncerebellar portion nuclei are divid- lateral in tegmentum of nuclei of medulla and
ed anatomically into three columns: the raphe, brain stem tegmental nucleus of
the pons
----- .------------~----------
11-22 CHAPTER 11
the rostral medullary levels, dorsal and medial The central tegmental tract is the principal
to the inferior olive. This nucleus gives origin fiber tract of the reticular formation. Its
to much of the lateral reticulospinal tract, descending portions are located in the medial
which is primarily an ipsilateral tract, running tegmentum, and its ascending portions are
in the lateral funiculus of the spinal cord in all located in the lateral tegmentum. The ascend-
levels and terminating on internuncial neu- ing system projects to the thalamic intralami-
rons. The axons from the nucleus reticularis nar and reticular nuclei, hypothalamus, basal
pontis oralis and caudalis form much of the ganglia, substantia nigra, and red nucleus.
medial reticulospinal tract, which runs in the The descending system synapses via the reticu-
anterior funiculus in all levels and terminates lospinal tract onto interneurons that mediate
on internuncial neurons. their effects through alpha and gamma motor
The lateral reticular nucleus is located in neurons in the spinal cord and via autonomic
the lateral margin of the reticular formation pathways and cranial nerves onto visceral neu-
dorsal to the inferior olive, while the ventral rons.
reticular nucleus is found in the caudal end of Ascending Reticular System. This fiber
the medulla, dorsal to the inferior olive. These system is the structural and functional sub-
two nuclei, in conjunction with the nuclei in strate for maintaining consciousness. It also
the pons and midbrain, form much of the receives proprioceptive, tactile, thermal, visual,
ascending reticular fibers in the central auditory, and nocioceptive information via the
tegmental tract distributing to neurons in the spinal and cranial nerves. Many sensations
thalamus (intralaminar and reticular), hypo- (cutaneous, nocioceptive, and erotic) activate
thalamus, and corpus striatum. The parame- the system. The reticular system is functional-
dian reticular nucleus is found near the midline ly important in controlling our "posture" by
at mid-olivary levels, dorsal to the inferior its reflex relationship to the position of our
olive, and provides direct input into the ante- body in space and in controlling our internal
rior lobe of the cerebellar vermis. milieu by maintaining the stability of our vis-
Input to Reticular Formation. The cera. The sensory information ascends via the
reticular formation receives information via the central tegmental tract into the limbic-mid-
ascending spinal tracts (spinotectal, spinoretic- brain area from which information can be
ular, spinothalamics, and spinocerebellar), more directly passed into the thalamus and
from the brain stem itself (olivoreticular, cere- hypothalamus. This midbrain to diencephalon
belloreticular, and vestibulospinal), from the TABLE 11-9: MAJOR PATHWAYS OF THE
cerebral hemispheres (corticoreticular), from RETICULAR FORMATION
the basal ganglia and hypothalamus. The cra-
nial nerves are another important source, espe- Tract Reticular Termination of
cially nerves I, II, V, VII, VIII, and X for sen- Origin Pathway
sory information that appears to project most Lateral Gigantocellularis spinal cord &
heavily onto the central nuclei. The hypothal- Reticulospinal autonomic
amus and striatum also project to the reticular interneurons
system via the dorsal longitudinal fasciculus on
Medial Pontis ora lis & spinal cord &
the floor of the cerebral aqueduct and fourth Reticulospinal cauda lis autonomic
ventricle and the more diffuse descending fiber interneurons
systems in the core of the reticular formation.
Output. The medial lemniscus is a specif- Central Lateral & ventral halamic-intralaminart
tegmental & reticular,
ic point-to-point relay system with few synaps- hypothalamus,
es (a closed system), while the fiber tracts of corpus striatum,
the reticular system are a multisynaptic non- substanita nigra
specific system (an open system). (Table 11-9).
to telencephalon circuit seems especially in the respiratory center in the upper medulla
important in determining our level of con- and pons. Sensory fibers from the lungs
sciousness and motivation. ascend via cranial nerve X and enter the soli-
The reticular formation is also important in tary tract and proceed onto the neurons in the
controlling posture and orientation in space. reticular formation in the medulla and pons.
Stimulation of the caudal medulla inhibits the Specific regions in the medulla control either
knee jerk. Laterally, stimulation facilitates the inspiration or expiration. The medullary res-
knee jerk. piratory center itself is responsive to the car-
The lateral part of the reticular formation is bon dioxide content in the blood. Increased
the receptor area, while the medial portion is carbon dioxide produces increased respiration
the effector zone and the origin of the central and decreased carbon dioxide produces
tegmental and reticulospinal tracts. Many of decreased respiration.
the functions vital to the maintenance of the In the pons the pneumotaxic centers are
organism are found in the medulla. related to the frequency of the respiratory
Neurochemically Defined Nuclei in the response. These centers play onto the
Reticular Formation Effecting Consciousness. medullary respiratory center to determine the
1. Cholinergic Nuclei. - a. located in the respiratory output. The axons from cells in
dorsal tegmentum of the pons and midbrain, the medullary reticular center descend to the
in the mesopontine nuclei, and in the basal appropriate spinal cord levels to innervate the
forebrain region and b project diffusely to the diaphragm and the intercostal and associated
cerebral cortex through the thalamus and have muscles of respiration. The vagus nerve itself
a modulating influence on cerebral cortical provides preganglionic innervation of the tra-
activity and wakefulness. chea, bronchi, and lungs.
2. Monoamine Nuclei. In the reticular The respiratory response is also modified
formation we find cells containing norepi- by cortical and hypothalamic control; i.e.,
nephrine and serotonin. emotionally stimulated individuals breathe
a. The norepepinephrine containing cells more rapidly because of the hypothalamic
are found in the locus ceruleus (blue staining) influence on the brain stem and spinal cord.
in the upper pons and midbrain and they pro- The actual respiration occurs with the inter-
ject widely upon nuclei in the spinal cord, costal muscles, the accessory muscles, and the
brain stem, thalamus, hypothalamus and cor- lungs expanding and contracting in concert
pus striatum which are important for main- with associated vascular changes (autonomic
taining attention and wakefulness. nervous system).
b. Serotinergic nuclei. These nuclei are C. CARDIOVASCULAR CENTERS
found in the raphe of the medial tegmental The carotid body (innervated by sensory
wne in the medulla, pons and midbrain. The fibers of cranial nerve IX) is found distal to the
nuclei in the pons and medulla project onto bifurcation of the common carotid artery, and
the spinal cord and brain stem while the nuclei the aortic body, innervated by the sensory
in the upper pons and midbrain project onto fibers of nerve X, is found near the origin of
to the thalamus, hypothalamus, corpus stria- the subclavian arteries. These carry informa-
tum and cerebral cortex. The serotinergic sys- tion on blood pressure into the solitary tract
tem facilitates sleep. An area outside of the
and then into the medullary respiratory cen-
reticular formation, the histamine containing ters. These sites are sensitive to oxygen-car-
area of the posterior hypothalamus, is also
bon dioxide pressure; when oxygen is reduced,
important in maintaining wakefulness.
ventilation increases; when oxygen increases,
B. RESPIRATION CENTERS ventilation decreases. Neural control over the
Respiration is under the control of neurons tone of the arterioles is exercised through
11-24 CHAPTER 11
vasoconstrictor fibers (and sometimes movement is noted externally as the bobbing

vasodilator fibers). A vasomotor center in the of the thyroid eminence (Adam's apple).
medulla extends from the midpontine to the 5. Finally the inferior constrictor muscle
upper medullary levels. In the lateral reticular contracts, pushing the bolus into the esopha-
formation of the medulla, stimulation elicits an gus where peristaltic waves and gravity carry it
increase in vasoconstriction and an increase in through the esophagus.
heart rate--pressor center. In the lower medul- Cranial nerves V, IX, X, and XII perform
la, stimulation of the depressor center pro- the motor part of the activity, while nerves V,
duces a decrease in vasoconstriction and a VII, IX and X form the sensory function.
decrease in heart rate. The carotid body ( cra- E. VOMITING
nial nerve IX) and the aortic body (cranial
Vomiting is produced by many stimuli and
nerve X) contain specialized pressure recep-
is usually a reflex activity. The vomitus is com-
tors stimulated by an increase in the size of
posed of the gastric contents.
these blood vessels. This information runs via
1. Caused commonly by irritation of the
nerves IX and X to the medulla and depresses
oropharynx, gastrointestinal mucosa, and gen-
acttVlty. Most sensory nerves, cranial and
itourinary and semicircular canals. Stimulation
spinal, contain some nerve fibers, which when
of the vestibular system including the semicir-
stimulated, cause a rise in arterial pressure by
cular canals and the nerve itself may also pro-
exciting the pressor region and inhibiting the
duce vomiting.
depressor centers. Higher centers also influ-
2. The afferent nerves travel via the vagus
ence respiratory and vascular centers in the
and glossopharyngeal tracts into the solitary
medulla and alter blood flow, depending on
tract. After synapsing on the dorsal motor
the psychic state; i.e., mental activity decreases
nucleus of cranial nerve X, the information is
peripheral blood (constricts vessels), while
conveyed via the vagus nerve to the stomach.
emotional states can produce increased blood
Impulses are also passed down to the cervical
flow, blocking vasodilation.
and thoracic level onto the ventral hom cells
D.DEGLUTITION that control the simultaneous contraction of
The act of swallowing starts volitionally the intercostal, diaphragmatic, and abdominal
but is completed by reflex activity. musculature.
1. The food is first masticated (motor 3. Nausea and excessive salivation precede
nucleus of nerve V) and reduced to smaller the deep inspiration associated with retching.
particles, called the bolus, which is lubricated The glottis is closed and the nasal passages are
by saliva from the salivary glands (nerves VII sealed off. The descent of the diaphragm and
and IX). the contraction of the abdominal muscles
2. The bolus is propelled through the oral exert the pressure that causes the stomach to
pharyngeal opening when the tongue is ele- contract in a direction contrary to normal peri-
vated against the soft palate (nerve XII), and stalsis and forces vomitus through the relaxed
the facial pillars are relaxed. cardia of the stomach and into the esophagus.
3. The oral pharyngeal pillars close and the F. EMETIC CENTER
superior and middle pharyngeal constrictor
The area postrema is found in the caudal
muscles (ambiguous nucleus of nerve X) force
end of the fourth ventricle above the obex of
the bolus along into the laryngeal pharynx
the medulla. This area is very vascular and con-
where the pharyngeal walls contract, closing
tains many venous sinuses. The blood-brain
the opening superiorly.
barrier is lacking in this region. The vagal,
4. At the same time, the tracheal opening
glossopharyngeal, and hypoglossal nuclei are
is closed by the epiglottis and glottis, as the lar-
strongly interconnected with the area
ynx, trachea, and pharynx move up. This
postrema. This region is very sensitive to
changes in pressure or to drugs whose passage pIes of close correlation occur frequently.
into this area is not inhibited by any blood- Thus, the combined progressive involvement
brain barrier. of the ipsilateral cranial nerve VIII (auditory
G. COUGHING. and vestibular), nerve VII (facial), and nerve V
(trigeminal), manifested by deafuess, tinnitus
Irritation of the lining of the larynx or tra-
(a buzzing or ringing sound in the ear), dizzi-
chea produces coughing. The stimulus is
ness, peripheral facial paralysis, and unilateral
picked up by free nerve endings associated
facial numbness, not only indicates the loca-
with the internal laryngeal branch of cranial
tion of the pathology (the cerebellar pontine
nerve X, which carries it up into the solitary
angle) but also suggests the actual nature of
tract, following the same pathway as in vomit-
the pathology: acoustic neuroma (tumor aris-
ing, except that the muscles contract alternate-
ing from Schwann cells of the sheath of nerve
ly rather than simultaneously with the inter-
costal muscle contracting suddenly.
VIII). While other pathological lesions may
occur at this site, they are much less common.
IV. LOCALIZATION OF DISEASE There are several possible approaches to
PROCESSES IN THE BRAIN STEM the problem of localization of disease process-
Pathological processes affecting the brain es in the brain stem. We will first consider a
stem can usually be well localized from an number of guidelines for localization. We will
anatomical standpoint. This is a direct conse- then consider in greater detail the particular
quence of the fact that these disease processes anatomical syndromes and the various types of
in general involve a particular combination of pathology in terms of specific extrinsic and
cranial nerves (as in acoustic neuroma at the intrinsic syndromes. When speaking of the
cerebellar pontine angle) or produce a partic- anatomical syndromes of the brain stem in
ular combination of ipsilateral cranial nerve clinical neurology, we will limit our considera-
dysfunction and contralateral long tract find- tions to the medulla oblongata, pons, and
ings (as in the midbrain infarction of Weber's midbrain.
syndrome which results in a combination of
A. GUIDELINES FOR LOCALIZING
ipsilateral third nerve dysfunction and con-
BRAIN STEM DISEASE
tralateral pyramidal tract findings).
1. Mental status is not directly involved
Moreover, when anatomical-pathological
(except that lesions involving the tegmentum
correlation is considered, the brain stem, of all
of the upper brain stem - reticular formation
sites in the central nervous system, provides
etc, may alter level of
the best example of how the anatomical pat-
consciousness) .
tern of involvement may allow the prediction
2. No muscle atrophy is presented, except
of the actual pathological processes. The stu-
that relevant to local involvement of cranial
dent has, of course, already encountered sever-
nerves.
al examples of this phenomenon at the level of
3. Limb weakness if present involves cen-
the spinal cord. Thus, the clinical finding of a
tral control and spasticity.
selective dissociated loss of pain and tempera-
4. Deep tendon reflexes are increased in a
ture in a cape-like distribution over the shoul-
bilateral or unilateral manner. A unilateral or
ders and upper extremities implies an anatom-
bilateral sign of Babinski maybe present.
ical process in a pericentrallocation involving
the anterior commissure. One could readily B. EFFECTS OF INTERRUPTING
deduce that an intrinsic pathological process LONG MOTOR PATHWAYS-
was present and, moreover, could assume that CORTICOSPINAL AND
in most cases the pathological process was that CORTICOBULBARPATHWAYS
of syringomyelia. 1. The pyramidal (corticospinal) tracts -
At the level of the brain stem such exam- decussate low in the medulla.
11-26 CHAPTERll
- Damage to the pyramidal tract above this type weakness of the muscles of the pharynx,
decussation will produce contralateral upper larynx, tongue, face (upper and lower mus-
motor neuron signs. Within the brain stem, cles) , and jaw. The resulting syndrome,
the left and right pyramidal tracts are situated termed a pseudobulbar palsy, will have the
closest together at the level of the pyramidal qualities which the student has come to asso-
decussation and are most widely separated at ciate with an upper motor neuron lesion:
the level of the upper midbrain-internal cap- impairment of voluntary control, weakness
sule. Lesions in the medulla will often pro- without atrophy, and a release of segmental
duce bilateral effects; in the midbrain, unilater- brain stem reflex activity from higher control.
al or bilateral effects. Thus, the jaw jerk, a stretch reflex, will be
Throughout their extent in the brain stem, hyperactive. Since the muscles and brain stem
the corticospinal tracts are located in a ventral motor nuclei are also involved in emotional
(or basilar) location. Lesions limited to the expression (consider laughing, crying, the
dorsal (tegmental or tectal) portions of the facial expression of rage, and so forth), bilater-
brain stem then are less likely to produce signs al corticobulbar lesions will result in a loss of
of pyramidal tract involvement. higher control and a release of these motor
2. Corticobulbar fibers - descend to the components of emotional expression.
cranial nerve motor nuclei in close proximity C. CEREBELLAR DYSFUNCTION
to the corticospinal tracts.
1. Cerebellar symptomatology may be
- lesions here produce a supranuclear
noted frequently in diseases affecting the brain
lesion, as regards motor control of the cranial
stem and may provide information as to local-
nerves, below the lesion.
ization. On the other hand, expanding lesions
- for each cranial nerve motor nucleus (V,
of the cerebellum may secondarily compress
VII, and XII, ambiguous) decussate, separate-
the brain stem. Diseases affecting the cerebel-
ly, somewhat above the level of that motor
lum will be considered later in greater detail
nucleus.
(Chapter 19), here we will simply indicate cer-
- In humans (compared to the cat) direct
tain general rules at this point.
corticobulbar fibers can be traced to the
1. Diseases affecting the midline cerebel-
trigeminal, facial, hypoglossal, and spinal
lum (vermis) or its fiber systems result in a dis-
accessory motor neurons.
turbance of equilibrium (sense of balance) and
- Corticobulbar control of the cranial
an ataxia (unsteadiness) of the trunk. This
nerve motor nuclei is bilateral to the laryngeal,
may be evident on sitting, standing, or walk-
pharyngeal, palatal, and upper facial muscula-
ing. If an ataxia in walking occurs, we speak of
ture.
an ataxia of gait.
- The motor neurons supplying the lower
2. Diseases affecting the lateral aspects of
half of the face and the genioglossus muscle of
the cerebellum or of the fiber systems related
the tongue receive predominantly unilateral
to the lateral cerebellum produce lateralized
corticobulbar fibers.
symptoms affecting the limbs. Thus, an
- The effects of a unilateral corticobulbar
unsteadiness (ataxia of dysmetria) of arm and
lesion then will be limited to an upper motor
leg movements will be noted. In addition, a
neuron type weakness of the contralateral
characteristic tremor will be present--intention
lower facial muscles (termed supranuclear or
tremor, in which oscillations of movement
central) and a minor weakness of the tongue
perpendicular to the line of movement occur
(with slight deviation of the tongue on
(in the finger to nose and heel to shin tests).
attempted midline protrusion to the side con-
The lateralized unsteadiness of the lower
tralateral to the lesion).
extremity will result in an impairment of gait.
- Bilateral damage to the corticobulbar
The ataxia of gait will have, however, a lateral-
fibers will produce an upper motor neuron
ized quality in the sense that the patient will cystic astrocytoma) of the lateral cerebellum
tend to fall or deviate to a particular side. will not have this association but rather will be
3. In general, pathology affecting the cere- associated with the signs and symptoms of
bellar hemisphere produces symptoms ipsilat- increased intracranial pressure. Common
eral to the side of involvement. This reflects midline lesions of the cerebellum secondarily
the fact that the dorsal spinocerebellar and compressing the brain stem are tumors such as
cuneocerebellar pathways are essentially medulloblastomas and hemangioblastomas.
uncrossed. Moreover, the major outflow from The ependymoma although arising from the
the cerebellar hemisphere, the denta- floor of the fourth ventricle is sometimes
torubrothalamic pathway of the superior cere- included in the midline cerebellar syndrome
bellar peduncle, decussates in the upper pons category.
before reaching the rubral and ventral lateral D. DECEREBRATE RIGIDITY
thalamic areas and then onto the motor cor-
Decerebrate rigidity is a consequence of a
tex. The major efferent pathways from the
pathological transection of the brain stem
motor cortex cross again in the pyramidal
between the vestibular nuclei and the mid-
decussation. Because of this double decussa-
brain. It is characterized by;
tion, data then from the right cerebellar hemi-
- a marked increase in extensor tone due to
sphere will eventually influence the anterior
the release of the extensor facilitory area in the
hom cells of the right arm and leg.
reticular formation in the tegmentum of the
Lesions of Cerebellar Peduncles: pons and midbrain and a marked increase in
Inferior cerebellar peduncle and the adja- stretch reflexes,
cent spinocerebellar and cuneocerebellar path- - level of transection is at a point between
ways in the lateral medulla will produce ipsilat- the vestibular nuclei and the red nuclei; in gen-
eral symptoms. eral, damage has occurred at a midbrain or
- Superior cerebellar peduncle below its upper pontine level,
decussation will produce ipsilateral symptoms; - pyramidal tracts and lesions of the pyra-
above the decussation, contralateral symp- midal tracts are not involved in the phenome-
toms. na. Refer to Chapter 18 for further discussion
4. Whether lateralized cerebellar symptoms E. INTERRUPTION OF LONG
reflect intrinsic disease of the brain stem or dis- SENSORY SYSTEMS-MEDIAL
ease of the cerebellum will depend on the asso- LEMNISCUS AND
ciated signs and symptoms. Thus, the ipsilat- SPINOTHALAMICS
eral intention tremor and ataxia seen in the lat-
Effects of Lesions: The spinothalamic
eral medullary infarction (see below chapter
tracts are on the lattermost margin of the brain
16) and due to damage of the restiform body
stem-therefore in the medulla they are separate
and the adjacent spinocerebellar and cuneo-
from the medial lemniscus. An intrinsic para-
cerebellar pathways is clearly associated with
median lesion is likely to produce bilateral
the signs and symptoms referable to the
involvement of the medial lemniscus. Since
involvement of the adjacent intrinsic struc-
the medial lemniscus is quite separate from the
tures: the ipsilateral descending spinal tract of
lateral spinothalamic pathway, selective
the fifth nerve; the lateral spinothalamic path-
involvement of contralateral position and
way (producing contralateral deficits in pain
vibratory sensation, as opposed to pain and
and temperature), the ipsilateral Homer's syn-
temperature sensation, may occur.
drome, and the ipsilateral nucleus ambiguous
- At the level of the midbrain and thala-
or vagal dysfunction producing hoarseness,
mus, such selective involvement is likely.
defective gag reflex, and dysarthria. On the
However, selective involvement of positional
other hand, the ipsilateral intention tremor
vibration as opposed to pain and temperature
and ataxia due to an abscess or tumor (e.g.,
11-28 CHAPTER 11
is less likely. eral tegmental portion of the medulla, e.g.,

F. CRANIAL NERVE DYSFUNCTION infarction of the territory of the posterior infe-
rior cerebellar artery which supplies this sector.
1. Motor Cranial Nerves
A similar combination may be found in the
a. The effects of a lesion involving the
infarction of the dorsolateral tegmentum of
motor nuclei of a cranial nerve or of the motor
the caudal pons: the territory of the anterior
fibers of a cranial nerve will be ipsilateral to the
inferior cerebellar artery.
lesion. The effects will be those of a lower
c. The descending spinal tract (analogous
motor lesion: atrophy and weakness, and a loss
to and, in a sense, the direct continuation of
of segmental reflex activity. With regard to the
Lissauer's tract) and associated nucleus (analo-
facial nerve, the effects are often referred to as
gous to the substantia gelatinosa), descends
peripheral. In a local lesion of the brain stem,
into the upper cervical spinal cord. Although
it is the segmental ipsilateral motor findings, in
there is considerable overlap the primary
association with the contralateral corticospinal
trigeminal fibers synapse on the nucleus of the
and corticobulbar findings below the level of
descending spinal nucleus at the following
the lesion, to specific levels of the brain stem
level:
which allow for localization (termed hemiple-
-mandibular division fibers at a lower
gia alternans or alternating hemiplegia).
pontine--upper medullary level;
b. The nuclei of the somatic motor cranial
- the maxillary division at a medullary level,
nerves (III, N, VI, and XII) are located close
- and the ophthalmic division fibers at a
to the midline. These nuclei tend to be
lower medullary and upper cervical cord level.
involved, then, by paramedian lesions rather
There is overlap at the upper cervical cord
than by lateral lesions. Intrinsic lesions in a
level between the upper cervical segment pain
paramedian location tend to produce, early in
fibers and the ophthalmic division pain fibers.
their course, a bilateral involvement of these
It is not surprising, then, that pain originating
nuclei. These nuclei are also all located in a
in the C2 and C3 roots or segments of the
relatively dorsal position. These nuclei would
spinal cord may sometimes be referred to the
be involved early by a lesion in a dorsal or
ophthalmic division of the face (orbit and
tegmental location. Except for cranial nerve
forehead), e.g. the pain of cervical 2 and 3-
N, the fibers of these cranial nerves all exit in
occipital neuralgia is often referred to the
a relatively paramedian ventral location.
orbit.
Sensory Cranial Lesions d. The secondary pain fibers decussate,
2. Cranial Nerve V Lesions: join the ventral secondary trigeminal tract
a. In the main sensory root of the trigemi- (also labeled trigeminothalamic or quintothal-
nal nerve, in its course within or external to amic tract) which, at a medullary level, is locat-
the midpons, will produce ipsilateral deficits in ed just lateral to the medial lemniscus. At a
pain, temperature, and touch over the face. pontine and midbrain location, the secondary
b. In the descending spinal tract of the trigeminal tract is just lateral to and essentially
trigeminal nerve or of its associated nucleus continuous with the medial lemniscus and
will produce ipsilateral deficit in pain and tem- adjacent to the lateral spinothalamic path. A
perature sensation over the face with sparing of lesion that involves this tract would then usu-
facial touch sensation. These structures are sit- ally produce contralateral deficits in pain and
uated close to the lateral spinothalamic tract, temperature over a variable portion of the face
the combination of contralateral pain and tem- in association with a contralateral deficit in
perature deficit over the body and extremities pain and temperature and/or position and
with ipsilateral pain and temperature deficit vibration were the affected arm, leg, and
over the face is frequently found as a conse- trunk.
quence oflesions which involve the dorsallat-
G. CLINICAL SIGNS AFTER not directly affect most aspects of mental sta-
LESIONS IN THE TEGMENTUM tus such as memory, abstract reasoning, com-
OF THE BRAIN STEM. prehension, and the ability to perform calcula-
Although all nuclei and tracts in the brain tion--functions usually associated with the
stem are important to the proper function of cerebral cortex. Brain stem lesions may inter-
the CNS, lesions in only certain tracts and fere with the ability to test these functions in
nuclei produce abnormal responses detectable the sense that a patient with a transection of
at the bedside and important for diagnosis and the upper pons or midbrain will usually be
treatment of disease. Remember injury to any unable to convey information from the cere-
cranial nerve usually produces a defect that bral cortex to the cranial nerve and spinal cord
helps you to localize just where in the brain motor neurons so that expression of the corti-
stem the lesion is located. (See also Chapters cal functions cannot occur. The patient is aki-
15 and 16.) Table ll-ll provides only a brief netic and mute. Lesions involving the reticu-
overview of the major deficits seen after lesions lar formation at the diencephalic and mesen-
in one of the five zones of the tegmentum. cephalic junction will interfere with mental sta-
1. Disease involving the brain stem does tus in the sense that the alertness and arousal
aspects of consciousness are defective. The
TABLE 11-11. CLINICAL DEFECTS FROM LESIONS IN
THE TEGMENTAL ZONES OF THE BRAIN STEM. patient then remains in a comatose state, either
failing to arouse from this state when stimulat-
Ventricular Zone: Interruption of motor cranial nerves III, ed or arousing only for brief periods. For addi-
IV, VI, X, and XII produce lower motor neuron signs. tional discussion refer to chapter on con-
Interruption of sensory nuclei of VIII produces dizziness sciousness.
and deficits in hearing while injury to the solitary 2. Pathological processes that involve the
nucleus produces deficits in taste
brain stem may have effects moreover which
Lateral Zone: Interruption of the spinothalamic tract are not simply limited to the brain stem. Thus,
produces contralateral decrease In pain and occlusion of the basilar artery may not only
temperature from the body. Injury to the rootiet or produce infarction (ischemic damage) of the
chief sensory or descending nucleus of CN V produces
brain stem but also may produce infarction of
sensory finding of Ipsilateral deficits in pain,
temperature, and touch from the head and ipsilateral the territory supplied by the posterior cerebral
weakness in chewing. arteries. This includes the calcarine cortex, the
medial and inferior aspects of the temporal
Medial zone: Interruption of the medial lemniscus, lobe, and the diencephalon. The medial
depending an the level of the lesion, produces loss
of touch, pain, and temperature from the head or aspects of the temporal lobe (the hippocam-
body; Injury to the medial longitudinal fasciculus pus) and the medial thalamic areas apparently
produces deficits in coordination of eye movements. provide the anatomical substrate for recent
memory (the learning of new information).
Central zone: Lesions here produce abnormalities In the
tunctions associated with cranial nerve nuclei of VII,
3. Space-occupying lesions of the brain
IX, Xand XI. The descending parasympathetic and stem or posterior fossa may also secondarily
sympathetic fibers can also be Interrupted affecting interfere with mental status through a block-
the pupil (Home(s) and sweat glands (See Chapter 11 ade of the ventricular system. With blockade
on Cranial Nerves). of the fourth ventricle or aqueduct (or for that
Basilar zone: Destruction of the corticospinal tract matter the third ventricle), cerebrospinal fluid
produces an upper motor neuron lesion with loss of pressure increases and is transmitted to the lat-
volitional movement in the contralaterol body muscles; eral ventricle. The lateral ventricles dilate and
interruption of the corticonuclear tract produces since the skull is a rigid container (after closure
weakness of volitional movement of the muscles in of the sutures), the white matter and gray mat-
the contralateral head and neCk.
ter of the cerebral hemisphere are subjected to
11-30 CHAPTERll
compression with an alteration in mental sta- to as the dolls' head eye or "Dolls eye" phe-
tus. The patient frequently presents a drowsy nomenon and serve to center fixation regard-
appearance and when roused he often mani- less of head positions ..
fests a diffuse defect in memory, comprehen- - Flexion of the neck leads to upward devi-
sion, and abstract reasoning. With relief of the ation of the eyes; extension of the neck to
obstruction to the flow of cerebrospinal fluid, downward deviation of the eyes. This reflex is
a rapid reversal in this state should occur. An not dependent on the presence of the cerebral
increase in intracranial pressure, particularly cortex. Although some have postulated a
when sudden, is often associated with vestibular basis for the reflex, it is clear that the
headache, nausea, and vomiting. reflex may be obtained in patients in whom the
More recent diagnostic approaches have ocular response to caloric vestibular stimula-
involved earlier diagnosis by CT or MRI scan tion can no longer be obtained. (A possible
(MRI is the preferred imaging approach). The role of the nucleus prepositus hypoglossi -
surgical approach may now include excision located below the floor of the ventricle has
via a supracerebellar or transtentorial approach been postulated).
to the tumor utilizing the operating micro- 2. Convergence. From a theoretical stand-
scope (see Stein 1979). point, selective damage to the nucleus ofPerlia
V. BRAIN STEM AND EYE could occur without involvement of the nuclei
MOVEMENTS supplying the medial rectus muscles. Such a
selective lesion, however, would not be com-
Cortical Control of Eye Movements.
mon in view of the fact that the entire oculo-
Conjugate eye movements originate in the
motor complex occupies a relatively small area.
frontal and occipital lobes, however the path-
An intrinsic lesion would be implied. A rela-
ways that coordinate these movements are
tive defect in convergence may be commonly
found in the pons and midbrain where they
encountered in any circumstance in which
are commonly affected. See Chapter 17.
consciousness has been impaired. A supranu-
Subcortical Control ofEye Movements
clear pathway from occipitoparietal cortex has
1. MLF Syndrome
been postulated.
a. superior division. Assume lesion above
3. Effect of Cranial Nerve Lesions on Eye
the abducens nucleus, when right lateral gaze
Movements.
is attempted:
a. Third Cranial Nerve symptoms. The signs
- the right eye will fully abduct but the left
may be frequently noted in mass lesions that
eye will fail to adduct fully,
involve the cerebral hemisphere. Thus lateral-
- -the left medial rectus, however, will usu-
ly placed, space-occupying lesions such as col-
ally be otherwise intact for adduction in other
lections of blood in the epidural or subdural
movements, such as convergence,
space, brain tumor, or abscess in the temporal
- horizontal nystagmus, whether occurring
lobe may all displace the temporal lobe medi-
spontaneously or induced by caloric stimula-
ally and downward. The medial aspect of the
tion, will be most prominent in the abducting
temporal lobe (uncus and hippocampal gyrus)
eye.
is then forced through the tentorial opening
b. Inferior division of the mediallongitudi-
compressing the third cranial nerve- hernia-
nal fasciculus-Dolls Eye Phenomena. This
tion of temporal lobe. As compression con-
pathway can be utilized in the comatose
tinues, the fibers to the levator palpebrae and
patient (but not in the conscious patient) to
then to the other extraocular muscles are
elicit eye movements and in a sense to test the
involved, resulting eventually in a complete
integrity of the medial longitudinal fasciculus.
third nerve paralysis.
The movements induced by head turning (the
b. Sixth Cranial Nerve symptoms. A small
oculocephalic reflex) are commonly referred
paramedian infarction in the tegmentum of
the lower pons may produce the combination tract. Rather than terminating in the lateral
of ipsilateral peripheral facial palsy and ipsilat- geniculate, these fibers diverge from the optic
erallateral rectus palsy, due to involvement of tract just rostral to the lateral geniculate and
the abducens nucleus and of the facial nerve enter the pretectal region at the level of the
fibers in the genu about the abducens nucleus. posterior commissure. Fibers then pass to the
As we have already indicated, such a lesion Edinger-Westphal nucleus of the same side
would also produce a paralysis of conjugate (for the direct pupillary response).
lateral gaze, due to involvement of the "lateral Accommodation and Pupillary constriction.
gaze center." This combination of cranial Accommodation (the shift in gaze from a dis-
nerve findings may be associated with a con- tant to near object) and to convergence
tralateral hemiplegia due to a more extensive depend on fibers in the optic tract reaching the
paramedian infarction (the Foville pontine occipital-calcarine cortex via the lateral genicu-
syndrome; see Wolf 1972). late. Fibers from the occipital association cor-
Disease processes in the posterior cranial tex then reach the superior colliculus and the
fossa, producing an extraocular palsy limited to nucleus of Edinger-Westphal. The lesion in
the lateral rectus muscle, may affect the sixth the pretectal area that has been postulated for
cranial nerve due to its long extramedullary tabes dorsalis then would affect pupillary
course. A bilateral involvement is frequently response to light but not to accommodation.
seen in any situation where an increase in Involvement of descending sympathetic fibers
intracranial pressure has occurred. A unilateral in this area could be postulated to explain the
paralysis is also frequently found in locally fact that in tabes dorsalis the pupil is relatively
invasive disease involving the base of the skull small and constricted in the resting state.
(nasopharyngeal carcinoma). Such a lesion Pseudotabetic pupil may occur in other dis-
would progress to involve other cranial nerves eases, e.g., diabetic peripheral neuropathy.
at the base of the skull.
4. Combined unilateral involvement of all CASES EFFECTING
extraocular muscles indicates disease extrinsic EYE MOVEMENTS
to the brain stem. These findings originate Case 11-1. (Full case on CD).
from growths within the orbit, compression at
This 75-year-old white male had the onset
the superior orbital fissure, or thromboses of
of diplopia in March. Examination in April
sinus due to spread of infection from face or
revealed only a variable possible lag in move-
orbit within the cavernous sinus may involve
ment of the left medial rectus muscle. On
all three nerves (III, IV, and VI). In addition
readmission in June there was now a clearly
the ophthalmic division of the trigeminal
defined left abducens nerve paralysis and nys-
nerve will be involved with the cavernous sinus
tagmus on right lateral gaze. A left peripheral
syndrome. At times, the adjacent maxillary
facial paresis was now also noted.
division is involved as well. Bilateral involve-
Cerebrospinal fluid examination was negative.
ment of the extraocular muscles may occur in
He was readmitted in July because of pro-
myasthenia gravis or in familial degenerative
gression of the left facial paralysis. On exami-
disease involving the extraocular muscles in
nation he was unable to close the left eye and
the process of muscular dystrophy (progressive
he was drooling from the left side of the
ophthalmoplegia and oculopharyngeal dystro-
mouth. He was also complaining of diplopia
phy). In these diseases the extraocular muscles
on gaze to either left or right side.
are selectively involved; the pupillary reactions
Examination of eye movements now demon-
remain intact.
strated severe problems:
5. Pupillary reactions.
1) On attempted gaze to the left; a total
Light Reflex. Fibers from the retinal gan-
paralysis of left CN VI plus a lesser paresis of
glion cells pass through the optic nerve and
11-32 CHAPTER 11
TABLE 11·12. DYSFUNCTIONS IN THE EYE PRODUCED BY SUBCORTICAL LESIONS
DYSFUNCTION IN EYE MOVEMENTS CLINICAL DEFICITS

Role of MLF . Moves the eyes in a ·Syndrome of MLF Is usually bilateral syndrome due to close paramedian
conjugate, coordinated manner location of MLF fiber systems of the two sides. Usually intrinsic disease:
as though yoked together. multiple sclerosis, vascular disease with infarction, or an infiltrating glioma
. Ascending fibers, the vestibular nuclei, ·Dolls Eyes Phenomena (Oculocephallc Reflexes) Side to side
the pontine center for lateral gaze rotation results in contraversive conjugate eye deviation.
(see below), the abducens nucleus,
and the oculomotor nuclei .
• Descending fibers; above nuclei &
proprioceptive information from cervical cord
Lateral Gaze Center in pons Section of the abducens nerve root results in only an ipsilateral lateral
rectus paralysis, while destruction of the abducens nucleus results in
a long-lasting Ipsilateral paralysis of conjugate lateral gaze with
ipsilateral lateral rectus palsy.
Disturbance of Conjugate Gaze-. Paralysis Damage to the pretectal area, the Edinger-Westphal nucleus (in rostral
of upward gaze Is often accompanied by position in the oculomotor complex) or to the fibers running between
a paralysis of downward gaze and by a these two areas.
paralysis of pupillary response to light.
Convergence- fixation on approaching visual Damage to nucleus of Perlla, in midline component

objects on the fovea and corresponding of third nerve complex
retinal points of the two eyes
DYSFUNCTION OF CRANIAL NERVES: LEADING TO ABNORMAL EYE MOVEMENTS

-Third Cranial Nerve-pupillary dilation & -Compression initial sign, paralysis of the pupillary constriction,
controls medial, superior, & lateral rectus, resulltng in a fixed dilated pupil ('blown pupil'), as constrictor
superior oblique and sup. Levator palpebrae. fibers are most peripheral among the third nerve fibers.
Lesion produces weakness In eye movements
and diplopia
-Sixth Cranial Nerve to lateral rectus and also Asmall paramedian infarction In the tegmentum of the pons produces
coordinates connections to CN III via MLF peripheral facial palsy and ipsilateral lateral rectus palsy, and also produces
lesions in pons usually also affects cranial a paralysis of conjugate lateral gaze, due to involvement of the
nerve VII. 'lateral gaze center: A more extenSive paramedian infarction produces
hemiplegia (the Foville pontine syndrome; see Wolf 1972).
PUPILLARY DYSFUNCTION PRODUCED BY DISEASE EXTRINSIC TO BRAIN STEM

Disturbance of Pupillary Reactions Compression of Cranial Nerve III produces dllaltons of pupil,
Cranial Nerve III Contains fibers that as only sympathetic fibers are stili unaffected.
constrict Pupil
-Tabetic Pupil (tertiary neurosyphilis) Selective impairment of the response to light, with preservation
of the response to accommodation. (See diseases of the spinal cord).
-Mie's syndrome Atonic pupil (once dilated Is slow to respond to light, once constricted
is slow to dilate In the dark) benign with absence of deep tendon
reftexes in the lower extremities.
-Sympalheltc Pupil -Constricted Pupil Injury to thoracic cord, superior cervical sympatheltc ganglia
or Interruption of sympathetiC fibers on aorta or In bralnstem
conjugate lateral gaze as regards the right eye. patient was unable to converge. There was a
2) On gaze to the right a) full abduction paralysis of upward and downward gaze.
of the right eye, b) some adduction of the left Bilateral lid ptosis was present. However,
eye but this was incomplete, and c) coarse nys- spasm of the eyelids was easily stimulated.
tagmus of the abducting right eye. Pupils were sluggish in response to light. The
3) In primary gaze, the left eye was slight- right pupil was slightly larger than the left.
ly medial. Horizontal nystagmus was present.
4) Convergence was intact for both eyes. b.The jaw jerk was hyperactive.
S) Up gaze was intact but minor vertical c.Guttural and lingual sounds were slurred
nystagmus was present. in a pattern that was consistent with pseudob-
Conclusions were: ulbar palsy.
1) Left CN VI paralysis. d. Hearing was decreased bilaterally.
2) Left lateral gaze center involved 3. Motor system:
3) Left medial longitudinal fasciculus a. Strength was intact.
involved. b. Spasticity was present on passive motion
The remainder of the neurological exami- in the lower extremities and possibly in the
nation was normal. upper extremities.
Clinical Diagnosis: Tumor in pons at the c. There was slowness in alternating hand
level of the facial colliculus. movements. A fixed facies was present.
d. A bilateral intention tremor was present
CASE mSTORY 11-2. on finger-to-nose testing.
e. Gait was broad-based with truncal
This 16-year-old, white male in November
ataxia.
was first noted to be lethargic. Gradually from
4. Reflexes:
November to March there was progressively
a. Deep tendon reflexes were hyperactive
poor performance in school with apathy and
bilaterally with ankle clonus.
somnolence. In December the patient had the
b. Plantar responses were extensor bilater-
onset of diplopia with difficulty in reading. In
ally (bilateral sign of Babinski).
March of the next year he began to sleep
throughout the day and could be awakened Clinical Diagnosis: Possible pineal region
only with difficulty. Headaches on arising, tumor.
with nausea and vomiting had been noted. In
April evaluation at the Buffalo General
Hospital had revealed that the pupils failed to
respond to light but did respond to accom-
modation. Upward gaze was intermittently
defective, and conjugate lateral gaze was
intact. Findings improved to some degree
over a 3-day period.
On the day of admission, an episode of uri-
nary incontinence occurred.
Neurological Examination:
1. Mental status: All areas were relatively
intact except for a slowness of response, emo-
tionallability, and immaturity of behavior and
questions.
2. Cranial nerves:
a. The right eye was deviated outward; the
CHAPTER 12
The Cranial Nerves
INTRODUCTION tion. This grouping of neurons with similar

The cranial nerves originate from a diverse anatomic and physiologic functions is called a
group of nuclei and ganglia and innervate pri- nerve component. In the spinal cord, the neu-
marily the skin and muscles of the shoulder, rons Innervate general structures such as skin
head and neck. The structures innervated by skeletal muscles, blood vessels, glands, and vis-
the cranial nerves are especially important for cera. They do not innervate the special sense
many of the communications skills of humans or-gans: the eye, the ear, or the taste buds.
including facial expression, language, sight, In the brain stem, cranial nerve nuclei that
smell, taste and hearing. Another major func- innervate structures of a similar embryonic ori-
tion of cranial nerves III, VII, IX and X is to gin are found in approximately the same posi-
provide the parasympathetic innervation to the tion throughout the medulla, pons, and mid-
eyes, heart and GI system in the body; that is brain. These nuclei are arranged in columns,
one of the major survival mechanisms for our near the ventricular floor or in the reticular for-
species. mation (Fig 12-1).
Components of the Cranial Nerves All the motor and sensory nuclei in the
In the spinal cord, the neurons are arranged spinal cord are of a general nature and are des-
in continuous columns of cells, each of which ignated in the nerve component scheme of
is connected to a structure with a specific func- Herrick (1948) as follows:
Edinger-westphal nucleus
Cranial nerve III nucleus -----:!,.....~.....:
Cranial nerve W nucleus ----~~-...

d,...-jt------ Infenor coIliculus
Cranial nerve V
mesencephalic nucleus
Cranial nerve V motor 1I. . " .. ' .... ooo;c

Cranial nerve VII nudeus _ _~_~_
Cranial nerve VI nooeus---:==i;:~
nerve Vdescending nucleus
Cranial nerve IX salivanry nucleus
Cranial nerve VIII cochlear nucleus
Cran' nerve IX nucleus
Cranial nerve VlII vestibular nucleus
Cranial nerve XII nudeus
Cranial nerve X dorsal molOr nucleus
Nucleus SoIitarius : Cranial nerve VIII
Nucleus Ambiguus: Cranial nerve IX
Cranial nerve IX
Cranial nerve X
Cranial nerve X
Cranial nerve XI
Cranial nerve XI nucleus
Figure 12-1. Posterior surface of brain stem showing cranial nerve nuclei.
12-2 CHAPTER 12
TABLE 12-1. COMPONENTS OF THE CRANIAL NERVES categories are present only in cranial nerves.
The discussion that follows will review the
Function Cranial Nerve functions and clinical disorders associated with
each of the 12 cranial nerves. At the end of this
1. Motor to Nerve III (midbrain), IV (midbrain),
skeletal muscles VI (pons), and XII (medulla). chapter we have included Table 12-5 that sum-
of somite origin Brain Slem Tegmental Zone = marizes the cranial nerve syndromes produced
ventricular by mass lesion.
2. Motor to the Edinger-Westphal Nucleus (midbrain), I. GENERAL FUNCTIONS AND
parasympalheHc superior salivatory nuclei nerve VII CLINICAL DISORDERS OF EACH
(See Fig 11-13) (pons), inferior salivatory nucleus of CRANIAL NERVE
nerve IX (medulla), dorsal motor
nuclei of nerve X(medulla). CRANIAL NERVE I - OLFACTORY
Brain Slem Tegmental Zone = The olfactory nerve (Fig. 12-2) originates
ventricular. from receptor cells in the nasal mucosa. The
unmyelinated nerve fibers combine into about
3. Motor to Motor nucleuses of nerves V, VII, IX,
skeletal muscles and X(pons and medulla). 20 bundles, pierce the cribriform plate, and
of pharyngeal and Brain Slem Tegmental Zone = end in the glomerular layer of the olfactory
visceral origin. ventricular bulb (See Chapter 22 for a discussion on
chemoreception). These fibers have an espe-
4. Sensory- SOlitary nucleus. Primary cell bodies are
visceral and located in the sensory ganglia of nerves cially important input to the amygdala of the
gustatory VII, IX, and X. General sensaHon from temporal lobe. This is the only cranial nerve
sensation. the viscera as well as the taste. associated solely with the telencephalon.
Zone = ventricular.
Clinical Disorders. Defects in smell
5. Sensory- Trigeminal nuclei--mesencephalic or Anosmia.
cutaneous and nucleus (midbrain), chief sensory The most frequent causes of unilateral or
propriocepHve nucleus (mid pontine), and descending bilateral Anosmia are:
from skin and nucleus of nerve V(lower pons, upper
muscles in the cervical level). General sensations 1. Disease of nasal mucosa producing
head and neck carried in by nerves III, IV, VI, VII, XI, swelling and preventing olfactory stimuli from
and XII synapse in the descending reaching the olfactory receptors.
nucleus. Zone = lateral 2. Head trauma - resulting in shear-effects
tearing the filaments of olfactory receptor cells
6. Special Olfaction I, vision II, hearing and
sensory balance VIII passing through the cribriform plate.
3. Less common causes of unilateral
Anosmia is an olfactory groove meningioma
Motor (efferent)
To skeletal muscle, CN III -VII, IX-XII
To smooth muscle & glands,
CNIII,IX &X
- To cardiac muscle, CN X
Sensory (afferent)
- From cutaneous and proprioceptive
receptors V, VII, IX & X
- From viscera, CNIX & X
In addition to these general categories in
nerves of the spinal cord, we find in the cranial
nerves, neurons innervating the special sen-
sory receptors (ear, eye, taste buds) or muscles
in the face, pharynx, and larynx, which origi-
nated from pharyngeal arches. These special Figure 12-2. The Olfactory Nerve - Cranial nerve I
CRANIAL NERVES 12-3
TABLE 12-2. CRANIAL NERVE COMPONENTS
CRANIAL NERVE LOCATION OF CELL BODIES FUNCTION

I Olfactory Neuroepithelial cells in nasal cavity Olfaction
II Optic-central Ganglion cells in retina Vision

pathways discussed
in Chapter 21 .
III Oculomotor -Oculomotor nucleus in tegmentum Eye movements, levator palpekal supenored,
of upper midbrain. superior medial and inferior rectus, inferior oblique
-Edinger-Westphal nucleus in teg-mentum Pupillary constriction and accommodation of lens
of upper midbrain - preganglionic to ciliary for near vision through ciliary ganglion
ganglion.
IV Trochlear Trochlear nucleus in tegmentum Eye movements (contralateral),
of lower midbrain superior oblique muscle
V. Trigeminal Primary trigeminal ganglion, Cutaneous and proprioceptive sensations from skin
Secondary Mesencephalic (midbrain), and muscles in face, orbit, nose, mouth, forehead,
chief sensory (Pons), and teeth, paranasal sinuses, meninges, and anterior
descending spiral nuclei (pons, two-thirds of tongue.
Medulla, upper cervical levels)
Motor nucleus in pons Muscles of mastication
VI. Abducens Abducens nucleus in tegmentum of pons Eye movements, ipSilateral, involving
lateral rectus muscle
VII Facial Primary geniculate ganglion: Gustatory sensations from taste buds in anterior
Secondary Nucleus solitarius two-thirds of tongue
-Motor nucleus in lateral margin of pons Muscles of facial expression and platysma; extrinsic
-Superior salivatory nucleus in pons and intrinsic ear muscles, stapedius muscle.
-preganglionic parasympathetiC to ganglia Glands of nose and palate and the lacrimal,
associated with these glands submaxillary and sublingual glands through
pterygopalatine and submandibular ganglia
VIII. Vestibulo- Primary vestibular & cochlear ganglion, Audition
acoustic. (Central temporal bone; Equilibrium, coordination, orientation in space
pathways discussed Secondary cochlear nuclei in medulla
in chapter 15) Secondary vestibular nuclei in medulla and pons
IX Glossopharyngeal Primary inferior ganglion; Interoceptive palate and posterior one-third of tongue,
Secondary Nucleus solitarius carotid body; Gustatory sensations from taste buds
Inferior salivatory nucleus in medulla in posterior one-third of tongue
Nucleus ambiguous Preganglionic Secretions from parotid gland through otic ganglion
to otic ganglion Swallowing, stylopharyngeus mm
Visceral sensations
XVagus Primary Superior inferior ganglion; Visceral sensations from pharynx, larynx
Dorsal motor nucleus - preganglionic aortic body and thorax and abdomen
(Parasympathetic innervation) Nucleus Gustatory Sensation from taste buds
ambiguous in medulla in epiglottis and pharynx
Skeletal muscles in pharynx & larynx
Smooth muscles in heart, blood vessels, trachea,
bronchi, esophagus stomach, intestine to lower colon
XI Spinal Accessory Cranial Portion Ambiguous nucleus in Innervation SternomastOid Trapezius and
medulla Spinal portion: C2 C3 & 4 mm 01 pharynx, larynx, except criCOthyroids
XII Hypoglossal Hypoglossal nucleus in medulla Innervation of intrinsic and extrinsic muscles of the
tongue except palatoglossal MM
12-4 CHAPTER 12
compressing olfactory bulb and tract. 3. Degeneration - retinitis pigmentosa

4. The normal process of aging and degen- 4. Optic nerve: optic neuropathy:
erative CNS disorders, including Alzheimer's S.Optic neuritis:
disease, Huntington's disease, and Parkinson's 6. Demyelination as manifestation of multi-
disease. ple sclerosis
CRANIAL NERVE II - OPTIC 7. Ischemic optic neuropathy
The optic nerve (Fig. 12-3) because it is 8. Toxic affects, e.g., methanol usually
invested with glial cells not Schwann cells is bilateral
actually a tract of the central nervous system. 12. Deficiency states: e.g., Thiamin and
The optic nerve originates from the axons of B12: usually bilateral
the ganglion cells (tertiary neurons) of the reti- 10. Compression: by masses - inner third
na, which are ensheathed with myelin as they sphenoid wing or olfactory groove menin-
leave the neural retina. These axons form the gioma
optic nerve, which exits the orbit via the optic - Glioma of optic nerve
foramen chiasm, and tract and terminate in the - Long-standing papilledema
optic thalamus (lateral geniculate nucleus) and - Pituitary masses (usually involve optic
superior colliculus. chiasm producing a bitemporal hemianopia
Clinical disorders
CRANIAL NERVE ID-
A Unilateral loss of vision is produced by:
OCULOMOTOR
1. Retinal disease as a consequence of,
vascular: transient - carotid occlusive The Oculomotor nucleus (Fig 12-4) is a
disease pure motor nucleus and is found in the
2. Central retinal artery thrombosis - sud- tegmentum of the midbrain in sections con-
den and persistent taining the superior colliculus. This nucleus
Figure 12-3. The Optic Nerve - cranial nerve II

CRANIAL NERVES 12-5
Figure 12-4. The Oculomotor, Trochlear, and Abducens nerves (respectively cranial nerves III, IV and VI), and
the location of their nuclei in the pons and midbrain of the brain stem.
indents the medial longitudinal fasciculus. The and reuniting in the interpeduncular fossa to
Oculomotor complex can be differentiated form nerve III. The III nerve emerges from
into a somatic and visceral portion. the midbrain superior to the pons between the
The somatic portion consists of the lateral superior cerebellar artery and the posterior
nuclear complex and a single central nucleus, cerebral artery. It then penetrates the dura,
the Edinger-Westphal. The individual muscles enters the cavernous sinus where it lies lateral
are represented in the lateral nuclear complex, to the internal carotid artery and enters the
but data on the exact location and extent of orbit via the superior orbital fissure (Fig. 12-4)
crossed and uncrossed innervation of the eye and separates into superior and inferior divi-
muscles is incomplete. sions. The superior division innervates the lava-
The visceral portion of the Edinger- tory palpebra superioris and the superior rectus
Westphal nucleus in the floor of the cerebral muscles, while the inferior division supplies the
aqueduct provides the preganglionic parasym- medial and inferior rectus and inferior oblique
pathetic fibers to the ciliary ganglion in the muscles and sends roots from the Edinger--
orbit. The postganglionic motor fibers pass to Westphal nucleus to the ciliary ganglion. The
the muscles of accommodation and pupillary superior rectus muscle elevates the eye-ball and
constriction, permitting, dilation of the pupil turns it upward and inward. The medial rectus
and an increase in the thickness of the lens for muscle adducts the eyeball. The inferior rectus
accommodation (focus on objects within 6 muscle depresses the eyeball and adducts it to
inches of the eye). some degree, turning the eye downward and
The somatic fibers from the nuclear com- inward. The major action of the inferior
plex of nerve III pass anteriorly through the oblique muscle occurs when the eyeball is
tegmentum of the midbrain. Some fibers run- adducted; contraction of the inferior oblique
ning through the red nucleus and others pass- muscle both elevates and rotates the eye. The
ing lateral or medial to it, finally entering the superior levator palpebra controls the eyelid.
medial margin of the of the cerebral peduncle
12-6 CHAPTER 12
Clinical Disorders. At 3:00 PM on the day of admission the

1. Complete paralysis of nerve III produces patient noted the sudden onset of diplopia,
ptosis of the lid, paralysis of the medial and which was more marked on horizontal gaze to
upward gaze, weakness in the downward gaze, the right and much less marked on horizontal
and dilation of the pupil. The eyeball deviates gaze to the left. At approximately the same
laterally and slightly downward: the dilated time he noted the rapid onset of ptosis involv-
pupil does not react to light or accommoda- ing the left lid.
tion. Paralysis of the intrinsic muscles (the cil- General physical examination: There was
iary sphincter, or pupil) is called internaloph- moderate resistance to flexion of the neck.
thalmoplegia, while paralysis of the extraocular Neurological examination:
muscles (recti and obliques) is called external 1. The left pupil was fully dilated to approx-
ophthalmoplegia. imately 7mm. There was no response to light
2. Causes of cranial nerve III dysfunction: or accommodation.
2. Total ptosis of the left eyelid was pre-
- Aneurysm of posterior communication
sent.
internal carotid artery junction
3. No medial movement of the left eye was
- Lesions within the cavernous sinus - SEE present; there was no upward movement of the
CDROM Case 12-9 left eye possible. The patient had minimal
-Herniation of temporal lobe downward gaze of the left eye. He had fulllat-
-Tumors - meningioma oftubercu1um sell- eral movement of the left eye. Movements of
ae or sphenoid wing (Compression involves the right eye were full.
both pupillary and extraocular muscles). Clinical diagnosis: Subarachnoid hemor-
rhage secondary to an aneurysm at the junc-
-Diabetic cranial neuropathy (vascular) -
tion of the posterior communicating and inter-
pupil may be spared, at time of extraocular
nal carotid arteries.
involvement. However, diabetes mellitus may
The occurrence on the day of admission, of
be associated with a pseudotabetic pupil
the worst headache ever experienced by the
The following case is an example of involve- patient suggested the possibility of a subarach-
ment of the occulomotor nerve 2nd to an noid hemorrhage. Most patients with an acute
aneurysm. subarachnoid hemorrhage have an underlying
Case 12-1. This 50-year-old right-handed, saccular aneurysm.
white male factory foramen was referred for There are three major locations for single
evaluation of ptosis and diplopia involving the intracranial aneurysms:
left eye. Approximately two weeks prior to 1) the junction of the posterior communi-
admission, the patient developed a bifrontal cating and the internal carotid arteries,
headache; during the week prior to his evalua- 2) the junction of the anterior communi-
tion the headache had become a left sided cating and anterior cerebral arteries and
aching pain. It increased in intensity during the 3) the bifurcation of the middle cerebral
two days prior to admission, and was present as artery in the Sylvian fissure.
a constant pain interfering with sleep. If the The posterior communicating artery is
patient were to cough he had additional pain in adjacent to and runs parallel to the 3rd cranial
the left eye. On the day of admission the nerve. With hemorrhage, compression of (or
headache became much more severe, it was bleeding into) the nerve symptoms will devel-
now the worst headache he had ever op relevant to cranial nerve 3. Thus in patients
experienced. with prodromal symptoms, a third nerve syn-
In retrospect, the patient reported that drome allows the prediction of this specific
lights had been brighter in the left eye for location of the aneurysm. Because of the
approximately one week. arrangement of the fibers within this nerve, the
CRANIAL NERVES 12-7
initial symptoms of compression often involve nerve IV paralyzes the contralateral superior
the pupillary fibers. In retrospect, the early oblique muscle while a lesion in the nerve roots
symptoms of lights being brighter in the left after decussation involves the ipsilateral muscle.
eye, one week before the ptosis and diplopia A thrombosis or tumor in the cavernous sinus
developed would be consistent with a pupil may also affect this nerve and cranial nerves III,
that was unable to constrict in response to V, VI.
light. We will discuss in greater detail in a later CRANIAL NERVE V. TRIGEMINAL
chapter, that one can predict the middle cere- The trigeminal nerve (Fig. 12-5) is the
bral location when symptoms and signs rele- largest cranial nerve and provides sensory fibers
vant to the middle cerebral artery occur. The from the face (the first branchial arch)-includ-
anterior communicating location is often diffi- ing the pos-terior surface of the ear, the scalp
cult to predict because, weakness in both legs up to the vertex, and the undersurface of the
may occur but may be accompanied by loss of lower jaw-and motor fibers to the mastication
consciousness due to bilateral frontal lobe muscles. The sensory root contains the semilu-
involvement. In many patients, in all locations, nar or gasserian ganglia, which is larger than
the bleeding may be so massive, that loss of the motor root. Within the brain stem are one
consciousness, rapidly follows the sudden motor and three sensory nuclei. The motor
headache, and localization is not possible. nucleus of nerve V is located at the midpontine
Management of intracranial aneurysms will be levels medial to the trigeminal root at the later-
discussed in the chapter on vascular syndromes. al part of the reticular formation. The three
CRANIAL NERVE IV - TROCHLEAR main branches of nerve V are ophthalmic, max-
The Trochlear nucleus (Fig. 12-4) is purely illary, and mandibular. Except for the mesen-
motor and located in the mediosuperlor part of cephalic nuclei, the primary cell bodies for the
the teg-mentum in the lower parts of the mes- sensory fibers are located in the trigeminal
encepha-Ion. It extends throughout the inferi- (semilunar or Gasserian) ganglion in the mid-
or collicular levels and is nearly continuous dle cranial fossae.
with the lateral nuclear complex of nerve lIn.
Primary Sensory Cell Bodies
The nucleus of nerve IV indents the medial
(Trigeminal Ganglion)
longitudinal fasciculis (MLF). Nerve IV is a
The primary sensory cell bodies of nerve V
unique cranial nerve as: 1) its rootlets are on
are found in the semilunar ganglion in
the posterior surface of the brain stem, and 2)
Meckel's cave (cavum Trigeminal). They are
the fibers cross as they exit the brainstem. The
unique as they are the only 1 0 sensory neurons
fibers proceed inferiorly and posteriorly in the
found within the cranial cavity. They are locat-
periaqueductal gray, decussate in the anterior
ed in the middle cranial fOssa, a recess in the
medullary velum, exit from the substance of
petrous portion of the temporal bone below
the brain at the caudal end of the inferior col-
the superior petrosal sinus).
liculus, and then run ventrally, lateral to the
Trigeminal Peripheral Branches
nerve III rootlets. In the cavernous sinus, the
1. The ophthalmic branch of the trigeminal
nerve is lateral to the nerve III rootlets and
nerve (VI). This nerve originates from the
enters the orbit through the superior orbit fis-
medial part of the semilunar ganglion, passes
sure, where it terminates in the superior
into the lateral wall of the cavernous sinus, and
oblique muscle. The major action of the supe-
divides into its terminal branches in the superi-
rior oblique muscle occurs with the eye
or orbital fissure. The smallest division of CN
adducted. With the eyeball in the physiologic
V (VI) innervates the skin of the forehead and
condition, contraction of this muscle results in
scalp to the vertex, the upper eyelid, the skin of
rotation of the eyeball.
the anterior and bridge of the nose, the eye-
Clinical Disorders. Trauma is the primary
cause of defects in CN IV. A nuclear lesion of balls, cornea, and ciliary body, conjunctiva, and
12-8 CHAPTER 12
iris , the mucosa in the frontal and nasal sinus- joint: the dura in the middle and anterior cra-
es, and the cerebral tentorium. nial fossa, the lower teeth and gums, the oral
2. The maxillary nerve springs from the mucosa and part of the ear.
middle of the semilunar ganglion in the cav- Secondary Sensory Nuclei in the brain
ernous sinus. It leaves the middle cranial fossa stem.
via the foramen rotundum and en-ters the The chief sensory nucleus of nerve V is
pterygopalatine fossa where it becomes the found in the midpontine tegmentum, lateral to
infraorbital nerve. The maxillary division of the root of nerve V. This nucleus is the equiv-
nerve V (V2) supplies: the skin on the temples, alent of the gracile and cuneate nuclei. It
lateral surface of the nose, the lower eyelid, the receives cutaneous sensory information from
upper cheek and the upper lip, the gums and the face and head and the nasal and oral cavi-
molar, premolar, and canine teeth (superior ties and transmits this in-formation to the thal-
dental plexus), and the mucous membranes of amus via fibers that travel with or adjacent to
the mouth, nose, and maxillary sinus. The the medial lemniscus.
maxillary nerve also supplies the dura in the The descending or spinal nucleus of nerve
middle cranial fossa (middle meningeal nerve). V is the equivalent of the substantia gelatinosa
3. The mandibular division of nerve V in the dorsal horn of the spinal cord. Pain and
(V3), the largest of the three divisions is temperature fibers synapse here. External to
formed by the union of the sensory and motor the descending nucleus of nerve V is the
root at the inferior border of the semilunar descending tract of nerve V. This tract is the
ganglion. The motor root exits the middle cra- equivalent of Lissauer's tract of the spinal cord.
nial fossa through the foramen ovale where it Within this tract the fibers from the ophthalmic
joins the sensory root. The motor portion of nerve descend to the third cervical level. The
the trigeminal innervates the muscle of masti- maxillary fibers descend to the first cervical
cation and the tensor tympani and tensor veli level. The pain fibers from the mandibular and
palatini. The sensory root supplies the skin of cranial nerves VII, lX, X, XI, and XII descend
the chin, lower jaw, and temperomandibular
Figure 12-5. The Trigeminal nerve - Cranial nerve V

CRANIAL NERVES 12-9
through the lower medullary lev-els. The sec- TABLE 12- 3. MUSCLES OF MASnCATION:
ondary fibers are principally crossed and they INNERVATION BY V3-MANDIBULAR BRANCH OF CN5
ascend in the medial lemniscus to the ven-tral
posterior medial nucleus in the thalamus. MUSCLE MOVEMENT OF MANDIBLE
The mesencephalic nucleus, located lateral Lateral Works in unison wHh the other muscles -
Pterygoid protrudes and depresses mandible.
to the fourth ventricle and the cerebral aque-
Working by Hself moves the jaw laterally.
duct in the upper pontine and midbrain levels,
is proprioceptive from muscles controlled by Medial Works in unison with the other muscles,
the facial, ocular, and trigeminal nerves. This is Pterygoid to elevate the mandible, assists the
external pterygoid muscle in protruding
the only primary sensory nucleus (dorsal root
mandible
ganglion equivalent) in the central nervous sys-
tem. The mesencephalic and motor nuclei pro- Temporal Elevates and retracts the mandible.
vide a two-neuron reflex arc for the jaw jerk.
Masseter Elevates and sllghny protrudes the
Motor Functions mandible
The motor root originates in the motor
nucleus of nerve V In the pons, and joins with Mylohyoid Elevates the floor of mouth and tongue.
the mesencephalic root, and exits from the Anterior belly Elevates and stabilizes the hyoid bone.
middle cranial fossa in the foramen ovale where of Digastric
it then unites with the sensory root. The
motor, or mandibular, nerve (V3) innervates
destructive, atrophy and fasciculations of the
the muscles of mastication. (Table 12-3)
affected muscles result. The jaw jerk is also
Function absent.
The combined actions of the muscles asso-
b. Since the cortical innervation of the mus-
ciated with the mandible are listed below in
cles of mastication is bilateral, unilateral
Table 12-4.
supranuclear lesions may produce only a slight
The mandibular branch of the trigeminal
weakness, with a minimal increase in the jaw
nerve also: innervates the tensor veil palatine
and tensor tympani muscle. TABLE 12-4. MOVEMENTS OF THE MANDIBLE:
1. Tensor veli palatine tenses the palate and
draws it to one side, that prevents food from In mastication the jaws move up and down, forward and
entering the nasal pharynx, and, backward, and laterally.
-----
2. Tensor tympani muscle located in the ACTION OF
inner ear pulls on the malleus that tenses the MANDIBLE MUSCLE GROUP
tympanic membrane and diminishes the ampli-
1. Elevation Masseter, temporal, and medial pterygoid
tude of the vibrations caused by a loud noise.
Clinical Disorders: 2. Depression - Lateral pterygoid muscle, in concert with
Injury to the trigeminal nerve paralyzes the and opening of - Suprahyoid muscles (mylohyoid,
the mandible digastric, geniohyoid, infra hyoid) and,
muscles of mastication, with the jaw deviating
- Depressors of the hyoid (sternohyoid
toward the side of the lesion. Injury may also &mylohyoid muscles),
block sensation of light touch, pain, and tem- - Along with gravHy.
...:...----
perature in the face and results in the absence
3. Protrusion -the medial and lateral pterygoid
of the corneal and sneeze reflexes.
of the jaw muscles, assisted by the masseter muscle
Localization of Motor dysfunction of
the trigeminal nerve. 4. Retraction - the temporal and digas-tric
a. Lesions in the pons may affect only the of the jaw muscles retract the jaw.
---=-------
motor nuclei and produce a paresis or paralysis 5. Side to side -the pterygoid muscles permit
of the ipsilateral muscles. If the lesion is movement Side-to-side movement
12-10 CHAPTER 12
jerk. A bilateral capsular or cortical lesion will often have compression of the trigeminal nerve
produce marked paresis or even paralysis in the by an anomalous loop of an artery compressing
muscles of mastication, with an exaggerated the nerve or root entry wne. Treatment in
jaw jerk. such cases that fail to respond to medications
c. Pontine lesions usually injure both the involves relocating the loop of the superior
main sensory and motor nuclei, causing paral- cerebellar artery or insulating the nerve from
ysis of the muscles of mastication and dimin- the pulsation of the vessel by and inserting a
ished tactile sensation ipsilaterally. Lesions of soft implant between nerve and vessel.
the lower lateral pontine tegmentum as the Other surgical procedures are designed to
dorsal lateral medullary tegmentum may dam- alter transmission through the Gasserian gan-
age the descending tract and nucleus of V. glion. Patients with an age of onset in the 20s
or 30s usually have an underlying disease of
d. Tumors in the cerebellopontine angle or
brain stem, such as multiple sclerosis or arteri-
acoustic nerve may compress the trigeminal
ovenous malformation, or may have an under-
tubercle and cause an ipsilateral loss of the
lying systemic disease.
corneal reflex.
e. Other causes of trigeminal neuralgia.
Localization of Sensory dysfunction of the - Compression or invasion of nerves by
trigeminal nerve. Trigeminal Neuralgia (tic, nasopharyngeal tumors which have infiltrated
douloureux) is a disorder charac-terized by the base of the skull through the foramen-
recurrent paroxysms of stabbing pains along rotundum (maxillary) or foramen - ovale -
the distribution of the involved branches. (mandibular) or other points of erosion.
Trauma, infections, or arterial compression -Dental pathology or maxillary sinusitis may
(superior cerebellar branch of basilar artery) produce pain within the appropriate divisions
may be responsible. Medication often can con- of the trigeminal nerve. tingling and
trol the pain, but surgery is sometimes neces- numbness in the mandibular or less often max-
sary for per-manent relie£ illary division may occur spontaneously or may
1. Clinical Signs of Trigeminal Neuralgia: follow dental procedures.
a. Etiology: "Idiopathic": with mean age of -Herpes zoster involvement of the Gasserian
onset in the 50s ganglion. Acute pain almost always in the oph-
b. Trigger points that produce the pain on thalmic division followed in 4-5 days by cuta-
tactile stimulation and they are of short dura- neous lesions. Treatment with Acyclovir will
tion - lancinating pain, usually occurring in decrease the period of pain. In other patients
clusters or paroxysms. Pain may resolve spon- post herpetic neuralgia may develop. [Note:
taneously only to recur months later. The H.zoster/varicella virus is often dormant
c. Location of pain -The second (maxillary in the gasserian ganglion].
division) is most frequently involved. The 3rd
(mandibular division) is next in frequency. The The following Case is an example of
1st (ophthalmic division) is least common. The Trigeminal Neuralgia
pain is unilateral, rarely bilateral. Case 12-2: This 28 year old single, black,
d. Clinical findings. There are no sensory or right handed female reported approximately
motor findings on examination although after 21 days of sudden lancinating jabs of pain plus
frequent repeated episodes the patient may a duller more steady pain involving the right
complain of minor numbness and a more per- maxillary and mandibular distribution. She
sistent aching type pain. was very aware that she could trigger her pain
e. Treatment. Though many of these cases by touching her nose, or the skin over the max-
respond to medication such as illary or mandibular area. The pain was so
Carbamazepine, some do not and require sur- severe that talking; chewing or eating would all
gical therapy. Patients with onset after age 40 trigger episodes. As a result, she has not been
CRANIAL NERVES 12-11
eating a great deal. There was no clear-cut CRANIAL NERVE VI - ABDUCENS.
extension of pain into the eye, although some The nucleus of nerve VI (Fig12-4) and the
of the background pain did spread into the fibers of nerve VII form a prominent structure
supraorbital area and back towards the interau- in the floor of the IV ventricle of the pons, the
ricular line. facial colliculus (Fig. 11-7). The abducens
Two years prior to admission, she had a less nucleus is a large purely motor nucleus sur-
severe episode in the same distribution that rounded by the looping fibers of nerve VII.
lasted three weeks. She denied any tearing of The fibers of nerve VI leave the nucleus medi-
the eye or nasal stuffiness. She had no tingling al to the rootlets of nerve VII. Associated with
of the face, change in hearing, facial paralysis, the nucleus of nerve VI is the parabducens
or diplopia. nucleus, or parapontine reticular formation,
Neurological Examination: Mental sta- that integrates impulses via the mediallongitu-
tus, motor system (including gait and cerebel- dinal fasciculus. This center coordinates con-
lar system) and sensory system were intact. tractions of the lateral rectus muscle of one side
Cranial nerves were not remarkable except for with the medial rectus muscle (cranial nerve
findings relevant to the right fifth cranial nerve. III) of the other, producing conjugate hori-
Although touch and pain sensation over the zontal deviations of the eyes. The parapontine
face was normal, there were clearcut exquisite reticular nucleus is also referred to as the later-
trigger points producing sharp pains on light al gaze center.
tactile stimulation of the nose or other maxil- The fibers pass inferiorly and emerge from
lary areas as well the mandibular skin areas as the pons near the midline at the pon-
well as the lower molars. tomedullary junction. The roots pierce the
Clinical Diagnosis: Trigeminal neuralqia: dura and enter the cavernous sinus (see Fig.
maxillary and mandibular divisions. 12-4) below and medial to nerve III and later-
Subsequent course: Evaluation by a den- al to the internal carotid artery. The fibers
tist indicated no relevant dental disease. enter the orbit via the superior orbital fissure
The following case is an example of exam- and innervate the lateral rectus muscle, which
ple of a H. Zoster involving the ophthalmic abducts or deviates the eye laterally.
division of the trigeminal nerve. Stimulation of the frontal eye fields in the
Case 12-3: This 44-year-old, right-handed posterior part of the middle frontal gyrus pro-
physician developed over 24 hours, increasing duces contralateral innervation to the parapon-
pain in the right supraorbital and orbital areas. tine reticular formation. Stimulation of the
Edema of the eyelid developed within 36 occipital lobe also produces conjugate move-
hours. Erythematous, edematous skin lesions ment in the contralateral side. Movement orig-
developed over the right supraorbital area and inating from the occipital lobe is different from
the anterior half of the right side of the scalp. that in the frontal lobes as it is primarily invol-
Edema of the lid was sufficient to produce clo- untary fixation and tracking of moving objects.
sure of the lid. Significant cervical lym- Clinical Disorders: This nerve has a long
phadenopathy, neck pain and low-grade fever intracranial course, and is thus commonly
developed. The acute pain gradually subsided affected by: any increase in intracranial pressure
over two weeks but the skin lesions persisted (may be unilateral or bilateral), and by
the skin lesions crusted and gradually cleared nasopharyngeal tumors invading the base of
over four weeks. Occasional episodes of right the skull in adults. Pontine gliomas produce
supraorbital pain continued to occur for one similar effects in children. See Cranial Nerve
year. Faded, depressed scars were still present Cases on CD
24 years after the acute episode. CRANIAL NERVE vn - FACIAL
Clinical diagnosis: Ophthalmic herpes
The facial nerve (Fig.12-6) contains a large
zoster.
12-12 CHAPTER 12
Brain Stem
Figure 12-6. The Facial nerve - cranial nerve VII
motor nerve with a small sensory component only the arachnoId sheaths on the nerves.
(the intermediate nerve supplying taste, In the meatus the motor and sensory roots
parasympathetic and somatic sensory.). In the of nerve VII combine and enter the facial canal
pons there is one large mo-tor nucleus con- of the temporal bone. Then continuing until it
trolling the muscles of facial expression and reaches the hiatus of the facial canal, it bends
one sensory nucleus for nerve VII, while around the anterior border of the vestibule of
peripherally there is one sensory ganglion the the Inner ear, forming the external genu of
geniculate. The motor fibers supply the mus- nerve VII. The geniculate ganglion located at
cles associated with the second branchial arch the external genu, contains the primary cell
(hyoid arch). bodies of the intermediate or sensory root of
The branchial motor fibers originate from nerve VII that innervates the external ear.
the motor nucleus of nerve VII in the lateral The motor root innervates:
part of the reticular formation at the caudal 1. the stapedius muscle,
pontine levels. The fibers leave the nucleus and 2. the posterior belly of the digastric
pass medially and dorsally toward the fourth muscle, and
ventricle. Under the floor of the fourth ventri- 3. the muscles of facial expression are
cle, they pass over the dorsal surface of the innervated by the five branches of the facial
nucleus of nerve VI and then turn anteriorly, nerve that arise in the parotid gland - temporal,
forming the internal genu of the facial nerve. zygomatic, buccal, marginal mandibular, and
The fibers then pass laterally and anteriorly cervical. The mimetic muscles are: the frontal,
through the lateral portion of the pontine orbicularis oculi, anterior auricular, corrugator
reticular formation and exit from the pons at its supercilium, zygomatic, orbicularis oris,
caudal most border between the rootlets of depressor Iabi, levator labi, and levator anguli
nerves VI and VIII in the cerebellopontine oris, nasalis, mentalis, platysma, buccinator,
angle. The nerve enters the posterior cranial and risorius muscles. Within the facial nucleus
fossa and passes into the internal acoustic mea- in pons there is a separation into subnuclei rep-
tus where the motor and sensory divisions and resenting each of these muscle groups.
nerve VIII lie separated from one another by Sensory Ganglion - Geniculate. The small
sensory root ongmates from the geniculate 1. Submandibular ganglia are suspended
sensory ganglia in the inner ear; fibers run from the lingual nerve on the lateral surface of
through the facial canal into the internal hypoglossal muscle. The chorda tympani con-
acoustic meatus and then enter the pons. The tain parasympathetic preganglionic fibers from
fibers then pass through the lateral part of the the submandiular ganglia the submaxillary and
reticular formation, and enter the tractus soli- sublingual glands to the anterior 2/3 of
tarius, which is found just lateral to the sulcus tongue.
limitans. The tractus solitarius is separated from 2. Pterygopalatine ganglia is suspended
the ventricular cavity by the aqueductal gray on from maxillary nerve in pterygopalatine fossa
the floor of the fourth ventricle. The sensory and provides innervation to glands and blood
root of nerve VII carries gustatory impulses vessels in the nasal cavity, palate, and paranasal
from the taste buds in the ante-rior two-thirds air sinuses (maxillary, ethmoid, sphenoid) as
of the tongue and cutaneous sensations from well as the lacrimal glands.
the anterior surface of the ear and the soft Clinical Considerations:
palate. The motor and sensory roots continue 1. Injury in the brain stem. A central injury
in the facial canal between the inner and mid- to the facial nucleus in the pons produces ipsi-
dle ear and then turn and descend to the stylo- lateral paralysis of the facial muscles. Injury to
mascoid foramen, where they emerge from the just the nucleus or tractus solitarius, although
temporal bone. rare, produces a loss of taste on half of the
Chorda Tympani. Just before leaving the tongue because the taste fibers from nerves VII
stylomastoid foramen, the chorda tympani, and IX are found together in the tractus soli-
carrying taste fibers, separates from motor por- tarius.
tion of nerve VII. It enters its own small canal 2. Peripheral injury. Injury to the facial
in the petrotympanic fissure, then enters the nerve near its origin or in the facial canal pro-
tympanic cavity and runs on the medial surface duces:
of the tympanic membrane (from whence it a. paralysis of the motor, secretory, and facial
gets its name), and onto the medial side of the muscles,
manubrium. The nerve leaves the tympanic b. a loss of taste in the anterior two-thirds of
cavity and then emerges from the skull near the the tongue, and
medial surface of the spine of the sphenoid and c. abnormal secretion in the lacrimal and
joins the lingual nerve at the medial surface of salivary glands.
the lateral pterygoid muscle. The patient has sagging muscles in the lower
Taste Sensation. In the nucleus solitarius the half of the face and in the fold around the lips
taste sensitive cells are located as follows: 1) and nose and widening of the palpebral fissure.
Hel (sour cells) are posterior, 2) sweet and Vol-untary control of facial and platysmal mus-
salty are anterior, 3) cells responsive to bitter cula-ture is absent. When the patient smiles,
are diffusely located. the lower portion of the face is pulled to the
The secondary axons ascend in the medial unaffected side. Saliva and food tend to collect
lem-niscus to the parabrachial nucleus. The on the affected side. When the injury is distal
taste information then ascends near the central to the ganglion, an excessive accumulation of
tegmental tract to the parvocellular ventral tears occurs because the eyelids do not move
posterior medial nucleus of the thalamus. This but the lacrimal glands continue to secrete.
information is then projected onto the parietal Injury to the facial nerve may also interrupt the
operculum. For regulation of feeding behavior, reflex arc for the corneal blink reflex, which
the information enters the lateral hypothala- includes the motor component to the orbicu-
mus and central amygdaloid nuclei. 1aris from nerve VII and the sensory corneal
Parasympathetic Ganglia of vn - nerves of VI. The muscles eventually atrophy.
Submandibular and Pterygopalatine. d. Injury to nerve VII at the stylomastoid
12-14 CHAPTER 12
foramen produces ipsilateral paralysis of the the brain stem.

facial muscles without affecting taste. Central/Cerebral Innervation of VIL The
e Injury to the chorda tympani results in ab- corticobulbar path-way to the lower half of the
sence of taste in the anterior two-thirds of the facial nucleus is a crossed unilateral
tongue. Innervation, whereas the upper half of the
3. Other Peripheral Sites of Injury to VII- facial nucleus receives a bilateral innervation. A
a. Tumors of the parotid gland often unilateral lesion in the appropriate part of the
involve the facial nerve. precentral gyrus will thus paralyze the lower
b. H. roster - involvement of the sensory half on the opposite side, while a bilateral cor-
geniculate ganglion, associated with the facial tical involvement paralyzes the upper and lower
nerve - will result in a facial nerve paralysis. facial musculature. The cerebral cortical con-
The cutaneous vesicular lesions, involve the trol of the muscles of facial expression through
small sensory distribution of the facial nerve in the motor strip is especially important in com-
the external auditory canal and tympanic mem- munication. If these upper motor neuron fibers
brane. The adjacent CN VIII nerve is often are destroyed other cortical regions, including
involved producing vertigo, tinnitus and deaf- the limbic system, will now cause inappropriate
ness. In some patients the dorsal root ganglion facial expressions (pseudobulbar palsy).
of cervical nerves 2 or 3 may also be involved. Pseudobulbar palsy represents excessive unin-
c. Bilateral facial nerve involvement (facial hibited brain stem activity. External stimuli will
diplegia) may occur in: then trigger excessive response e.g. excessive
Guillain-Barre syndrome crying to a sad story or excessive laughter.
Sarcoidosis - uveoparotid fever The following case is an example of one of
Hemifacial Spasm: Spontaneous contrac- the more common disorders of the facial nerve,
tions of the facial muscles occur but often trig- Bell's palsy.
gered by attempted movement. There is often Cranial Nerve Case 12-5.5. This 37-year
synkinesis - an overflow - of movement so that old, right-handed, white, housewife was
attempts to smile result in closure of the eye, referred for emergency room consultation
etc. Hemi-Facial Spasm relates to a previous regarding left facial paralysis. Three days prior
facial nerve paralysis that has partially recovered to evaluation, the patient had developed a dull
but in which anomalous reinnervation has pain above and behind the left ears. She then
occurred. In the majority of cases in which the noted occasional muscle twitching about the
etiology is unrelated to a previous Bell's palsy, left lower lip and some vague sti.ffuess on the
the etiology relates to a compression of the left side of the face. The morning of the evalu-
facial nerve root close to the brain stem by a ation, the patient noted she had difficulty with
blood vessel such as the anterior inferior cere- eye closure on the left. She noted that she was
bellar artery or posterior inferior cerebellar drooling from the left side of her mouth. She
artery. With compression, demyelination will denied any alteration in sensation over the face
occur with subsequent ephaptic transmission and any actual deficit in hearing and denied any
between adjacent fibers. The treatment, both tinnitus. She had no crusting in the ear and no
medical (carbamazepine) and surgical (decom- actual pain within the ear.
pression of the nerve placing a soft implant Neurological Examination: Cranial
between the vessel and the nerve) is similar to Nerves: The patient had an incomplete paraly-
the treatment of trigeminal neuralgia. sis of the entire left side of the face. She had
Facial myokymia is sometimes confused sufficient eye closures sitting or recumbent to
with hemifacial spasm. This is a fine rippling of cover the cornea. She was able to have minor
muscles - arrhythmic involuntary fibrillations. elevation of the eyebrow in fore-head wrin-
Etiology: Pontine glioma, Multiple sclerosis - kling. She had minimal elevation of the lower
producing demyelination of the nerve within lip in smiling. Taste for sugar was slightly
decreased but not absent on the left side of the border with the pons lateral to the root of
tongue (anterior two-thirds). All other cranial nerve VII. The cochlear nerve is smaller than
nerves were Intact. Examination of the exter- the vestibular nerve and is lateral to it. (See
nal canal and of the tym-panic membranes Discussion on auditory and Vestibular
demonstrated no abnormality. Pathways in Chapter 15 and on Special
Motor system, reflexes, sensory system, and Sensory Systems on CD ROM).
mental state: All intact. COCHLEAR NERVE
Bell's Palsy related to involvement of the The cochlear nerve is concerned with hear-
peripheral portion of the facial nerve. This usu- ing and originates from the spiral ganglion of
ally transient impairment of a facial nerve is the Corti in the petrous portion of the temporal
result of swelling of the nerve within the rela- bone. The peripheral process originates from
tively narrow bony facial canal. The etiology of the hair cells in the spiral ganglion.
this swelling is often uncertain but infections The cochlear division of cranial nerve VIII
with the herpes simplex virus or the spirochetal originates from the spiral ganglion and termi-
agent producing Lyme's disease have been nates in the dorsal and ventral cochlear nuclei
implicated. located on the external surface of the inferior
More precise localization depends on cerebellar peduncle. The primary auditory
whether this motor function alone is involved, fibers enter the cochlear nuclei and bifurcate,
as opposed to additional involvement of taste ending in the dorsal and ventral cochlear
or the anterior two-thirds of the tongue, or of nuclei. Throughout the auditory system a
parasympathetic supply to the facial and sali- tonotopic arrangement occurs. The secondary
vary glands. This will be discussed above. auditory fibers arise from the dorsal and ventral
CRANIAL NERVE vm - cochlear nuclei and form the three acoustic
VESTIBULOCOCHLEARNERVE striae. The ventral acoustic stria originates from
The vestibulocochlear nerve (Fig. 12-7) has the ventral cochlear nucleus and courses
two divisions: the vestibular and cochlear through the ventral boundary of the pon-tine
nerves, which are attached to the medulla at its tegmentum, forming the trapezoid body.
GalMlk]n of Cochlea Ampulla of Superior Semicircular Duct
Brainstem
Figure 12-7. The Vestibulocochlear nerve- cranial nerve VIII
12-16 CHAPTER 12
tory fibers synapse in the medial geniculate

nucleus and are then projected into the audito-
ry cortex, areas 41 and 42, the transverse tem-
poral gyri of Heschl.
One of the most fascinating pathways in the
central nervous system is the olivocochlear
bundle of Rasmussen, or the efferent cochlear
bundle. Crossed fibers originate from the areas
dorsal to the accessory olivary nucleus, while
uncrossed fibers originate from the superior
olivary nucleus, join with the crossed pathway,
exit with the inferior division of the cochlear
nerve, and anastomose upon the hair cells in
the cochlea. This prime example of central ner-
vous control of peripheral receptors is most
noticeable when loud sounds are quickly
reduced to more moderate levels (e.g., the
intensity of loud rock and roll is reduced to
that of mood music). Note that similar mecha-
nisms exist in the visual, olfactory, and gustato-
Figure 12-8 The Cochlear nerve. - a division of ry systems.
cranial nerve VIII Throughout the auditory system there are
These fibers pass through the medial lemnis- crossed and uncrossed fibers, so that represen-
cus, reach the superior olive, and migrate later- tation is bilateral throughout.
ally to form the lateral lemniscus. The dorsal Clinical Disorders
and intermediate striae arise from the dorsal Auditory --Symptoms and Signs:
cochlear nucleus and the dorsal half of the ven- Deafuess: Classification
tral cochlear nucleus. The dorsal stria crosses Conductive: External and middle ear dis-
the midline ventral to the medial longitudinal ease: (loss oflow frequency sounds)
fasciculus and joins the contralateral lateral Sensory neural (nerve deafuess - loss of
lemniscus (Fig. 12-8). The intermediate stria high frequency sounds)
runs through the center of the reticular forma- 1. Disease of Cochlea - often bilateral,
tion, crosses the midline, and enters the con- hereditary or related to loud sound exposure.
tralateral lateral lemniscus. Antibiotic use - aminoglycosides, dih-
Some secondary auditory fibers end in the drostreptomycin and Vancomycin.
su-perior olivary, trapezoid and laterallemnis- If sudden and unilateral consider vascular
cus nuclei and the reticular formation. In these etiology: occlusion of the internal auditory
three nuclei tertiary axons originate which artery.
ascend, primarily crossed, to the inferior col- 2. Disease of Eighth Nerve: Small tumors
liculus, where many of the axons terminate or (acoustic neuroma) of 8th nerve within the
send collaterals into the inferior collicular bony canal may produce limited CNVIII
nuclei. Fibers from the Inferior colliculus and symptoms. Large tumors, such as acoustic
lateral lemniscus form the brachium of the infe- neuromas, meningiomas, etc., at the cerebellar
rior colliculus that ends in the medial genicu- pontine angle produce involvement of a cluster
late nucleus of the thalamus. Auditory infor- of cranial nerves (VIII, VII, ±V, ±IX, X).
mation ascends bilaterally to the medial genic- Note that these "acoustic neuromas" arise
ulate nucleus, with the contralateral informa- from the Schwann cells of the vestibular divi-
tion forming the largest component. All audi- sions of the nerve. A more correct term is
vestibular schwannoma. The vestibular nerve originates from the
Tinnitus - various forms of ringing in the vestibular ganglia. The primary fibers terminate
ear- mostly in the four secondary vestibular nuclei
Etiology- middle or inner ear or 8th nerve * in the floor of the fourth ventricle. The sec-
Usually associated with hearing loss. ondary vestibular nuclei are the inferior
NOTE: Paroxysmal tinnitus may occur in (descending), lateral, medial, and superior
association with various other symptoms of nuclei (Fig. 12-9).
seizures - arising in the temporal lobe (trans- The primary vestibular fibers bifurcate into
verse gyrus of Heschl- is the auditory projec- ascending and descending portions. The
tion) ascending axons end in the superior, lateral,
Central lesions of cochlear pathway. Note and rostral portions of the medial nucleus,
that beyond the cochlear nuclei, central con- while the descending axons run in the Inferior
nections of the auditory system are both nuclei and provide collateral's to the medial
crossed and uncrossed. Therefore, a unilateral nucleus. The lateral nucleus forms the vestibu-
lesion is unlikely to produce a unilateral hear- lospinal tract, which ex-tends to sacral levels.
ing defect. Massive intrinsic lesions are The inferior vestibular nucleus extends
required to produce "brain stem deafuess." from the entrance of the vestibular nerve root,
Vestibular Nerve at the medullopontine junction, through the
The vestibular nerve is concerned with lower medullary levels. The medial vestibular
equilibrium. Its primary neurons are bipolar nucleus is found medial to the inferior nucleus
and located in the vestibular ganglia in the at the same levels. The medial and inferior
internal acoustic meatus. The fibers terminate vestibular nuclei form the prominent vestibular
in the vestibular nuclei located in the ventricu- area on the floor of the fourth ventricle, lateral
lar floor of the medulla. The vestibular nerve to the sulcus limitans. The myelinated bundles
originates from the hair cells in maculae of the of the primary descending vestibular axons can
scale and utricle and from the cristae of the delimit the inferior nucleus. The lateral
ampullae of the three semicircular canals. It has vestibular nucleus is found lateral to the roots
five branches of nerve VIII in the tegmentum. The superior
vestibular nucleus lies in the angle formed by
the floor and wall of the fourth ventricle and
extends through the upper pontine levels in
this position. The superior cerebellar peduncle
forms its dorsal border.
Primary vestibular fibers also run directly
into the ipsilateral cerebellum, forming the
Juxtarestiform body and projecting to the floc-
culus, nodulus, and uvula of the cerebellum
(portions of the midline cerebellum which are
old from a phylogenetic standpoint). The sec-
ondary vestibular axons originate from the sec-
ondary vestibular nuclei and project to the
cerebellum, reticular formation, motor cranial
Inferior
nerve nuclei, and all levels of the spinal cord.
(Caudal)
{ Fibers from all the vestibular nuclei join the
Vestibular Medial
Nudei Lateral me-dial longitudinal fasciculus and are crossed
Superior 'Aos and uncrossed with ascending and descending
branches.
Figure 12-9. The secondary vestibular nuclei.
Vestibular Ascending Pathway. The vestibu-
12-18 CHAPTER 12
lothalamic pathway fibers arise from the lateral vertical.

vestibular nucleus and ascend with the cervical 4). Unsteadiness: Severe or mild.
fibers proprioceptive fibers in the mediallem- Etiology - Multiple, Labyrinthine disease is
ruscus. They terminate in the ventral posterior the most common
nucleus and MGN. The vestibular impulses - Meniere}s disease: Paroxysmal attacks of
and responses have been noted in the cervical vertigo, ± vomiting and ataxia are associated
area of the postcentral gyrus and temporal lobe with tinnitus and deafuess. The etiology relates
of the cerebrum. to endolymphatic hydrops - increase in volume
Clinical Disorders: Vestibular: and distention of the endolymphatic system of
Symptom: the semi circular canals.
1) Vertigo: a sensation of movement (usually - Benign positional vertigo (nonbenign forms
rotation) of the environment or of the body of positional nystagmus may occur with the
and head: brain stem disease, e.g., posterior fossa
- When due to involvement of the horizon- tumors). Sudden vertigo and associated symp-
tal (lateral) canals, the sense of movement is toms of nystagmus, nausea - selectively occur
usually rotation in the horizontal plane. on sudden tilting of head from the upright to
- When due to involvement of the posterior recumbent position. This syndrome may occur
or vertical canals, the sense of movement may as a late complication of head trauma. The
be in the vertical or diagonal planes with a proposed etiology relates to detachment of
sense of the floor rising up or receding. otolithic crystals that then float free in the
- Vertigo must be distinguished from the more endolymph. In particular positions of the
general symptom of dizziness - or light-head- head, this debris - intermittently blocks the
edness, which has many causes. Simple light- flow of fluid into the cupula.
headedness as a symptom of pre-syncope (the - Antibiotic damage (streptomycin and
sensation one is about to faint) mayaccompa- aminoglycosides)
ny any process which produces a general reduc- Vestibular Nerve-Vestibular neuropathy acute,
tion in cerebral blood flow (cardiac arrhythmia, self-limited syndrome - which follows a viral
decreased cardiac output, peripheral dilatation infection. Symptoms are vestibular without
of vessels, decreased blood pressure or hyper- cochlear involvement. There is unilateral
ventilation) Hypoglycemia and various drugs vestibular paresis.
also produce dizziness. Some patients cannot Tumors - arising from or compressing
make the distinction and a series of operational vestibular nerve, "acoustic neuroma." Note
tests may be necessary to reproduce symptoms. that this tumor actually arises from the
- Rotation, hyperventilation, orthostatic Schwann cells of the vestibular nerve.
changes in blood pressure Brain stem: Infarcts involving the vestibular
Additionally, caloric testing, cardiac ausculta- nuclei will produce vertigo and/or nystagmus.
tion, EKG, and Holter monitor maybe neces- Almost always other brain stem signs are
sary in selected cases. present.
2) Nausea and vomiting. Vertigo of vestibular Cerebral cortex: Stimulation of temporal
origin is accompanied by these symptoms - lobe in-patients with seizures of temporal lobe
because of the connections of the vestibular origin produces dizziness.
system to the emetic center of the medulla.
CRANIAL NERVE IX,
3). Nystagmus: a jerk of the eyes - slow com-
GWSSOPHARYNGEAL
ponent alternating with a fast component is
The glossopharyngeal nerve (Fig. 12-10) is
associated with stimulation or disease of the
a mixed nerve with sensory and motor nuclei
vestibular system. Nystagmus is named from
in the medulla. The functions of cranial nerve
the fast component - and the direction of
IX are often discussed with the vagus, as is
movement is specified: rotatory, horizontal or
Inferior
Nucleus
Parotid
Gland
Figure 12-10. The Glossopharyngeal Nerve - Cranial Nerve IX
done here. The rootlets of nerve IX are found The postganglionic fibers pass via the auricu-
in the medulla in a postolivary position. The lotemporal nerve of the mandibular nerve and
nerve trunk exits from the skull via the jugular form the secretory pathway to the parotid
foremen, where it lays anterolateral to the gland.
vagus nerve. In the jugular foramen are found Clinical Disorders.
two swellings on the nerve trunk of nerve IX, - Lesions restricted to the nuclei or nerve
the superior and inferior ganglia. roots of nerve IX are rare, but if they occur,
Sensory Division. The primary sensory cell taste is lost on the posterior third of the tongue
bodies are located in the superior and inferior and the gag reflex is absent ipsilaterally. There
ganglia and carry gustatory sensations from the is no response when the posterior pharyngeal
taste buds in the poste-rior third of the tongue wall and soft palate are stimulated. The func-
and cutaneous sensations from the pharynx, tion of the parotid glands may also be impaired
soft palate, auditory tube, middle ear, palatine but can be easily evaluated by placing a highly
tonsils, Eustachian tube, and carotid sinus. The seasoned food on the tongue and seeing if a
general and special visceral axons enter the copious flow from the duct occurs.
medulla and run in the tractus solitarius in the
- Isolated lesions are uncommon. A com-
middle and posterior medullary level, synaps-
ing in the nucleus solitarius. Mferent fibers are bined involvement with vagus and accessory
derived from baroreceptors in the wall of the nerves at the jugular foramen is discussed
below.
carotid sinus (BP regulation) and chemorecep-
tors in the carotid body (ventilatory response - Glossopharyngeal neuralgia is one of the
to hypoxia). few isolated syndromes: Symptoms are similar
Motor Division. The motor fibers of nerve to those of trigeminal neuralgia, but localized
IX originate from the most superior part of the to the posterior tongue and pharynx with swal-
nucleus ambiguous in the medulla. They pass lowing, coughing or sneezing, providing the
posteriorly and laterally into the jugular fora- trigger. However, syncope may also occur.
men. The preganglionic parasympathetic fibers
originate from the inferior salvatory nucleus in CRANIAL NERVE X - VAGUS
the medulla, join the rootlets of IX and run via The vagus nerve (Fig. 12-11) has one sen-
the lesser petrosal nerve to the otic ganglion. sory and two motor nuclei in the medulla and
12-20 CHAPTER 12
vation to the ganglion in the walls of the phar-

ynx, trachea, bronchi, esophagus, stomach,
small intestine and ascending portions of the
large intestine, and the heart. The fibers of X
end in the parasympathetic ganglia found in
Auerbach's plexus (myenteric plexus). The
other motor division of the vagus nerve origi-
nates from the posterior two-thirds of the
nucleus ambiguous in the reticular formation
of the medulla, the ventral motor nucleus, and
connects to the striate muscles of the soft palate
and pharynx, and the intrinsic muscles of the
larynx. It is thus important in swallowing and
speech. The ambiguous portion of nerve X
innervates the following muscles:
- esophagus; the upper third is skeletal mus-
cle, middle third is skeletal and smooth and the
lower third smooth,
- pharynx: the superior, middle, and inferior
Infenor constrictors of the pharynx
GanglIOn - palate: the palatoglossus, palatopharyn-
of Vagus n. geus, salpingopharyngeal, and levator palatine
velum of the soft palate,
- larynx: cricothyroid, the posterior cricoary-
tenoid, arytenoid, lateral cricoarytenoid, and
thyroarytenoid.
Sensory Functions
Figure 12-11. The Vagus Nerve- Cranial nerve X The primary cell bodies of the sensory
fibers are located in the inferior ganglion and
also has the most extensive peripheral distribu- carry gus-tatory information from taste buds in
tion of any cranial nerve. Its roots are located the epiglottis and pharynx, cutaneous innerva-
in a postolivary position in the posterolateral tion from the base of the tongue and epiglot-
sulcus of the medulla, in line with the fibers of tis, and general visceral sensation from all the
nerve IX but inferior to them. They exit from structures receiving motor innervation (phar-
the posterior cranial fossa via the jugular fora- ynx, larynx, heart, tracheal bronchi, esophagus,
men. The superior ganglion, the jugular, is small and large intestines. external ear, and
found in the jugular foramen, while the inferi- dura of the sigmoid sinus). The fibers enter the
or ganglion, the nodose, is found just as the medulla and synapse in the nucleus solitarius.
nerve leaves the Jugular foremen. In the neck The secondary axons subserving pain and tem-
the vagus nerve is found in the carotid sheath perature ascend in close proximity to the medi-
close to the common carotid artery and al lemniscus to the ventroposterior thalamic
Jugular vein. nuclei.
Motor Nuclei The taste fibers ascend ipsilaterally to the
The dorsal motor nucleus of the vagus parabrachial nuclei in the central tegmental
nerve forms the vagal trigone on the floor of tract and terminate in the cranial (medullary)
the fourth ventricle at the medullary levels. It and spinal portions. The taste fibers synapse in
provides preganglionic parasympathetic inner- the parvocellular region ofVPM and are then
projected to the cortical taste area in the pari- larynx resulting in a weak gag reflex, paralysis
etal operculum. of the cricothyroid muscle, and the laryngeal
Reflexes. The vagus nerve is also important muscles tire easily.
in many visceral reflexes: gag, vomiting, swal- The recurrent laryngeal nerve may also be
lowing, coughing, sneezing, sucking, hiccup- injured during the following circumstances:
ing, and yawning, and in the aortic sinus reflex. - Aneurysm of the thoracic aorta may
Ab-normal responses usually involve structures involve the left recurrent laryngeal nerve.
in addition to the vagus nerve. - Apical lung (superior sulcus) tumors, pha-
Clinical Disorders. Bilateral lesions of the ryngeal carcinoma and metastatic involvement
vagal portion of the nucleus ambiguous in the of cervical lymph nodes may all have effects on
medulla are usually fatal because of its proxim- the vagus or recurrent laryngeal nerves.
ity to the pneumotaxic, apneustic, and
- Diphtheria may involve the nerves.
medullary respira-tory centers. Unilateral
lesions of the vagus nerve mayor may not pro- - Myasthenia or D. botulinum toxin may
duce autonomic dysfunction. The heart rate, affect the relevant neuromuscular junctions.
respiratory system, and gastrointestinal tracts - Dissections of the neck for carotid
appear to function normally, but there may be endarterectomy or for thyroid surgery may
minor difficulty in swallowing. Injury to pha- damage the vagus or recurrent laryngeal
ryngeal branches produces difficulty in swal- nerves.
lowing.
Central Lesions of the Vagus Nerve in the
Lesions of peripheral branches of the vagus Brain Stem. Lesions in the upper medulla pro-
nerve. duce dysphagia, while lesions in the lower
1. Lesions of the superior laryngeal nerve medulla cause dysarthria. The palate on the
effect the motor innervation to the cricothy- affected side is paralyzed, and the uvula devi-
roid mm and the inferior constrictor of the ates to the unaffected side (see discussion of
pharynx. However, it also effects the internal lateral medullary syndrome in chapter 13).
laryngeal branch, the "watch dog of the lar-
The dorsal motor nucleus of the vagus nerve
ynx". This innervation of the mucosa of the
inhibits and depresses heart rate and constricts
laryngeal region produces coughing when for-
the coronary circulation. Paralysis of the vagus
eign particles lodge in this region, thus keeping
nerve produces smooth muscle contractions in
the airway open. When this reflex is not present
the trachea, bronchi, and bronchioli with nar-
due to injury to the nerve or an overdose of
rowing of the lumens. The dorsal motor
drugs, foreign objects can then enter the tra-
nucleus of the vagus nerve simulates general
chea and block the airway, which may produce
alimentary function by causing the secretion of
aspiration pneumonia or even lead to death.
gastric and pancreatic juices important in peri-
2. The recurrent laryngeal nerve supplies all
stalsis. It also stimulates the liver and spleen
of the intrinsic muscles of the larynx (except for
and inhibits the suprarenal glands. Isolated
the cricothyroid muscle) and the mucosa of the
central lesions are rare. The nucleus ambigu-
larynx below the vocal cords. Interruptions of
ous may be affected in syringobulbia and
the recurrent laryngeal nerves produce paraly-
vascular lesions of the lateral medulla in associ-
sis of the vocal cords, hoarseness, and dyspho-
ation with other findings, as noted below, or in
nia. Bilateral involvement of both recurrent
the poliomyelitis or the bulbar variant of amy-
laryngeal nerves produces aphonia and inspira-
otrophic lateral sclerosis.
tory stridor. Isolated peripheral lesions are
more frequent and occur especially with oper- Supranuclear lesions involving the extrapyra-
ations on the thyroid gland. When the recur- midal pathways to the dorsal motor or ambigu-
rent laryngeal is injured there is weakness in ous nuclei usually cause difficulty in swallowing
speech and anesthesia of the upper part of the but only become clinically significant when
12-22 CHAPTER 12
muscles. Injury to the nucleus ambiguous in

the medulla causes paralysis and atrophy of the
trapezius and sternomastoid muscles, resulting
in weakness in head movements to the oppo-
site side and shrugging of the shoulder.
Supranuclear lesions of the corticobulbar
system produce only paresis of the muscles.
Clinical Disorders.
Isolated involvements of XI by intracranial
lesions are rare, however, combined involve-
ment at the jugular foramen is more common
(See CASE 12-9 on CD). Dissections in the
posterior triangle of the neck may also damage
Sternocleidomastoid the nerve.
and Trapezius
I CRANIAL NERVE XII HYPOGLOSSAL
Cord
Brainstem
Hypoglossal N
Figure 12-12. The Spinal Accessory NerPe- cranial
nerve XI
they are bilateral.
CRANIAL NERVE XI -
SPINAL ACCESSORY
The spinal accessory nerve (Fig.12-12) is a
purely motor nerve that originates from both
the medulla and spinal cord and is consequent-
ly divided into cranial (medullary) and spinal
portions.
Exbinsic
The cranial root arises from the most Muscles or Hypoglos
posterior/part of the nucleus ambiguous, exits TOf9Je erve
in a postolivary position, enters the jugular (GeriogIossus. SI)4ogIoaus, and tiyogIr&us
forarnen, and then combines with the spinal
root. This root innervates the uvula, levator Figure 12-13. The hypoglossal nerPe - cranial nerPe
veli palatini, and pharyngeal and laryngeal XII.
muscles in concert with cranial nerve X (to
which it is accessory). The hypoglossal nerve (Fig. 12-13) is a
The spinal portion arises from the ventro- purely mo-tor nerve that originates from the
lateral part of the ventral horn in the upper four hypoglossal nucleus, which forms the
cervical segments. The innervation to the ster- hypoglossal trigone in the medullary floor of
nocleidomastoid originates primarily from C2 the fourth ventricle. The fibers pass anteriorly,
while the innervation to the large trapezius passing inferiorly between the olive and pyra-
muscle originates in C3 and C4. The fibers mids. The fibers exit from the cranium via the
from the spinal portion of XI pass up through hypoglossal canal and supply all the extrinsic
the foremen magnum, combines with the cra- muscles (styloglossus, hypoglossus, and
nial roots, and distribute to the sternomastoid genioglossus) and the intrinsic muscles (su-
and trapezius muscles. Branches of the trigem- perior and inferior longitudinal, transverse, and
inal also carry general sensations from these vertical) of the tongue with the exception of
the palatoglossal that is innervated by the bly neurofibroma.
vagus. Branches from V3 of the trigeminal ill. Voluntary Control of the
nerve carry general sensations from the tongue Cranial Nerves-Corticobulbar and
musculature. Corticomesencephalic Pathways.
Clinical Disorders. This system distributes to the motor nuclei
Unilateral injury to the nerve or nucleus of the cranial nerves (Cranial Nerves V. VII,
pro-duces atrophy and paralysis in the ipsilater- IX, X XI, XII) and provides voluntary and
al tongue with the tongue protruding toward involuntary con-trol of the muscles and glands.
the injured side. This is due to the unopposed Voluntary Control of Cranial Nerves V,
action of the intact genioglossus muscle push- VII, IX-XII. The corticobulbar pathway con-
ing the tongue up and out from below. trols the cranial nerves in the medulla and
Bilateral paralysis of the nucleus or nerve pons, the bulb. The cranial nerves controlled in
causes difficulty in eating and dysarthria. the pons are V, VI, VII, while in the medulla
Lesions limited to this nerve are unlikely to IX, X and XII. We have used the term corti-
occur with brain stem pathology. The conuclear as it reminds the student of the key
hypoglossal nucleus may be involved as part of role of the cranial nerve nuclei in movement.
a more generalized somatomotor neuron These fibers are found anterior to the corti-
process in poliomyelitis or amyotrophic lateral cospinal fibers in the genu of the internal cap-
sclerosis (bulbar palsy). Limited lesion may sule and medial to the corticospinal tract in the
occur along the extra-medullary course of the cerebral peduncle, pons, and medullary
nerve, but rarely at the hypoglossal foramen, pyramids.
more commonly with radical cervical dissec- From the lower third of precentral gyrus,
tions, or as a complication of carotid area 4 fibers supply the muscles of facial expres-
endarterectomy. Supranuclear lesions rarely sion (motor nerve VII), and the muscles of
produce paralysis of the tongue. mastica-tion (motor nerve V), and deglutina-
II. Effects of Extrinsic Lesions tion (ambiguous nuclei of nerves IX and X).
on Cranial Nerves From the Inferior frontal gyrus and frontal
Cranial nerves are commonly affected by operculum, the posterior part of the par trian-
mass lesion and the syndromes produced by gularis, area 44, and fibers supply the larynx.
these extrinsic lesions are summarized in Table It appears that many corticonuclear axons
12-5. end on interneurons and not directly on the
Cases demonstrating combined CRANIAL motor neuron of the cranial nerve. The corti-
NERVE SYNDROMES are found on the CD cal innervation of the majority of the cranial
as follows: nerves is mostly bilateral with the exception for
the contralateral control of the lower facial
Cavernous Sinus Syndrome
muscles; consequently unilateral lesions in the
Case 12-6: Lesion base of skull involving
cortical bulbar system produce usually only
left cavernous sinus plus possible involvement
weakness and not paralysis.
of foramen ovale region
Clinical Disorder: A bilateral supranuclear
CEREBELLOPONTINE ANGLE SYN-
lesions of the corticonuclear system produces
DROME.
upper motor neuron signs and also inappropri-
Case 12-7:. Cerebellar pontine angle
ate behavioral signs, incontinence, pseudobul-
tumor, a vestibular Schwannoma acoustic neu-
bar palsy.
roma.
Pseudobulbar Palsy. A bilateral corticobul-
Vestibular
bar lesion produces a pseudo bulbar syndrome
Case 12-8: Vestibular Schwanoma
- characterized by a release of bulbar functions.
JUGULAR FORAMEN SYNDROME This is an upper motor neuron lesion with
Case 12-9: Jugular foramen tumor-proba-
hyperactive jaw jerk, and spasticity- affecting
12-24 CHAPTER 12
speech, and gag reflexes. Cranial nerve compo- cranial nerves III, IV, and VI. Eye movements
nents of emotions are released - emotional originate from the frontal eye fields in the cau-
lability. This most likely represents the release dal part of the middle frontal gyrus and the
of cortical control via the corticobulbar inner- adjacent inferior frontal gyrus, area eight. In
vation of the muscles controlled by the cranial upper midbrain levels, fibers to cranial nerves
nerves and now the limbic control to these III and IV leave the corticomesencephalic
same nuclei takes over via descending auto- tract. Fibers to cranial nerve VI descend and
nomic pathways with the emotional state being terminate on contralateral parabducens/para-
undampened by the frontal lobes. ALS pro- pontine reticular nuclei of the pons that coor-
duces upper and lower motor paralysis. dinates movements with CN III and IV
Voluntary control of eye movements. through the MLF.
The corticomesencephalic portion controls
TABLE 12-5. SYNDROMES OF THE ADJACENT CRANIAL NERVES DUE TO EXTRINSIC MASS LESIONS
[Modified from Adams, Victor, & Ropper 1994]

SITE CRANIAL NERVES INVOLVED CAUSE
1. Superior orbHal fissure III, IV, V, (ophthalmic), VI Meningiomas
(sphenoidal fissure) Aneurysm
2. OptiC foramen II Meningioma, inner 1/3 Sphenoid wing
3. Cavernous sinus III, IV, VI, V1 ophthalmic V2 maxillary Intracavernous carotid aneurysm
Case 12-6 CD ROM Note: with pituHary optic chasm also Traumatic carotid cavernous fistula
involved& CN findings may be bilateral. Thrombosis of cavernous sinus
Invasive tumors of sinuses & pituitary
4. Apex of petrous bone V, VI Innammation of bone (Gredenigo syndrome
5. Internal auditory canal VII, VIII Tumors and chronic infection
6. Cerebellar pontine angle VII, VII, + V, + IX Tumors: acoustic neuroma & meningiomas
Case 12-9
7. Jugular foramen IX. X. XI* Tumors - e.g., neurofibroma

Case 12-7
* Large lesions may olso involve CNXlI

Figure 12-14: The Twelve Cranial Nerves
CHAPTER 13
Brain Stem:
Clinical Considerations
LOCALIZATION OF THE DISEASE have already been considered in chapter 12 and
PROCESSES IN THE BRAIN STEM are summarized in table 12-5. When speaking
Of all sites in the central nervous system, of the anatomical syndromes of the brain stem
the brain stem provides the best example of in clinical neurology, we will limit our consid-
how the anatomical pattern of involvement erations to the medulla oblongata, pons, and
may allow the prediction of the actual patho- midbrain. The thalamus, hypothalamus, and
logic process. The student has, of course, subthalamus represent a natural rostral contin-
already encountered several examples of this uation of the midbrain and diseases involving
phenomenon at the level of the spinal cord. the midbrain sometimes also involve the adja-
For example, the clinical finding of a selective cent diencephalon. From the standpoint of
dissociated loss of pain and temperature in a vascular anatomy, the midbrain, and the dien-
cape-like distribution over the shoulders and cephalon do share a vascular supply from the
upper extremities implies an anatomical process penetrating branches of the posterior cerebral
in a pericentral location involving the anterior arteries
commissure. One could readily deduce that an SPECIFIC SYNDROMES AND
intrinsic pathological process was present and, DISEASE EN'ITI1ES
moreover, could assume that in most cases the Specific syndromes and disease entities will
pathological process was that of syringomyelia. now be considered. Our emphasis will be on
At the level of the brain stem such examples various classic syndromes, each of which
of close correlation occur frequently. Thus, the implies a single level lesion. The reason for this
progressive combined involvement of the ipsi- emphasis in the teaching of clinical anatomical
lateral cranial nerve VIII (auditory and vestibu- correlation is obvious. However, the student
lar), nerve VII (facial), and nerve V (trigemi- should realize that, in actuality, a number of
nal), with the manifestations of deafness, tinni- the diseases involving the brain stem are not
tus (a buzzing or ringing sound in the ear), simply limited to a single level but rather affect
dizziness, peripheral facial paralysis, and unilat- multiple levels; that is, they are multifocal or
eral facial numbness, not only indicates the they are system disorders. Thus, although we
location of the pathology (the cerebellar pon- will consider in detail patients with limited focal
tine angle) but also strongly suggests the actu- infarcts, it is more frequent to have infarction at
al nature of the pathology: vestibular several levels of the brain stem in occlusive dis-
Schwannoma (acoustic neuroma was the old ease of the basilar-vertebral system (perhaps the
term). While other pathological lesions may most common disease involving the brain
occur at this site, they are much less common. stem). Another rather common disease of the
There are several possible approaches to the brain stem, multiple sclerosis, almost always
problem of localization of disease processes in follows a multifocal pattern.
the brain stem. We have already considered in
DIFFERENTIATION OF EXTRINSIC
Chapter 11 a number of guidelines for local-
VERSUS INTRINSIC DISEASES.
ization that should be reviewed at this time.
We will now consider in greater detail the par- The same categories of disease already
ticular anatomical syndromes and the various familiar to the student from his study of the
spinal cord will be employed: extrinsic and
types of pathology in terms of specific extrinsic
and intrinsic syndromes. Many of the extrinsic intrinsic. At the level of the spinal cord, extrin-
sic diseases were much more common and
syndromes related to cranial nerve syndromes
13-2 CHAPTER 13
were emphasized. At the level of the brain TABLE 13-1. PATTERNS OF EXTRINSIC VS INTRINSIC
stem, the intrinsic diseases occur much more DISEASE OF THE BRAIN STEM
frequently. (This is also the case at the level of
the cerebral hemisphere). Nevertheless, extrin- PATTERNS OF EXTRINSIC PATTERNS OF INTRINSIC
sic diseases have an importance outside of their LESIONS: LESIONS:
actual frequency of occurrence. As we have a. Successive unilateral a. Simultaneous segmental
already noted, at the level of the spinal cord, involvement of muHlple involvement of the cranial
extrinsic diseases represent progressive com- cranial nerves early in the nerve nuclei and of long
pression type problems such as tumors or course of the disease, wHh tracts, as in a lateral
fiber systems involved only medullary infarction.
degenerative disk disease. Early diagnosis and
later in the disease.
surgical relief of the compression will prevent
the development of disability and will preserve b. Early involvement of the b. Progressive bilateral
life. All lesions compressing the brain stem are eighth cranial nerve (as in involvement of cranial
potentially life-threatening potential if they acoustic neuroma). nerves and long tracts,
as in infiltrating glioma.
progress to the vital centers of the medulla
involved in the control of respiration, blood c. Asyndrome in which c. Involvement of the fifth
pressure, swallowing and changes in intracra- symptoms are limited to the cranial nerve- descending
nial pressure (ICP) etc. Moreover involvement midline cerebellum: loss of spinal tract with selective
of those areas essential for motor control equilibrium and truncal involvement of pain
ataxia. sensation over the face.
(reticular formation of pons and medulla) or Involvement of the MLF, as
those areas in the midbrain reticular formation in MS, glioma, or infarction
essential for the maintenance of consciousness with the occurrence of inter
will result in a severe bedridden state. nuclear ophthalmoplegia
In distinguishing extrinsic and intrinsic dis- and verlical nystagmus
eases, several differential points have already d. Symptoms of ICP d. If an infiltrating tumor,
been mentioned. (Table 13-1). occurring early in the course the symptoms of ICP tend
The development of techniques such as the of the disease - headache, to occur late in the disease.
CT and MRI scan has markedly increased our nausea, and vomHing.
ability to confirm the anatomical localization of Occasionally, as in midline
cerebellar lesions, the
disease involving the brain stem. Magnetic
symptoms of ICP (with or
resonance angiography has provided a nonin- without truncal ataxia)
vasive method of imaging the blood supply of may be the only symptom.
the brain stem (See chapter 2).
EXTRINSIC DISEASES OF THE e.g., cystic astrocytomas of the cerebellum,
BRAIN STEM medulloblastomas, and ependymomas. Some
EXTRINSIC TUMORS AND OTHER are locally invasive malignant tumors, e.g.,
MASS LESIONS nasopharyngeal carcinoma infiltrating the bone
As indicated, almost all of the problems of the skull or carcinoma of the lung or breast,
within the extrinsic category are tumors. metastatic to the cerebellum. (In general, car-
When we use the term "extrinsic" in the pre- cinomas only rarely spread in a metastatic man-
sent context, we mean extrinsic to the actual ner to the brain stem per se).
substance of the brain stem. Some of the (1) The Cerebellar pontine
tumors to be considered are actually invasive Angle Syndrome.
tumors intrinsic to the cerebellum, or arising Vestibular schwannoma (acoustic
from the ependymal cells lining the 4th ventri- Neuroma) (Fig. 13-1, 13-2): Tumors at the
cle that are secondarily compressing or infil- cerebellar pontine angle account for 10% of all
trating the brain stem. Some of these tumors central nervous system tumors. Most tumors
are actually derived from cells of the glial series, encountered at the cerebellar pontine angle are
BRAIN STEM: CLINICAL CONSIDERATIONS 13-3
nerve VIII (progressive loss of hearing of a
neural type and a dead labyrinth on caloric
stimulation). As the tumor enlarges, symp-
toms referable to nerves VII and V and to the
cerebellum develop .An illustrative case has
been presented in Chapter 12.
Other tumors in the cerebellar pontine angle:
Although less frequent, other types of patholo-
gy are found in this location: meningiomas
(Fig.2-1 0) arising from arachnoidal cell nests)
and cholesteatomas (epidermoids). A large
series from the Mayo Clinic (Laird et al1985)
Figure 13-1. Vestibular schwannoma ("acoustic neu- indicated 20 meningiomas over a six-year peri-
roma") at the cerebellar pontine angle. (Courtesy of od compared to 160 acoustic neuromas over a
Dr. Jose Segarra and Dr. Remedios Rosales, Boston similar period (Harner et al 1985). Specific
Veterans Administration Hospital) neurological deficits were as frequent as in
patients with acoustic neuromas. Diagnosis
may be made with contrast enhanced MRI or
if not available contrast enhanced CT Scan.
(2) Syndromes of the cerebellum:
a. Midline Cerebellum (Fourth Ventricle)
Syndrome). The midline cerebellar syndrome is
frequently encountered in neurology. Clinical
deficit: The patient often a child presents with
a disturbance of balance and ataxia of the trunk
and gait but no clearly lateralized symptoms.
In general, the etiology is neoplastic. The type
of tumor varies as a function of age. The most
common cause in an infant or child is a medul-
loblastoma (Fig. 13-3). This tumor arises from
nests of external granular cells in the nodulus,
an older portion of the cerebellum relating to
Figure 13-2. Cerebellar pontine angle tumor: vestibu-
lar schwan noma. MRl. A large mass exteniU from an the vestibular system. Since this portion of the
enlarged right internal auditory canal compressing cerebellum projects as a roof into the fourth
and distorting the pons and medulla. (Courtesy ventricle, early obstruction of the ventricle is to
Drs.Milton Weiner&' Alex Danylevich) be expected. A typical case is presented in
vestibular neuromas arising from the Schwann Chapter 19 ( cerebellum). Occasionally this
cells about cranial nerve VIII .As already noted tumor may present in adolescents and young
the tumor actually arises from Schwann cells adults. The cells may seed via the CSF, so that
within the vestibular component of cranial rarely the early symptoms may those of a lum-
nerve VIII within the internal auditory canal. bar radiculopathy.
This is a disease of the middle-aged or older In children and young adults, the most com-
adult. (Onset of symptoms in the teens or early mon cause is the ependymoma that arises from
20s-should suggest the possibility of neurofi- ependymal cells in the floor or roof of the
bromatosis 2 in which bilateral acoustic neuro- fourth ventricle (Fig. 13-4). The tumor mass
mas occur (see Martuza and Eldridge 1988 grows into the ventricle, obstructing this cavity
and chapter 9) The early symptoms and find- but also exerting upward pressure on the mid-
ings relate to a progressive involvement of line nodulus (and other aspects of the cerebel-
13-4 CHAPTER 13
toma and the ependymoma constitute the

most common central nervous system tumors
in the pediatric age group.
In the adolescent and young adult the low-
grade cystic astrocytoma, must also be consid-
ered, although, a lateral hemisphere location is
the much more common location.
In the middle-aged adult, the most com-
mon cause of the syndrome is a midline
hemangioblastoma. These are tumors derived
from embryonic vascular elements. In contrast
to the medulloblastoma and the ependymoma,
the hemangioblastoma and the cystic astrocy-
toma are surgically curable neoplasms. It is
often found that a nodule of tumor exists with-
in a nonneoplastic cystic cavity, allowing for
removal of the tumor without sacrifice of a
Figure 13-3. Medulloblastoma. MRI (['1). This large large amount of the cerebellum.
tumor arising from the midline cerebellum in this 4- When the patient is 50 years old, heman-
year-old child fills the 4th ventricle producing hydro-
gioblastomas and metastatic tumors constitute
cephalus and compressing the medulla. (Courtesy Dr.
Milton Weiner) the major midline entities. Metastatic carcino-
mas in general, however, are more often found
in a non-midline cerebellar hemisphere
location.
b.Lateral Cerebellar Hemisphere Syndrome.
Clinical Deficit: lateralized symptoms affecting
the ipsilateral arm and leg have already been
mentioned. The syndrome is discussed in
greater detail with an illustrative case history in
chapter 20 on the cerebellum. As regards the
specific mass lesions, this in large part depends
on the patient's age:
- In the child and young adult, the most
common lesion is probably the cystic astrocy-
toma.
Figure 13-4. Ependymoma of the 4th ventricle. MRI - In the middle-aged and older age groups,
(['1). This 14-year-old male had a 4-month history of the most common lesions are metastatic carci-
headache and neck pain, with gait ataxia and nystag- noma and the hemangioblastoma. The
mus. This large mass obstructs the 4th ventricle, pro- metastatic carcinoma may represent a solitary
ducing hydrocephalus, displaces the cerebellar vermis metastasis from a primary lesion in lung, breast,
and extends out the 4th ventricular foramen then ovary, or kidney or may be only one of multi-
down through the foramen magnum to compress the
ple lesions. The cerebellar lesion in any case is
spinal cord. (Courtesy ofDrs. Gerald McGuillicuddy,
Milton Weiner &Artinian). often surgically removed since it does represent
a relatively acute life-threatening lesion. The
lar vermis). At times however, the ependymo- hemangioblastoma has already been discussed.
ma may extensively invade the tegmentum of Other mass lesions of the cerebellar hemi-
the medulla and pons. At times the tumor is a sphere in the pre antibiotic era included brain
mixture of ependymoma and astrocytic com- abscess (the source of infection was usually the
ponents. Taken together, the medulloblas-
adjacent middle ear and mastoid) and tubercu- arising from congenital cell nests of a mixed
lomas. . Hypertensive cerebellar hemorrhages type and occurring at any age but most com-
may also present as acute mass lesions as may monly in males under 10 years. Histologically
acute edematous cerebellar infarcts. these tumors are identical to congenital tumors
(3) Extrinsic Midbrain syndromes: of the testes (seminoma) or dysgerminoma of
a. Syndrome of compression of the pretectal the ovary. (2) In addition to the malignant
area and superior colliculus (Fig.13-S, 13-6). germinoma, non-invasive congenital germ cell
These are essentially three causes of this syn- tumors may occur and may be resected: ter-
drome: a. tumors of the pineal (pinealomas) atomas, dermoids, and epidermoids. (3) Other
occurring primarily in men and boys b. hydro- types are astrocytomas and ependymomas,
cephalus in infants, c. hypertensive hemor- pineal parenchymal tumors (pineocytomas),
rhages of the posterior thalamus occurring meningiomas and arachnoid cysts.
most commonly in middle age or older For additional discussion see DeGirolami
patients. Tumors of the pineal are of several & Schmidek(1975), Stein (1979), and
types. (1) The most frequent (50%) are germ MaGieruiez et al1983.
cell tumors: germinoma, or atypical teratomas: An illustrative case history (11-2) has been
presented in the brain stem chapter on func-
tionallocalization.
b. Syndromes of the tentorium
The Tentorial Notch syndrome: Herniation
of the medial aspects of the temporal lobe
(uncus and parahippocampal gyrus) secondary
to supratentorial mass lesions is the most com-
mon syndrome found in relation to the tento-
rium More lateral supratentorial masses as in
temporal lobe tumors produce a lateral hernia-
Figure 13-5. Tumor of the pineal. This is an enlarged tion syndrome characterized initially by an ipsi-
nonmalignant cyst arising from the pineal gland lateral fixed dilated pupil and then an ipsilater-
(arruw). (Courtesy of Dr. John Hills, and Dr. Jose
al CN 3 paralysis. Additional compression will
Segarra).
shift the midbrain and compress the opposite
cerebral peduncle against the rigid tentorial
edge resulting in an ipsilateral hemiparesis in
addition to the already present contralateral
hemiparesis. As compression and displacement
of the brain stem progresses, hemorrhages
(Duret hemorrhages) into the substance of the
midbrain and pons develop. A progressive
sequence of midbrain, then pontine and even-
tually medullary symptoms evolve.
Supratentorial masses in a more parasagittal
location produce central herniation with bilat-
eral midbrain (CN III) and subsequently pon-
tine - medullary involvement. (Fig.13-7, 13-8,
13-9).
Tentorial meningiomas: These are rare. A
Figure 13-6. Tumor of the pineal region. MRl. This variety of syndromes may occur: (1) midline
68-year-old female presented with apraxia of, gait, obstructing mass with increased intracranial
urinary incontinence and dementia. Symptoms pressure but without definite localizing fea-
resolved following a shunt procedure and radiotherapy.
13-6 CHAPTER 13
Figure 13-9. Dura hemorrhage. Multiple small hem-

orrhages are present in the pontine tegmentum and to
a lesser extent in the basilar pons secondary to massive
infarction of cerebral hemisphere, temporal lobe her-
niation and brain stem compression. (Courtesy of Dr.
John Hills)
er through the jugular foramen An illustrative
case history is presented in Chapter 12.
Figure 13-7. Herniation of the parahippocampal (5) Foramen Magnum Syndromes.
gyrus secondary to a subdural hematoma. Note residu- a. Herniation syndrome (Fig. 13-1 0). This is
als of Dura hemorrhages in pons (Courtesy of
the most common process at the foramen
Pathology department St. Vincent Hospital).
magnum and is sometimes referred to as cere-
bellar pressure cone. Any mass lesion in the
posterior fossa may produce herniation of the
cerebellar tonsils compressing the lower end of
the medulla and the upper cervical spinal
cord. When gradually acquired, head tilt and
stiff neck and pain in the neck may be early
symptoms. When acutely acquired, a rapid and
fatal arrest of respiratory and circulatory func-
Figure 13-8. Tentorial herniation with brain stem tion is likely to occur. Such an acute event may
compression. A large intracerebral hematoma and be precipitated by the performance of a lumbar
hemorrhagic infarction (single arrow) in right cere-
bral hemisphere has produced herniation of the medial
aspect of temporal lobe (double arrow). Shift of the
brain stem has occurred with compression and infarc-
tion of the left cerebral peduncle against the tentorium
(triple arrow). (Courtesy of Pathology Department,
Tufts New England Medical Center.)
tures, (2) mass lesion extending above the ten-

torium to involve the temporal and occipital
lobes, (3) mass lesion extending below the ten-
torium, displacing or invaginating the cerebel-
lum and compressing the brain stem and cra- 13-10. Herniation of the cerebellar tonsils. The cere-
nial nerves. bellar tonsils have been compressed downward through
(4) Jugular foramen syndrome: the foramen magnum (arrow). secondary to a ter-
This is caused by neurofibromas or other atoma of the pineal, compressing the caudal medulla
tumors arising from the lower cranial nerves and upper ccrPual spine. (Courtesy of Dr. John Hills
and Dr. Jose Segarra)
(CN IX, X and XI) as these nerves pass togeth-
puncture in a patient with a posterior fossa formation and excessive bone destruction.
mass lesion. At times in subacute cases, this Bony overgrowth may result in pressure on
final stage of arrest of respiration and fall in nerve roots, on cranial nerve VIII and on the
blood pressure is preceded by a period ofirreg- facial nerve. Involvement of the vertebrae may
ular respiration, slow pulse, and rising blood result in spinal cord compression. Involvement
pressure. of the skull is common. When the disease
Once tentorial herniation has occurred in a process affects occipital and sphenoid bones at
supratentorial mass lesion, increased mass is the base of the skull, a softening, flattening,
present in the posterior fossa. In addition, and distortion occurs. As a result, the odon-
hemorrhage into the brain stem and edema of toid process projects up into the posterior
the brain stem act to increase the mass in the fossa. The posterior fossa in its normal state is
posterior fossa. Tonsillar herniation with a relatively small cavity. The end result is a
medullary compression would then in this sit- compression of the contents of the posterior
uation also be the expected terminal event. fossa -- medulla, cerebellum, and lower cranial
(For a more complete discussion of the clinical nerves -- in addition to the upper cervical
pathophysiology of the tentorial and tonsillar spinal cord.
herniation syndromes, the student is referred Case 13-1 presented on CD ROM illus-
to Plum and Posner, 1980). trates this problem in detail.
b. Meningiomas: These are rare in this loca- VASCULAR SYNDROMES
tion and produce a variable picture. Their AFFECTING THE BRAIN AS
growth may be primarily in the posterior fussa EXTRINSIC LESIONS:
with compression of the lower cranial nerves, (1) Aneurysms: At points of congenital
brain stem, and cerebellum. On the other
weakness in the wall of an artery (usually points
hand, the tumor may extend down through
of bifurcation) a dilated thin-walled sac may
the foramen magnum, compressing the upper
form, termed an aneurysm. Intracranial
and middle cervical roots and then the long
aneurysms produce symptoms in several ways:
tracts on one or both sides of the spinal cord.
(1) the dilated sac may act as a space-occupying
In some cases, a mixture of posterior fossa and
lesion compressing adjacent structures such as
cervical cord findings will be present.
cranial nerves, (2) rupture of the aneurysm
may occur with leakage of blood into the sub-
SYNDROMES DUE TO
arachnoid space, (3) the sudden hemorrhage
DEVEWPMENTAL AND BONY
into this space may also dissect into the brain
ABNORMALITIES
with the furmation of a hematoma and/or
These syndromes primarily occur at the rupture into the ventricular system may occur,
foramen magnum. (4) the circulation of blood in the artery
(1) The Arnold Chiari syndrome has been beyond the point of the aneurysm may be
discussed and illustrated in chapter 9. impaired, producing ischemia and destruction
(2) Deformation of the bones at the base of of tissue supplied by the artery, (5) additional-
the skull occurs in platybasia, a flattening of the ly blood in the subarachnoid space about arter-
sphenoid and occipital bones (sometimes ies may produce vasospasm,( 6) blood in this
referred to as basilar impression because the subarachnoid space and ventricles may also
bones about the foramen magnum are pushed block the circulation of CSF resulting in hydro-
into the posterior fossa). There are essentially cephalus.
two causes for this deformation: Paget's The majority (85 to 90 per cent) of
disease, and various developmental aneurysms arises from what is termed the ante-
malformations. rior circulation at essentially three locations: (1)
Paget's disease is a chronic metabolic dis- the anterior cerebral-anterior communicating
ease of bone occurring in the adult, in which junction, (2) the middle cerebral artery bifur-
there is both excessive and disorganized bone
13-8 CHAPTER 13
cation, and (3) the junction of the posterior years and the bulbar variety of amyotrophic lat-
communicating and internal carotid arteries. eral sclerosis (occurring predominantly in the
As already discussed in the cranial nerve chap- age group over 40 years).
ter, Case 12-1 at this last location, an enlarging
saccular aneurysm may compress cranial nerve ISCHEMIC-OCCLUSIVE DISEASE
III. The finding of a fixed, dilated pupil and OF THE BASILAR VERTEBRAL
ptosis of the lid in a patient with subarachnoid ARTERIES
hemorrhage may provide a valuable clue for Stenosis (narrowing) or occlusion of the
localization of the aneurysm at the junction of vertebral and basilar arteries may occur at a
the posterior communicating -internal carotid number of sites. In general, maximum areas of
junction. Approximately 10 to 15 per cent of atherosclerosis disease occur at the points of
saccular aneurysms are found in relation to the origin, bifurcation, or angulation of the
basilar vertebral system. Common sites include extracranial and intracranial portions of the
the bifurcation of the basilar artery. In addition large and medium size cerebral arteries. There
to saccular aneurysms, fusiform dilatation of is no one-to-one relationship of a particular site
the basilar artery may occur in atherosclerosis of stenosis or occlusion to a specific pattern of
resulting in an enlarged tortuous vessel that clinical symptoms. Thus, occlusion of a verte-
may compress adjacent structures. bral artery may occur with no resultant clinical
(2) Hypertensive cerebellar hemorrhage symptoms in evidence. In other instances,
(chapter20). The hematoma may secondarily such an occlusion may result in transient symp-
compress the fourth ventricle and brain stem. toms indicating ischemia that is a temporary
The early symptoms of acute onset of decrease in blood flow (perfusion) below a crit-
headache, dizziness, vomiting, and ataxia are icallevel, within the distribution of a particular
often followed by coma and evolving extraoc- vessel or combination of vessels arising from
ular muscle findings. Similar symptoms and the vertebral or basilar arteries. In still other
findings may also occur in acute large cerebel- instances, such an occlusion may result in actu-
lar infarcts due to the effects of edema. al tissue destruction, infarction (encephaloma-
INTRINSIC DISEASES lacia) within the distribution of one or more
OF THE BRAIN STEM vessels taking origin from the vertebral or basi-
lar arteries; e.g., the posterior inferior cerebel-
The disease entity affecting the brain stem
lar artery arising from the vertebral artery or
that is most frequently encountered in clinical
the posterior cerebral artery from the basilar
practice is vascular disease, predominantly of
artery.
the ischemic-occlusive type. Ischemic-occlu-
In still other instances, one may find that
sive cerebrovascular disease usually produces its
infarction within the distribution of a particular
initial clinical manifestations in patients over
vessel has occurred without actual occlusion of
the age of 50. The basic pathological process
that particular vessel or even of the parent ves-
of atherosclerosis which underlies occlusive
sel. Instead, stenosis with a decrease in blood
vascular disease (the deposition of lipids such as
flow has occurred.
cholesterol in the walls of vessels) certainly may
Factors accounting for this lack of corre-
begin in an asymptomatic manner earlier in life.
spondence between the state of a particular
On the other hand, multiple sclerosis, which is
vessel and the vascular status of the region sup-
the second most frequent brain stem disease
entity encOlUltered, usually produces its initial
plied by that vessel include the following:
1. There are significant congenital varia-
manifestations in the age group 20 to 40. Of
tions with regard to the normal patency of the
the other intrinsic diseases affecting the brain
two vertebral arteries. One vertebral may be
stem, the next most frequently encountered
hypoplastic. (Fig. 2-27).
are brain stem gliomas (occurring predomi-
2. There are significant congenital varia-
nantly in the pediatric age group under 20
tions in the circle of Willis often representing
persistence of an earlier fetal pattern. field.
3. There are significant leptomeningeal As regards large vessel disease, in terms of
anastomoses over the surface of the cerebellum the location of sites of >50% stenosis due to
between the posterior inferior, anterior inferior atherosclerosis, among 260 patients, 44%
and superior cerebellar arteries. involved the extra cranial portion of the verte-
4. To a variable degree anastomoses bral artery, 42% the intracranial portion of the
between extracranial and intracranial arteries vertebral artery, 42% the basilar artery and 15%
may occur. the posterior cerebral artery. Clearly some
5. Variations may also reflect the fact that patients had stenosis or occlusion at multiple
often atherosclerosis affects more than one sites.
major artery. Specific vascular syndromes
6. Considerable variability may also occur
Basic anatomy: We will now consider syn-
because of certain general systemic and meta-
dromes involving the territories of particular
bolic factors.
arteries. In addition to the large vessels, the
7. Certain mechanical factors may intro-
vertebrals and basilar, we will deal with the
duce a degree of variability. Thus, a patient
major branches of these vessels. There is a gen-
may have stenosis of a vertebral artery without
eral plan of brain stem vascular architecture.
clinical symptoms when the head is in a neutral
The basilar artery and the two vertebral arter-
position. Hyperextension or rotation may pro-
ies are placed on the basal (ventral) surface of
duce symptoms. Postural effects may also
the brain stem. One can visualize a midline or
occur related to a relative decrease in blood
paramedian wedge-shaped area extending into
pressure in the upright position compared to
the brain stem with a base on this ventral area.
the recumbent position.
Penetrating vessels, termed paramedian, supply
Not all-occlusive disease is due to athero-
this paramedian wedge. The lateral tegmental
sclerosis. Emboli account for a significant pro-
portions of the brain stem are supplied by
portion of disease involving the posterior cir-
branches, long circumferential arteries, named
culation. Among the 407 well studied patients
for their areas of supply over the surface of the
in a posterior circulation registry, ( Caplan
cerebellum: posterior inferior, anterior inferior,
2000) at least 40% had embolism as the single
and superior cerebellar arteries. In addition, at
most likely diagnosis, as opposed to 32% with
the upper midbrain level, quadrigeminal arter-
large vessel disease (atherosclerosis-thrombo-
ies arise from the posterior cerebral arteries
sis) and 14% with penetrating artery disease.
which function as long circumferential arteries
The most common sources of embolism were
with regard to this area of the brain stem.
cardiac (60%) and intra-arterial (35%), usually
Variable transverse arteries, termed short cir-
the vertebral arteries. Cardiogenic emboli were
cumferential, supply ventral lateral portions of
most likely to produce distal infarcts within the
the pons and midbrain arising from the long
territory of the posterior cerebral and posterior
circumferential arteries of the basilar artery.
inferior cerebellar arteries. Emboli originating
Short circumflex branches also arise from the
from the external vertebral artery were more
vertebral arteries to supply ventral lateral
likely to produce proximal infarcts within the
medulla. At each level of the brain stem, we
territory of the intracranial vertebral artery and
will be dealing primarily with paramedian as
the origin of the basilar artery plus or minus
opposed to lateral tegmental syndromes. T~e
additional more distal infarcts. Overall of the
paramedian branches always supply the corU-
156 patients with embolic infarcts, 53% had
cospinal tracts and the paramedian exiting
distal infarcts only, (distal basilar artery-posteri-
motor cranial nerves: III, VI and XII. In the
or cerebral and superior cerebellar), 17% had
case of cranial nerve III, the paramedian vessel
proximal infarcts only and 6% had middle terri-
arises from the posterior cerebral artery.
tory infarcts (basilar artery and branches). The
Vertebral Arteries (Refer to Fig 2-27, 2-
remainder were mixed including the distal
13-10 CHAPTER 13
28) The vertebral arteries usually arise from the Medullary Syndromes
subclavian artery (the left vertebral artery may Lateral (dorsolateral) medullary syndrome
arise directly from the aorta in 6 per cent of (Syndrome of the posterior inftrior cerebellar
cases). The artery ascends to enter the fora- artery or Wallenbet;g's syndrome) (Fig 13-11).
men of the transverse process of the sixth cer- Of all the various classic vascular syndromes of
vical vertebra, and then passes upward through the brain stem, this syndrome, either alone in a
the foramina of the successive cervical verte- relatively pure form or in a modified form, is
brae; then, after passing behind the superior the one most frequently encountered. (It is
articular process of the atlas, it enters the fora- important to emphasize that nonclassic vascu-
men magnum. After passing upward and lar syndromes of the brain stem are more com-
medially, the artery unites with its opposite monly encountered than the classic syndromes
number at the lower border of the pons to involving isolated vascular territories).
form the basilar artery. During its course in the
neck, the vertebral artery gives rise to radicular
branches (which anastomose with the anterior
and posterior spinal arteries) and to muscular
branches whose anastomoses have already been
considered. The intracranial branches are the
posterior inferior cerebellar, the anterior spinal,
the posterior spinal, and the paramedian
arteries.
Syndromes associated with occlusive dis-
ease of the vertebral artery are variable:
1. Occlusion or absence of one vertebral
artery, particularly at a proximal point in an
otherwise intact individual, is usually well tol-
erated (as we have indicated, it is not unusual Figure 13-11 Dorsal-lateral medullary infarct
to find one vertebral artery hypoplastic). (arrows) due to occlusion of the posterior inferior cere-
2. Stenosis. a. Stenosis or Occlusion of the bellar artery (arrow) in a 72 year old diabetic with
proximal portions of both vertebral arteries in the correlated clinical syndrome of acute onset nystag-
the series of patients reported by Fisher (1970) mus on left lateral gaze, decreased pain sensation on
was associated with transient symptoms: faint- the left side offace and right side of body, with diffi-
ness, blurred vision, dizziness, loss of balance, CUlty swallowing, slurring ofspeech, and deviation of
the uvula to the right. (Courtesy ofDr. Jose Segarra.
diplopia, numbness of an arm or of the face.
The symptoms are essentially those of transient The brain stem territory of the posterior
insufficiency of circulation in the more distal inferior cerebellar artery (PICA) includes the
distribution of vertebral and basilar arteries. following structures ( a) the restiform body
b. Stenosis or occlusion of the intracranial (the inferior cerebellar peduncle) and the adja-
segment of the vertebral artery or arteries may cent dorsal and ventral spinocerebellar path-
result in infarction over a variable area: the dis- way, (b) the descending spinal tract and nucle-
tribution of the basilar artery, and/or the dis- us of the trigeminal nerve, the lateral spinothal-
tribution of the paramedian branches of the amic tract, (d) the descending sympathetic
vertebral and/or the distribution of the poste- pathway, (e) the nucleus ambiguus and the
rior inferior cerebellar artery. Actually, occlu- fibers of cranial nerve X, and (f) the vestibular
sive disease of the intracranial segment of the nuclei (primarily spinal and medial at this level).
vertebral artery is a much more frequent cause The clinical findings of a lateral medullary
of the lateral medullary syndrome than is limit- infarction are illustrated in the following case
ed occlusion of the posterior inferior cerebellar 13-2. It is important to note that occlusion of
artery. the posterior inferior cerebellar artery may pro-
duce infarction of the lateral medullary territo- sugar: random elevated to 225 mg; fasting ele-
ry or of the PICA cerebellar territory or of vated to 196 mg'lAJ. Total cholesterol: elevated
both areas. Prior to CT scan and MRI, the to 340mg'lAJ compared to normal of <200mg%,
cerebellar infarct in a patient who also had a lat- with low density lipoproteins (LDL) elevated
eral medullary syndrome would have been to 261 mg%, and high density lipoproteins
overlooked, since infarction of the cerebellar (HDL) 42mg%.
peduncle, as part of a lateral medullary syn- MRI (Fig. 13-12): A significant acute or
drome would produce effects similar to the subacute infarct involved posterior inferior
cerebellar infarct. cerebellar artery territory of the left cerebellum
Case 13-2: This 53 year old male customer and dorsolateral medulla. The MRA suggested
service representative on the morning of decreased flow in the left vertebral artery.
admission (01-07-2001) while seated had the Subsequent Course: A percutaneous
sudden onset of vertigo accompanied by nau- endoscopic gastrostomy (PEG) tube was
sea and vomiting, incoordination of his left arm placed since he was unable to swallow for the
and leg and numbness of the left side of his first six days. By the time of transfer to a reha-
face. On standing, he leaned and staggered to bilitation facility, 12 days after admission, finger
the left. Several hours later, he noted increasing to nose tests and gait had improved, he could
difficulty in swallowing and his family walk with a walker. Speech and sensory exami-
described a minor dysarthria. He had a 2 pack nation had returned to normal. Additional dis-
per day cigarette smoking history for > 10 cussion and analysis of this case will be found
years. on the CD ROM.
Physical Examination: Elevated blood An additional example of a lateral
pressure of 166/90. medullary infarct (Case 13-3) will be found on
Neurologic Examination: Cranial nerves:
The right pupil was 3mm in diameter; the left
was 2mm in diameter. Both were reactive to
light. There was partial ptosis of the left eyelid.
A horizontal nystagmus was present on left lat-
eral gaze, but extraocular movements were full.
Pain and temperature sensation was decreased
over the left side of the face but touch was
intact. Speech was mildly dysarthric for lingual
and pharyngeal consonants. Secretions pooled
in the pharynx. Although the palate and uvula
elevated well, the gag reflex was absent. Motor
system: a dysmetria was present on left finger to
nose test and heel to shin tests. He tended to
drift to the left on sitting and was unsteady on
attempting to stand, falling to the left. Reflexes:
ankle jerks which were absent. Plantar respons-
es were flexor. Sensory system: Pain and temper-
ature sensation were decreased on the right
over the right arm and leg but all other modal-
ities were normal.
Clinical diagnosis: I.Dorsolateral Figure 13-12: Tomlleft posterior inferior cerebellar
artery syndrome. MRl12. Both the lateral medullary
medullary infarct. 2. Decreased ankle jerks due
territory and the posterior inferior cerebellum are
to possible diabetic peripheral neuropathy infarcted. The MRA indicated decreased flow in the
Laboratory Data: Serum Studies: Blood vertebral artery. (Refer to Fig. 2-27C)
13-12 CHAPTER 13
the CD ROM.
Paramedian Medullary Syndrome.
Occlusion of the paramedian penetrating
branches from the vertebral artery may result
in a syndrome characterized by ipsilateral paral-
ysis and atrophy of one-half of the tongue
(hypoglossal fibers or nucleus) in addition to a
contralateral hemiparesis (medullary pyramid).
There may be involvement of the adjacent
medial lemniscus as well, producing a con-
tralateral deficit in position and vibratory sen-
sation and a relative decrease in tactile sensa- Figure 13-14. Vembral Amry Syndrome, MR1
tion. This syndrome, which bears the name of demonstrates extensive infarction in the paramedian
Hughlings Jackson, is rarely encountered in its vertebral amry terrirory with lesser involvement of
pure form. the cerebellum. Severe stenosis was present in vembral
Combined syndrome: lateral medullary plus amry.
paramedian ± cerebellum (Fig. 13-13): An
lar artery which supplies the dorsolateral
example of a patient with infarction of the para-
tegmentum of the lower one half of the pons
median vertebral territory in addition to
(Fig. 13-15A): including the eight nerve and
involvement of the cerebellum and pons is pre-
the cochlear nuclei, the vestibular nuclei, the
sented in the MRI of Figure 13-14.
facial nerve the descending spinal tract and
nucleus of the fifth nerve, the lateral spinothal-
amic tract, the sympathetic pathway, the mid-
dle and inferior cerebellar peduncles, and the
anterior inferior portion of the cerebellum.
The area of supply may also include the main
sensory nucleus of the fifth nerve at a midpon-
tine level. The internal auditory artery that
supplies the inner ear may arise from this vessel
or independently from the basilar artery.
Whether, there is some supply as well to the
Figure 13-13. Left vertebral and posterior inferior nucleus ambiguous is uncertain-this area may
cerebellar amry occlusions: lateral plus paramedian constitute a border zone.
medullary. This 65-year-old hypemnsive male expired The next long circumferential branch is the
5 years after an acute event characterized by difficulty superior cerebellar artery which supplies the
swallowing, ((di2:ziness," ataxia, numbness of the left tegmentum of the upper pons and caudal mid-
side of the face and the right side of the body plus a left- brain (Fig. 13-15B), including the brachium
sided Horner's syndrome, a decrease in pain sensation
conjunctivum, the medial longitudinal fascicu-
on the left side of the face, deviation of the rongue ro the
left but increased deep tendon reflexes on the right side. Ius, the motor and main sensory nucleus of the
trigeminal nerve, the medial lemniscus, the lat-
eral spinothalamic tract, and the central
The Basilar Artery tegmental tract, and then proceeds to supply
Anatomy (Refer to Fig. 2-27B, 2-28): the the superior cerebellum.
union of the two vertebral arteries forms the Posterior Cerebral Artery. The basilar artery
basilar artery. As with the vertebral artery, it is then terminates at the pontine-midbrain bor-
customary to distinguish paramedian and cir- der into two posterior cerebral arteries l . From
cumferential branches. The initial long circum- the top of the basilar and from each posterior
ferential branch is the anterior inferior cerebel- cerebral artery in its proximal segment a series
al 1981). Short circumferential vessels from
the posterior cerebral artery supply the remain-
der (lateral one-half) of the cerebral peduncle
and red nucleus. Somewhat longer circumfer-
ential branches also called quadrigeminal arter-
ies supply the lateral tegmentum and tectum of
the midbrain.
The main posterior cerebral artery then
passes around the cerebral peduncle and mid-
brain close to the tentorial opening, supplying
branches to the medial aspect of the temporal
R
lobe and then dividing into the parieto-occipi-
tal and calcarine branches to supply the occipi-
tal lobe.
The syndromes of the posterior cerebral
arteries relevant to the thalamus , subthalamus,
and the temporal and occipital lobes are dis-
cussed in the chapters on the cerebral hemi-
spheres and motor system2 .
SYNDROMES OF THE BASILAR
ARTERY AND ITS BRANCHES
As atherosclerosis involves the basilar and
vertebral arteries, there may be transient symp-
Figure 13-15 Syndromes of the basilar artery circum-
ferential branches. A: Inferior pons. The cross hatched toms suggesting ischemia in the distribution of
portion of lateral pons is the territory of the anterior the various vessels originating from these major
inferior cerebellar artery. B: Superior pons: The cross- arteries. In some cases, infarction may occur
hatched portion of lateral pons is the territory of the within the distribution of these branches.
superior cerebellar artery. At times, there is overlap Thus, the patient may experience episodes of
with the paramedian tegmental territory. vertigo or dizziness and diplopia, a bilateral
blurring of vision, or a weakness or numbness
of vessels arise to supply the midbrain: pene-
of one side of the body or face, and then in a
trating paramedian branches from this vessel
later attack, of the contralateral side of the face
supply the medial one-half of the cerebral
or body. In some cases, the transient symp-
peduncle, the third nerve fibers, the third nerve
toms are precipitated by extension or rotation
nucleus, and the medial one-half of the red
of the head that reduces blood flow in the ver-
nucleus. Other penetrating branches (thalam-
tebral arteries. Sudden drop attacks without
operforating and thalamogeniculate) of the
loss of consciousness are not unusual, due to
posterior cerebral artery and top of the basilar
ischemia of paramedian branches supplying the
artery in this location supply the subthalamus,
motor pathways: corticospinal tracts and the
hypothalamus and much of the thalamus: pul-
pontine-medullary reticular formation.
vinar, ventral lateral, ventral posterior, medial
Episodes of bilateral blindness may occur due
geniculate, lateral geniculate , centromedian,
to ischemia of the territory supplied by the pos-
and the dorsal median nuclei (see Castalgne et
terior cerebral arteries.
1 Some authors refer to the short segment ofposte-

2 The student should realize that this is an artif
rior cerebral artery between the top ofthe basilar
artery and the posterior communicating artery ical separation: thus 75% of patients with para-
as the basilar communicating artery (see median midbrain infarcts also have paramedi-
Caplan 1986). an thalamic infarcts. (See Jelliger 1986).
13-14 CHAPTER 13
With total occlusion of the basilar artery, paramedian vessels of the basilar artery supply-
various combinations of cranial nerve findings, ing the lower half of the pons, if unilateral
coma, decerebrate rigidity, and quadriplegia results in the combination of an ipsilaterallat-
will be found. Before we examine the situation eral rectus weakness and a contralateral hemi-
of total basilar artery occlusion, we will consid- plegia due to involvement of the emergent
er the various syndromes of the branch territo- fibers of nerve VI and the corticospinal tract in
ries. In general, the partial segmental syn- the basilar portion of the pons. If the area of
dromes of the circumferential branches are infarction extends into the tegmentum, there
rare. In contrast the branch syndromes of the would be evidence of involvement of the
paramedian arteries are relatively common par- nucleus of nerve VI (with an ipsilateral paraly-
ticularity in diabetic and hypertensive patients sis of lateral gaze) and of the genu of nerve VII
(see Caplan 1986, Fisher and Caplan 1971). about the nucleus of nerve VI (with an ipsilat-
The student, moreover, will recognize that the eral peripheral palsy of cranial nerve VII), (syn-
histories presented do not really provide pure drome ofFoville). The medial longitudinal fas-
examples. There will be some signs or symp- ciculus would often be involved, with a unilat-
toms in each case suggesting involvement at eral (or bilateral) internuclear ophthalmople-
several segmental levels of the brain stem. As gia. Involvement of the medial lemniscus
with the vertebral artery we will distinguish would produce a contralateral hemianesthesia
between paramedian (penetrating branch) and with deficits in position and vibratory sensa-
lateral tegmental (circumferential branch) syn- tion. Damage to the central tegmental tract in
dromes. the pontine tegmentum may result in rhythmi-
Inferior Pontine Syndromes: cal contractions of the palate (palatal
myoclonus). Bilateral infarcts of the pons are
Lateral Tegmentum (Syndrome of the
more frequent. A bilateral paramedian mid-
Anterior Inferior Cerebellar Artery).
pontine infarct producing a locked -in syn-
Infarction of the lateral tegmentum at a caudal
drome is demonstrated in Figure 13-16.
pontine level results in a sudden unilateral deaf-
ness in association with an ipsilateral peripheral
facial weakness, ipsilateral Horner's syndrome,
vertigo (due to involvement of the vestibular
nucleus), and ipsilateral cerebellar symptoms.
There may be involvement of the descending
spinal tract and nucleus of the trigeminal nerve
resulting in an ipsilateral loss of pain and tem-
perature over the face, or the main sensory
nucleus may be involved resulting in involve- Figure 13-16. Middle-lower pontine basilar infara
ment of facial tactile sensation as well. If the with locked in syndrome. Two weeks before death, this
lateral spinothalamic tract is involved, a con- 74-year-old female was found motionless and speechless
tralateral loss of pain and temperature will be in bed. She could, however, open and close her eyes on
command. (Courtesy ofDr. John Hills).
evident over the arm, leg, and trunk.
In Case 13-4 presented on the CD ROM Superior Pontine Syndromes:
the major area of infarction was the territory of Lateral tegmental superior pontine
the anterior inferior cerebellar artery involving Syndrome: Territory of the Superior Cerebellar
both the brain stem and the cerebellum. Artery (Fig. 13-15B). Ischemia or infarction of
However the initial area of ischemia suggested the tegmentum of the rostral pons involves the
a much wider area of the territory of the basi- medial lemniscus and the lateral spinothalamic
lar artery pathways, producing a contralateral hemianes-
Paramedian Lower Pontine Syndromes: thesia and hemianalgesia. Since the secondary
Infarction within the territory supplied by the trigeminothalamic (quintothalamic) fibers have
already crossed the midline below this level and
have essentially merged with the mediallem-
niscus, the sensory deficit involves the con-
tralateral side of the face as well as the con-
tralateral arm, leg, and trunk. There is, in addi-
tion, damage to the superior cerebellar pedun-
cle (the brachium conjunctivum). The cere-
bellar symptoms are ipsilateral to the lesion
when the damage to the brachium conjunc-
tivum occurs below the level of decussation.
However, since the superior cerebellar artery
also supplies the lateral tegmentum of the mid- Figure 13-17. Paramedian syndrome of the upper pons
brain at a caudal level, the brachium conjunc- Case 13-8. This 64-year old patient had transient
tivum may be involved above its decussation. ischemic attacks chara-mrized by left or right-sided
If so, the cerebellar symptoms will be con- hemiplegia and then a thrombosis of the basilar artery.
tralateral to the lesion. Moreover, the distur- (Courtesy of Dr. John Hills and Dr. Jose Segarra.
bance of movement is likely to be more vari-
2 months previously but had resolved over
able. Thus, a coarse tremor at rest or instabili-
2weeks. There was a past history of non-insulin
ty of sustained posture may be seen in addition
dependent diabetes mellitus for which the
to the expected intention tremor. As at lower
patient had been receiving an oral hypo-
levels of the pons, the central tegmental tract
glycemic agent. He had been taking 3 aspirin
may also be involved. The lesion (and the ter-
tablets per day (325mgx3).
ritory of the superior cerebellar artery) may
Neurological Examination: Cranial
extend into the paramedian tegmentum. If so,
nerves: flattening of the right nasolabial fold
damage to the medial longitudinal fasciculus
and slurring of speech. Motor system: pronator
may occur.
drift in the outstretched right arm with 4+/5
Paramedian upper pons: When unilateral weakness in the right iliopsoas. Reflexes: deep
infarction of the corticospinal and corticobul-
tendon stretch reflexes were increased in the
bar tracts of the basilar pons occurs, the clinical
right arm. A Babinski sign was present on the
effect is a contralateral, upper motor neuron
right. Sensory system: intact.
paralysis of the face, arm, and leg (Fig. 13-
Clinical diagnosis: Lacunar infarct: pure
18A). This produces a relatively pure motor
motor syndrome probable location left internal
syndrome as demonstrated in the following
capsule with paramedian pons less likely.
case. Note that the more common location for
Laboratory Data: The MRI demonstrated
a lacunar infarct producing a pure motor syn-
a well-defined left sided paramedian upper
drome is the internal capsule. It is, moreover,
pontine infarct (Fig.13-18B). The MRA study
important to realize, as demonstrated in
was within normal limits.
Figures 13-16 and 13-17 that disease of the
Hospital Course: The following morning
basilar artery often produces a bilateral para-
the right arm was now plegic, and the patient
median syndrome with a bilateral infarction of
needed assistance with walking. By the 4th
the basilar pons. Basilar artery thrombosis thus
hospital day, dysarthria, and strength in right
occludes the paramedian branches in a bilater-
leg were improving. He was discharged to a
al manner.
rehabilitation facility on the 5th hospital day.
Casel3-5: This 70 year old right handed
white male retired salesman, on the day prior Midbrain Syndromes
to admission while working in his garden, had Paramedian syndromes (mberJs Syndrome)
the acute onset of weakness of the right arm (Fig. 13-19) 13-20). A unilateral infarction in
and leg a right central facial weakness and slur- the territory supplied by paramedian-penetrat-
ring of speech. A similar episode had occurred ing branches from the proximal posterior cere-
13-16 CHAPTER 13
Figure 13-19. Weber's syndrome. An area of infarc-

tion is noted in the right cerebral peduncle (arrow), so
located as to involve the fibers of the right third cra-
nial nerve. This 61-year-old patient with rheumatic
heart disease, endocarditis, and auricular fibrillation
had the sudden onset ofparalysis of the left face, arm,
Figure 13-18A Paramedian infarct upper pons and leg, plus a partial right third nerve palsy
demonstrated on cr scan. (Courtesy of Dr. John Hills, and Dr. Jose Segarra).
Figure 13-18B. Paramedian infarct Case 13-5. MRI

1'2 with contrast.
bral artery (or basilar communicating artery)
involves the cerebral pedw1Cle, the ipsilateral Figure 13-20: Posterior cerebral artery ischemia and
third nerve fibers, and, to a variable degree, the infarction right paramedian midbrain and medial
substantia nigra. The resultant clinical syn- temporal. cr scan. This 86 year old male had a tran-
drome is that associated with the name of sient episode of bilateral blindness, then transient
Weber: contralateral upper motor neuron bilateral weakness and dysarthria followed by a left
facial weakness, left hemiplegia, bilateral medial rec-
paralysis of the face, arm, and leg, in association
tus weakness and a non responsive right pupil.
with an ipsilateral paralysis of third nerve func- (Courtesy ofDr. Joel Kaufman).
tion. The clinical effects of the damage to the
the upper basilar artery. In other cases both the
substantia nigra may not be apparent. (Refer to
penetrating (paramedian) branches and the
Chapter19). At times, the symptoms related to
cortical branches of the posterior cerebral
the cerebral peduncles may be bilateral since
artery may be involved resulting in a Weber's
the basic process of ischemia may have involved
syndrome plus a homonymous hemianopsia
(due to involvement of the calcarine artery the cerebral peduncle produces a contralateral
branch supplying the occipital /visual cortex. hemiparesis.
In addition confusion may be present due to Paramedian periventricular mesencephalic-
involvement of the cortical branches supplying diencephalic junction: This involves the peri-
the mesial temporal structures. As noted aqueductal, pretectal, posterior-medial thalam-
above, thalamic infarcts may also be found in ic, and subthalamic areas. Bilateral infarction of
patients with paramedian midbrain infarcts this territory supplied by the penetrating
because the same process may occlude the pen- branches of the proximal posterior cerebral
etrating branches to both areas. arteries results in a drowsy, relatively immobile
The following case 12-6 presents an exam- state (apathetic akinetic mutism) from which
ple of the more limited midbrain syndrome. the patient can be roused with strong stimula-
Case 12-6: This 66 year-old white male tion. The lesion interrupts the ascending retic-
awoke two days prior to admission with weak- ular system within the upper mesencephalon
ness of both his legs. He attempted to stand and its intralaminar diencephalic extension.
but fell to the floor. Third cranial nerve findings are often present
Neurological Examination: Cranial as associated findings, due to involvement of
nerves: The right pupil was slightly larger than the third nerve nuclei. This syndrome has
left; both were reactive to light. Ptosis of the been considered in greater detail by Segarra
right lid was present. Motor System: Weakness (1970), Plum and Posner (1980) and
of the left upper extremity and minor weakness Castaigne et al1981 (Refer to Chapter 29 for
of both lower extremities was present, more additional discussion).
marked on the left. The patient was unable to Combined Syndrome: Thrombosis Of The
walk without support. When supported the Basilar Artery.
patient walked with a left hemiplegic gait. Case 13-8, on the CD ROM illustrates a
Reflexes: A left Babinski sign was present. case of thrombosis of the basilar artery in
Sensory System: Intact. which several midbrain and pontine syndromes
Clinical diagnosis:Possible paramedian previously discussed were combined.
midbrain infarct: Weber's syndrome Treatment: Prevention is of major impor-
Laboratory Data: A lumbar puncture tance. Control of hypertension and of eleva-
demonstrated normal cerebrospinal fluid. tions of the low density lipid component of
Hospital Course: Two days following cholesterol (LDL) and of the triglycerides
admission, the patient demonstrated neurolog- should be beneficial. If dietary alterations are
ical progression with more complete third insufficient then the use oflipid lowering drugs
nerve palsy. During the subsequent one month (the statins) should be considered. Increase in
improvement occurred, with the only residual the high density lipoprotein (HDL) produced
a minimal weakness of the left leg and a left by common sense exercise may also be benefi-
Babinski sign. cial. In patients with cardiac disease, (valvular
Case 13-7 presented on the CD ROM pro- disease, mural thrombi, and particularly atrial
vides an example of a patient with more exten- fibrillation), long term anticoagulation may
sive infarction of the territory of the posterior prevent cerebral emboli. In addition, for car-
cerebral artery. diac arrhythmias, other measures will be con-
Paramedian syndrome with associated sidered by the cardiologist. The use of aspirin
tegmental involvement (Benedikt's Syndrome): or related compounds to alter platelet aggrega-
Involvement of the adjacent midbrain tegmen- tion may be of value in preventing additional
tum (red nucleus, dentatorubral thalamic ischemic events. In patients with symptomatic
fibers) will produce a contralateral tremor and disease of the subclavian or proximal vertebral
movement disorder in association with an ipsi- artery surgical procedures to bypass sites of
lateral third nerve lesion. The involvement of occlusion may be considered. The treatment of
13-18 CHAPTER 13
a basilar artery thrombosis presents a major

problem. Previously intravenous heparin, an
anticoagulant was utilized in patients with
evolving basilar artery thrombosis, but the
results were often disappointing. Because of
the poor prognosis of these patients, intra-arte-
rial thrombolysis with urokinase has been uti-
lized. In a series from the Mayo Clinic
(Wijdicks et. al 1997) recanalization of the
thrombosed basilar artery was achieved in 7/9
patients treated within 2-13 hours with 5 of
the 7 recanalized patients recovering fully, Figure 13-21. Pontine hemorrhage. This 58-year-old
hypertensive patient had had a presumed brain-stem
including 2 patients who had a locked in syn-
infarct 4 weeks previously then this massive pontine
drome. Failure to recanalize resulted in coma hemorrhage possible related to anticoagulant therapy.
and death. A complication is the occurrence of (Courtesy of Dr. John Hills)
hemorrhage in a small number of patients. An
additional study of 22 patients (Cross et. al sive hemorrhages is intracerebral (putamen
-1997) confirmed the beneficial effects of predominantly, thalamus and cerebral white
recanalization achieved by this method, in matter somewhat less commonly). In a small
terms of survival and improvement in neuro- percentage of cases, the pons is the primary
logic status. Patients with distal clots did signif- location of the hemorrhage. A large hemor-
icantly better than those with proximal or mid rhage in the relatively small space of the pons
basilar clots. produces rapid effects: coma and bilateral
The major vascular syndromes of the brain involvement of the long tracts within seconds
stem are reviewed in Table 13-2, which will be or minutes, death within minutes or hours.
found on the CD ROM. Rupture into the ventricular system is com-
mon. Although the illustrations present the
HEMORRHAGE
typical course of such large hemorrhages, small
Intrapontine Hemorrhage (Fig. 13-21; 13- pontine hemorrhages have been recognized in
22). The most common location of hyperten- the era of CT and MRI Scan.
Figure 13-22. Pontine hemorrhage. This 67 year old obese and hypertensive female collapsed with sudden onset of
deep coma, no purposive responses to painful stimuli. The right pupil was fixed and dilated, the left pinpoint
(lmm) and minimally responsive to light. No oculocephalic or corneal responses were present. Bilateral Babinski
signs were present. Respirations, which initially were spontaneous and rapid (central neurogenic hyperventila-
tion), subsequently became irregular and shallow. She expired within 24 hours.
Arteriovenous malformations of the brain acterized by the progressive development of
stem may produce repeated small hemorrhages bilateral long tract and bilateral cranial nerve
and infarct with a course characterized by a findings. The cranial nerve findings suggest
variable progressive series of stroke like involvement over adjacent segments of the
episodes. At times such cases have been mis- brain stem, rather than a single segmental level.
taken for multiple sclerosis (Aba and Juellber, This tumor occurs primarily in children, ado-
1989, Stahl et alI980). lescents, and young adults. At the present time
Primary Intracerebellar Hemorrhages. See the diagnosis is easily confirmed by MRI scan
above and chapter 20. which has replaced the earlier techniques ofCT
SUBARACHNOID HEMORRHAGE scan, pneumoencephalograms, ventriculo-
(see above and chapter 26) grams and posterior fossa-myelograms.
Case 13-9: This 20 year old single female
INTRINSIC TUMORS had the onset of occasional horizontal diplopia
The substance of the brain stem is a rela- and headache. Five months later clumsiness
tively uncommon site for metastatic tumors and weakness of the left arm and leg developed
(however see example in Chapter 11). Almost accompanied by increased intracranial pressure.
all tumors found within the substance of the MRI demonstrated a mass within the pons
brain stem are intrinsic, arising from glial ele- with compression of the 4th ventricle and cere-
ments, generally the astrocyte. Various histo- bellum (Fig. 13-24). Treatment with dexam-
logical grades of malignancy may be encoun- ethasone, (a powerful corticosteroid) ventricu-
tered. In contrast to gliomas of the cerebral loperitoneal shunt and radiotherapy resulted in
hemisphere, the majority of which are of a very shrinkage of the tumor and resolution of all
malignant variety (the glioblastomas), the neurological signs. Symptoms recurred 30
majority of those involving the brain stem are months later.
astrocytomas with a lower grade of malignancy Case 13-10 presented on CD ROM
and with a longer course. The tumor slowly records in greater detail the entire course of a
infiltrates the pons and medulla, producing a patient with a pontine glioma.
gross external enlargement of these structures
DEMYELINATING DISEASES
(Fig. 13-23). On section, the distinctions
between gray and white matter are obliterated. A general discussion of demyelinating dis-
Areas of necrosis may be found within the eases particularly multiple sclerosis will be
tumor. The essential clinical syndrome is char- found in Chapter 9, Clinical Consideration of
the Spinal Cord. In one of the illustrative
cases, there were several episodes suggesting
discrete lesions at various levels of the brain
stem in addition to lesions involving the spinal
cord.
Multiple sclerosis, the most common type
of demyelinating disease, frequently involves
the white matter of the brain stem and cerebel-
lum (Figs. 13-25, 12-26) The classic triad of
Charcot includes: nystagmus, intention
tremor, and scanning speech-symptoms
which are often present in the later stages of
progressive cases, but which may be absent
early in the disease course or in non-progres-
Figure 13-23. Brain stem glioma. Marked enlarge- sive cases.
ment of the pons has occurred with obscuration of the The following example illustrates a case of
usual anatomical landmarks and obstruction of the
multiple sclerosis with predominant involve-
4th ventricle. (Courtesy of Dr. John Hills)
13-20 CHAPTER 13
Figure 13-25A Multiple Sclerosis affecting the brain

stem. Multiple irregular areas of myelin loss and glio-
sis are eJlitient are eJlitient in a 58 year old male with
a long history ofprogressive multiple sclerosis.
A. Myelin stains B. glial stain (darkly staining
areas). See also spinal cord section Fig. 9-21A.
Figure 13-24. Pontine glioma. MR1 scan (1'1). Case Courtesy Dr. Jose Segarra).
13-9: refer to text. A) Normal for comparison.
B) Pontine Glioma abducting eye on attempted lateral gaze to
right or left. Vertical gaze up and down was
ment of brain stem and cerebellar pathways
now intact. Motor system: rapid alternating
early in the course of the disease.
hand movements were somewhat slow. The
Case 13-11: This 38 year old divorced
gait was slightly broad based and mildly ataxic
right handed white female employed as a tape
.She would fall to either side on attempted tan-
library supervisor had been in excellent health
dem gait. Reflexes: Deep tendon reflexes were
until, 1 year prior to admission when she devel-
bilaterally hyperactive. The left plantar
oped vomiting, vertigo, numbness of her right
response was extensor Sensory System.; Intact.
leg and difficulty walking. All symptoms
Clinical diagnosis: Acute exacerbation of
cleared over 1 month. One year later, she
multiple sclerosis with predominant involve-
awoke to find that she had diplopia, divergence
ment of brain stem and cerebellar system.
of both eyes, limited upgaze, blurring of vision
Laboratory Data: MRI (Fig 13-27): there
in the left eye, and ataxia.
were well defined foci of increased signal par-
Neurological Examination: Mental sta-
ticularly in the T2 weighted images in the
tus: A mild degree of indifference to her diffi-
periventricular white matter, the corpus callo-
culties was present. Cranial nerves: On prima-
sum, the subcortical white matter of the right
ry gaze, the left eye was divergent (exotropia).
parietal lobe, the left midbrain and the cerebel-
Neither eye could adduct past the midline.
lar peduncles. CSF: protein was high
Dissociated nystagmus was present in the
prednisone. Within 10 days of the intravenous
therapy, the patient had significant improve-
ment: diplopia disappeared and walking
improved. When beta interferon became avail-
able, she was begun on that medication and
had no significant exacerbations for the next 5
years.
Case history 13-12 presented on CD ROM
concerns a patient with multiple sclerosis who
began with symptoms and signs relevant to
brain stem but then pursued a progressive 7
year course of increasing disability resulting in
a bed ridden terminal state.
DEGENERATIVE DISEASES
1 Focal Disease: syringobulbia: Discussed in
Figure 13-26. Multiple sclerosis. Multiple areas of chapter 9 in relation to syringobulbia
demyelination in the whiu matter of brain sUm and 2. System Diseases.
cerebral hemispheres are demonstraud in this myelin
a. Amyotrophic lateral sclerosis: This disor-
stain. (Coumsy ofDr. Harry Zimmerman,
Monufiore Hospital). der has been discussed in detail in chapter 9 on
the spinal cord. Case 9-8 provides ample evi-
dence of bulbar and corticobulbar involve-
ment.
2. Spinocerebellar degenerations: Discussed

in detail in chapter 20 cerebellum, and
Chapter 9.
TOXIC METABOLIC DISORDERS:
1. Wernicke's encephalopathy: Discussed in
detail in chapter 30 in relation to memory.
2. Central pontine myelinolysis (fig 13-28
on CD ROM)
INFECTIONS OF THE BRAIN STEM:
1. Poliomyelitis: discussed in detail in chap-
ter 9 on the spinal cord
2. H.simplex and other infections.
Figure 13-27.Multiple sclerosis affecting brain sUm,

cerebellum on clinical evaluation. MRI demonstraus
brain sUm, cerebellar peduncle and cerebral involve-
ment. Case 13-11.
(60m~Al), 1 oligoclonal band was present; 3

lymphocytes were present (normal).
Subsequent Course: The patient was
treated with a 5-day course of high dosage
intravenous methylprednisolone (1000 mg
/day) followed by a tapering course of oral
CHAPTER 14
Problem Solving II:
Brain Stem and Cramal Nerves
LESION DIAGRAMS: for each of the fol-

lowing diagrams indicate the structures
involved by the cross hatched lesion(s).For
each structure involved, indicate the expected
clinical signs or symptoms with appropriate
lateralization i.e. left or right (ipsilateral or
contralateral). Where appropriate ,indicate the
vascular territory involved or the designation
of the type of pathology and or the various
names of the syndrome.
R
Figure 14-3.
R L
Figure 14-1.
Figure 14-4.
R L
Figure 14-2.
R
Figure 14-5.
14-2 CHAPTER 14
R L
Figure 14-6.
Figure 14-9.
Figure 14-7.
Figure 14-10.
CASE mSTORY PROBLEM SOLVING

PART II - BRAIN STEM
Each of the following case histories deals with
disease at the level of the brain stem or of the
cranial nerves. In some cases, it will be evident
that the disease process involves the spinal
cord as well as the brain stem. Some of the
cases deal with intrinsic disease, some with
extrinsic disease. For each case indicate and
diagram the location of the lesion and indicate
the nature of the pathological process. Where
appropriate, indicate the name(s) of the syn-
Figure 14-8. drome, and or the vascular territory.
Case 14-1: (Patient of Doctor John Sullivan):
A 31-year-old white policeman entered the
hospital with symptoms of progressive difficul-
CASE HISTORY PROBLEM SOLVING PART II: BRAIN STEM 14-3
ty in speech, in swallowing, and with weakness Reflexes:
of his grip in both hands. Fifteen months a) Deep tendon reflexes were increased
before admission, he first noted hoarseness, symmetrically in the lower extremities.
fatigability of his voice and faulty articulation. b) Plantar responses were extensor bilater-
This has been slowly, steadily progressive, such ally (positive Babinski sign).
that now speech was barely intelligible. Three Sensory System: Normal.
months after onset of symptoms, he noted dif-
QUESTIONS
ficulty in swallowing both solids and liquids.
1. Does this patient have a level lesion or a
He had a tendency to regurgitate liquids
system disease?
through his nose. Finally, 3 months before
2. Indicate the significance of the hyperac-
entry, the patient began to note increasing
tive jaw jerk and of the hyperactive gag reflex.
weakness of handgrip. He had no complaints
3. Indicate the significance of the fascicula-
referable to his legs. He denied any sensory
tions in the facial muscles, the atrophy of the
symptoms. Six months before admission he
tongue and fibrillations seen in the tongue.
noted the presence of muscle twitching with a
4. Indicate the significance of the atrophy
diffuse distribution, but particularly in the
in the hands and the wide spread
arms and shoulders. He had lost ten pounds
fasciculations.
in weight and was easily fatigued. System
5. Indicate the significance of the hyperac-
review was otherwise entirely negative and
tive deep tendon reflexes in the lower extrem-
general physical examination was well within
ities and the bilateral Babinski signs
normal limits.
6. Where is the pathology?
NEUROLOGIC EXAMINATION: 7. What is the pathology?
Mental Status: Normal. 8. Which diagnostic laboratory studies
Cranial Nerves: Positive findings in cranial would assist in the diagnosis?
nerve function were: 9. What would a muscle biopsy reveal?
a) Stiffuess and weakness of jaw muscles, 10. Which neuroimaging studies, if any, are
with jaw clonus. indicated in this case? What results are
b) Weakness of facial musculature, includ- expected?
ing eye closure, incomplete retraction of the 11. What is the prognosis? Discuss in terms
comers of the mouth. of this patient in particular and then in terms
c) Fasciculations were seen in the facial of patients in general with this disease.
muscles.
Case 14-2: [Patient of Dr. John Sullivan]
d) Gag reflex was very brisk, but palate
This is a 63 year old woman, who on the
moved weakly.
day before admission was suddenly seized by a
e). Tongue would not be protruded; it was
sensation as though a weight had descended
atrophic with fibrillations seen beneath the
upon her head. She felt dizzy, staggered to a
mucous membrane.
chair and called for help. It was noted that her
£) Speech, as noted, was slurred, slow and
speech was slurred and indistinct. As she
strained.
looked at an object, it seemed to her to be
Motor System:
indistinct. Since then she has had great diffi-
a) Weakness of handgrips.
culty in swallowing liquids because of a ten-
b) Atrophy was present in the thenar emi-
dency to regurgitate through her nose. Solid
nence and dorsal interosseus spaces. The prox-
foods did not seem to pass down. She also
imal muscles were strong, without atrophy; leg
noted clumsiness of her right hand and of the
muscles were strong and revealed no atrophy.
right leg with staggering to the right side.
c) Widespread muscle fasciculations were
seen in both upper and lower extremities.
14-4 CHAPTER 14
GENERAL EXAMINATION: QUESTIONS:

Blood pressure was 210/100 and she was 1. Diagram the lesion using anatomical
obese with cardiomegaly. diagrams--be specific. Mark this case 1. Be cer-
NEUROLOGICAL EXAMINATION: tain to indicate laterality. Prepare a list of
symptoms and signs in one column-anatomi-
Mental Status: Brief mental status examination
cal structures involved in the opposite column.
revealed her to be alert and cooperative, exact-
2. What is the nature of the pathological
ly oriented and rather apprehensive; there was
process?
no evidence of organic intellectual deficit.
3. If vascular, indicate the vascular territory
Cranial Nerves:
in terms of specific vessel.
a) examination of her fundi showed
4.Which labels or names are attached to
marked tortuousity of the retinal vessels; discs
this syndrome? Are other syndromes also pre-
were normal; there are no hemorrhages or
sent?
exudates
b) visual fields were full CASE 14-3: This 54 year old right-handed,
c) Left pupil was 7 mm in size; the right 4 obese white female was referred for evaluation
mm; both reacting briskly to light and accom- of diplopia and ataxia. The patient had a 19-
modation; there was a partial ptosis on the year history of diabetes mellitus initially treat-
right and slight enophthalmos on the right ed with insulin and more recently with diet
d) There were no ocular palsies, but there alone. The patient also had experienced signif-
were fairly well sustained quick nystagmoid icant pain in both lower extremities related to
jerks on gaze to either side intermittent claudication, initially occurring
e) Right corneal reflex was absent; pain and on exercise but more recently occurring also at
temperature sensation on the right side of the rest. Evaluation by the vascular surgery service
face were lost, but touch sensation was intact had indicated bilateral carotid bruits.
f) Hearing was acute bilaterally On the night prior to admission, the patient
g) Voice was somewhat hoarse; speech was had the acute onset of a diplopia. At the same
slightly slurred and scanning. The right vocal time, she noted that she was no longer able to
cord was paralyzed; gag reflex was not move her eyes upward and that in order to
elicited on the right, present on the left; uvula look up she had to turn her head back. At the
pulled to the left; 11th and 12th cranial nerve same time, she developed a sense of unsteadi-
function were normal ness. This morning she had a persistence of
Motor Examination: symptoms.
a) There was instability of posture of the NEUROLOGICAL EXAMINATION:
right arm with dyssynergia and intention Mental Status: Intact with marked anxiety
tremor, which was also present in the right leg. Cranial Nerves:
b) Strength of arms and legs was approxi- a) She had significant bilateral impairment
mately normal of upward gaze
Reflexes: b) As she attempted to gaze upward, she
a) Deep tendon reflexes in upper and lower had significant lid retraction.
extremities were equal. c) In addition there was an indication of a
b) Right and left plantar responses were weakness of right medial rectus.
flexor. d) The pupils were equal and responded to
Sensory rystem: light
a) There was a loss of pain and temperature e) There was now no evidence of ptosis.
sensibility throughout theleft half of the body There was no definite fatigue of the lids by
b) Position and vibration sensation were repetitive movement.
intact
Motor System: GENERAL PHYSICAL
a) strength intact EXAMINATION:
b) on examination of gait, patient walked The patient had a blood pressure of 110/80.
on a broad base. She tended to fall to the left. There was a cold, clammy perspiration over his
She was unable to walk a tandem gait. She had entire body. No other gross physical abnor-
a minor tremor of outstretched hands but no malities were discovered.
definite appendicular cerebellar findings.
Reflexes:
a) deep tendon reflexes were 2+ except Mental Status: The patient was extremely rest-
Achilles which were absent (probably) related less and confused
to diabetes mellitus Cranial Nerves:
b) plantar responses flexor. a) He had a paralysis of left external rectus
Sensory system: muscle
Intact except for a decrease in vibration of toes b) There was a coarse, irregular nystagmus
(consistent with diabetes mellitus). on gaze to either side
Hospital Course: c) His fundi were quite normal
The patient had no additional progression. By d) The pupils and pupillary reflexes were
day five, she had shown improvement in right normal
medial rectus function and had improvement e) there was a selective diminution of pain
in her ability to look up. sensation on the left side of the face. Left
corneal reflex was diminished.
QUESTIONS: £) He had a left facial paralysis of peripher-
1) The bilateral lid retraction and the bilat- al type
eral impairment of conjugate upward gaze in g) Hearing was markedly diminished on
this case probably reflect involvement of the left
-----? h) Gag reflex on the left was diminished;
2) The blood supply of this area is derived uvula pulled to the right; patient's speech was
from branches of the artery. hoarse and he had a left vocal cord paralysis;
3) In this case impairment of upward gaze He was unable to swallow without choking
was due to an ischemic event, however, i) His tongue protruded slightly to the
impairment of conjugate upward gaze is also right
commonly noted in relation to other patho- Motor System:
logical processes. SpectlY_ _ _ _ _ __ a) On examination of his limbs, there was
CASE 14-4 [Patient of Dr. John Sullivan]: an intention tremor on the left involving both
arm and leg
This 65-year-old man entered another hospital
complaining of headaches, severe vertigo, nau- b) His arms and legs were strong and there
sea and vomiting. The diagnosis oflabyrinthi- seemed no increased resistance to passive
movement
tis was made and the patient seemed to recov-
er after a few days. He remained well, howev- Reflexes:
er, only a few days when he again had severe a) Deep tendon reflexes were increased on
vertigo and vomiting. The latter was so persis- the right side throughout
tent and severe that he became dehydrated. b) Both plantar responses were extensor
On the morning of transfer to this hospital, at (positive Babinski Signs)
about 3:00 AM, the patient noted the sudden Sensory system:
onset of weakness and numbness of his right a) There was a loss of pain and temperature
thigh. sensibility throughout the entire right side
b) Other forms of sensation could not be
adequately tested because of patient's inability
to cooperate
14-6 CHAPTER 14
QUESTIONS: right naso-Iabial fold and a poorer degree of

1. Considering in isolation the left lateral eye closure on the right side than the left
rectus palsy, the left peripheral facial weakness, (orbicularis oculi).
the decrease in hearing in the left ear, the c) There was no perception of voice in the
severe vertigo and the decrease in pain sensa- right ear.
tion on the left side of the face and right side d) No vestibular response was present to
of body. Diagram this specific lesion at the ice water caloric testing in the right ear.
proper level. Label this Case #4. e) Minimal rotatory nystagmus was pre-
2. What specific vessel supplies the area you sent on horizontal gaze with a minor degree of
have outlined above? vertical nystagmus on upward gaze.
3.Now take into account those additional £) A minimal degree of dysarthria was
findings in this case that were not included in apparent as regards guttural sounds.
the consideration of Question 1. Indicate ves- Motor System:
sel responsible for the entire episode (there are a) Strength and tone were intact.
2 possibilities). b) Cerebellar tests revealed a slight clumsi-
CASE 14-5: This right-handed, 43-year-old ness in fine finger movements of the right
white housewife had the onset of deafuess in hand.
the right ear. Rapid progression of deafuess c) Gait was slightly ataxic when performed
was noted; some tinnitus (sensation of ring- on a narrow base with eyes open.
ing) was also noted. Caloric testing of Reflexes:
labyrinthine function at that time indicated no a) Deep tendon reflexes were symmetrical
response to cold or hot water on the right side. and physiologic.
In the following month, the onset of a minor b) Plantar responses were flexor.
unsteadiness of gait was noted. Approximately Sensory syatem: All modalities were intact.
five months later the patient noted defects in LABORATORY DATA:
coordination of the right hand, particularly in Cerebrospinal fluid protein was slightly
typing, with a progression of unsteadiness of elevated to 50 mg./IOO ml. Skull x-rays were
gait. At the same time a "numbness" sensa- negative.
tion of pins-and-needles -- "like Novocain
given by a dentist" -- was noted over the entire QUESTIONS:
right side of the face. Relatively continuous 1. This patient presents a typical example
pain was noted extending from the right side of classic neurological syndrome. Locate the
of the neck to the sub occipital area and right lesion.
post auricular area. One month later difficul- 2. What is the most likely pathology to be
ty in swallowing solids and liquids was noted. found by the neurosurgeon in this location?
Which pathological processes are also possible
PAST mSTORY: but less likely?
Episodes of vertigo 5 to 6 years prior to admis- 3. The initial involvement of the functions
sion. Right frontal headache since age 33. of cranial nerve VIII prior to involvement of
NEUROLOGICAL EXAMINATION: other cranial nerves should provide a clue as to
Mental Status: Intact. the structure from which this lesion arises.
Cranial Nerves: 4. Does the pattern of sensory disturbance
a) Pain and touch sensation were decreased over the right side of the face indicate prima-
over all divisions of the trigeminal nerve on the ry involvement of the trigeminal nerve extrin-
right side, including the face, cornea, and the sic to the brain stem or of the descending
right side of the tongueb) spinal tract and associated nucleus of the
b) There was minimal flattening of the trigeminal nerve within the brain stem?
5. Were long sensory and motor tracts
within the brain stem involved by this lesion? several months prior to admission.
6. Predict the clinical picture that would
PHYSICAL EXAMINATION: The
have occurred if the lesion had progressed.
patient was obese and anxious with blood
7. During the course of surgery, aimed at
pressure elevated to 160/100.
total resection in these cases, the facial nerve
must often be sacrificed or damaged. Based NEUROWGICAL EXAMINATION:
on your lll1derstanding of the anatomical con- Mental status: the patient was alert and ori-
siderations in these cases, indicate why this ented. Recent memory was poor and delayed
occurs. Which studies may be performed dur- recall was limited to 2/4 objects. (All similar
ing surgery in early cases to preserve residual to 18 months previously)
hearing or facial nerve function? Cranial nerves:
8. Which critical diagnostic studies would a) Ptosis of the right eyelid was present,
you perform? but pupillary responses were intact.
9. When should these studies be b) At rest, the right eye was deviated out to
performed? the right and down. No medial or upward
CASE 14-6: This 57-year-old housewife one movement of the right eye was possible. (Note
day prior to admission suddenly developed change).
double vision and a drooping of the right eye- c) A mild left central (supranuclear) facial
lid. In addition, she had difficulty walking. weakness was now present.
Examination of the patient in the emergency Motor system: Strength was intact.
room revealed weakness of adduction of the Reflexes: There were changes compared to
right eye, ptosis of the right eye and a left examinations 22 and 18 months previously.
extensor plantar response. She was admitted to a) Deep tendon reflexes were now
the neurology service. increased in the left lower extremity.
b) A left Babinski sign was now present
PAST mSTORY: with an absent left abdominal reflex.
1. Moderate hypertension had been pre- Sensory system: All modalities were intact.
sent for many years. Carotid pulses: Strong bilaterally.
2. Four years previously, the patient had
begllll to have sudden 30-minute episodes of LABORATORY DATA:
right-handed weakness and dysarthria. 1. Skull x rays demonstrated calcifications
Twenty-six months prior to admission, she in the cavernous carotid arteries.
had a 15-20 minute episode of bilateral 2. Electrocardiogram was normal.
blurred vision, lll1steadiness of gait and tin- 3. Electroencephalogram demonstrated
gling paresthesias of the right hand and face. scattered multifocal slow waves.
Twenty-two months prior to admission, she 4. Blood studies: Complete blood COlll1ts,
had episode of paresthesias involving either the serology, blood sugar and total cholesterol
left leg and arm or the right arm and leg. were normal.
Examination at that point demonstrated 5. Prothrombin time was 68% of normal.
increase deep tendon reflexes on the right side. 6. The patient refused lumbar plll1cture
Eighteen months prior to admission, she expe- and angiography.
rienced 10-minute episodes of numbness of QUESTIONS:
the left hand and face accompanied by 1. This is clearly a more complex case.
renewed numbness of the right hand. Three However the new symptoms of diplopia, pto-
days prior to admission she had a brief episode sis of the right eyelid plus the new findings of
of right hand weakness. a paralysis of medial and upward movement of
3. The patient had been receiving antico- the right eye plus increased deep tendon
agulant therapy (Coumadin) for phlebitis for reflexes in the left lower extremity plus a left
14-8 CHAPTER 14
Babinski sign and a left central facial weakness al defect in upward movement and of lateral
should allow for the diagnosis and localization movement of the right eye. The defect in lat-
of at least one syndrome. What name do you eral and upward movement was bilateral but
assign to this syndrome? Does this syndrome was more marked on exercise.
involve a specific vascular territory? c. The patient was able to smile for 8 sec-
2. How do you explain the earlier onds and then his smile began to evaporate
episodes? bilaterally.
a) Episodes of right hand weakness and d. The patient had weakness in jaw muscles
dysarthria on repetitive opening and closure of jaw.
b) Bilateral blurring of vision, plus Motor System.
unsteadiness plus tingling of the right hand The patient had weakness in shoulder abduc-
and face. tion, which developed after 10 repetitive
c) Paresthesias left leg and arm followed by movements. He had weakness in forward head
paresthesias of the right arm and leg. movement which developed after 4 repetitive
3. Are there any additional questions, movements. No definite atrophy was present,
which you might pose for this patient? no definite weakness was otherwise present in
4. If this patient had a severe headache at the extremities.
the time of admission, why might a lumbar Reflexes: Deep tendon reflexes were intact,
puncture have been considered? plantar responses were flexor.
5. Why was angiography considered? Sensory System: intact.
6 The patient refused both lumbar punc-
QUESTIONS:
ture and angiography. Would you have
1. Indicate the diagnosis. Be specific.
requested these studies or would you have
2. Where is the defect located in this
requested other studies? If so present your
disease? Be specific!!
plan of workup justifYing each study.
3. Discuss the underlying pathophysiolo-
7 Present your working diagnosis and final
gy.
diagnosis. (There are several possible ways to
4.Which tests would confirm the diagnosis
tie together all of the episodes).
and produce temporary improvement?
CASE 14-7: This 69-year-old white male was 5. Outline therapeutic approaches.
seen for outpatient neurological re-evaluation.
CASE 14-8: This 56-year-old white house-
His neurological problems began four years
wife was admitted for evaluation of episodes of
previously. The patient had a history of inter-
stupor and cyanosis associated with severe
mittent ptosis of the left lid. In addition, at
laryngeal stridor (high pitched and harsh res-
times significant ptosis of both lids had been
piratory sounds) and stertorous breathing.
noted. Over the years, he had intermittent
Laryngeal stridor had been present for 20
episodes of diplopia. He had also noted weak-
years and had grown worse during the last 5 to
ness of his jaw in chewing and weakness in
6 years. An episode of anoxia during a
shoulders or in his neck on exercise of these
Cesarean section 18 years prior to admission
muscle groups.
may have been a complication of this problem.
NEUROLOGICAL EXAMINATION: Sixteen years prior to admission numbness and
Mental Status: intact weakness of the right leg had been noted.
Cranial Nerpes: Progression had occurred in the last 2 years
a. The patient demonstrated a significant and episodic unsteadiness of gait had been
bilateral ptosis that was variable, it was signifi- noted. During this same period, weakness of
cantly increased by exercise; it was more the right hand had developed. During the one
marked in the left eye. year prior to admission the patient had three
b. The patient showed a significant bilater- hospital admissions related to episodes of
coma and cyanosis. Each had followed a sev- b.Pain and temperature were selectively
eral-week period in which there was increased decreased in a cape-like distribution over the
stridor and increased accumulation of tracheal- shoulders.
bronchial secretions with frequent periods of LABORATORY DATA:
daytime sleepiness.
1. Cerebrospinal fluid: normal (pressure
NEUROLOGICAL EXAMINATION: 150, cell count 0, protein 45 mg./l00 mI.)
Mental Status: Intact. 2. Skull x-rays were negative.
Cranial Nerves: 3. Cervical spine x-rays revealed minor
a. Pain sensation was selectively decreased non-significant degenerative changes at C5-
over all three divisions of the right side of the C7.
face with decreased right corneal reflex.
SUBSEQUENT COURSE:
b. Laryngoscopy revealed paralysis with
The patient was readmitted to the hospital 10
atrophy of the left vocal cord. The right cord
weeks later in a semi comatose and cyanotic
moved but was inhibited on abduction, indi-
condition. She required an emergency tra-
cating partial paresis.
cheostomy and 48 hours of respiratory assis-
c. Horizontal nystagmus was present on
tance. Subsequent neurological examination
lateral gaze with minimal vertical nystagmus
was unchanged from that recorded earlier.
on upward gaze.
Motor System: QUESTIONS:
a. Atrophy of the right upper extremity was 1. Where is the lesion? Does this lesion
present including the shoulder, arm, and hand. involve a single localized segment or are sever-
b. Weakness was present in the right upper al segments involved?
extremity -- approximately 50 per cent of nor- 2. Is the pathology limited to the brain
mal strength at shoulder, elbow, wrist, and fin- stem or to the spinal cord?
gers. Weakness without atrophy was present 3. Indicate what structures are involved to
in the right lower extremity and to a lesser produce:
degree in the left lower extremity. a. laryngeal paralysis,
c. Spasticity was present on passive move- b. cape-like deficit in pain and temperature
ment at the right knee and ankle and to a less- but sparing touch and vibration,
er degree at the left knee. c. atrophy of all muscle groups in right
d. Gait: There was circumduction of the upper extremity,
right leg with unsteadiness on rapid turns. d. a bsence of deep tendon reflexes in both
e. Cerebellar tests were negative. upper extremities, and
Reflexes: e. defective pain sensation on the right side
a. Deep tendon: of the face.
Biceps: right, 0; left, 0 4. Indicate the most likely pathology and
Triceps: right, 0; left, 0 the probable prognosis.
Radial: right, 0; left, 0 5. What diagnostic tests should be under-
Patellar: right, 4+; left, 3+ taken to establish the diagnosis?
Achilles: right, 4+; left, 3+ 6. Why did the patient have episodes of
b. Superficial reflexes: coma and excessive daytime sleepiness? (There
Plantar: extensor on the right and are several explanations)
possibly extensor on the left
Abdominal: right, 0; left, 0
Sensory system:
a. Position, vibration, and touch were
intact.
CHAPTER 15
Diencephalon
The diencephalon appears as a large region at

the upper end of the brain stem. All the ascend-
ing fiber pathways from the spinal cord and brain
stem terminate upon nuclei in the diencephalon.
From these nuclei the information is relayed
onto the cerebral cortex.
Due to the convergence of all major ascend-
ing sensory, motor and reticular systems con-
sciousness for general sensations are first realized
at this level. In addition, the ascending motor
information from the cerebellum mixes with the
striatal and cortical motor fibers in the dorsal
thalamus producing a motor thalamic region.
Finally, the hypothalamus and limbic cortical
regions have major input onto the dorsomedial
nucleus of the thalamus.
THALAMUS & INTERNAl CAPSULE lB
...",..... Lmb
I. DIENCEPHALIC BOUNDRIES
_Lmb
F.-.-1JaCCl
""'~-
The border between the diencephalon and
the midbrain is indistinct and may be arbitrarily ~ncl
u_ El<IrwMy. (A)
Tha<ax & _ . (T)
defined by passing a line from the inferior surface ~ E"'*"'Y' (l)
of the mammillary bodies to the posterior border eon-_t.t\OaJ
of the habenula. Portions of the substantia nigra
and red nucleus are also seen in the posterior
portion of the diencephalon.
In order to identify the majority of the nuclei
in the diencephalon and basal nuclei the cerebral
cortex and corpus callosum are carefully separat-
ed and removed revealing the diencephalon (Fig
15-1). Then one finds the slit-like third ventricle Figure 15-1. Brain in Sagital plain demonstrating.
The relationship between brain stem, diencephalon
in the midline. At the rostral end of the dien-
and cerebrum. (MRI weighted T1.) Location of
cephalon we can identifY the anterior tubercle thalamus. A MRI B. Gross Brain..
(containing the anterior thalamic nuclei) and at
the posterior margin the pulvinar. The major new diencephalon becomes smaller and the caudate
white matter bundles at this level are the internal enlarges.
capsule, fornix, and stria terminalis. The basal The body of the lateral ventricle along with
nuclei of the cerebrum can now also be visualized the corpus callosum and fornix form the superi-
(Figure 15-2), and consist of caudate, putamen or border of the diencephalon (Fig. 15-3). The
and globus pallidus. The globus pallidus is found posterior limb of the internal capsule and the
lateral to the internal capsule, and the putamen is optic tract mark its lateral boundary, and the slit-
adjacent to it. The caudate nucleus is found like third ventricle denotes its medial border.
medial to the internal capsule. In the posterior Inferiorly, the diencephalon is continuous with
levels of the diencephalon, the caudate is rela- the tegmentum of the midbrain, while rostrally it
tively small, but as one proceeds anteriorly, the ends at the lamina terminalis.
The tegmentum of the midbrain is continu-
15-2 CHAPTER 15
ous with the hypothalamus (Fig 15-4). The dien- about a third of the way up from the floor of the
cephalon consists of five distinct nuclear subdivi- third ventricle. All nuclear structures superior to
sions: thalamus, epithalamus, hypothalamus, the sulcus are included in the dorsal thalamus,
metathalamus, and subthalamus (Figure 15-2). and all nuclei below it are included in the hypo-
As can be seen from the terminology associated thalamus (Fig. 15-3).
with the diencephalon, all structures are
described by their spatial relationship to the thal-
Corpus Callosum
amus, being above, below, or behind them. The Lateral Ventricle
(Body) 3A
(Body)
epithalamus and hypothalamus are discussed in
caudate
Chapter 16. Fomlx
(Body)
Insula
Lat
Sulcus
utamen
Amygdala
Hypothalamus
Figure 15-2. Dorsal view ofgross specimen of brain

stem, diencephalon, and basalganglia. Medulla, pons,
Figure 15-3. Mid thalamic level. A. MRI B.
midbrain, thalamic regions and internal capsule
Schematic coronal section showing nuclei of thalamus,
labeled.
hypothalamus, subthalamus, basal ganglia and the
white matter internal capsule.
n. NUCLEI OF THE THALAMUS
The thalamus and metathalamus is the major Thalamic Borders. The external medullary
relay center between the brain stem and the cere- lamina forms the lateral boundary of the thala-
bral cortex. The thalamus is the largest portion of mus, and separates it from the reticular nucleus
the diencephalon. It is ovoid in shape; the poste- of the thalamus. There is also an intrinsic bundle
rior limb of the internal capsule, medially by the of white matter, the internal medullary lamina,
third ventricle, bound it laterally inferiorly by the which divides the thalamus into three major
subthalamus and hypothalamus, and superiorly nuclear masses the anterior, medial and lateral.
by the body of the lateral ventricle and corpus The anterior mass includes the anterior nuclei;
callosum. The boundary between the thalamus the medial mass includes the dorsomedial nuclei
and hypothalamus (Fig 15-3) is the hypothalam- and the midline nuclei, with the lateral mass
ic sulcus on the medial wall of the diencephalon including all of the other nuclei. Cell and fiber
DIENCEPHALON 15-3
Figure 15-4. 3D Reconstruction of the thalamic nuclear grouping throughout the thalamus. It is
nuclei with the upper portion showing the three major bounded medially by the internal medullary lam-
nuclear subdivisions and the lower portion showing ina of the thalamus and laterally by the external
individual nuclei. Modified After Carpenter Core medullary lamina of the thalamus. In a stained
Text, Williams& Wilkins 1992 preparation its ventral border with the ventral
stains are used to further subdivide the thahullus. nuclear mass is distinct. The lateral nuclear mass
With these stains the following nuclei are identi- starts near the anterior end of the thalamus and
fiable: anterior, medial, midline, intralaminar, lat- runs the length of the thalamus with its posteri-
eral, posterior, reticular, and metathalamus. or portion, the pulvinar, overhanging the genic-
Each of these nuclear groupings can be further ulate bodies and the midbrain.
subdivided as follows Table 15-1; Nuclei in the The lateral posterior part of the lateral
Thalamus nuclear mass projects to the superior parietal lob-
ule and receives input from specific thalamic
m. FUNCTIONAL ORGANIZATION OF nuclei. The lateral dorsal part is included above
THALAMIC with the limbic nuclei.
A. SENSORY AND MOTOR RELAY The ventral basal nuclear mass consists of
NUCLEI-THE VENTROBASAL COM- three distinct regions: ventral anterior, ventrallat-
PLEX, LATERAL POSTERIOR, (FIGURE eral, and ventral posterior. The ventral anterior
15-4). nucleus (VA) is the smallest and most rostral
These nuclei (Fig 15-4) are part of the somat- nucleus of this group. It can be identified by the
ic brain as they receive direct input from the presence of numerous myelinated bundles. The
ascending sensory and motor systems, from the magnocellular portion of this nucleus receives
cerebellum, and from the optic tract. fibers from the globus pallidus, via the lenticular
The special sensory medial and lateral genic- and thalamic fasciculi, and from the intralaminar
ulate nuclei are discussed below. nuclei and has some projections to areas 4 and 6.
The lateral nuclear mass is divided into three Stimulation of this nucleus produces the same
parts: lateral dorsal, lateral posterior, and pulv- effects as stimulation of the intralaminar nuclei.
inar. It occupies the upper half of the lateral The ventral lateral and ventral posterior
nuclei contain cell bodies that project onto the
15-4 CHAPTER 15
TABLE 15-1: NUCLEI IN THE THALAMUS motor and sensory cortex. In the thalamus the
head is found medial and posterior and the leg
A. ANTERIOR NUCLEI (Limbic) anterior and lateral. The ventral lateral nucleus
1. Anterior dorsal (VL, somatic motor thalamus) occupies the mid-
2. Anterior medial dIe portion of the ventral nuclear mass. It is a
3. Anterior ventral (Anterior principalis) specific relay nucleus in that it receives fibers
from the contralateral deep cerebellar nuclei (via
B. MEDIAL NUCLEI (Limbic & Specific Associatlonal)
the superior cerebellar peduncle/ denta-
1. Nucleus medialis dorsalis
torubrothalamic tract) and the ipsilateral red
a. Pars parvocellulares
nucleus. This nucleus also receives fibers from
b. Pars magnocellularis
the globus pallidus and from the intralarninar
C. MIDLINE NUCLEI (Non specific Associational) nuclei. This nucleus projects to area 4 and to
1. Nucleus parataenialis area 6 and has a topographic projection to the
2. Nucleus paraventricularis motor cortex. This nucleus is important in inte-
3. Nucleus reuniens grative somatic motor functions because of the
4. Nucleus rhomboideus interplay between the cerebellum, basal ganglia,
D. INTRALAMINAR NUCLEI - in the internal medullary lam- and cerebrum in this nucleus.
ina (Nonspecific Associational) The ventral posterior nucleus occupies the
1. Nucleus centrum medianum posterior half of the ventral nuclear mass and
2. Nucleus parafascicular consists of two parts: the ventral posterior medi-
3. Nucleus paracentralis al nucleus and the ventral posterior lateral nucle-
4. Nucleus centra lis lateralis us. Both of these nuclei receive input from the
5. Nucleus centra lis medialis specific ascending sensory systems.
E. LATERAL NUCLEI The ventral posterior medial nucleus (VPM,
1. Pars dorsalis (Specific Associational) the arcuate, or semilunar, nucleus) is located lat-
a. Nucleus lateralis posterioris eral to the centromedian nucleus and medial to
b. Nucleus latera lis dorsalis the ventral posterior lateral nucleus. The sec-
c. Pulvinar ondary fibers of the trigeminal and gustatory
(1) Pars inferioris pathways terminate in this nucleus; thus this
(2) Pars latera lis nucleus is concerned primarily with taste and
(3) Pars medialis with general sensation from the head and face.
2. Pars ventralis/Ventrobasal complex (Motor & The basal region of the ventromedial nucleus
Sensory Relay). receives the taste fibers and probably some of the
a. Ventralis anterior vagal input. General sensation from the face,
b. Ventralis latera lis including pain, temperature, touch, pressure,
c. Ventralis ventralis and proprioception, terminate in the other por-
d. Ventralis posterior tions of this nucleus. This nucleus projects infor-
(1) Posterolateral mation from the face, ears, and head, and tongue
(2) Posteromedial regions onto the inferior part of the postcentral
F. RETICULAR NUCLEI (Nonspecific Associational) gyrus, areas 3, 1,2
The ventral posterior lateral (VPL) nucleus
G. METATHALAMIC NUCLEI (Sensory Relay) receives fibers from the posterior columns and
1. Lateral geniculate (Vision-opticothalamic) the direct spinothalamic tracts with the bulk: of
2. Medial geniculate (Audition-auditothalamic) the input originating in the upper extremity. The
H. POSTERIOR NUCLEI (Nonspecific Associational) VPL nucleus projects to the body and neck
1. Limitans regions on the postcentral gyrus (areas 3, 1,2).
2. Suprageniculate
3. Posterior (Nociceptive System)
DIENCEPHALON 15-5
B. UMBIC NUCLEI - THE ANTERIOR, 11, 12; see Chapter 22)
MEDIAL, LATERAL DORSAL, MIDLINE The medial nuclear complex is an important
AND INTRALAMINAR NUCLEI relay station between the hypothalamus, amyg-
(Fig 15-9). dala and the prefrontal cortex and is concerned
The limbic nuclei may also be called the with the multimodal associations between the
nuclei of the emotional brain. limbic (visceral) and somatic impulses that con-
The anterior nuclei (15-4) are at the most tribute to the emotional makeup of the individ-
rostral part of the thalamus and form the promi- ual. Destruction of this nucleus in cats results in
nent anterior tubercle in the floor of the lateral a lower threshold for rage, so that the animal is
ventricle. The tubercle includes a large main easily aroused. In human beings, ablation of the
nucleus (anteroventral) and small accessory nuclei medial nucleus or a prefrontal lobotomy has
(anterodorsal and anteromedial). been used as a therapeutic procedure to relieve
The internal medullary lamina of the thala- emotional distress (SEE CHAPTER 22).
mus surrounds the anterior nuclei. The mammil- C. SPECIFIC ASSOCIATIONAL- MULTI-
lothalamic fibers form the bulk of the fibers in the MODAL/ SOMATIC NUCLEI-THE
internal medullary lamina. This zone is an impor- PULVINAR NUCLEI (fig 15-4).
tant relay station in the limbic brain and receives
The Pulvinar Nuclei
input from the subiculum, presubiculum and
mammillary body via the mammillothalamic The pulvinar (Fig 15-4) is the largest nucleus
tract. in the thalamus and is continuous with the pos-
The anterior nuclear complex is part of the terior part of the lateral division. All the major
Papez circuit: (hippocampal formation --> fornix ascending sensory pathways have some termina-
--> mammillary body --> mammillothalamic tract tions in the medial and lateral nuclei. The pulv-
--> anterior thalamic nucleus --> anterior thalam- inar therefore is the major multimodal associa-
ic radiation --> cingulate cortex --> cingulum --> tion nucleus of the thalamus integrating sensory,
perforant pathway -->hippocampus). This nucle- motor, visual, and limbic information.
us projects to the anterior cingulate gyrus (areas The pulvinar is divided into three major
23, 24, 32) and receives input from the hypo- nuclei: the medial pulvinar nucleus, the lateral
thalamus, habenula, and cingulate cortex. pulvinar nucleus and the inferior pulvinar nucle-
Stimulation or ablation of this nuclear complex us. The medial pulvinar nucleus projects onto
alters blood pressure and may have an effect on the prefrontal and anterior temporal limbic cor-
memory. tex. The lateral pulvinar nucleus projects onto
The lateral dorsal nucleus, like the anterior supramarginal, angular, and posterior temporal
nucleus, is surrounded by the rostral portion of lobe. The inferior pulvinar nucleus is related to
the internal medullary lamina of the thalamus and the visual system and projects onto the visual
should be considered a caudal continuation of the association cortex, areas 18 and 19. Because of
anterior nuclear group. This nucleus projects to the strong projections of the lateral pulvinar
the rostral cingulate cortex and onto the parahip- nucleus onto the cortex surrounding the posteri-
pocampal gyrus. or end of the lateral sulcus, lesions in the pulvinar
The medial nuclear complex or the dorsome- in the dominant hemisphere produce distur-
dial nucleus consists of both a large-celled and a bances in language.
small-celled division. This medial region is found E. SPECIAL SENSORY NUCLEI-
between the internal medullary laminae and the METATHALAMUS: VISION AND AUDI-
midline nuclei lining the third ventricle (Fig. IS- TION, THE LATERAL GENICULATE
S). The magnocellular portion of the dorsomedi- and MEDIAL GENICULATE Nuclei (Fig
al nucleus is interconnected with the hypothala- 15-4.
mus, amygdala, and midline nuclei and connects AUDmON (Also see Chapter 22)
to the orbital cortex; the large parvicellular divi-
The medial geniculate nucleus (MGN) is
sion is interconnected with the temporal,
located on the most caudal portion of the thala-
orbitofrontal and prefrontal cortices (areas 9, 10,
15-6 CHAPTER 15
mus receives the ascending auditory fibers origi- to delimit in human beings, but these nuclei are
nating from the following nuclei: cochlear, trape- intimately connected to the hypothalamus and
zoid, superior olivary, laterallemniscal, and infe- the intralaminar nuclei, and their function must
rior colliculus. The auditory fibers end on the be interrelated.
medial geniculate pars parvocellulares. Vestibular The intralaminarnuclei (Figs. 15-3 and 15-
fibers end in the magnocellular portion of the 5) are found in the internal medullary laminae of
medial geniculate and are projected onto post- the thalamus. The most prominent intralaminar
central gyrus. This nucleus projects to area 41 in nucleus is the posteriorly placed centromedian,
the temporal lobe, the transverse temporal gyrus which is located in the midthalamic region
of Heschl. The ventral nucleus of the medial between the medial and ventral posterior nuclei
geniculate receives input from the inferior col- and receives many nociceptive fibers. The
liculus. parafascicular nucleus is also easily delimited
VISION (Also see Chapter 23) because it is at the dorsomedial edge of the habe-
The lateral geniculate nucleus (LGN) is a nulopeduncular tract. The intralaminar nuclei
horseshoe-shaped six-layered nucleus with its receive input from many regions throughout the
hilus on its ventromedial surface. The LGN central nervous system, including ascending
receives the optic tract and projects to areas 17 axons from the reticular nuclei, indirect
and 18. Figure 15-5 demonstrates the visual spinothalamic pathways, midbrain limbic nuclei,
radiation onto the calcarine cortex of the occipi- subthalamus, hypothalamus as well as other thal-
tal lobe). This nucleus contains the six neuronal amic nuclei. The intralaminar nuclei have some
layers separated by bands of myelinated axons. direct projections onto the frontal lobe however
The four outer layers contain small- to medium- their major influence is on the cerebral cortex by
sized cells, that project onto layer iv of the striate their connections to the specific thalamic nuclei.
cortex with the two innermost layers contain Electrical stimulation of the intralaminar
large cells (magnocellular) projecting onto layer I nuclei activates neurons throughout the ipsilater-
and deep portion of layer IV. al cerebral hemisphere. As the stimulation con-
Crossed fibers of the optic tract terminate in tinues, more and more cortical neurons fire,
laminae 1,4, and 6, while uncrossed fibers end in which is called the recruiting response, and there
laminae 2,3, and 5. This nucleus also connects is a waxing and waning, the response finally peaks
with the inferior pulvinar, ventral, and lateral then decreases but may increase again. The cen-
thalamic nuclei. Some optic fibers proceed tromedian nucleus has a strong projection to
directly to the pretectal area and the superior col- ventral anterior and ventral lateral nuclei and has
liculus with or without synapsing in the lateral
geniculate nucleus. There they partake in the
light reflex and accommodation reflex (see
Chapter 21).
F. NON-SPECIFIC ASSOCIATIONAL.
The thalamic reticular nucleus forms a cap
around the thalamus, medial to the internal cap-
sule. All fibers systems leaving the thalamus and
projecting onto the cerebral cortex and the fibers
coming back from these same cortical areas pass
through this nuclear complex with many specific Visual
systems terminating in this nucleus. This nucleus Radiations
contains GABA-ergic neurons and has a modu-

lating effect on thalamic neurons. Figure 15-5. Horizontal section, demonstrating the
The midline thalamic nuclei (Fig. 15-4) are anterior limb,genu, and posterior limb of the inter-
located in the periventricular gray above the nal capsule. Note the putamen andglobus pallidus are
hypothalamic sulcus. They are small and difficult external to the internal capsule. (MRJ weigl!ted 12.)
DIENCEPHALON 15-7
THALAMUS & INTERNAL CAPSULE

Anterior Limb
Frontopontine tracct
Ant. Thalamic Radiations
Posterior Limb
Corticospinal tract:
Upper Extremity - (A)
Thorax & Abdomen - (T)
Lower Extremity - (L)
Cortico- tecta I & rubral
Sup. Thalamic Radiations to;

somatosensory cortex &
parietal lobe
Auditory Radiation
Post Thalamic Radiation
Optic Radiation
Geniculate
Body
Figure 15-6. A horizontal section similar to 15-6. The major fiber tracts of the in the riglrt internal capsule are
labeled. Modified After Carpenter Core Text, Wiliams & Wilkins 1992.
a direct projection to the caudate and putamen the major white matter bundle that connects the
which permits interrelationship with the diencephalon and the cerebrum, internal capsule.
extrapyramidal motor system (see Chapter. 17). Internal Capsule (Fig 15-6).
In Table 15-2, the principal thalamic nuclei
The internal capsule is a large myelinated
are grouped as to the type of modality that reach-
region that marks the border between the dien-
es the individual nuclei. This table demonstrates
cephalon and telencephalon. The internal cap-
that the thalamus receives input from gray mat-
sule, consisting of the anterior limb, genu, and
ter in the spinal cord, brain stem, cerebellum and
posterior limb, is best visualized in a horizontal
cerebrum. The type of input is identified func-
section, where it forms an obtuse angle. All fibers
tionally as sensory, motor, limbic or
projecting from the thalamus onto the cerebral
associational.
hemispheres must pass through this region,
m. WHITE MATIER OF THE while all fibers leaving the cerebral cortex and
DIENCEPHALON going either to the diencephalon, basal nuclei,
brain stem, or spinal cord must also pass through
At the lateral margin of the diencephalon is
its parts. In the following diagrammatic horizon-
15-8 CHAPTER 15
TABLE 15-2. FUNCTIONAL GROUPS OF THALAMIC diencephalon on the lateral wall of the lateral
NUCLEI ventricle and is the point at which the fibers are
displaced laterally by the increasing bulk of the
Modalily Nuclei diencephalon. The corticobulbar fibers are found
Sensory Relay Nuclei: ventral posterior medial (touch in the genu.
and taste), ventral posterior lateral The posterior limb of the internal capsule
(touch & vestibular), medial geniculate consists of three subdivisions: thalamolentiform,
(hearing), and lateral geniculate sublenticular, and retrolenticular:
(vision). Input from ascending specific
1. The thalamolenticular portion (between
sensory modalHles and project to
cortical area subserving that modality. the thalamus and lenticular nuclei) contains the
corticospinal, corticorubral, corticothalamic,
Motor Relay Nuclei: ventral lateral and ventral thalamoparietal, and superior thalamic
anterior. Input from the contralateral radiations.
cerebellar hemispheres, superior 2. The sublentiform portion (passing inferior-
cerebellar peduncle, medial globus
pallidus, and the nigrostriatal fibers
ly and posteriorly) includes the posterior thalam-
from the area compacta of the ic radiations that include optic radiation (Fig. 15-
substantia nigra. 6), acoustic radiation, corticotectal, and temporal
pontine fibers.
Limbic Nuclei: dorsal medial, anterior, and 3. The retrolenticular portion (passing poste-
lateral dorsal, Receive a well defined riorly into the temporal and occipital lobes) con-
Input from the mammillothalamic tract
of the Papez clrcuH and project onto tains the posterior thalamic radiation to the
the prefrontal and clngulate gyrus. occipital and temporal lobes and the parieto-
occipital fasciculus.
Specific Nuclei: dorsal medial, lateral, and Within the diencephalon many other myeli-
Assoclanonal pulvinar nuclei. Forms the bulk of the nated fiber bundles can be identified Table 15-3.
thalamus and receive a muHlmodal
Input and projects onto cortical areas IV. RELATIONSHIP BE1WEEN THE
that also receive a mulnmodal THALAMUS AND THE CEREBRAL
Intracortical assoclatlonallnput. CORTEX. FIG 15-7.
Nocicepnve Nuclei: Dorsomedial, VPL &Posterior. The thalamus has several major roles;
Receive input from ascending 1) To receive input from the brain stem, cere-
anterolateral system, spinothalamic, bellum and corpus striatum,
splnorencular and splnomesencephallc
2) To project this information, after some
Nonspecific Nuclei: intralamlnar, midline, and processing, onto the cerebrum, and
Associanonal reticular. Receive Input from diverse 3) To receive reciprocal projections from the
subcortical regions, Including the same cerebral areas. The relationship between
reftcular formation, visceral brain, and many thalamic nuclei and specific cortical areas is
corpus striatum, project to specific so intimate that when a cortical region is
thalamic nuclei or associanonal
areas in the cortex. destroyed the neurons in a particular thalamic
nucleus atrophy (Walker 1938). This degenera-
tion is a consequence of the thalamic projection
tal section the three major parts of the internal and its reciprocal from the cortex, being restrict-
capsule are identified and their constituent fiber ed to only a single specific cortical region and is
systems discussed: the anterior limb, genu and seen in portions of the following nuclei: anterior,
posterior limb (Figure 15-6). ventral lateral, ventral posterior, lateral genicu-
The anterior limb lies between the caudate late, medial geniculate, and magnocellular por-
nucleus and putamen, and this portion of the tion of the medial dorsal. and pulvinar. The
capsule contains the anterior thalamic radiation intralarninar, midline, posterior, portions of the
and the frontopontine fibers. pulvinar, and medial nuclei are unaffected by cor-
The genu is found at the rostral end of the tical lesions.
DIENCEPHALON 15-9
TO a fROM PREFRONTAL CORTEX RE-"C\JL"'!<,'~"'" FIBEIIS
MAIIII L LOTHALAMIC
TRACT
TRACT
TO
CORTEX
(15& B)
THALAMIC
fASCICULUS
TO SENSOR'!' COIITEX
'ACI
TO MOTOR CORTEX (4)

BRACHIUM CO JUNCT,VUM
;1t,::::::'.J .._--. ~.~~:!~ .~~l.~~n
MEOIAL LEMNISCUS. SPINOTHAL..... ,CS
A
ETICULOTHALAhllC FIBERS
To & From Parietal Lobe,

Occip 18 & 19, temp 20-
22, 11,12,45
LAT. GENICULATE BODY
Figure 15-7; Representation of the thalamic nuclei: A-showing connections of ventrobasal, midline, anterior, lat-
eral nuclei and geniculate nuclei. B- demonstrating connections of lateral dorsal, lateral posterior and pulvinar
nuclei.. (After Truex, RoC., and Carpenter, M.B.: Human Neuroanatomy. Baltimore, Williams and Wilkins,
1970)
15-10 CHAPTER 15
TABLE 15-3: MAJOR FIBER BUNDLES ASSOCIATED WITH thalamic nuclei. This is an extensive projection.
THE DIENCEPHALON:
Superior radiations- connects motor sensory
strip and adjacent frontal and parietal lobes with
Pathway Connections fibers from the ventrobasal nuclei. This is also a
External Includes fibers from medial lemniscus, large projection.
medullary superior cerebellar peduncle,
Posterior radiation- connects occipital and
lamina spinothalamics, and pafhways
between cortex and thalamus posterior parietal areas with pulvinar, and lateral
geniculate nucleus (geniculocalcarine radiations -
Fornix Subiculum and hippocampus to septum optic radiations). This is an extensive radiation
& hypothalamus (Part of Papez Circuit) due to the optic radiations.
Habenulo- Habenula to interpeduncular nucleus
Inferior radiations- connections from medial
peduncular and tegmentum of midbrain geniculate (auditory radiations) and pulvinar
with temporal lobe. This is the smallest group of
Internal Thalamus and cerebral cortex, fibers between the thalamus and cortex.
capsule and cerebral cortex to brain stem In Figure 15-7 the afferents and efferents of
includes: and spinal cord the individual thalamic nuclei are presented.
Anterior limb,
genu, posterior In figure 15-8 we have shown the cortical
limb projections of the same thalamic nuclei.
In figures 15-9, 15-10, 15-11, and 15-12 we
Internal Contains mammillothalamic, discuss the major afferent pathways to the thala-
medullary ascending reticular and mus and metathalamus.
lamina spinothalamic fibers.
In the table that follows, Table 15-4, we have
Mammillo- Mammillary bodies with anterior summarized the cortical projections of the major
thalamic thalamic nuclei (Part of Papez Circuit) thalamic nuclei and also included the functions of
these regions.
Mammillary Mammillary nuclei with tegmentum Other Possible Inputs to Thalamus. In
peduncle of midbrain
addition to the major pathways discussed above
there are other subcortical sources of input onto
Thalamic input onto the cortical layers.
the cerebral cortex that pass through the dien-
The most important input the cerebral cor- cephalon, and they may well have modulating
tex receives is from the thalamus. The densest effects on the thalamus (see discussion in chapter
input from the specific relay projectional nuclei 17) these include:
(e.g. VPL, VPM) is to layer 4, but as indicated 1. Noradrenet;gic (norepinephrine) pathway
above, pyramidal cells in layers 3 and 5 many also from the locus ceruleus of the midbrain project-
receive direct or indirect inputs. There is a ing in primates predominantly to layer 6 of the
modality specific columnar arrangement. With motor and somatosensory cortex and related
many nuclei having an extensive input onto the frontal and parietal association cortex.
cortex there is always a reciprocal cortical input. 2. Serotoninet;gic pathway from the raphe
The nonspecific nuclei (midline & intralarninar) nuclei in the pons and medulla and the pontine
have a more diffuse input and project onto reticular formation.
layer I. 3. Dopaminet;gic pathways from ventral
Thalamic Radiations and the tegmental - rostral mesencephalic nuclear
Internal capsule. groups. The strongest projection is to the pre-
The fibers that reciprocally interconnect the frontal cortex, and limbic system.
cortex and the thalamus form the thalamic radi- 4. Cholinet;gic pathways from the basal
ations (Fig 15-6). The thalamic radiations are forebrain nucleus of Meynert project widely to
grouped in the internal capsule into 4 peduncles: cerebral cortex.
anterior, superior, posterior and inferior. 5. GABA-et;gic pathways from basal fore-
Anterior radiations- connects frontal lobe brain, ventral tegmental area and zona incerta to
and cingulate cortex with median and anterior sensory and motor cortex.
DIENCEPHALON 15-11
perature, touch, and pressure are usually elevated
contralaterally. A mild sensory stimulus now
produces exaggerated sensory responses on the
affected side and may even cause intractable pain.
A change in emotional response may also be
noted.
Lesions restricted to the medial thalamic
nucleus produce memory and personality distur-
bances; lesions in the lateral nuclei produce sen-
sory deficits (see Chapter 20).
SUBTHALAMUS (FIG. 15-3)
The subthalamus region is included in the
diencephalon, but functionally it is part of the
basal ganglia. The subthalamic nucleus, rona
incerta, and prerubral field together form the
subthalamus. This region is medial to the poste-
rior limb of the internal capsule, lateral to the
hypothalamus, and below the thalamus. The
ansa lenticularis, subthalamic fasciculus, lenticular
fasciculus, and thalamic fasciculus provide input
TABLE 15-4: CORTICAL PROJECTION OF MAJOR

THALAMIC NUCLEI
Figure 15-8. Thalamic Projections onro Cerebral
Cortex. A. Projections onro Lateral surface of a cere-
bral hemisphere (B), Projections onro medial surface NUCLEUS CORTICAL FUNCTION
of cerebral hemisphere PROJECTION
Clinical Considerations. Anterior & Clngulate and limbic
The thalamus is the final processing station Lateral Dorsal parahippocampal
gyrus
for systems that project to the cerebral cortex;
thus it serves an important integrative function. Medial Dorsal Prefrontal & limbic
Many sensations are first crudely appreciated at rostrallemporal
thalamic levels, including pain, touch, taste, and
vibration. The discriminative processes associat- Lateral Calcarine Cortex Vision
Geniculate
ed with these sensations, as well as tactile dis-
crimination, vision, audition, and taste, are ele- lateral Superior parietal Sensory
vated to consciousness in the cerebral hemi- Posterior lobule Associalional
sphere. Glutamate is the principal transmitter in
Medial Transverse Temporal Hearing
the thalamus.
Geniculate of Superior Temporal
Thalamic syndrome (of Dejerine). In the
human a large lesion in the thalamus results in PulVinar Inferior parietal lobule, Multlmodal
the thalamic syndrome, causing diminished sen- posterior temporal Assoclational
sation on the contralateral half of the head and lobe, and occipital
body. (Complete anesthesia results from injury association cortex
to the ventral posterior lateral nucleus.) Some Ventral Anterior Premotor Motor
pain and temperature sensation from the con- Associalional
tralateral side of the body may be retained.
The internal capsule is usually involved, pro- Ventral lateral Precentral Motor Cortex
ducing an upper-motor-neuron lesion of the Ventral Posterior Postcentral Sensory Cortex
contralateral limb. The thresholds for pain, tem-
15-12 CHAPTER 15
from the globus pallidus to the subthalamus. ascend in the medial lemniscus to the dorsal thal-
The zona incerta lies between the thalamus and amus.
lenticular fasciculus. The adjacent substantia Posterior Columns (Fasciculus Gracilis and
nigra also projects onto the subthalamus. Cuneatus).
The medial portion of the globus pallidus The posterior columns--the fasciculus gra-
provides the principal input to the subthalamus cilis, and the fasciculus cuneatus (Fig. 15-9)--
via the subthalamic fasciculus, which runs conduct proprioception (position sense), vibra-
through the internal capsule. The motor and tion sensation, tactile discrimination, object
premotor cortex also project to this region. The recognition, deep touch (pressure) awareness,
subthalamus projects back to both segments of and two-point discrimination from the neck,
the globus pallidus, and substantia nigra via the thorax, abdomen, pelvis, and extremities. The
subthalamic fasciculus, and projects to the thala- sensory receptors for the system are the Golgi
mus and contralateral subthalamus. The gluta- tendon organs, muscle spindles, proprioceptors,
minergic cells in the subthalamus form the main tactile discs, and Pacini an corpuscles (deep
excitatory projection from the basal ganglia. touch, or pressure). The primary cell body is
In the human, a lesion in the subthalamus, located in the dorsal root ganglion.
usually vascular in origin, produces hemiballis- The well-myelinated fibers of this system
mus: purposeless, involuntary, violent, flinging enter the spinal cord as the medial division of the
movements of the contralateral extremity. These dorsal root and bifurcate into ascending and
movements persist during wakefulness, but dis- descending portions, which enter the dorsal col-
appear during sleep. This lesion represents umn.
underactivity in the indirect pathway in contrast The fasciculus gracilis contains fibers from
to over activity that produces Parkinsonism. (See the sacral, lumbar, and lower thoracic levels,
Chapter 18). while the fasciculus cuneatus contains fibers from
THE MAJOR SENSORY PATHWAYS OF the upper thoracic and cervical levels. Fibers
THE CENTRAL NERVOUS SYSTEM from the sacral levels are the first to enter and lie
This discussion will focus on the sensory sys- most medial, followed by lumbar, thoracic, and
tems that form the bulk of the afferents to the finally, cervical fibers. The primary axons ascend
thalamus. The voluntary motor pathways are dis- in the dorsal columns of the spinal cord to the
cussed in the end of this chapter while the other secondary cell body of this system located in the
motor pathways are discussed in Chapters 11, nucleus gracilis and the nucleus cuneatus in the
12, and 17. lower medullary levels.
Basic Principal of Sensory System: All sen- From the secondary cell bodies the fibers
sory systems have three neurons: cross the midline, join the medial lemniscus, and
1st neuron in periphery the dorsal root gan- ascend to the ventral posterior lateral nucleus in
glion or ganglion of cranial nerves V, Vii, IX, the thalamus. From this thalamic nucleus these
or X, fibers are projected to the postcentral gyrus
2nd neuron within CNS spinal cord or brain (areas 1,2,3).
stem; its axon u crosses to the contralateral side, Fibers also descend in the dorsal columns,
and but their functional significance is unknown.
3rd order neuron is the final neuron in the The fibers responsible for proprioception
sensory systems and its axons reach the cerebral cross in the medial lemniscus. The fibers for
cortex. vibration sensation and tactile discrimination
ascend bilaterally in the medial lemniscus to the
Medial Lenmiscus--General Somatic Tactile
ventral posterior lateral nucleus. Consequently, a
Sensation (Fig 15-9).
unilateral lesion can abolish proprioception, but
The ascending sensory fibers from the body
tactile discrimination and vibration sensation will
for touch (posterior columns), from the face for not be entirely lost.
touch and pain (trigeminothalamic), and from
the viscera for general and special sensation Clinical Lesions.
DIENCEPHALON 15-13
Injury to the posterior column appears not to recognize differences in the shape and weight of
affect pressure sense, but vibration sense, two- objects placed in the hand is impaired. Since the
point discrimination, and tactile discrimination extremities are more sensitive to these modalities
are diminished or abolished, depending on the than any other body regions, position sense is
extent of the lesion. Interruption of the medial impaired more severely in the extremities than
fibers (cervical-hand region) affect the ability to elsewhere, and the person has trouble identifying
small passive movements of the limbs.
Consequently, performance of voluntary acts is
impaired and movements are clumsy (sensory
ataxia). Lesions in lateral fibers of the posterior
column, gracilis, may be devastating due to the
interruption of one of the most important senso-
ry mechanisms the ability to detect the sole of the
foot. This is a major handicap in walking in dim
lighted or a dark room, in driving a car etc.
The discussion of the analysis of tactile infor-
mation in the cerebral cortex is found in Chapter
21 with several cases also illustrating lesions in
this region of the brain.
Tracts Originating from Secondary
Trigeminal Nuclei in the Brain Stem (Fig. 15-
10). Above all, remember that the primary cells
of the trigeminal nerve are located in the trigem-
inal ganglion in Meckel's cave in the middle cra-
nial fossa.
Proprioception from the Head.
Mesencephalic Nucleus. These unique pri-
mary cell bodies are located not only in the
trigeminal ganglion but also within the pons and
midbrain along the ascending trigeminal
rootlets, where they form the mesencephalic
nucleus of nerve V. The primary axons project to
the motor nucleus of nerve V and the reticular
Figure 15-9 Posterior columns, the funiculus gra- formation. Axons are also projected to the cere-
cilis and the funiculus cuneatus. This fiber bundle bellum and inferior olive.
originates from tactile and J!roprioceptive receptors. The origin of the secondary neuron is unclear
The J!rimary and secondary cell bodies are on the (but probably the descending nucleus of nerve
ipsilateral side of the spinal cord. The secondary V). The secondary axons ascend near the medi-
neurons are found in the medulla. The secondary
axons cross the midline and ascend in the contralat-
al lemniscus to the ventral posterior medial
eral medial lemniscus to the ventral posterior later- nucleus of the thalamus.
al nucleus (VPL) in the thalamus. In the spinal Pain and Temperature from the Head.
cord the posterior columns are uncrossed and divid- Descending Nucleus of Nerve V. The cell
ed into the medial gracile faseiculus (lower extrem-
bodies of primary neurons are located in the
ity) and the lateral cuneate faseiculus (upper
extremity). Fibers from the upper extremity form 50
trigeminal ganglion, and the primary axons are
%of the posterior columns with the lower extremity numerous. These fibers enter the pons, lie on the
25% and the remainder from the thorax and external surface of the descending tract of nerve
abdomen. These fibers cross in the sensory decussa- V, and then terminate in the descending nucleus
tion and form the bulk of the medial lemniscus of nerve V. The ophthalmic fibers descend to
along with trigeminal and other fibers. C3, the maxillary to C1, and the mandibular to
15-14 CHAPTER 15
the lower medulla. The secondary axons leave

the descending nucleus of nerve V and ascend
bilaterally in the medial lemniscus to the ventral
posterior medial nucleus of the thalamus. The
predominant component is crossed.
Tactile Discrimination, Vibration Sensation,
and Pressure Sense from the Head,
Chief Nudeus ofV. The cell bodies ofpri-
mary neurons are located in the trigeminal gan-
glion. The primary axons enter the pons and end
on the main sensory nucleus of nerve V, from
which the secondary axons ascend contralaterally
in the medial lemniscus or ipsilaterally in the dor-
sal trigeminothalamic tract to the ventral posteri-
or medial nucleus, primarily on the contralateral
side of the brain stem.
Lesions in the sensory nuclei cause an
absence of sensation on the same side of the
head, while lesions of the tracts produce dimin-
ished sensation.
Anterolateral Pathways- Spinothalamic and
Trigeminothalamic Tract--Pain Pathways (Fig.
15-10)
Pain from the Body. Fig 15-H.
Anterolateral PathwayjSpinothalamic.
This tract conducts pain and temperature sensa-
tion from the neck, thorax, abdomen, pelvis, and
extremities. The receptors for pain are the naked
free nerve endings, and the corpuscles of Ruffini
and of Krause detect warmth and cold. The pri-
mary cell bodies are located in the dorsal root
ganglion; the axons enter the spinal cord and
Figure 15-10 &nsory Portion of Trigeminal System. ascend or descend one segment ipsilaterally
Touch and Pain from the head. This is the largest before ending on neurons in the dorsal horn
cranial nerve in the brain stem and has three divi- lamina 1 to 3. The axons of the secondary cells
sions: Ophthalmic (V1), Maxillary(V2) and
cross in the anterior commissure of the spinal
Mandibular (V3). Each of these divisions brings in
sensation from pain, temperature, touch and pres- cord and ascend in the ventrolateral part of the
sure receptors in the skin, muscles and sinuses they lateral funiculus in the spinal cord and medulla.
innervate. The tactile fibers synapse with the chief In the pons they are found at the lateral margin
sensory nucleus in the pons. The Proprioceptive fibers of the medial lemniscus and continue up to the
(not shown) enter and ascend through pontine and ventral posterior lateral nucleus and the intralam-
midbrain levels and synapse on the mesencephalic inar nuclei of the dorsal thalamus. The axons in
nucleus of nerve V which then synapses on the motor this tract convey information from the contralat-
nucleus of V in the pons for the "jaw jerk". The eral side.
secondary axons ascend in the medial lemniscus to
The pain fibers in this tract are arranged seg-
the ventral posterior medial nucleus (VPM) in the
thalamus. The pain fibers cross while the touch fibers mentally with the most lateroposterior fibers rep-
run bilateral up to the thalamus, and end in VPM resenting the lowest part of the sacral levels of the
and are then projected onto the lower third of the body, and the more medioanterior fibers repre-
postcentral gyrus. senting the upper extremities and neck. The
DIENCEPHALON 15-15
temperature fibers have this same arrangement
but are internal to the pain fibers. For surgical
relief of pain this tract is located by identifYing
the denticulate ligament and then sectioning
about 1 mm. below the ligament (Fig7-29).
The sharp pain noted with most injuries is
associated with the heavily myelinated direct, or
spinothalamic, pathway to the ventral posterior
lateral nucleus. In addition to the stabbing pain,
dull throbbing pain is usually noted; it is carried
up more slowly by a multisynaptic pathway,
probably via the reticular system, and is called the
spinoreticulothalamic pathway.
A unilateral lesion of the spinothalamic tract
in the spinal cord produces an almost complete
absence of pain (analgesia) and temperature sen-
sation (thermoanesthesia) on the contralateral
side. At the upper pontine levels, the lateral
spinothalamic tract is usually closely associated
with the medial lemniscus. Consequently, a uni-
lateral lesion at these levels diminishes pain and
temperature sensation from the opposite side of
the body--as well as touch, vibration sensation,
and proprioception--.
Anterior Spinothalamic Tract--Light Touch
Light touch awareness from the neck, tho-
rax, pelvis, and extremities is carried up the
anterior spinothalamic tract (Fig 15-11). The
primary neuron is located in the dorsal root gan-
glion; the secondary neuron is located in the dor-
sal hom of the same side. The secondary fibers
ascend contralaterally in the lateral funiculus,
joining the medial lemniscus at the upper pon-
tine levels. Stroking a hairless area of the skin
with cotton evokes light touch. Lesions involv-
ing this tract produce no definite clinical defi- L~ ,
ciencies, probably because somewhat similar sen-
sations are also carried in the uncrossed dorsal
columns (fine touch, pressure). Figure 15-11 Anterolateral pathway-lateral
Pain and Temperature Sensation from the spinothalamic fibers. The Pain Pathway. Originate
from pain and temperature receptors in the skin.
Head. This information is carried by the
Primary cell bodies are dorsal root ganglia of the
descending nucleus and root of nerve V. The
spinal cord. The axons synapse in the dorsal horn, cross
primary cell bodies are found in the trigeminal within 3 spinal cord segments and form the spinothal-
ganglion located in the middle cranial fossa, and amic fibers. These fibers pass into the thalamus. The
the secondary cell bodies originate in the direct pathway, for localizing the pain on the body,
descending nucleus of nerve V. The descending fibers end in VPL which projects onto postcentral
nucleus is very large and extends from pons into gyrus. How one responds to pain comes from the indi-
medulla and upper cervical spinal cord. This rect pain pathway that ascends to the dorsomedial
nucleus is divided into three regions pars - oralis thalamic nucleus and is then projected onto the pre-
frontal gyrus.
15-16 CHAPTER 15
(in pons and upper medulla), pars - interpolar (in Cerebellar Tracts--Unconscious
medulla), and pars - caudalis (in cervical cord). Proprioception See chapter 21.
These fibers enter the spinal trigeminal nucleus The cerebellar cortex must have propriocep-
external to the descending nucleus on the lateral tive information to insure proper muscle tone
surface of the pons and are somatotopically orga- and coordination. Fibers carrying this informa-
nized with V3 dorsal, VI ventral, and V2 inter- tion run to the cerebellum in the following path-
mediate. Fibers of cranial nerves VII, IX and X ways: posterior spinocerebellar, anterior spin-
are dorsal to V3. These fibers descend and end in ocerebellar, cuneocerebellar.
the spinal trigeminal nucleus with VI ending in Posterior Spinocerebellar Tract
pars caudalis in cervical levels, V2 to interpolar (Fig. 15-12). The primary neuron is located in
nucleus in medulla, and V3 to pars oralls in upper
medulla and pons. The secondary axons ascend
contralaterally in the medial lemniscus to the
ventral posterior medial nucleus of the thalamus
or to the intralaminar nuclei.
VIsceral Referred Pain.
Referred pain is caused by painful impulses
originating in the viscera that are transmitted by
the sympathetic nerves and referred to the
periphery of the body. The organ in which the
pain is felt belongs to the same sensory der-
matome as the visceral structure where it origi-
nates as follows: lungs, C8 to T8; heart, C8 to
T8; bladder, TI to 1'9; testes, TIO to TI2; kid-
neys, TIl to Ll, and rectum, S2 to S4.
Unconscious proprioception from the lower
extremity, Thorax, Abdomen and Pelvis
This information is carried up to the cerebel-
lum by the anterior and posterior spinocerebellar
tracts. The receptors for both tracts are the neu-
romuscular spindles and the Golgi tendon
organs.
Unconscious Proprioception from the
Lower Extremity, Thorax, Abdomen, and
Pelvis. This information is carried up to the
cerebellum by the anterior and posterior spin-
ocerebellar tracts.
Unconscious Proprioception from the Upper
Extremity and Neck and Head.
Cuneocerebellar Pathway. The primary
neurons are found in the dorsal root ganglion at
cervical levels and in the trigeminal propriocep-
tive fibers. Their axons ascend in the dorsal
columns and end in the external cuneate nuclei Figure 15-12. Anterior and posterior Spinocerebellar
(external to the cuneate nucleus) in the lower Pathways. -Unconscious proprioception to the cerebel-
medullary levels. The secondary axons ascend lum. These tracts carry information from
bilaterally with the posterior spinocerebellar tract Proprioceptive receptors in the body into the cerebel-
and enter the cerebellum primarily uncrossed. lum with the anterior pathway crossed and the posteri-
or uncrossed.
DIENCEPHALON 15-17
the dorsal root ganglion; the secondary neuron is and insular gyrus, with the largest group of fibers
located in Clarke I s column in the dorsal hom at coming from the somatosensory strip and pre-
levels C8 to 13 of the cord. The secondary motor cortex. These corticopontine fibers
axons ascend uncrossed in the lateral funiculus, synapse upon the pontine gray and then pass into
enter the cerebellum via the inferior cerebellar the contralateral cerebellar hemisphere. Lesions
peduncle, and terminate in the ipsilateral vermis in these fibers systems do not cause any clinical
(midline portion of the cerebellum). deficit although these fibers must be important
Anterior Spinocerebellar Tract (Fig. 15- in all fine movements.
12). The primary neuron is in the dorsal root The corticopontine fibers end on the pontine
ganglion, while the secondary neuron is in cells nuclei. The axons from the pontine nuclei are
at the margin of the dorsal hom that are scattered crossed and constitute part of the mossy-fiber
throughout the spinal cord, especially in the lum- input to the granule cells.
bar levels. The secondary axon crosses the mid- The inferior cerebellar peduncle (restiform
line and ascends anterior to the posterior spin- body) connects the brain stem and spinal cord
ocerebellar tract in the lateral funiculus and with the cerebellum (Fig. 15-12). The climbing
medulla; it enters the cerebellum via the superior fibers from the inferior olive enter this peduncle
cerebellar peduncle and terminates in the same and extend to the Purkinje cells in the deep cere-
parts of the cerebellar vermis as the posterior bellar nuclei. The fibers from the vestibular
spinocerebellar tract except it is located on the nuclei, reticular formation, and trigeminal nuclei,
contralateral side. as well as the dorsal spinocerebellar fibers, enter
The receptors for both tracts are the neuro- through this peduncle. Many of these fibers con-
muscular spindles and Golgi tendon organs. tribute to the mossy-fiber input to the cerebel-
Cerebellar Peduncles (see Chapter 20). lum. The aminergic fibers from the raphe and
The cerebellum is interconnected to the brain locus ceruleus also enter the cerebellum through
stem by three major fiber bundles, or brachium: the inferior cerebellar peduncle. There is a major
the superior cerebellar, middle cerebellar, and cerebellar projection onto the reticular formation
inferior cerebellar peduncles. of the pons and medulla and onto the vestibular
The axons in the superior cerebellar peduncle nuclei from the fastigial nucleus, as well as a
(brachium conjunctivum) are primarily efferent strong cerebellar input onto the vestibular nuclei
and ascending axons originating in the deep from the flocculonodular lobe.
cerebellar nuclei - dentate, emboliform, SPECIAL SENSORY
These fibers cross in the tegmentum of the CRANIAL NERVE VIII
lower midbrain (decussation of the superior cere- VISual Pathway. Discussed in Chapter 21
bellar peduncle) with some fibers ending on the
on VISion.
red nucleus and oculomotor complex. However,
The inner ear that contains the receptors for
the majority of the fibers in the superior cerebel-
the auditory and vestibular systems and their cen-
lar peduncle distribute to the motor nuclei of the
tral projections are discussed in the Special
thalamus - ventral lateral and ventral anterior
Sensory Section on the CD that also includes the
nuclei. This cerebellar projection to the motor
Chapter on Vision.
cortex permits the well-controlled volitional acts
CN VIII - Auditory Pathway. The audito-
of the corticospinal and corticobulbar systems.
ry nerve, Cranial Nerve VIII, terminates in the
The ventral spinocerebellar fibers enter the cere-
dorsal and ventral cochlear nuclei in the medulla.
bellum through the superior cerebellar peduncle.
Each sound has a specific location on the
The middle cerebellar peduncle (brachium
cochlea. The termination is in a tonotopic pat-
pontis) is the largest cerebellar peduncle and is
tern in each nucleus with the low frequency
purely afferent (Fig. 15-12). The largest group of
fibers terminating ventrally and the high fre-
descending fibers from the cerebral hemispheres
quency fibers dorsally creating a series of fre-
is directed upon the pontine gray. These fibers quency sensitive layers. The frequency of sounds
form the bulk of the cerebral peduncle and
descend from all cortical lobes and the cingulate
15-18 CHAPTER 15
is from 100 - 15,000Hz. Taste and General Sensation

The dorsal cochlear nucleus projects con- from the VIScera
tralaterally through the lateral lemniscus to the General sensation from the gastrointestinal
inferior colliculus while the ventral cochlear system (cranial nerve X) and from the taste buds
nucleus projects bilaterally to the medial superior on the tongue (cranial nerves, VII, IX, and X)
olivary nucleus and ipsilateral lateral superior oli- enters the brain stem to terminate on the nucle-
vary nucleus. Frequencies above 2000 Hz are us solitarius in the medulla. Fibers ascend pri-
recorded in the lateral superior olivary nucleus. marily uncrossed either in the central tegmental
The lateral superior olive projects to the con- pathway or in the medial lemniscus to reach
tralateral inferior colliculus while the medial basomedial portion of ventral posterior medial
superior olivary nucleus projects ipsilaterally to (VPM) nucleus in the dorsal thalamus. Many of
inferior colliculus, medial geniculate and audito- the gustatory fibers terminate in the ipsilateral
ry cortex. parabrachial nucleus before reaching the ven-
Cortical Projection. The laminated ventral trobasal portion of VPM nucleus. The cortical
medial geniculate projects onto the primary region for taste is in the parietal lobe in the upper
auditory cortex area 41 while the dorsal medial banks of the lateral sulcus.
geniculate projects onto auditory association
MAJOR VOLUNTARY
areas 42.
MOTOR PATHWAYS
CN vrn - Vestibular Pathway (These
fibers should be considered part of the proprio- In the older literature the motor pathways
ceptive system). were divided into pyramidal (corticospinal and
The vestibular fibers originated from two corticonuclear) and extrapyramidal (rubrospinal,
ganglia the superior and inferior ganglia of tectospinal, and so on). These terms are no
Scarpa. There are 4 major vestibular nuclei: supe- longer used, and each pathway is now usually
rior (SVN), lateral (LVN), medial (MVN) and described in terms of its function.
inferior (IVN). Trunk and limb somatosensory Basic Principal of Motor System. The
pathways send information to LVN, MVN and motor system consists of two portions: an upper
IVN. Visual information also indirectly reaches and lower motor neuron. The portion originat-
ing in the gray matter of the motor sensory strip
these same nuclei. The semicircular input reach-
es SVN, MVN, and LVN. The utricle projects of the cerebral cortex is called upper motor neu-
mainly to LVN, the saccule to IVN. The fastigial rons. The pathway from the upper motor neu-
nucleus of the cerebellum is excitatory to the rons, corticospinal or corticonuclear, descends
vestibular nuclei while the cerebellar cortex is and crosses over to innervate the lower motor
inhibitory. The vestibular nuclei project to deep neurons in the brain stem or spinal cord.
layers of the superior colliculus adjacent to pro- The axons of the upper motor neurons either
jections from cervical proprioceptive endings. synapse on interneurons or end directly on the
Cortical Projection. From the LVN there is a lower motor neurons. The axons of the lower
motor neurons leave the central nervous system
small contralateral input to ventroposterior and
and form the motor division of the peripheral
medial magnocellular of MGN. Ventroposterior
projects to SI arm region of 3a, while the MGN nervous system.
projects to area 5 and the neck region of area 2. CORTICOSPINAL TRACTS--
Stimulation of either of these cortical regions VOLUNTARY CONTROL
produces vestibular sensations. The cortical neu- OF THE LIMBS, THORAX, AND
rons respond to both vestibular and propriocep- ABDOMEN. (Fig. 15-13)
tive stimuli from neck trunk and proximal joints This tract innervates the motor neurons that
and the response are excitatory for one rotation control the skeletal muscles in the neck, thorax,
in one direction and inhibitory in the other. abdomen, pelvis, and the extremities. It is essen-
tial for accurate voluntary movements and is the
only direct tract from the cortex to the spinal
motor neurons.
DIENCEPHALON 15-19
fibers pass through the genu of the internal cap-
sule into the middle third of the cerebral pedun-
cles and enter the pons, where they are broken
into many fascicles and are covered by pontine
gray and white matter. In the medulla, the fibers
are again united and are found on the anterior
medial surface of the brain stem in the medullary
pyramids.
About 75 to 90% of the corticospinal tract
fibers cross at the medullospinal junction and are
thereafter found in the lateral funiculus of the
spinal cord. (The majority of fibers from the
dominant hemisphere cross at the medullospinal
junction.) Some corticospinal fibers remain
uncrossed in the anterior funiculus but will slow-
ly cross at cervical levels. About 50% of the cor-
ticospinal fibers end at the cervicallevels--about
30% go to the lumbosacral levels, and the
remainder to the thoracic levels.
Most of the corticospinal fibers end on inter-
nuncial neurons in laminae 7 and 8 of the spinal
cord, but in regions in the spinal cord where the
digits are represented (in the cervical and lum-
bosacral enlargements) the corticospinal fibers
sometimes end directly on the motor horn cells.
The internuncial neurons are located in lamina 7
of the spinal cord. Lesions in the corticospinal
tract produce contralateral upper motor neuron
symptoms, while lesions in the spinal motor neu-
rons or rootlets cause lower motor neuron symp-
toms.
CORTICONUCLEAR SYSTEM--
VOLUNTARY CONTROL OF THE
MUSCLES CONTROLLED BY
CRANIAL NERVES V, VII,
AND IX TO XII (Figs. 15-14)
This system distributes to the motor nuclei of
the cranial nerves V, VII, IX, X, XI, and XII and
provides voluntary and involuntary control of
the muscles and glands innervated by these
nerves. In the older literature this pathway was
Figure 15-13. Corticospinal Patlnvay. Voluntary called corticobulbar because the medulla and
MOfIement of the Muscles in the upper and lower pons containing these nuclei are collectively
extremities, thorax and abdomen. called the bulb. We prefer the term corticonu-
clear because it makes the student realize the key
This system originates from the pyramidal role of the cranial nerve nuclei in movement.
cells and giant cells of Betz in the upper two- These fibers are found anterior to the corti-
thirds of the precentral gyrus, area 4, and to a cospinal fibers in the genu of the internal capsule
lesser degree from area 6 and parts of the frontal, and medial to the corticospinal tract in the cere-
parietal, temporal, and cingulate cortices. The
15-20 CHAPTER 15
bral peduncle, pons, and medullary pyramids. through the tegmentum, usually in the medial
The fibers supplying the cranial nerves have lemniscus (corticomesencephalic tract). Fibers to
the following cortical origin: cranial nerve VI also descend in this way to the
I. Muscles of facial expression (motor nerve parabducens and parapontine reticular nuclei of
VII), mastication (motor nerve V), and degluti-
tion (ambiguous nuclei of nerves IX and X) orig-
inate from pyramidal cells in the inferior part of
the precentral gyrus, area 4.
2. Muscles in the larynx are controlled from
the inferior frontal gyrus and from the frontal
operculum (the posterior part of the pars trian-
gularis, area 44). It appears that many corti-
conuclear axons end on interneurons and not
directly on the motor neuron of the cranial
nerve.
3. The cortical innervation of the cranial
nerves is bilateral, with the exception of the lower
facial muscles, which are innervated by the con-
tralateral cortex. Consequently unilateral lesions
in the corticonuclear system produce only weak-
ness and not paralysis. Paralysis results only from
bilateral lesions in the corticonuclear system.
4. Lower motor neuron lesions of motor cra-
nial nerves. A lesion of the motor nucleus or
rootlet produces a lower motor neuron syn-
drome with paralysis, muscle atrophy and
decreased reflexes.
Supranuclear lesions produce upper motor
neuron symptoms. Associated with bilateral
lesions of the corticonuclear system is pseudo-
bulbar palsy with bilateral UMN signs and inap-
propriate behavioral. This probably represents
the release of cortical control via the corticonu-
clear innervation of the muscles controlled by the
cranial nerves. Limbic control to these nuclei
takes over, via descending autonomic pathways,
and the emotional state is undamped by the
frontal lobes
CORTICOMESENCEPHALIC SYSTEM--
VOLUNTARY CONTROL OF
MUSCLES ASSOCIATED WITH EYE
MOVEMENTS--CRANIAL NERVES ill, modu '"
IV,ANDVI.
The fibers controlling eye movements origi-
Figure 15-14. Corticobulbar/Corticonuelear
nate from the frontal eye fields in the caudal part Patlrway. Voluntary MOPements of the muscles associ-
of the middle frontal gyrus and the adjacent infe- ated with Cranial Nerves V, VII, and IX, X, XI,
rior frontal gyrus (area 8). At upper midbrain lev- XII. Control of the cranial nerves that mope the mus-
els, fibers to cranial nerves III and IV leave the cles (III, IV & VI) of the eyes is through the
cerebral peduncles and take a descending path Corticomesencephalic patlrway
DIENCEPHALON 15-21
the pons, which coordinate movements under Major Sensory and Motor Pathways in the
the control of cranial nerves III and VI ascend- human central nervous system
ing through the medial longitudinal fasciculus.
The table that follows, Table 15-5, lists the
TABLE 15-5. MAJOR SUBCORTICAL TRACTS WITHIN THE BRAIN STEM AND DIENCEPHALON
Pmhway ____~F=un=d=lo=n_________________________
Sensory Pathways Functions
Spinothalamics and Trlgemlnothalamics Pain and temperature from body, head and neck
SolHary tract Toste and general sensation from the viscera
Cerebellar Peduncles: Unconscious sensory and motor

Superior (Cerebellum-Cerebrum)
Middle (Cerebrum-Cerebellum)
Inferior (Cerebellum with brain stem
and spinal cord & CN VIII)
Optic Pathway - from retina via lateral Vision & light reflexes
geniculate to calcarine cortex (Chapter 21).
Auditory Pathway - cochlear nuclei via lateral lemniscus Auditory

to inferior colliculus, brachium of inferior colliculus
to medial geniculate and to auditory cortex,
(Chapter 11 & Inner Ear- Special Senses on CD).
Vestibular Pathway (Port of Proprioceptive Pathway)- Proprioceptive

lateral vestibular nucleus to Ventral posterior and
MGN then to postcentral gyrus. (Chapter 11 &
Inner ear -Special Senses on CD)
Motor Pathways Functions

----------------------------------------
Corticospinal. Voluntary control of muscles In limbs thorax and abdomen
Corliconuclear Voluntary control of:

Facial expression by innervation of cranial nerves V, VII, IX-XII.
larynx by innervation of cranial nerves
----------------------
Corticomesencephalic Voluntary control of eye movements by innervation
of cranial nerves III, IV and VI.
Rubrospinal, rubronuclear, tectospinal &tectonuclear Backup to voluntary motor system
Reticular Limbic (emotional)
MedlallongHudinal FaSCiculus Coordinate eye movements in brain stem

via cranial nerves III, IV & VI
Monamine Containing: Set tone in motor system and effect limbic system.
Norepinephrine, dopaminergic, serotonerglc
Descending sympathelics & parasympathelics Autonomic functions

------------------------------
CHAPTER 16
Hypothalamus, Neuroendocrine System,
and Autonomic Nervous System
Case History 16-1. A 25-year old white learning disabilities. A trans-sphenoid excision of
male auto body mechanic in July, developed the pituitary adenoma was performed. Except for
numbness in the median nerve distribution of transient diabetes insipidus, he did well and all
the left hand with pain at the left wrist, shooting symptoms disappeared.
into the index, middle and ring fi8ngers. And Comments.
aching pain in finger joints. To a lesser degree,
The patient presented with a chief complains
similar symptoms had developed in the right
relevant to compression of the median nerve at
hand. The clinical impression of bilateral carpal
the carpal tunnel. Usually the carpal tunnel syn-
tunnel syndrome was confirmed by nerve con-
drome occurs in one hand or the other and may
duction studies. In addition the patient present-
reflect local swelling in the tendons and soft tis-
ed many of the facial features of acromegaly; sues. This is at times a result of occupation-relat-
coarse lips, large jaw and nose. None of his fam-
ed repetitive motion at the wrist. In occasional
ily had similar facial features and according to his
case, an underlying systematic conditions is pre-
mother, these features had emerged about age
sent, these include; rheumatoid arthritis, preg-
12.
nancy, myxedema of the hypothyroid state and
Growth hormone levels were consistently
acromegaly associated with excessive secretion of
elevated to 17-20 ng/ml (normal is less that 5
growth hormone by pituitary adenomas.
ng/ml fasting and recumbent). A glucose load
In this case, the neurologist noted the facial
produced no suppression. Prolactin level was
feature characteristic of acromegaly. In retro-
moderately increased to 37 ng/ml (normal in
spect, the patient's mother was able to date these
men if less that 1-20 ng/ml). MRI demonstrat-
changes to his teen years. Excessive production
ed an enlarged pituitary gland with a hypodense
of growth hormone, prior to closure of the epi-
lesion, consistent with an adenoma (Fig 16-1). . A physeal plates in long bones, result in excessive
partial agenesis of the corpus callosum (spleruum
growth or gigantism. While excessive e produc-
and posterior one-third of the body) was also
tion of growth hormone after epiphyseal closure
present and may have related to long-standing
Figure 16-1. Adenomas. A) MRI, T1-weighted midline sagital sections; B) Control MRI, T1, weighted
16-2 CHAPTERl6
results in enlargement of facial bones, jaw, hand insipidus often is present reflecting temporary
and feet. The pain in the finger joints may have damage to the posterior pituitary or pituitary
reflected an early stage of enlargement of the stalk.
fingers. HYPOTHALAMUS
In the present case, the adenoma had
The hypothalamus is a very small nuclear
enlarged the pituitary gland, but the tumor had
mass found at the base of the third ventricle in
not expanded out of the sella turcica. The pitu-
the diencephalon. Its functional potency is relat-
itary gland sits in the sella turcica, which is part
ed to its control of the hypophysis and its
of the sphenoid bone. Suprasellar, or upward
descending autonomic fibers, which affect pre-
extension of the tumor may result in compres-
ganglionic parasympathetic and sympathetic
sion of the optic chiasm. A characteristic visual
nuclei in the brain stem and the thoracic, lumbar
field defect occurs; a bitemporal hemianopsia
and sacral spinal cord. In addition, this dien-
(loss of the outer halves of both visual fields).
cephalic region with its important tracts form
Lateral extension of the tumor into the cav-
part of the Papez circuit and must be included ~
ernous sinus may compress the III, IV and VI
any discussion of the limbic (or emotional) braID
cranial nerves, resulting in diplopia (double
in Chapter 22.
vision). Headaches may reflect unusual pressure
The hypothalamus bilaterally forms the
on the diaphragm sella. Acute headache may
medial inferior part of the floor of the dien-
reflect sudden increase in mass within the tumor
cephalon and is located on the wall of the third
due to infarctions of hemorrhage (so called
ventricle, extending from the anterior margin of
"pituitary apoplexy". Pain in the eye of face may
the optic chiasm to the posterior margin of the
reflect compression of the maxillary or oph-
mammillary bodies. It is bounded dorsally by
thalmic division of the trigeminal nerve with the
the dorsal thalamus and laterally by the subthala-
cavernous sinus.
mus and internal capsule. It is connected to the
Careful removal of the tumor, in this case uti-
hypophysis by the hypothalamic-hypophyseal
lizing the trans-sphenoidal approach and the
tract and the hypothalamic-hypophyseal portal
operating microscope, allowed preservation of
system. The hypothalamus consists of more than
residual pituitary function. Transient diabetes a dozen nuclei with their associated fiber systems.
Paraventricular N.
Anterior
Commissure
Suprachiasmatic N.
Optic chiasm
and nerve
Arcuate N. Ventromedial N Mammillary N.
Fig 16-2. The zones and nuclei of the hypothalamus. The hypophysis and the nuclei of the hypothalamus.
HYPOTHALAMUS, NEUROENDOCRINE & AUTONOMIC NERVOUS SYSTEM 16-3
Although the hypothalamus weighs only 4 dial, ventromedial, lateral, and tuberal nuclei
gm, this small area controls our internal home- (Fig. 16-3).
ostasis and influences emotional and behavior 3. The posterior zone (Fig. 16-4), including
patterns. the posterior hypothalamic nuclei and mammil-
Hypothalamic Nuclei lary nuclei (both large- and small-celled).
The lateral zone includes the lateral nucleus,
Anatomically the hypothalamus is divided
the lateral tuberal nucleus, and the medial fore-
into a medial and a lateral zone (Fig. 16-2).
brain bundle. In addition, Periventricular nuclei
The medial zone consists of three regions:
are adjacent to the third ventricle at all levels of
1. The anterior zone, including the preoptic,
the medial region.
supraoptic, pariventricular, anterior, and
Anterior Group (Fig 16-3). The preoptic,
suprachiasmatic nuclei (Fig. 16-2).
suprachiasmatic, supraoptic, and paraventricular
2. The middle zone, including the dorsome-
Supraoptic N.
Lateral
SuprachiasmatIC N OptIC chiasm
MammlliaryN
Figure 16-3. Myelin stain of diencephalon at the level
of the anterior hypothalamus and optic chiasm shuw- Figure 16-5. Myelin and cell stain (Kluver-Berrera)
ing corpus callosum, precommissural anterior com- of diencephalon at posterior hypothalamus. (Corpus
missure, and corplls striatum. callosum rem(Jved.)
Fig.
InfundoOu Ilt (ArCuale) N
Figure 16-4. Myelin and cell stain (Kluver-Berrera) nuclei are found in this region. The supraoptic
of diencephalon at mid-hypothalamus, demonstrating and paraventricular nuclei contain secretory
tuberal nuclei and mammillary bodies. (Inset mag- granules (containing oxytocin and vasopressin)
nifications)
that leave these nuclei and pass down the hypo-
16-4 CHAPTER 16
thalamic-hypophyseal pathway, which terminates mammillary body (medial and lateral nuclei) and
at the capillaries in the posterior lobe of the pitu- posterior hypothalamic nuclei. A major part of
itary, or neurohypophysis. the fornix projects onto this region with the
The supraoptic nucleus functions as an mammillary nuclei then projecting via the mam-
osmoreceptor; it releases vasopressin in response millothalamic tract onto the anterior thalamic
to an increase in osmotic pressure in the capillar- nuclei. The mammillary nuclei also project onto
ies. Vasopressin or ADH (antidiuretic hormone) the brain stem tegmentum through the mam-
that increases water resorption in the kidneys.
The suprachiasmatic nucleus, which receives
direct input from optic fibers in the chiasm, is
important in the endocrine response to light lev-
els and may well be the location of the biological
clock.
Middle Group (Fig 16-4). This region
includes the dorsomedial, ventromedial arcuate
(infundibular), lateral, and lateral tuberal nuclei.
The ventromedial nucleus has extensive projec-
tions onto the diencephalon, brain stem, and
spinal cord. Lesions here affect feeding behavior
(e.g., obesity or anorexia). Arising from the
tuberal nuclei, the tuberoinfundibular pathway
terminates on the hypophyseal portal veins, per-
mitting releasing factors produced in the hypo-
thalamus to reach the anterior lobe of the pitu-
Figure 16-6 Affrrent pathways into the hypothalamus.
itary.
Posterior Group (fig 16-5 consists of the millary peduncle. Lesions in these nuclei are seen
TABLE 16-1. REVIEW OF FUNCTIONAL LOCALIZATION in Korsakoff's psychosis with accompanying ret-
IN HYPOTHALAMIC NUCLEI: rograde amnesia (See Chapter 30).
Table 16-1 Review functional localization in
Hypothalamic the Hypothalamic Nuclei.
Nuclei Function Afferent Pathways
Supraoptic & Osmoregulatlon--release of vasopressin The hypothalamus is so situated that it func-
Paraventricular or oxytocin. lesion here produces
nucleus diabetes insipidus
tions as an important integrating center between
the brain stem, reticular system and the limbic
Ventromedial Feeding centers. lesion In ventromedial forebrain structures.
nucleus and produces overeating; lesion in lateral The major subcortical (afferent) inputs into
lateral hypothalamus produces anorexia. the hypothalamus include (FIG 16-6:
hypothalamus FIG 16-6
Anterolateral Stimulation of anterolateral region 1. Reticular input from the ascending multi-
region and excites parasympathetic nervous system synaptic pathways in the mesencephalic reticular
posterior and inhibits sympatheffc nervous system nuclei via the medial forebrain bundle, dorsal
hypothalamus (posterior region) and produces slow longitudinal fasciculus, and mammillary pedun-
wave sleep. cle; 2.The globus pallidus through lenticular fas-
Stimulation of posterior hypothalamus
excites sympatheffc and inhibits
ciculus and ansa lenticularis (see chapter 18).
parasympathetic and is Important in 3. Thalamic input from the dorsal medial
arousal and waklng from sleep. nucleus and intralaminar nuclei via direct con-
lesions in anterolateral produce nections onto the hypothalamus.
sympatheHc response while lesion in 4. Fibers from the optic nerve, retinohypo-
posterior produces parasympathetic thalamic fibers, which end in the suprachiasmat-
response.
ic nucleus (see chapter 20). and autonomic neurons in the brain stem associ-
5. The major cortical input into the hypo- ated with cranial nerves VII, IX, and X and the
thalamus comes from the temporal lobe - hip- spinal cord.
pocampal formation (fornix), amygdala (stria ter- 5. Hypothalamic-hypophyseal tracts, or neu-
minalis), from cingulate gyrus (cingulohypothal- rosecretory system (Fig. 16-8), which connects the
amic), and frontal associational cortex (cortico- supraoptic, paraventricular, and magnocellular
hypothalamic fibers). Thus we see that the hypo- nuclei via the hypophyseal stalk with the neural
thalamus is so situated that it serves as an impor- hypophysis.
tant integrating center between the brain stem 6. Hypothalamic-hypophyseal portal system,
reticular system and the limbic forebrain struc- which permits releasing factors made in the
tures. hypothalamus to reach the adenohypophysis (see
Efferent Pathways (Figs. 16-7) below).
Fiber tracts and the neurosecretory system Functional Stability.
mediate the output of the hypothalamus. The The hypothalamus through its relation with
efferent pathways from the hypothalamus are: the autonomic nervous system and hypophysis,
1. MammilWthalamic tract, which intercon- maintains a more-or-Iess stable, controlled, inter-
nects the medial mammillary nucleus with the nal environment regardless of the external envi-
anterior thalamic nucleus and, ultimately, with ronment. It affects body temperature, water bal-
the cingulate cortex. ance, neurosecretion, food intake, sleep and the
2. Periventricular system, which arises in the parasympathetic and sympathetic nervous sys-
supraoptic, tuberal, and posterior nuclei in the tems.
hypothalamus to supply the medial thalamic NEUROENDOCRINE SYSTEM, THE
nucleus and joins the medial forebrain bundle HYPOTHAlAMUS AND ITS RElATION
and dorsal longitudinal fasciculus. TO THE HYPOPHYSIS
3. Mammillotegmental tract, which connects In addition to the direct control of the auto-
the medial mammillary nuclei with the midbrain nomic nervous system by central pathways, the
reticular nuclei and autonomic nuclei in the brain hypothalamus has a powerful influence on other
stem. homeostatic mechanisms of the human by its
-
4. Medial forebrain bundle and dorsallongi-
tudinal fasciculus, which receive fibers from the
lateral hypothalamic nucleus and paraventricular
nuclei and connect to the midbrain tegmentum
Figure 16-8. The hypothalamic-hypophyseal tract

(neurosecretory system). This tract pr0J7ides a direct
connection between the hypothalamus and the neuro-
hypophysis. The neurosecretory granules pass down the
Figure 16-7. Hypothalamic Efferent Pathways axons of this tract and are srored in the neural lobe
until they are released into the bloodstream.
16-6 CHAPTER 16
Peripheral Central Endocrine Target

Nervous Nervous Gland Organ
System Systom Hypothalamus Pituitary
Figure 16- 9. Information flow between the brain and endocrine system.
direct control of the hypophysis. The discussion

that follows is an overview of this information
flow that is the basis of the neuroendocrine sys-
tem (Fig 16-9
Hypophysis Cerebri
The hypophyseal gland or pituitary gland
consists of two major divisions the anterior lobe
or adenohypophysis and the posterior lobe, the
neurohypophysis. There is also a smaller pars
intermedia associated with the anterior lobe. The
adenohypophysis is the larger component and
contains cords of different cell types closely asso-
ciated with capillaries of the hypothalamic-
hypophyseal portal system. The neurohypophysis
consists of the infundibular stalk and the bulbous
neurohypophysis and includes neurolglia like Figure 16-10. The hypothalamic- hypophyseal venous
pituicytes, blood vessels and some finely myeli- portal system. These venous channels provide vascular
nated axons. The hypophysis is directly connect- continuity between the hypothalamus and the adeno-
ed to the hypothalamus by the hypophyseal stalk hypophysis with releasing.factors from the hypophys-
(Figs. 16-5 and 16-7) and indirectly connects to iotrophu area of the hypothalamus drain into the
the hypothalamus by the hypothalamic hypophy- veins of the hypothalamus, which connect to the capil-
seal venous portal system. The hypophys- lary bed in the infundibular stalk and median emi-
nence. The factors are then carried to the adenohy-
iotrophic area of the hypothalamus is necessary
pophysis.
for hormone production in the adenohypoph-
ysis. The hypophysiotropic area includes parts of and supply the median eminence, infundibular
the ventromedial and other hypothalamic nuclei. stalk, and adenohypophysis. In the infundibular
These peptidergic neurons are termed parvicellu- stalk and median eminence the arteries terminate
lar (composed of small cells). The cells forming in a capillary network, which empties into veins
the neurohypophyseal tract are magnocellular that run down the infundibular stalk. In the
neurons. anterior lobe these veins form another capillary
network, or sinusoid.
Hypothalamic-Hypophyseal Portal System.
The inftrior hypophyseal arteries leave the
The hypothalamus and adenohypophysis are
internal carotid and distribute to the posterior
connected by the hypothalamic- hypophyseal
lobe, where they form a capillary network that
venous portal system (Fig. 16-10). Releasing fac-
flows into the sinus in the adenohypophysis.
tors travel from the hypothalamus to the adeno-
The hypophyseal veins finally drain into the cav-
hypophysis by this means.
ernous sinus. The releasing factors enter the
The hypophysis receives its blood supply from
venous drainage of the hypothalamus, which
two pairs of arteries: the superior hypophyseal
drains into the median eminence and hypophy-
arteries and the inferior hypophyseal arteries.
seal stalk. These factors are then carried via the
The superior hypophyseal arteries leave the inter-
hypophyseal portal system to the adenohypoph-
nal carotid and posterior communicating arteries
ysis.
The capillary loops in the infundibular stalk the kidney causing resorption of water.
and neural hypophysis drain in close proximity to Oxytocin is formed primarily in the paraven-
the neurosecretory axons of the hypothalamic- tricular nucleus and to a lesser degree in the
hypophyseal tract. supraoptic nucleus and is carried down the hypo-
Hypophysiotrophic Area. thalamic-hypophyseal tract. This substance stim-
The hypophysiotrophic area is a paramedian ulates the mammary gland, causing it to contract
zone that extends rostrally at the level of the and expel milk concomitant with suction on the
optic chiasm dorsally from the ventral surface to nipple. During delivery, oxytocin also contracts
the paraventricular nuclei. Caudally this area nar- the smooth muscle in the uterus and dilates the
rows down to include only the ventral surface of uterus, cervix, and vagina.
the hypothalamus at the level of the mammillary Hormones Produced in
recess of the third ventricle. The hypophys- Adenohypophysis. Releasing factors from the
iotrophic center includes neurons in the follow- hypothalamus traverse the hypothalamic-
ing hypothalamic nuclei: paraventricular, anteri- hypophyseal portal system and trigger the forma-
or, arcuate, ventromedial, and tuberal. tion and eventual release of the glandotropic or
Releasing and inhibitory factors, listed in tropic hormones from the adenohypophysis list-
Table 16-2, are produced in the parvicellular ed in Table 16-3.
hypophysiotrophic area and stimulate the adeno-
TABLE 16-3. HORMONES PRODUCED
hypophysis to produce and release hormones IN ADENOHYPOHYSIS
into the circulation.
TABLE 16- 2. RELEASING FACTORS AND HORMONES RELEASING HORMONES:
PRODUCED IN THE HYPOTHALAMUS -AdrenocorticotropiC (ACTH)
-lactogenic (prolactin);
Releasing Factors Produced in parvicellular -gonadotrophic:
region of hypothalamus: Luteinizing (LH) In females &
Corticotrophin Interstitial cell stimulating in males (ICSH)
Growlh hormone (somatotropin hormone) -Follicle-stimulating (FSH) In females
Growlh hormone<->inhibiting factor -Melanocyte-stimulating (MSH);
Luteinizing hormone -Somatotropin-somatotropin (STH);
Melanocyte-stimulating hormone -Thyrotropic hormone (TSH);
Melanocyte-stimulating hormone<->inhibltlng factor INHIBITORY HORMONES:
Prolactin-inhibitory factor -Iactogenic(dopamine)
Thyrotropin -Melanocyte
-somatotopic
Hormones produced or stored In neurohypophysis:
Vasopressin from paraventricular nucleus
Oxytocin from suprooptic nucleus
Hormones Produced in Adenohypophysis
Releasing factors from the hypothalamus tra-
Hormones Produced by Hypothalamus. verse the hypothalamic-hypophyseal portal sys-
Two hormones, vasopressin and oxytocin, tem and trigger the formation and eventual
are manufactured in the hypothalamus, carried release of the glandotropic or tropic hormone
down the hypothalamic-hypophyseal tract, and (listed in table 16-2 from the adenohypophysis.
stored in the neurohypophysis before being All of the tropic (switch on) hormones produced
released into the bloodstream. in the anterior lobe are at the same time trophic
Vasopressin is an antidiuretic hormone (growth promoting or maintaining) hormones,
(ADH) formed primarily in the supraoptic nucle- in whose absence their target organs atrophy Fig
us and to a lessor degree in the paraventricular 16-11).
nucleus and carried down the hypothalamic- Hormones produced in the adenohypoph-
hypophyseal tract. This substance acts on the ysis:
distal convoluted tubules and collecting ducts in 1. Adrenocorticotrophic Hormone (ACTH).
16-8 CHAPTERl6
in females; or interstitial celk->stimulating hor-

mone [ICSH] in males). In females
gonadotropin is necessary for ovulation. It caus-
es luteinization of follicles after they are ripened
by FSH (follicle-stimulating hormone). In males
gonadotropin activates the interstitial cells of the
testis to produce testosterone that is essential for
the development and maturation of the sperm.
4. Follicle-Stimulating Hormone (FSH).
This substance stimulates growth of the ovarian
follicle in the female and stimulates spermatoge-
nesis in males.
5. Growth Hormone (somatotropin, or
KiIi1eys _--i~r
(ADH)
STH). This honnone is important for growth
after birth. It specifically affects the growth of
Ovaries --4-.#--i~~4t the epiphyseal cartilage but is also important in
(LH & FSH) the metabolism of fat, protein, and carbohy-
drates. Cessation of growth follows hypophysec-
tomy. The inhibitory fonn of this honnone con-
trols the release of the honnone. Gigantism
results from an excessive somatotropin before the
epiphyseal plate'S close. The following case 16-2
is different from Case 16-1 as the pituitary tumor
in this instance produces defects in vision and an
increase in the growth hormone after the epi-
physeal plates have closed with resultant acrome-
galic (enlarged extremities) gigantism and also
effects the libido.
6. Thyrotrophic Hormone (ISH). TSH stim-
ulates the thyroid gland to produce triiodothyro-
nine (T3) and thyroxine (T4), which regulate the
rate of breakdown of fats and carbohydrates.
When circulating levels of T3 and T4 rise, thy-
rotropic-releasing honnone (TRH) release from
Figure 16-11 Target glands for adenohypophyseal hor-
mones. the adenohypophysis is inhibited by a drop in
TRH production in the hypothalamic neurons
This honnone is produced by basophilic cells and until the preferred levels returns
stimulates the formation of adrenal glucocorti- Case History 16-2. Patient of Dr. Elliott
coids (hydrocortisone) and, to a lesser degree, Marcus.
mineral corticoids (aldosterone). In conditions This 51-year-old married lumber salesman
of stress (cold, heat, pain, fright, flight, inflam- was admitted for evaluation of a progressive dis-
mation, or infection), ACTH is produced. turbance of vision. Approximately 8 years previ-
Cushing's disease is caused by excessive secretion ously, the patient noted blurring of print on the
of ACTH while Addison's disease results from labels of paint cans. Glasses were obtained and
ACTH insufficiency. produced improvement, but within a short time,
2. Lactogenic Hormone (Prolactin). This symptoms recurred. During the succeeding
substance in combination with the growth hor- years, the glasses had to be changed eight times.
mone promotes development of the mammary For 6 to 7 months, the patient had noted diplop-
glands and lactation. ia, especially on right lateral gaze when driving at
3. Gonadotropin (luteinizing hormone [LH] night. For 3 to 4 months, a left frontoparietal
and left orbital headache had been present. One 2.1-to 2.3 mg/24 hr. (normal = 3 to 10 mg/24
month prior to admission, progression of visual hr).
symptoms occurred. The patient had a marked 3. Urinary 17-ketosteroids were 4.0 mg/24
decrease in visual acuity and was unable to find hr normal = 10-25 mg/24 hr).
objects on shelves. He reported also that he was 4. Despite these low urinary steroid levels, no
unable to drive his automobile because he was FSH was detec-table in the urine.
unable to see the sides of the road. The patient 5. Skull x-ray revealed marked enlargement
consulted an ophthal-mologist who noted visual of the sella turcica (length 3 em, depth 2 em)
field defects and referred the patient for neuro- without calcification.
logical evaluation. 6. Electroencephalogram was abnormal with
History: bilateral frontal, slow (5 cps) waves, suggesting a
The patient denied any significant change in bilateral frontal dysfunction.
physical appearance, appetite, or fluid intake. The 7. Bilateral carotid arteriograms demonstrat-
patient's sexual interests had declined. He had no ed a marked elevation of the distal segment of the
sexual intercourse for the last ten years. internal carotid arteries, with elevation of the ori-
gins of both the anterior and middle cerebral
General Physical Examination: arteries; consis-tent with a large tumor extending
1. The patient was obese with large puffy superiorly out of the pituitary fossa.
hands and feet, a prominent jaw, and prominent 8. Pneumoencephalogram large lesion
frontal skull area. extending out of the pituitary fossa was again
2. Pallor of skin and mucous membranes was demonstrated.
noted. 9. Cerebrospinal-fluid protein was elevated
3. Axillary hair was absent; pubic hair was to 85 mg/dl.
normal.
Hospital Course
4. Testes were of normal size but were
described as soft. Replacement therapy with cortisone acetate
and thyroid was begun. Doctor Bertram
Neurological Examination: Selverstone performed a right frontal cranioto-
1. Cranial Nerves: my.
a. Visual acuity was reduced bilaterally, how- Clinical Diagnosis -Necrotic chromophobe
ever, the patient could read 1 cm print at 14 adenoma.
inches.
Comment
b. On visual field examination a complete
bitemporal defect was present, cutting the central Although the patient did not emphasize an
vision (Fig. 23-11). acute history of a bitemporal hemianopsia, he did
c. Examination of the fundi revealed pallor of mention that his ability to drive had been limited
the left optic disk, suggesting optic atrophy. not only by the decrease in visual acuity but also
d. On testing extraocular movements, a by his inability to see the road at the sides of the
diplopia was present in a pattern that suggested car, that is, the peripheral temporal fields.
bilateral medial rectus involvement (that is, bilat- The patient presented with many of the stig-
eral third-nerve damage). mata of acromegaly but claimed that he had large
hands, feet, jaw, etc., for all of his adult life.
Laboratory Data:
Changes in libido had apparently been pre-
The following abnormal levels were: sent for at least 16 years. Axillary hair had never
1. Thyroid studies indicated borderline low been present. One may only speculate that per-
function with a protein bound iodine of 4.0 haps a mixed tumor of the pituitary had been
).lg/dl. (Normal = present almost all of the patient's life, only
8 ).lg/dl) and radioactive iodine of 23.3% in becoming symptomatic once extrasellar (that is,
24 hours (normal = 20 to 50%). suprasellar) extension had compressed the optic
2. Adrenal-function studies indicated sub- nerves and chiasm.
normal values. Urinary 17-hydroxysteroids were Today, blood levels of growth hormone and
16-10 CHAPTER 16
prolactin would be obtained and, in all likeli- the ventromedial hypothalamic nuclei produce
hood, would have been found to be elevated hyperphagia, resulting in obesity. Stimulation of
long before the visual symptoms appeared. this center inhibits eating. Experiments have
Today such symptoms would have prompted shown that animals with ventromedial lesions are
neuroimaging studies such as MRI or CT with not motivated to eat more; they just do not
the diagnosis probably being established much know when to stop eating. For this reason it is
earlier. thought that the satiety center is located here.
Tables 16-2 and 16-3 review the functions of Bilateral lesions in the lateral hypothalamic
the anterior and posterior lobes of the pituitary. region produce anorexia; the animal refuses to
Hypothalamus and the Autonomic eat and eventually dies. However, if this region
Nervous System is stimulated but not destroyed, the animal
overeats. Appetite, the stimulus for eating, is
An individual performing daily functions
usually has a balance between the parasympa- dependent on many factors, including glucose
concentration in the blood, stomach distension,
thetic and sympathetic nervous system.
Stimulation of the anterior hypothalamus smell, sight, taste, and mood. Lesions in other
portions of the limbic system may also affect
(anterolateral region) excites the parasympathet-
ic nervous system and inhibits the sympathetic appetite.
Although obesity in humans usually does not
nervous system. The heart beat and blood pres-
sure decrease (the vagal response), the visceral have a neurological cause, in rare cases some
vessels dilate, peristalsis and secretion of digestive overweight individuals have had a ventromedial
nuclei lesion.
juices increase, the pupils constrict, and salivation
Sleep Cycle. The hypothalamus helps set
increases.
Stimulation of the posterior hypothalamus our level of alertness with the assistance of input
from the reticular system and cerebral cortex (see
(posteromedial region) excites the sympathetic
Chapter 11 & 30). The medial preoptic region
nervous system and inhibits the parasympathetic
can initiate slow wave sleep. The lateral hypo-
nervous system. The heartbeat and blood pres-
thalamus receives input from the ascending retic-
sure increase, the visceral vessels constrict, peri-
stalsis and secretion of gastric juices decrease, ular system that produces arousal. The posterior
pupils dilate, and sweating and piloerection portion, including the mammillary body, is
important in controlling the normal sleep cycle.
occur.
Lesions in this region may produce an inversion
A lesion in the anterior or parasympathetic
zone produces a sympathetic response; destruc- in the sleep cycle, or hypersomnia. Lesions in the
anterior hypothalamus may produce insomnia.
tion of the posterior or sympathetic zone may
The amount of light is monitored in the
produce a parasympathetic response. The effects
hypothalamus by input from the optic nerve
on blood vessels are produced by stimulation of
directly to the suprachiasmatic nucleus. The
the smooth muscles in the tunica media, and the
sympathetic innervation to the pineal monitors
effects on the sweat glands result from the stim-
the dark levels, and melatonin release from the
ulation of the glands through the cranial or
pineal is part of the sleep mechanism.
peripheral nerves.
Body Temperature. Maintenance of a con-
Functional Localization stant body temperature is vital to a warm-blood-
The hypothalamus, through its relation with ed animal. The hypothalamus acts as a thermo-
the autonomic nervous system and hypophysis, stat, establishing a balance between vasodilation,
maintains a more-or-Iess stable, controlled, inter- vasoconstriction, sweating, and shivering. It
nal environment regardless of the external envi- does this by means of two opposing thermoreg-
ronment. It affects body temperature, water bal- ulatory centers: one regulates heat loss, and the
ance, neurosecretion, food intake, sleep, and the other regulates heat production. Lesions in
parasympathetic and sympathetic nervous sys- either of these centers interfere with the regula-
tem. tion of body temperature.
Food Intake. Bilateral lesions restricted to Control Center for Heat Loss. A destruc-
tive lesion in the anterior hypothalamus at the may be relieved by the administration of vaso-
level of the optic chiasm or in the tuberal region pressin (Pitressin), an antidiuretic hormone
renders an animal incapable of controlling its (ADH), or extract from the hypophysis.
body temperature in a warm environment; a The hypothalamic-hypophyseal tract controls
tumor in the third ventricle may produce a simi- the formation and release of ADH, which causes
lar result. The human can no longer control the water to be reabsorbed from the distal convolut-
heat-loss mechanism, which consists of cuta- ed tubules and collecting duct of the kidneys into
neous vasodilation and sweating. Without this the bloodstream, thereby limiting the amount of
mechanism the body temperature rises (hyper- water lost in the urine. Ingestion of large
thermia), and the patient becomes comatose and amounts of water causes a drop in the ADH level
may even die. reduces tubular reabsorption with resultant
Control Center for Heat Production and diuresis. Water deprivation increases the ADH
Conservation. Lesions in the posterior hypo- level and causes increased reabsorption and con-
thalamus above and lateral to the mammillary centrated urine.
bodies disrupt an animal's ability to maintain The cells in the supraoptic nuclei form much
normal body temperature in either a warm or of the ADH or its precursors. ADH is formed in
cold environment. Normally, exposure to cold the cell body, travels down the axons of the
produces vasoconstriction, shivering, piloerec- hypothalamic-hypophyseal tract, and is stored in
tion, and secretion of epinephrine in mammals, the posterior lobe of the hypophysis as neurose-
all of which tend to increase body temperature. cretory granules. The osmoreceptors in the aor-
Following a lesion in the posterior hypothala- tic and carotid body and in the hypothalamus
mus, the body temperature tends to match that itself detect the concentration of water in the
of the environment, whether warmer or colder, blood. This information is passed on to the
relative to 37°C. (poikilothermy). Poikilothermy hypothalamic nuclei, which then control the
probably reflects damage to the fibers descend- release of ADH into the circulation.
ing from the heat-loss center as well as direct Water intake is also controlled by hypothala-
injury to the heat production and conservation mic neurons, with the area dorsal to the paraven-
center. tricular nuclei being one of the water intake cen-
The thermoreceptors are located in the skin ters.
(end bulbs of Krause and end bulbs of Golgi- HYPOTHALAMUS AND EMOTIONS.
Mazzoni; see Fig. 3-22) or in the hypothalamus As noted in Case 16-2 above and in Chapter 21,
itself, which monitors the temperature of the cra- the hypothalamus sets the foundation for emo-
nial blood. Some receptors respond to cold and tional responses and controls visceral functions.
others to warmth. Cold receptors excite the cau- It exerts these powerful influences through the
dal heat production and conservation center and multisynaptic descending autonomic pathways in
inhibit the rostral heat-loss center. Warm recep- the lateral margins of the reticular formation and
tors reverse this pattern. by controlling the release of the catecholamine--
Water Balance and Neurosecretion (Fig.16- epinephrine (adrenaline) and norepinephrine
10). Water balance is regulated by the hypothal- (noradrenalin)--from the adrenal medulla.
amic-hypophyseal tract, which originates in the Most postganglionic sympathetic fibers
supraoptic and paraventricular nuclei and runs release a substance that is 80% epinephrine and
through the median eminence and hypophyseal 20% norepinephrine, which acts on alpha- and
stalk to terminate in close proximity to blood beta-adrenergic receptors in the organs; these are
vessels in the neural hypophysis. A lesion in the called adrenergic fibers. Small doses of acetyl-
region of the supraoptic nucleus or in the hypo- choline injected into the bloodstream produce
thalamic-hypophyseal system causes diabetes the same effect as stimulation of the cholinergic
insipidus with polyuria (excessive formation of endings of craniosacral column.
urine). The patient drinks copious amounts of Norepinephrine causes constriction of the
water (polydipsia) and may excrete 20 liters of peripheral vessels, with resultant increased blood
urine a day. The symptoms of diabetes insipidus flow in the large vessels. The blood pressure and
16-12 CHAPTERl6
pulse rate rise and blood flow to the coronary Langley's description of the autonomic ner-
muscles increases. Epinephrine increases the vous system includes three parts: the sympathet-
heart rate and the force, amplitude, and frequen- ic, parasympathetic and enteric nervous systems.
cy of heart contractions. It also dilates the pupils The enteric nervous system is recognized as a
and the urinary and rectal sphincters, causing separate portion of the autonomic nervous sys-
voiding and defecation. It inhibits the motility of tem because peristalsis and other spontaneous
the gut and causes the bronchial musculature to movements persist after it is isolation from all
relax, thereby dilating the bronchial passages. nervous input (Gershon 1981).
Epinephrine increases oxygen metabolism Much of the effectiveness of the hypothala-
and the basic metabolic rate, causes hyper- mus is due to its innervation of the nuclei in the
glycemia by increasing phosphorylase activity, central nervous system that form the autonomic
which accelerates glycogenesis in the muscles and nervous system. In this section we identifY these
liver. And it increases the rate of synthesis oflac- neurons in the central and peripheral nervous
tic acid to glycogen, thereby prolonging the con- systems and list the responses produced by the
traction of the skeletal muscle. autonomic nervous system in each organ. Note
HYPOTHALAMUS AND
that normally an antagonistic balance exists
LIGHT LEVELS
between the functions of the parasympathetic
and sympathetic systems. However, this equilib-
Light to produces dramatic effects that are
rium may be modified by environmental stresses
mediated by the hypothalamus via the retinohy-
or disease processes.
pothalamic tract to the suprachiasmatic nucleus.
The somatic nervous system has its own
In many animals abnormal variations in light lev-
receptors and effectors, which provide cutaneous
els alter the sexual cycle and prevent estrus.
and motor innervation to the skin and muscles in
Light levels also affect the formation of melanin.
the head, neck, and body. The visceral, or auto-
Pineal Body (Fig. 1-17). The pineal, or epi-
nomic, nervous system also has its own receptors
physis cerebri, is a small pinecone<->shaped and effectors, which provide dual motor and sen-
gland found in the roof of the third ventricle.
sory innervation to the glands, smooth muscles,
This richly vascularized gland contains glial cells
cardiac muscles, viscera, and blood vessels.
and pinealocytes and is innervated by the sympa- These axons run part of the way with somatic
thetic nervous system from the superior cervical
fibers, but they also have separate pathways.
sympathetic ganglion with synapses on the
In the somatic nervous system the efferent
pinealocytes.
neuron is the ventral horn cell or motor cranial-
Pinealocytes contain serotonin, mela-
nerve nucleus. Its axon leaves the central ner-
tonin, and norepinephrine. The pineal makes
vous system to innervate a skeletal muscle.
melatonin from serotonin; the enzyme levels In the visceral nervous system two efferent
necessary for this transformation are controlled neurons are found: the preganglionic neuron
by the suprachaismatic nucleus. This nucleus
and the postganglionic neuron.
sends fibers via the descending sympathetic path-
The preganglionic neuron is found in the
way into the medial forebrain bundle, and via the intermediate horn at the thoracic and lumbar lev-
descending spinal fibers to the intermediolateral els of the spinal cord. The axon of this cell leaves
cell column of the upper thoracic cord and then the central nervous system via the ventral root
on to the superior cervical ganglion. The
and ends in an autonomic ganglion, which paral-
pinealocytes are related to the photoreceptor lels the spinal cord or is found near the target
cells seen in this region in fish and amphibians.
organ
Pinocyte secretion of serotonin and melatonin is The preganglionic cell bodies are found in
a cyclic response to stimulation from the optic the CNS at the following sites:
system. These 24-hour circadian rhythmns may
Parasympathetic (Craniosacral):
well be the biological clock.
1. Cranial parasympathetic (cranial nerves
AUTONOMIC NERVOUS SYSTEM (Fig.
III, VII, IX, and X).
16-12)
2. Sacral parasympathetic (sacral segments 2
to 4). the astrocytes in the central nervous system. The
Sympathetic (Thoracolumbar): astrocytes enwrap the neurons and their process-
es and also form a barrier between the blood and
1. All thoracic segments and lumbar seg-
the enteric nervous system. There are extensive
ments 1 and 2.
connections within the enteric nervous system
The postganglionic neuron, or the motor
and projections onto the pancreas, gallbladder,
ganglion cell, is located outside the central ner-
and elsewhere. The unipolar and bipolar neu-
vous system and ends in the appropriate gland,
rons appear to function as sensory neurons with
smooth muscle, or cardiac muscle.
the multipolar cells forming many of the connec-
The nerve fibers are further classified as being
adrenergic or cholinergic, depending on which tions.
The noradrenergic sympathetic postgan-
nerve transmitter is involved--epinephrine or
glionic fibers project onto the submucosal and
ac~ty~choline. The lumbar sympathetic pregan-
myenteric plexus, where they are inhibitory to
glioruc axons to the adrenal gland activate chro-
the cholinergic neurons. (The cholinergic vagal
maffin cells (modified nerve cells) in the adrenal
input from the dorsal motor nucleus of the vagus
medulla, which release epinephrine (80%) and
to the submucosa and mucous membrane is exci-
norepinephrine (20%) into the circulation and
act on alpha and beta-adrenergic receptors in the tatory.)
PARASYMPATHETIC SYSTEM (FIG. 16-
hollow organs, glands, and skin. Injections of
epinephrine into the blood stream produce an 12)
effect similar to the stimulation of the thora- CRANIAL NERVES
columbar or sympathetic nervous system. Small
Cranial Nerve III. The fibers originate in
doses of acetylcholine injected into the blood-
the Edinger-Westphal nucleus in the midbrain
stream produce the same effect as stimulation of
and innervate the constrictors of the pupil via the
the craniosacral column. Most postganglionic
ciliary ganglion.
parasympathetic fibers release acetylcholine at
Cranial Nerve VII. The axons originate in
their terminals.
the superior salivatory nuclei of the pons and
The axons ending on sweat glands, though
inner:ate glands in the nasal cavity and palate,
receiving innervation from the thoracolumbar
and m the lacrimal (pterygopalatine) sub-
system, are cholinergic. Pilomotor axons, which
mandibular, and sublingual (submancllbular)
also receive thoracolumbar innervation, are
glands.
adrenergic.
Cranial Nerve IX. The fibers originate in
The two systems provide dual innervation to
the inferior salivatory nucleus in the medulla.
glands and viscera and act to produce optimal
The axons exit with nerve IX and end in the otic
balances of internal conditions under any envi-
ganglion, which innervates the parotid gland.
ronmental condition.
Cranial Nerve X. The dorsal motor nucleus
ENTERIC NERVOUS SYSTEM of the vagus nerve provides preganglionic
parasympathetic innervation to the pharynx, lar-
. ~ the alimentary canal (esophagus, stomach,
ynx, esophagus, lungs, heart, stomach and
mtesnnes, and rectum) there are about 100 mil- . . '
mtesnnes up to the transverse colon. The post-
lion neurons (Gershon, 1981). One network of
neurons, Meissner's (submucosal) plexus, lies in ganglionic fibers originate from ganglia in the
the connective tissue between the longitudinal respective organs and in the nodes of the sub-
muscle coat and the circular musculature coat in mucosal plexus of Meissner and the myenteric
the alimentary canal. Another, Auerbach's plexus of Auerbach in the enteric nervous system
(myenteric) plexus, lies in the connective tissue associated with the alimentary tract.
between the circular muscle coat and the muscu- Sacral Plexus
l~s mucosa. Each plexus consists of multipolar, The parasympathetic sacral plexus originates
bIPOlar, and unipolar neurons. The enteric ner- from sacral segments S2 and S4 and supplies the
vous system includes glia that appears similar to genitalia, sigmoid colon, rectum, bladder, and
16-14 CHAPTERl6
ureter. The ganglia are located in the organ and The ganglia of TI to T4 provide postgan-
are named for the organ. glionic fibers to the heart and lungs. The post-
Sympathetic System (Fig. 16-12) ganglionic fibers from T5 to TI2 form the
The preganglionic fibers originate in the splanchnic nerves. The greater splanchnic nerve
intermediolateral colwnn of gray matter in the is formed by preganglionic rootlets from T5 to
spinal cord from TI to L2; they exit in the white TIO; the axons pass through the thoracic ganglia
rami and enter the paravertebral sympathetic and end in the celiac ganglion. From there post-
ganglionic chain. The student is reminded that ganglionic axons run above the aorta, esophagus,
cranial nerves are not part of the sympathetic thoracic duct, and azygos vein to reach the stom-
nervous system. The ganglia form a continuous ach, small intestine, and adrenal glands. The less-
paravertebral trunk: in the cervical, thoracic, lum- er and least splanchnic nerves arise from spinal
bar, and sacral segments. cord segments TIl and TI2 and run through
The postganglionic fibers originate in the the paravertebral ganglion to the celiac and supe-
ganglia and exit via the gray communicating rior mesenteric ganglia. From there the post-
rami. The postganglionic fibers reach their des- ganglionic axons run to the small intestine, the
tinations via plexuses enwrapping the arteries or ascending portion of the colon, and the kidneys.
via cranial and spinal nerves. Lumbar Sympathetic Ganglia
Cervical Sympathetic Ganglia The lumbar sympathetic trunk: consists of
The cervical ganglia extend posterior to the small ganglia that lie along the anterior border of
great vessels from the level of the subclavian the psoas muscle. The preganglionic fibers orig-
artery to the base of the skull. There are usually inate from the intermediate colwnn of spinal
three ganglia in the cervical region: superior, cord, segments Ll and L2, pass through the
middle, and inferior. lumbar ganglia, and end in the inferior mesen-
The superior cervical ganglion is flat and the teric ganglion, where they innervate the descend-
largest, (25 to 35 mm). The internal carotid ing colon, rectum, urinary bladder, ureter, and
nerves leave the superior border of the superior external genitalia.
cervical ganglion and pass into the cranial cavity Autonomic Dual Innervation of Specific
with the carotid artery in the carotid canal. Structures (Fig. 16-12)
These fibers form the plexus around the carotid
artery and in the cavernous sinus. This ganglion EYE
provides postganglionic innervation to the eye, Parasympathetic. The preganglionic cell
lacrimal gland, parotid gland (otic ganglia), sub- bodies are found in the Edinger-Westphal nucle-
maxillary and sublingual glands (sublingual gan- us associated with cranial nerve III. These fibers
glia), and some branches to the heart. run on the outside of the third nerve and end in
The middle cervical ganglion is small and the ciliary ganglion. The postganglionic fibers
variable and is found at the level of the cricoid run in the short ciliary nerve, providing innerva-
cartilage. It provides postganglionic fibers to the tion to the ciliary muscle and the constrictor of
heart. the iris, which permit accommodation for near
The inferior cervical ganglion is usually fused vision.
with the first thoracic ganglion to form the stel- Sympathetic. Preganglionic axons originate
late ganglion. It is also small and irregular in from the intermediolateral nucleus at cord levels
shape and lies posterior to the vertebral artery. C8 to T2. The fibers ascend in the sympathetic
The postganglionic fibers innervate the heart. chain to the postganglionic neurons in the supe-
rior cervical ganglion. The postganglionic axons
Thoracic Sympathetic Ganglia
join the carotid plexus and then the ophthalmic
The thoracic portion of the sympathetic branch of nerve V to innervate the dilator mus-
trunk: extends anterior to the heads of the first cle of the iris and the levator palpebrae and radi-
ten ribs and then passes along the sides of the
al ciliary muscles, producing eye opening (lifting
lower two thoracic vertebrae. The number of of the lid) and dilation of the pupil for distant
thoracic ganglia varies from 10 to 12. vision.
LACRIMAL GLANDS originate in the upper thoracic and lowest cervi-
Parasympathetic. Preganglionic fibers origi- cal ganglia. The result in this case is dilation of
nate in the superior salivatory nucleus of nerve the bronchi and increased respiration.
VII and run to the pterygopalatine ganglion. ABDOMINAL VISCERA
The postganglionic fibers join the maxillary divi- Parasympathetic. These fibers ongmate
sion of nerve V, resulting in vasodilation and from the dorsal motor nucleus of nerve X and S2
secretion. to S4, and end in the intrinsic plexus in the
Salivary Glands organ. They stimulate peristalsis and gastroin-
Parasympathetic. The preganglionic axons testinal secretions.
to the submaxillary and sublingual glands origi- Sympathetic. The sympathetic fibers origi-
nate in the superior salivary nucleus of nerve VII nate from the lower thoracic and lumbar seg-
and enter the submandiublar gland from which ments, pass through the paravertebral ganglia
the postganglion axons enter the salivary glands. and form the splanchnic nerves, which end in the
The preganglionic axons to the parotid originate celiac and superior and inferior mesenteric gan-
in the inferior salivatory nucleus of nerve IX glia. Postganglionic fibers from these ganglia
(medulla) and leave the central nervous system end on smooth muscle or glands. They inhibit
ens and enter the otic ganglion. The resulting peristalsis and gastrointestinal secretion; stimu-
action is vasodilation and secretion. late secretion from the adrenal medulla and cause
Sympathetic. These fibers originate from the vasoconstriction of the visceral vessels (see dis-
intermediolateral column at the upper thoracic cussion of enteric nervous system above).
level, exit from the central nervous system, run
PELVIS
up to the superior cervical ganglion, and then
proceed to the glands. Vasoconstriction and Parasympathetic. These fibers ongmate
reduced secretion result. from segments S2 to S4 and end in ganglia in the
HEART organs. Postganglionic fibers supply the uterus,
vagina, testes, erectile tissue (penis and clitoris),
Parasympathetic. The preganglionic fibers
sigmoid colon, rectum, and bladder. They cause
originate in the dorsal nucleus of nerve X, exit
contraction and emptying of the bladder and
from the central nervous system, and run in the
erection of the clitoris or penis.
vagus nerve to the postganglionic ganglia in the
Sympathetic. These fibers originate from
cardiac plexus and atria. These axons reach coro-
the lowest thoracic segments and segments Ll to
nary vessels and atrial musculature, causing car-
L3 and run in the hypogastric nerves to the tar-
diac deceleration.
get viscera, where the ganglia are found. They
Sympathetic. The preganglionic fibers orig-
cause vasoconstriction and ejaculation of semen,
inate in the Tl to T4 segments, exit from the
and inhibit peristalsis in the sigmoid colon and
central nervous system, and reach the postgan-
rectum.
glionic neurons in the upper thoracic ganglion
and all three cervical ganglia. The fibers form the CUTANEOUS AND DEEP VESSELS,
cardiac nerves and enter the cardiac plexus. The GLANDS, AND HAIR
resulting effect is cardiac acceleration. Blood vessels receive only sympathetic post-
LUNGS ganglionic innervation from the appropriate par-
avertebral ganglion. Activation of this system
Parasympathetic. The preganglionic fibers
produces vasoconstriction (cooling of the skin),
originate in the dorsal motor nucleus of nerve X
sweating, and piloerection.
and run in the vagus to the pulmonary plexus in
The innervation of the peripheral blood ves-
the bronchi and blood vessels. They cause con-
sels and glands is summarized in Table 16-1.
striction of the bronchi and decreased respira-
tion. Disorders of the Autonomic Nervous System
Sympathetic. The preganglionic fibers orig- Disorders of the autonomic nervous system
inate in Tl to T4. The postganglionic fibers can affect any of the organs innervated by the
16-16 CHAPTER 16
autonomic nervous system. Only a few will be tex). The urine passing through the urethra con-
discussed here. The student is referred to any tinues the stimulation until the bladder is empty.
standard neurology text for further details. The external sphincter then closes. We can also
Eye. A lesion in the nucleus or nerve root of initiate closing voluntarily with the assistance of
cranial nerve III injuring the fibers from the the abdominal muscles.
Edinger-Westphal nucleus produces pupillary Interruption of the cortical pathways (bilater-
dilation (due to only sympathetic input). Injury al involvement of the cerebral hemispheres) pro-
to the descending sympathetic fibers produces an duces the uninhibited bladder, in which sensa-
ipsilateral Homer's syndrome (pupillary constriction is normal, but the patient no longer has con-
tion and drooping of the eyelid). The Argyll- trol over voiding. Thus, as the bladder fills and
Robertson pupil does not react to light but will becomes distended, it voids suddenly without
accommodate and is commonly seen in neu- cortical control.
rosyphilis in the central nervous system. (See dis- Destruction of the parasympathetic supply by
cussion of tabes dorsalis in Chapter 9.) injury to the motor roots produces the auto-
Blood Vessels. Reynard's disease (vasomotor nomic bladder, in which there is no sensation and
disease), most common in young women, causes no longer any reflex or voluntary control. The
the patient to be abnormally sensitive to cold. need to void arises from abdominal discomfort
On exposure to cold the extremities become produced by increasing intra-abdominal pres-
cyanotic and then red and very painful. sure.
Sympathetic innervation does not seem to dilate Injury to the sensory roots or ganglia or to
the vessels. Vasodilators help, but resection of the dorsal column produces the sensory paralytic
the preganglionic sympathetic innervation to the bladder, in which there is no sensation and no
limb usually brings permanent relief reflex ability to void. The bladder visibly enlarges
Heart and Gastrointestinal Tract and then dribbles. Voiding is also difficult with-
These organs respond to any change in our out sensory feedback.
emotional state. Consequently, psychosomatic Isolation of the bladder from the upper
diseases, e.g., hypertension and ulcers, affect motor neurons either by transection of the spinal
them. cord above the sacral level or by extensive brain
disease produces the reflex bladder. In this con-
BLADDER dition the descending autonomic fibers are inter-
The bladder is a reflex organ and contracts in rupted as well as the corticospinal fibers, but the
response to stretch. The afferents are carried spinal reflex circuit remains intact. Micturition is
into the sacral spinal cord; efferent are supplied involuntary and results from just the stretch
by the parasympathetic (S2<->S4) and sympa- reflex alone. Voiding is sudden and uncontrol-
thetic (Ll<->L2) ganglia. The parasympathetic lable.
axons initiate the reflex contraction of the blad-
der during urination (micturition)--a voluntary
action initiated through the nerve to the external
sphincter. Sympathetic axons do not participate
in micturition but control blood vessels and clo-
sure of the internal sphincter during sexual inter-
course.
Normally, the bladder fills and expands,
stretching the receptors in the bladder walls. The
pressure buildup is carried into the central ner-
vous system by the sensory nerves. Following
the voluntary contraction of the external sphinc-
ter, the bladder contracts reflexively; the internal
and external sphincters open and the muscles in
the pelvic floor relax (control from cerebral cor-
SYMPATHETIC (BLUE) PARASYMPATHETIC (RED)

- Preganglionic fibers - Preganglionic fibers
- Postganglionic fibers Lacrimal gland - Postganglionic fibers
Figure 16-12. Autonomic Nervous System: Left, Sympathetic (thoracolumbar); right,parasympathetie (eran-
iosacral).
CHAPTER 17
Cerebral Cortex: Cytoarchitecture, Physiology
and Overview of Functional Localization
PART I. ANATOMICAL CONSIDERATIONS 2.0 mm.). In addition to differences in overall

A firm knowledge of the structure and thickness, some areas differ in the thickness of
function of the cerebral cortex and the rela- the various layers that constitute the laminar
tionship of the cerebral cortex to the subcorti- pattern.
cal centers is of crucial importance for all who 2. Relative density of the various cell types
wish to understand the behavior and accom- (evident in Nissl stains for cells or Golgi silver
plishments of man as opposed to other .animal stains) to be discussed below e.g.: pyramidal, vs
forms. The use of the thumb and fingers for stellate, It must also be noted that within a
fine manipulations with tools, the use of lin- given area of cortex, the various layers of cor-
guistic and mathematical symbols for commu- tex differ as regards the relative distribution of
nication in the auditory and visual spheres, and these various types of cells (Fig.17-1)
the capacity for postponement of gratification
3. Density of horizontal fiber plexuses
all reflect the evolution of the cerebral cortex.
(stripes) (evident on myelin and silver stains)
This development of the cerebral cortex has led
and density ofaxodendritic and other synapses
to a laminar arrangement of 16 billion nerve
(evident on Golgi stain and Fink-Heimer
cells with an almost infinite number of synaps-
stains).
es. Beaulieu and Colonnier have estimated that
in a cubic millimeter of neocortex there are 4. Degree of myelination of intracortical fiber
2.78 times 10\8 synapses 84% of which are type systems (evident on myelin stain). To some
I (excitatory) and 16% type II (inhibitory). extent the various myelinated bands may be
The almost infinite number and variety of seen with the naked eye in freshly cut sections
circuits present not only has provided the of the cerebral cortex. For example, Gennari in
anatomical substrate for the recording of an 1782 and Vicq d'Azyr in 1786 independently
infinite number of past experiences but has also had noted a white line in the cortex near the
allowed for a plasticity of future function pro- calcarine fissure. The various features to be
jected both in time and in space. noted in the several types of stains are demon-
The attempt to relate functional differences strated in Figure 17-1.
to the differences in structure of the various
areas of the cerebral cortex was a scientific out-
CYTOLOGY
growth of the earlier philosophical arguments
concerning the relationship of mind and body. From the standpoint of cytology the neu-
We may indicate at the onset that to a certain rons within the cerebral cortex may be classi-
degree cytoarchitectural differences do reflect fied into two major categories pyramidal and
functional differences. This is never, however, stellate (Fig.17-2). The axons of pyramidal cells
a one-to-one relationship. Moreover, at times, (Type I cells/neurons with long axons) form
architectural differences are not sharp; strict the majority of association, callosal and subcor-
borders may not be present. tical projections while the stellate cells (type
The various areas of cerebral cortex differ as II/ neurons with short axons) form the local
regards several parameters: circuits (Refer to chapter 3 for additional dis-
1. Thickness, evident on simple visual cussion).
inspection (average thickness is 2.5 mm., Neurons may also be classified on the basis
motor cortex: 4.5 mm., visual cortex 1.45 to of whether the dendrites have spines or an
17-2 CHAPTERl7
Figure 17-1. Diagrllm of the structure of the cerebrlll

cortex. The results ohtlJined with (II) II Golgi stlJin, (b)
II Nissl stlJin or other cellula.r stlJin, lind (c) II myelin
Figure 17-2. PyramidIJl and stellate cells as demon-
stlJin lire contrRSted. I =molecula.r la.yer; II =exter- strated in Golgi stlJin ofcat cerebral cortex. PC =
nlJlIJrllnula.r lIJyer; III =externIJl pyrllmidlJl la.yer; pyramidIJl cells; arrow =stellate cell; AD =apical den-
IV =internlfl grllnula.r la.yer; V =la.rIJe orIJilint drite ofpyramidlJl cell; BD =baml dendrite ofpyra-
pyrllmidIJl la.yer (gllnIJ1ionic /a.yer); VI =fusiform midIJl cells; AX =IlXOns ofpyramidIJl cell.
1Ifyer. The followinIJ folltures should be noted in the 25 u; large 45 to 50 u, and giant 70 to 100 u.
myelin stlJin: 111 =molecula.r la.yer 3111 =blind of KIIeS The giant pyramidal cells are characteristic of
Bechterew; 4 =outer blind of Ba,Ula.rIJer; 5b =inner
blind of Ba,illa.1'!Jer. (After Brodmllnn, from Ra.nson, the motor cortex. The upper end of the pyra-
S. w., lind Cla.rk, S. L : The AnlJtomy of the Ner1IOUS midal cell continues on toward the surface as
System, Philtulelphill, W. B. Sa.unders, 1959, p. 350). the apical dendrite. Numerous spines are
fOWld on the dendrite providing sites for
absence of spines. synaptic contact. The pyramidal neurons have
From the standpoint of electrophysiology the largest dendritic trees and also contain
the neurons may be classified as fast spiking, axons that form associational, callosal and pro-
regular spiking or bursting (repetitive dis- jectional connections. In general, the larger the
charge). cell body, the larger the apical dendrite and the
I. Neurons whose dendrites have spines wider the spread in terms of ramifications of
(spiny neurons) accoWlt for the majority of the the terminal horizontal branches. The wider
neurons in cerebral cortex. These are excitato- the spread of the apical dendrite, the greater
ry and are of two types: the number of possible axodendritic synapses.
a. Pyramidal cells: constitute 2/3 of all neu- The larger the cell body, the greater the num-
rons in the neocortex. These cells are defined ber of possible axosomatic synapses. In addi-
by a prominent apical dendrite extending tion to the apical dendrite, shorter basal den-
through all layers of the cortex to layer drites arise from the base of the cell body and
l.Pyramidal neurons have cell bodies of vari- arborize in the vicinity of the cell body. The
able height--smalllu to 12 u; medium 20 to axon emerges from the base of the cell body
CORTEX: ANATOMY AND FUNCTIONAL LOCALIZATION 17-3
and descends toward the deeper white matter. body (soma). These neurons are found primar-
In general the axons of small- and medium- ily in layer 4 of sensory cortex. Their axons
sized pyramidal cells terminate as association project locally within the area and not to dis-
fascicles within the cortex. The axons of large tant sites.
and giant pyramidal cells enter the deeper Physiology: Most spiny neurons/pyramidal
white matter as (a) association fibers to other cells utilize glutamate as a synaptic transmitter
cortical areas, (b) commissural fibers to the and demonstrate "regular" spiking that is an
contralateral hemisphere, or (c) projection adapting pattern of discharge in response to a
(efferent) fibers to subcortical, brain stem, and constant current injection. These cells general-
spinal cord areas. In addition, recurrent collat- ly demonstrate a significant after hyperpolariza-
eral association fibers may branch off from tion (AHP). Some of the pyramidal cells locat-
these axons within the cortex. In addition to ed in deeper layers, primarily layer 5 may
functioning as the main efferent outflow of the demonstrate a bursting pattern at low thresh-
cerebral cortex to subcortical areas (thalamus, old. These neurons respond to depolarization
basal ganglia, brain stem and spinal cord), and by generating repetitive spikes, usually 3 in
to other cerebral cortical areas (ipsilateral, and sequence. The regular firing pyramidal cells are
A Recumnl or feedbaclllnhlbition 8 anerenl collateral or feed fOlW3nf Inhibition
Figure 17-3 Diagram indicating possible function ofstellate cells as inhibirory interneurons. Two mechanisms are
demonstrated. A) R&current or feedback inhibition and B) aJfrrent collateral or feed forward inhibition.
Modified from Eccles,].G. in Jasper, H.et al Basic Mechanisms of the Epilepsies &ston, Little Brown p.249, 1969.
contralateral hemispheres), the pyramidal cells characterized by thin apical dendrites that do
also provide a massive collateral net work to not branch extensively in layer 1. In contrast,
other neurons with in the local area. Each pyra- the burst firing pyramidal cells have thick apical
midal cell also receives multiple inputs on to its dendrites and extensive branching in layer 1. As
dendritic spines .The Betz cells, the giant pyra- we will discuss below, this may have consider-
midal neuron of the motor cortex have at least able significance for the difference in excitabil-
10,000 spines each with a type I excitatory ity of the various cortical areas for example
synapse. motor cortex compared to visual cortex.
b. Spiny stellate neurons: the prominent api- II. Smooth neurons without spines former-
cal dendrite is not present. Instead dendrites of ly referred to as smooth stellate cells. Multiple
almost equal length radiate out from the cell types have been described. The most common
17-4 CHAPTERl7
is the basket cell that has axons that form bas- FUNDAMENTAL TYPES
kets around the soma of the pyramidal cells. OF CEREBRAL CORTEX:
The Retzius-Cajal neurons are horizontally ori- Brodmann in 1903 distinguished 2 funda-
ented cells found in layer 1. The Martinotti mental types of cerebral cortex: Homogenetic
cell, the double bouquet cell of Cajal and the or Heterogenetic.
chandelier cell have a vertical orientation. 1. Homogenetic. This type as already illus-
Physiology: The smooth cells are generally trated in Figure 17-1 has a 6-layer pattern at
fast spiking and make type II inhibitory con- some time during development recognizable
nections utilizing gamma aminobutyric acid by the end of the 3rd fetal month. This type of
(GABA) as the transmitter. In contrast to pyra- cortex is also called neocortex or isocortex, or
midal neurons, the action potentials of these neopallium, or supra limbic.
fast-spiking cells are brief; the repolarization 2. Heterogenetic: This type of cortex does
phase is rapid and followed by a significant not have 6 layers at any time during develop-
under shoot. This has been correlated with ment or during adult life. This type of cortex is
very large, fast repolarizing potassium current. also called allocortex and has 3 layers. There is
The inter-relationship of neurons within a transitional zone between allocortex and the
the neocortex is demonstrated in Figure 17-3. neocortex: the mesocortex that corresponds to
the cingulate gyrus, the parahippocampal
BASIC DESIGN AND gyrus, the piriform area and the anterior perfo-
FUNCTIONAL ORGANIZATION rated substance (Fig.17-4).
OF CEREBRAL CORTEX:
The cerebral cortex is characterized by two SUMMARY OF THE
essential design principles: 1) the neurons have FUNDAMENTAL 6 LAYERED
a horizontal laminar arrangement, 2) connec- SCHEME OF NEOCORTEX
tions occur in a vertical columnar manner. (refer to Figure 17-1):
These vertical columns extend from pial Sur- Layer L· The molecular or plexiform layers.
face to white matter. A specific region, a spe- This layer primarily consists of dendrites and
cific stimulus, or a specific stimulus orientation axons from other cortical area, deeper layers
activates each cylindrical column. Activation of and nonspecific thalamic input. A tangential
a specific column also activates inhibition in plexus of fibers composed of the apical den-
adjacent columns, the concept of inhibitory drites, ascending axons and axon collaterals
surround. (See Angevine and Smith 1982). In provides a dense collection ofaxodendritic
the primary sensory each column is concerned synapses.
with a particular modality of sensation for a Layer II: The external granular layer. This
particular representation of the body or specif- layer is a relatively densely packed layer of small
ic sector of a field of stimulation. This colum- stellate granule cells and small pyramidal cells
nar organization first was described by whose apical dendrites terminate in the molec-
Mountcastle for somatosensory cortex and has ular layer and whose axons are sent to lower
been subsequently found in other sensory and cortical layers.
associational cortex. As discussed by Rakic Layer III: The external pyramidal layer.
(1988) this columnar or radial organization This layer is composed of medium and large
maybe a reflection of the ontogenetic in- pyramidal cells whose apical dendrites extend
growth of neurons from the ependymal surface to layer I. The axons of these cells may function
via glial guide to the cortical surface to be dis- as association, commissural or intra cortical
cussed in chapter 4. A similar columnar organi- association fibers.
zation of the callosal system has also been Layer rv.. The internal granular layer. This
demonstrated (See Jones -1985). layer is densely packed with granular/stellate
Figure 17-4. Frontal semon through the diencephalic part of the prosencephalon of an 87 mm. (crown to rump), 3-
1/2-month embryo. a and al =anlage of the hippocampus (heterogenetic or rhinal allocortex); b =anlage of the
parahippocampal cortex (limbic mesocortex); c =supra limbic isocortex (or homogenetic). Mg =marginal layer; Mt
=mantle layer; Mx =matrix layer. From TakOPiev, P.I.: &s. Pool. Atm. nerP. ment. Dis., 39:3-46, 1962 (Wiliams
and Wilkins).
cells. A dense a horizontal plexus of myelinated of layer 3, layers 5 and 6 also provide such an
fibers, the external band of Baillarger is also output. Note that there is some overlap of the
present composed of the branches of the spe- functions of pyramidal cell of layers 5 and 6.
cific thalamo-cortical projection system. These Collaterals of the axons also function as intra
fibers synapse with the stellate cells of this layer cortical association fibers. In the deeper por-
or the basilar dendrites of the pyramidal cells of tion of this layer a dense horizontal plexus of
layer III or with the apical dendrites of the fibers is present the internal band of Baillarger.
pyramidal cells of layers V and VI. Layer VI: The fusiform or spindle cell mul-
Layer v.. Internal or large and giant pyrami- tiform layer. This layer is composed of a mix-
dal cell layer also called the ganglionic layer ture of spindle shaped cells, pyramidal and stel-
This layer serves as the major source of outflow late cells. Dendrites ascend to various cortical
fibers particularly to motor areas of the basal levels. The axons enter the white matter as
ganglia, brain stem, and spinal cord and possi- short association fibers or ascend to other cor-
bly to the projection nuclei of the thalamus. tical layers. However the corticothalamic out-
Although cortico- cortical out put arises pri- flow usually occurs from pyramidal cells in this
marily from the more superficial pyramidal cells layer.
17-6 CHAPTER 17
CLASSIFICATION OF THE
VARIOUS TYPES OF NEOCORTEX:
It is evident that in the adult not all areas of
neocortex have the same appearance.
Brodmann termed those areas of homogenetic
neocortex that demonstrated the typical
6-layered pattern seen in Figure 17-1 as homo-
typical.
At one extreme is the agranular motor cor-
tex. This has many giant pyramidal cells present
in layer 5 but with a virtual absence of an inter-
nal granular layer 4. At the opposite extreme is
the granular primary sensory projection cortex.
Layers 2,3, and 4 appear as an almost contin-
uous granular layer. Layers of 5 and 6 are thin
and few large pyramidal cells are present.
Von Economo divided the cerebral cortex
into 5 basic categories (Fig.17-5):
Type 1 is the agranular motor cortex.
Type 2 is referred to as homotypical or Figure 17-6. Distribution of the jive cortical types of
frontal granular cortex and is found in the Figure 17-5 O'Per the lateral and medial surfaces of the
superior frontal gyrus of the prefrontal area. cerebral surface. The Sylvian fissure has been laid
Type 3 is the midpoint and is best seen in open. (From Vim Economo, c.: The Cytoarchitectonics
the inferior parietal lobule. of the Human Cerebral Cortex. Lonlum, Oxford
Type 4 is referred to as polar and is repre- University Press, 1929, p. 18).
sented by the non striate visual association cor- al projection cortex. Because the large number
tex of area 18 close to the occipital pole of granule cells in this type of cortex resembles-
Type 5 is the granular striate occipital visu- - a cloud of dust, - the Greek word konios is
employed -thus the term koniocortex.
Figure 17-6 demonstrates the distribution
of these various cortical types. Von Economo
and Koskinis (1925) then developed a classifi-
cation that dealt in a logical manner with the
variations of cytoarchitecture in terms of defin-
able histologic gradations using a letter termi-
nology. Thus motor cortex received the desig-
nation FA, premotor cortex FB, and the frontal
eye field, Fe etc. In this textbook we will fol-
low the classification of Brodmann that has
been most commonly employed (Fig.17-7)*.
Numbers were initially assigned as histological-
ly distinct areas were identified in successive
Figure 17-5. The jive fundamental types ofcortical horizontal slices moving in anterior and poste-
structure: Type 1= agranular motor cortex. Type 2 = rior directions from the central sulcus. The
frontal homotypical (frontalgranular). Type 3 = crest of the postcentral gyrus would then
parietal homotypical. Type 4 =polar, e.g., area 18.
Type 5 =granular koniocortex. (From Vim Economo,
c.: The Cytoarchitectonics of the Human Cerebral * For a comparison of the 2 systems in the mon-
Cortex. London, Oxford University Press, 1929, p. 16). key see fig. 17-8.
20
B
Figure 17-7. Cytoarchitectural areas of cerebral cortex as designated by Brodmann. (From Ranson and Clark:
The Anatomy of the Nervous System. Philtulelphia, W. B. Saunders, 1959, p. 356).
17-8 CHAPTER 17
appear in the 1st horizontal section and would sciousness, confusion and amnesia.
be assigned the number 1 .The primary motor Partial seizures or partial epilepsy must be
cortex is assigned 4,the premotor cortex 6 and distinguished from those seizures which are
the frontal eye field 8. Thus there is no logical nonfocal that is bilateral or generalized in their
reason why the numbers 6 and 8 are assigned onset (generalized or idiopathic epilepsy in the
to areas of the frontal lobe and 5 and 7 to areas International Classifications).
in the parietal lobes. Nevertheless, some of the Other methods of stimulation:
numbers are used with sufficient frequency in Electrical stimulation, of the cerebral cortex
everyday neurological language that the stu- may be carried out, in the human patient
dent should commit these to memory. Before undergoing operative procedures on the cere-
we review these areas with their correlated bral cortex to identifY specific cortical areas or
function, it is necessary to consider the meth- may be employed on animal preparations in
ods employed in the study of functional local- the experimental laboratory. Transcranial elec-
ization. trical and magnetic stimulation of cerebral cor-
tex has been developed as a clinical technique.
PART n. METHODS FOR THE STUDY Evoked potentials: stimulation of afferent
OF FUNCfIONAL LOCALIZATION pathways may be utilized to identifY short
IN CEREBRAL CORTEX latency responses evoked from specific cortical
areas. When stimulating the lower extremity
(or sciatic nerve) response is limited to that
A HOW DO WE STUDY FUNCfION? specific area of the contralateral postcentral
In considering functional localization, and gyrus devoted to the representation of the
the correlation with cytoarchitecture, it has lower extremity. Stimulation of the upper
been customary to consider the effects of two extremity will elicit a similar response from a
general categories: stimulation and ablation. different portion of the contralateral postcen-
Stimulation: Various disease processes in tral gyrus: that devoted to representation of the
man involving the cerebral cortex may produce upper extremity. Eventually it is possible to
a local area of excessive discharge, in a sense, a prepare a map of the somatosensory projection
local area of stimulation resulting in focal cortex of the postcentral gyrus. It is possible to
seizures refine this technique at the response end by
Actually our first understanding of cortical using microelectrode recordings from within
function was derived from the systematic study or just outside neurons at particular depths of
of such cases of focal discharge (termed focal the cortex. It is also possible to define more
seizures, or focal convulsions, or focal epilepsy, or carefully the parameters of stimulation as
epileptiform seizures) by Rughlings Jackson in Rubel and Wiesel have done in their analysis of
1863 and 1870. Jackson was able to predict responses in the visual cortex to specific types
that an area existed in the cerebral cortex that of visual stimuli (see Chapter 23). The evoked
governed isolated movements of the contralat- potential method has been subsequently devel-
eral extremities. Such focal seizures are also oped as a practical noninvasive method to
referred to as partial seizures in the study conduction in the visual, auditory and
International Classification (see Commission, somatosensory systems.
1981, 1989). These partial seizures are subdi- By stimulating particular thalamic nuclei,
vided into simple partial (simple motor or sen- one may map out specific thalamocortical rela-
sory or psychic symptoms) as contrasted to tionships.
complex partial (complex motor sequences of A modification of the technique is that of
automatic behavior and/or alterations in men- antidromic stimulation of an efferent pathway,
tal function as regards perception, memory and such as the pyramidal tract, to map out the cor-
affect) accompanied by impairment of con- tical nerve cells of origin of fibers in this tract.
Chemical agents locally applied to the pial responses of the patient with seizure discharges
surface of cerebral cortex may be employed in involving the prefrontal or temporal lobe areas
the laboratory preparation to produce an acute are also similar to the effects obtained on abla-
or chronic focus of discharge. The most com- tion of these areas and suggest release of other
mon agent employed for the acute focus peni- centers.
cillin. Chronic foci are produced by cobalt, or 4. In the interpretation of the relationship
alumina cream. of location of the pathology to the seizure
Interpretation of results: The results manifestation, the threshold for discharge of
obtained by the method of stimulation are sub- the underlying cortex must be considered.
ject to several possible interpretations from the Thus, in the large series of parasagittal menin-
standpoint of functional localization: giomas reported by Cushing and Eisenhardt
1. The effect observed may be clearly relat- (1938), seizure invariably accompanied those
ed to the actual function of the area stimulat- overlying the Rolandic cortex ("middle third
ed, e.g., stimulation of the motor cortex results parasagittal") at a relatively early point in the
in discrete movements. clinical history, whereas, anterior or posterior
2. The effect observed may be in part relat- one-third parasagittallesions, had seizure man-
ed to the spread of discharge to other cortical ifestation at a much later point corresponding
areas via corpus callosum to the opposite hemi- to a larger size of tumor. Motor cortex has a
sphere or association pathways, within the much lower threshold for seizure discharge
same hemisphere. than other areas of cerebral cortex.
The effects observed may in part reflect the Ablation: This method involves destruc-
spread of discharge to various subcortical and tion of a specific area by operative resection,
brain stem centers. The generalized convulsive coagulation, or freezing to the point of tissue
seizure that may develop secondary to the focal death. In man, the method of clinical patho-
seizure represents such a spread. logical correlation has produced considerable
At times, the secondary spread to other information. The destructive lesions have been
cortical and subcortical areas may be so rapid the result of a local area of tissue destruction
that the focal origin of the seizure discharge due to blood vessel occlusion, hemorrhage,
may be difficult to ascertain and it may be dif- solitary metastatic tumor, or intrinsic tumor. In
ficult on clinical grounds to separate such the laboratory transient focal depression may
seizures from non-focal (primary, generalized) be produced by focal cooling or by application
epilepsy. ofKCl.
3. The effects observed may indicate that Interpretation of results:
the remainder of the central nervous system is 1. The observed effects may indicate
functioning without the participation of the deficits directly related to a failure of a positive
area stimulated. Thus, if all the neurons of a function normally sub-served by the area
given cortical area are involved in a seizure dis- destroyed. For example, after destruction of
charge, .they may be unable to participate in parietal somatosensory projection areas,
their usual activities, be they of an afferent, deficits in stereognosis and position sense
integrative, or efferent nature. Thus, the occur.
effects of seizure discharges involving pre- 2. The effects may reflect the release of cen-
frontal or hippocampal areas may be in some ters in other cortical areas or at other levels of
aspects quite similar to the effect of ablation of the neural axis. This presumes that the area
these areas as regards intellectual functions, ablated usually inhibits certain functions of
personality, and memory or learning. This these other centers. The end result then is an
concept also implies, in a sense, to release of enhancement of certain fimctions. Spasticity
function in other areas (cortical and subcorti- several days' weeks or months after ablation of
cal). Therefore, certain of the emotional the motor cortex is an example.
17-10 CHAPTER 17
3. A temporary loss of function of a lower The techniques of CT scan, MRI, PET and
center may follow acute ablation of higher cen- SPECT have been discussed previously
ters. For example, following acute unilateral (Chapter 2).
ablation of all motor cortex in man, there will Concept of representation and re representa-
be observed a temporary loss or depression of tion of function: In considering functional
deep tendon reflexes and of other stretch localization, one must keep in mind that a
reflexes in the contralateral extremities. There given function may be represented and re rep-
will be initially a flaccid paralysis. This state resented at the various levels of the neural axis.
(referred to as the "diaschisis of Von Ontogenetic factor. In considering the
Monakow") is analogous to spinal shock or effects of ablation, one must also consider the
pyramidal shock. As recovery from this state ontogenetic factor. Bilateral ablation of the
occurs, deep tendon reflexes return and prefrontal cortex in the adult monkey produces
become progressively more active. The flaccid impairment in the capacity to delay responses.
paralysis is replaced by a spastic paresis. Trans Bilateral prefrontal ablation at one week of age
hemispheric effects also occur as discussed by in the infant monkey does not have this effect.
Andres (1991). Such a monkey when tested at 4 months, the
usual age when delay response appears, is able
B. HOW DO WE CONFIRM THE to manifest this capacity. Similar observations
LOCATION OF THE PATHOLOGY? may be made with regard to somatosensory
and visual pattern discrimination in the infant
Initially, data as to the actual location of the
cat as compared to adult cats following the
disease process and its nature (old scar from
appropriate resection of the somatosensory or
traumatic injury, old area of tissue damage due
visual projection cortex. Similar observations
to ischemia, infection, local compression, or
may be made in man. Thus, extensive destruc-
invasive brain tumor) were dependent on final
tion in most adults of the speech areas in the
examination of the brain at autopsy. One may
left hemisphere will result in a marked and last-
then speak of the method of clinical patholog-
ing deficit in linguistic expression (so-called
ical correlation. With the development of neu-
Broca's expressive aphasia). Destruction of this
rosurgery it became possible to define and to
same area in the infant or young child does not
confirm during life the anatomical boundaries
produce an enduring defect.
of some disease process, often allowing for
treatment or cure of the basic disease process.
The specialized techniques of electroen- C. CORRELATION OF
cephalography, arteriography, pneumoen- NEOCORTICAL
cephalography, and radioactive brain scan were CYTOARCHITECTURE
developed during the 1930s, 1940s, 1950s, to AND FUNCTION
provide some information about localization General observation: Those neocortical
prior to surgery. areas with specialized cytoarchitecture deviat-
The subsequent development of the more ing from the classical 6-layered cortex have
precise noninvasive imaging techniques of very specialized function for example primary
computerized axial tomography, (CT scan), motor or sensory cortex. In contrast the classi-
magnetic resonance imaging (MRI scan) and cal6-layered pattern tends to occur in associa-
positron emission tomography (PET scan) tion areas such as prefrontal, which have more
during the 1970s and 1980s now provide the complex and not such limited highly special-
closest correlation of clinical findings and ized functions.
anatomical location of the lesion in the living The more commonly used Brodmann
patient, supplanting the earlier radiological numbers are listed in the following outline with
techniques of arteriography, pneumoen- a brief note as to function. The corresponding
cephalography and radioactive brain scans. terminology of Von Economo and Koskinis is
Brodmann (Fig 17-7) are noted in the frontal
lobe: Primary motor area - 4, Premotor - 6 &
8, inferior frontal (Broca's) 44,45,47; Frontal
eye fields area 8, Prefrontal/Orbital- 46, 9,10,
11, 12, 13, 14. It is customary to divide the
frontal lobe into those more posterior areas
devoted to motor functions and those more
anterior areas devoted to non-motor functions.
MOTOR AREAS:
Figure 17-8. Reforence diagrammatic cytoarchitectur-
Area 4 (FA) corresponds in general to the
al map of monkey brain relating number system ter-
minology of Brodmann ro the letter system terminology precentral gyrus and functions as the primary
of Von Bonin and Bailey (after W1n &onomo and motor cortex. It is continued onto the medial
Koskinis). The borders are only approximate. (From surface as the paracentral lobule (Fig.17-1 0, 17-
Ruch, T. c., and Patton, H.D.: Physiology and 11).
Biophysics. 19th Edition, Philtulelphill, W.B.Sa.unders, Stimulation: discrete repetitive focal move-
1965, p.156.)
ments are produced based on the area stimu-
indicated in parentheses. The list is not all
lated for example repetitive jerks of the thumb
inclusive and does not include the areas of
or of the foot. A march of focal movements
mesial temporal lobe. Since many studies have
may occur, for example starting in the thumb,
been performed in the monkey a comparison
then spreading to hand, then to arm, then to
guide for cytoarchitecture is provided in Figure
face and leg etc.
17-8.
Ablation: an upper motor neuron type
Figure 17-9 demonstrates the lobes, gyri
weakness occurs with a contralateral monople-
and major sulci visible on the lateral surface of
gia or hemiparesis.
the cerebral hemisphere. Figure 17-10 demon-
Area 6 (FB) located anterior to area 4 and
strates the lobes, gyri and major sulci visible on
thus referred to as premotor cortex, functions
the medial surface of the cerebral hemisphere.
as motor association or elaboration area (Fig.
The orbital surface is illustrated in Figure 22-1.
17-8, 18-6). This area also functions to inhib-
it certain functions of the primary motor cor-
FRONTAL LOBE tex. The supplementary motor cortex repre-
The following cortical areas according to sents the continuation of this area onto the
medial aspect of the hemisphere (Fig.17-11)
TABLE 17-1. MAJOR GYRI IN THE FRONTAL LOBE. 18-12).
Stimulation: patterns of movement occur,
Gyrus Major Function for example tonic rotation of head eyes and
Precentral Origin af volitional motor pathways, trunk to the opposite side associated with tonic
the corticospinal and corticonuclear abduction of the arm at the shoulder and flex-
pathways (upper motor neurons) ion of the arm at elbow. Stimulation of the
supplementary motor cortex produces similar
Superior frontal Premotor and prefrontal regions
complex patterns of tonic movement .In addi-
Middle frontal Prefrontal and frontal eye fields tion there are bilateral movements of the trunk
and lower extremities.
Inferior frontal Broca's motor and speech area
in the dominant hemisphere Ablation: Transient release of "primitive"
automatic reflexes mediated by the primary
Orbital limbic motor cortex such as instinctive grasp, and suck
occurs. A more persistent release of these
Gyrus rectus limbic
instinctive reflexes follows the combined abla-
17-12 CHAPTER 17
SULCI
'UI
Figure 17-9. Lobes, gyri and major sulci. IAteral surface.
Figure 17-10. Lobes, gyri and major sulci. Medial surface

ing crossed connections to the pontine center
for lateral gaze
Stimulation: (Fig.I8-18) a conscious repet-
itive conjugate eye movement to the opposite
t'", «/.. ~.' .
./' -'" .-. field occurs. More specific effects can also be
" " , q"'e f
... .. ..
";
,'
"".,s/,AL f. s':;PA-e·~ · '" .. , achieved by discrete stimulation within this
~""'A.CI
0' . f MIlltHTAAY' .)
",eH/SPHe",, :"
!.-
_MOTO~ :.
area for example eyelid opening, repetitive eye-
: - . -. :: lid movements' pupillary dilatation. (Fig.I8-
- - - :~'I._:.:
- ...:.....-J"
...... .... :.;.t
-
19). Bilateral stimulation will result in conju-
~AT'RAL gate upward eye movements.
$U"'ACI
of'
H~MISPH'R6
Ablation: transient paralysis of voluntary
conjugate gaze to the contralateral visual field
occurs. In general, in man, this paralysis of vol-
untary gaze does not occur in isolation but is
MOTOA-+ associated with those processes such as infarc-
tion which have also produced a severe hemi-
paresis. The patient then lies in bed with the
contralateral limbs in a hemiplegic posture and
with the head and eyes deviated toward the
intact arm and leg. This deviation most likely
reflects the unbalanced effect of the adversive
Figure 17-11. Map of somatic motor and sensory areRS. eye center of the opposite intact hemisphere.
Note that the primary motor and sensory areRS extend The effect is usually transient clearing in a mat-
into the depth of the rolandic fissure and extend onto ter of days or weeks. A transient neglect syn-
the medial surface of the hemisphere. Note that the pre- drome primarily involving the contralateral
motor cortex, area 6 also extends onto the medial sur- visual field occurs although contralateral tactile
face of the hemisphere RS the supplementary motor cor-
and auditory stimuli may also be neglected.
tex. Note the location of the adl1ersil1e gaze field in
relation to motor cortex. (From Penfield, w., and Bilateral ablations within this area in the mon-
Jasper, H.: Epilepsy and the Functional Anatomy of key, resulted in animals that had a bilateral
the Human Brain. Boston, Little, Brown and neglect of the environment, remained apathet-
Company, 1954, p. 103.) ic and continued to have a "wooden expres-
tion of areas 6, 8 and supplementary motor sion". Similar findings may occur in the human
cortex. Such lesions also produce a significant patient with degenerative disorders involving
gait apraxia -an impairment of the ability to these frontal areas.
walk. without actual weakness or sensory Areas 44 and 45 (FeB) These areas cor-
deficit. Other deficits in the initiation of pat- respond in general to the inferior frontal gyrus
terns of movement in relationship to triangular and opercular portions. In the dom-
somatosensory or visual stimuli may also occur. inant (usually left) hemisphere this constitutes
Area 8 (FC) (Fig.I8-18) located anterior Broca's motor speech center or the anterior
to area 6 in the middle frontal gyrus in the speech center (Fig.24-I).
human is often grouped with area 6 as premo- Stimulation (Fig. 24-2): arrest of speech
tor cortex. This area functions in relation to occurs. Occasionally, simple vocalization
conscious eye turning and is often referred to occurs. A similar arrest of speech may also
as the frontal eye field or frontal center for occur on stimulation of the other speech cen-
adversive or contraversive eye movement. This ters -posterior and superior.
area is involved when the subject responds to Ablation: a non-fluent aphasia occurs. The
the command "turn your eyes to the left (or patient is mute. With limited lesions, consider-
right)" The effects are mediated by descend- able language may return. While isolated
17-14 CHAPTER 17
lesions (for example embolic infarcts) involving TABLE 17-2. MAJOR GYRI IN THE PARIETAL LOBE.
this area may occur, more often this type oflan-
guage defect is associated with a contralateral Gyrus Major Functions
hemiparesis. Postcentral Sensory cortex
Superior parlefallobule Sensory associational

PREFRONTAL -NONMOTORAREAS
Inferior pariefallobule: Sensory language areas in
Areas 9, 10, II and 12 (FD), the pre- --Pars supramarginal the dominant hemisphere
frontal areas, are concerned with emotional --Pars angular
control and other aspects of cognitive function
(Fig. 18-21). Areas 13,14 (FE, FF, FG, FH) Precuneus Sensory associafional
are also often included in this group.
Stimulation: Complex partial seizures with inferior parietal lobule (the angular and supra-
alteration ofpersonality, emotion, and behavior marginal gyri). These areas in the dominant
occur often accompanied by tonic motor com- hemisphere function in relation to reading and
ponents. Note that 25% of complex partial writing as higher integrative areas for language.
seizures originate in frontal lobe structures but This area is part of the posterior speech area. In
75% originate in temporal lobe. the nondominant hemisphere these areas relate
Ablation: An alteration in personality, affect to our concepts of visual space.
and control of emotion may occur and / or Stimulation: In the dominant hemisphere,
there may be an alteration in cognitive/execu- arrest of speech occurs.
tive function. Ablation: In the dominant hemisphere,
defects in reading, writing and calculations
PARIETAL LOBE occur. These deficits along with difficulty in
Areas 3, 1,2 (PA, PB, PC) These areas finger identification and left/right confusion
correspond to the postcentral gyrus and func- constitute aspects of the Gerstmann syndrome.
tion as the somatosensory projection areas A variety of fluent aphasia occurs. In the non-
(continue into paracentral lobule ). dominant hemisphere, a denial or neglect syn-
Stimulation: Episodes of localized tingling drome occurs.
paresthesias occur which may spread as with
focal motor seizures. TEMPORAL LOBE:
Ablation: Deficits in cortical sensory (dis- The temporal lobe is a complex structure
criminative sensory) modalities will occur, for that includes neocortex, allocortex, mesocor-
example stereognosis, position sense, graphes- tex and a subcortical nucleus (the amygdala).
thesia, and tactile localization. At its posterior borders it merges into the pari-
Areas 5, 7 plus in hwnan 39, 40 (PD, etal and occipital lobes.
PE, PF, PG): The Parietal LobulesAbout Major areas in the Temporal Lobe from fig-
half way up the postcentral sulcus, the intra- ure 17-7:
parietal sulcus extend posteriorly, dividing the Auditory (Transverse Temporal) 41;
parietal lobe into superior and inferior parietal Auditory associational42 and 22; middle tem-
lobules. The inferior parietal lobule consists of poral 21; inferior temporal 20; posterior tem-
the supramarginal and angular gyri. The poral37; entorhinal27, 28,35.
supramarginal gyrus surrounds the posterior The temporal lobe lies below the lateral sul-
ascending limb of the lateral sulcus. The angu- cus and on its lateral surface has a sequence of
largyrus is behind the supramarginal gyrus and three anterior to posterior arranged gyri: the
surrounds the posterior end of the superior superior, middle, and inferior temporal gyri.
temporal sulcus (Table 17-2). The inferior temporal gyrus extends onto
Areas 39, 40 (PG, PF) correspond to the the ventral surface of the cerebrum. The supe-
TABLE 17-3 GYRI IN THE TEMPORAL LOBE Ablation: limited unilateral lesions may
produce a disturbance in the ability to localize
Gyrus Major Functions sounds. Bilateral lesions of a limited nature
- Hippocampal formation - Limbic and memory would be rare but could produce "cortical
- Amygdala - Limbic deafness"
Parahlppocampal Limbic Area 22 (TA) corresponds to the superior
temporal gyrus and surrounds areas 41-42.
Occlpilotemporal limbic This is an auditory higher association center.
In the dominant hemisphere, the posterior half
Inferior temporal Limbic
of this area represents an auditory association
Middle temporal Limbic and facial area concerned with the reception and inter-
recognition pretation of spoken language. This is one com-
- Superior temporal - Sensory language area ponent of the posterior speech area. The area
- Transverse temporal gyri in the dominant is often referred to as Wernicke's receptive
hemisphere; aphasia center. In the nondominant hemi-
- Auditory area sphere this area is more concerned with visual
aspects of space.
rior temporal gyrus forms the temporal oper- Stimulation: Stimulation of the posterior
culum. Near its posterior end two gyri are seen speech (Wernicke's) area (Fig.24-2) produces
running into the lateral fissure (Table 17-3). an arrest of speech. Seizures originating in the
These are the transverse temporal gyri, consist- superior temporal gyrus are also characterized
ing of the primary receptive auditory cortex, by "experiential "phenomena: distortions of
area 41. auditory and visual perception alterations in
One of the first conclusive bits of evidence the sense of time and in well formed visual and
on the significance of anatomic asymmetry in auditory hallucinations (psychical seizures). As
the cerebrum was noted by Geschwind and will be discussed in chapter 22,complex partial
Levitsky (1968) in the temporal lobe. They seizures that may begin with these phenomena
made a horizontal section through the lateral but subsequently proceed to impairment of
sulcus and removed the overlying parietal and awareness; amnesia and automatisms (uncon-
occipital cortex. They called this exposed scious stereotyped patterns of movement)
region of the superior temporal gyrus, the reflect involvement of or spread to the mesial
planum temporale. They noted a larger planum temporal areas of hippocampus and amygdala.
temporale in the left temporal area than on the Fear that may also accompany these seizures
right side in right handed humans. In left- reflects involvement of the amygdala. Olfactory
handed individuals the area was the same on hallucinations that may also accompany these
both sides. Their observations on the anatom- seizures reflects involvement of the mesial tem-
ical basis of cerebral dominance have since poral structure, the uncus.
been supported by radiological and other Ablation: Damage to Wernicke's area a part
anatomical studies. of the posterior speech area produces a deficit
Areas 41, 42 (TC, TB) the transverse gyri in the comprehension of speech, a type of flu-
ofHeschl function as primary auditory projec- ent aphasia.
tion areas. Additional information about more exten-
Stimulation: Episodic tinnitus (a ringing sive unilateral or bilateral damage to the tem-
sensation) occurs. Usually such seizures are not poral lobe will be considered in chapters 22
limited to this symptom in isolation, since and 30. Suffice it to say, that bilateral damage
other aspects of temporal lobe are involved to to the hippocampus will produce severe deficits
produce the more complex phenomena of the in the ability to record new memories. Damage
temporal lobe seizure. to the amygdala will alter emotional control
17-16 CHAPTERl7
TABLE 17-4 MAJOR GYRI IN OCCIPITAL LOBE. NEOCORTEX:

The topics of prenatal development, post-
Gyrus Functions
natal development and abnormalities of
Lateral occipital Visual associational
cortical neuronal migration are discussed in
Lingula Superior visual field chapter 4 and on this chapter's CD ROM.
Cuneus Inferior visual field

IV. SUBCORTICAL WlllTE MATTER
AFFERENTS AND EFFERENTS
OCCIPITAL WBE
Essentially three types of fiber systems
The lateral occipital gyri consist of visual occupy the subcortical white matter: (1) pro-
associative cortex. The visual receptive cortex jection fibers, (2) commissural fibers, and (3)
(calcarine-cortex) is found on the medial sur-
association fibers.
face of the hemisphere (Table 17-4). Projection fibers consist of the corticopetal
Areas in the Occipital Lobe: visual (cal- afferent fibers, such as the thalamocortical radi-
carine) 17; visual association 18 & 19. ations, and the corticofugal efferent fibers such
Area 17 (OC) corresponds to the striate as the corticospinal, corticoreticular, and corti-
cortex bordering the calcarine fissure and func- corubral tracts (Fig. 17-12).
tions as the primary visual projection area. In The major commissural systems are the
modern physiological terms the designation corpus callosum, anterior commissure, and
VI is utilized. hippocampal commissure. The corpus callo-
Stimulation: Seizures originating in this sum is the major commissure for the neocorti-
area produce simple unformed visual hallucina- cal areas (except the middle and inferior tem-
tions such as flashing lights, stars or jagged poral gyri) (Fig. 17-13) and the rostral portions
lines. The phenomena may be localized to the
contralateral visual field or at times to the con-
tralateral eye.
Ablation: Homonymous visual deficits are
produced for example, a homonymous hemi-
anopsia or quadrantanopsia.
Areas 18, 19 (DB, OA) form surrounding
stripes around area 17. These areas function as
visual association areas of varying complexity.
The terms V2-V4 are utilized. These areas are
also involved in the fixation and following of
objects in the contralateral visual field. Note
that visual areas V4 and V5 extend into the
adjacent temporal-parietal cortex.
Stimulation: Some of the effects are similar
to stimulation of area 17. In addition conju-
gate deviation of the eyes to the contralateral
field will occur.
Ablation: Selective lesions may produce
deficits in some of the more complex visual
activities. In addition defects in visual fixation TO oc.,"T.tL _
and following may occur. Figure 17-12. Projection fiber syrtems passing through
the internal capsule. The superior thalamic radiation
ill. DEVELOPMENTAL ASPECTS OF includes fibers projecting from ventral thalamus to
sensory and motor cortex.
sphere. Thus area 6 has widespread connec-
tions in the contralateral hemisphere not only
to area 6 but also to areas, 4, 5, 7, and 39,
whereas area 4 has discrete contralateral con-
nection only to the homotypic points.
The anterior commissure interconnects the
rostral portions of the superior, middle and
inferior temporal gyri, inferior-posterior orbital
gyri and paleocortex (parahippocampal gyrus).
The hippocampal commissure2 interconnects
the hippocampal formation and dentate gyri
Figure 17-13. RJui.iation offibers from corpus callo- (archicortex) and the surrounding presubicu-
sum as dissected in human brain.
lum, entorhinal and adjacent inferior temporal
of the superior and inferior temporal gyrus (see gyrus. These fibers are conveyed via the fim-
Pandya and Posene 1985- for a more detailed bria of the fornix and cross at the point beneath
discussion). In general, homologous areas of the splenium of the corpus callosum, where the
the two hemispheres are interconnected. posterior pillars of the fornix converge.
However, there are significant regional varia- Two types of subcortical association fibers
tions between homologous areas as regards may be distinguished (excluding from this dis-
fiber density (Fig. 17-14). Thus, there is a high cussion, the intracortical association fibers): (a)
density of callosal fibers connecting the premo- short subcortical U or arcuate fibers which
tor areas of the two cerebral hemispheres. On interconnect adjacent gyri and (b) long fiber
bundles which reciprocally interconnect distant
cortical areas. The following long fiber bun-
lThe O1;ganization of callosal projections is more

complex than the picture provided by the early
degeneration maps. Thus within somatosensory
cortex callosal connections are most dense in
areas 2, less dense in area 1 and least dense in
areas 3B. Within each of those areas differences
also occur. In area 3B, relatively dense connec-
tions are present for trunk and head but rela-
Figure 17-14. Pattern of distribution of commissur- tively sparse connections for hand and foot. In
al fibers lJ1Ier the cortical surface of the left hemi- contrast within area 2 relatively dense
sphere of the monkey (Macaca mulatta) as studied connections are present for all parts of the body.
following section of major commissures. (From Significant changes occur during development
Myers, R. E.: In Ettlinger, E. G. (ed.): Functions of in part related to the overlap with thalamocorti-
the Corpus Callosum. Boston, Little, Brown &
cal afferent input. For a more complete discus-
Company, 1965, p. 142).
sion see Killackey 1985, Killackeyand Chalupa
the other hand, a primary visual projection area 1986, Dehay et a11988. The end result is in part
- area 17 - has almost no direct callosal con- a complementary relationship to the distribution
nection to the contralateral hemisphere. Area of thalamocortical fibers.
17 transmits to the adjacent area 18 that has 2In the monkey two hippocampal commissures
connection to contralateral area 18 1 . have been identified-based on relationship to the
Cortical areas also differ as regards the fornix. (For a more complete discussion of the
spread of fibers to asymmetrical as well as to topography ofcommissural fibers see Pandya and
symmetrical points in the contralateral hemi- Rosene, 1985).
17-18 CHAPTERl7
AND EFFERENT PROJECTIONS

OF NEOCORTEX:
AFFERENT INPUTS:
THALAMUS:
The thalamus is the major source. The
transmitter is glutamate. With the exception of
the olfactory system, all sensory information
passes through the thalamus'.
In many classifications, the thalamus has
been divided into three major divisions: 1) the
Figure 17-15. Disseaion of long fiber systems; the dorsal thalamus, 2) the ventral thalamus, and
uncinate fasciculus (C) passing from orbital frontal
3) the epithalamus.
(A) to anterior temporal areas (B).
The dorsal thalamus is by far the largest
dles may be distinguished on blunt dissection component and at times the term thalamus has
of the cerebral hemisphere: been applied only to the dorsal thalamus. This
1. The uncinate fasciculus interconnects the structure is composed of a series of relay nuclei
orbital and medial prefrontal areas and the that connect in a reciprocal manner with the
anterior temporal area (Fig. 17-15). cerebral cortex and the striatum (Refer to
2. The superior longitudinal fasciculus inter- chapter 15) these nuclei can be subdivided into
connects the superior and lateral frontal, specific projection (or relay) nuclei and non-
parietal and temporal, and occipital areas specific or diffuse projection (or relay) nuclei.
(Fig. 24-5). The extension of this fiber sys- The specific nuclei have specific afferent
tem into the temporal area, passing through inputs and project in a relatively precise topo-
the subcortical white matter of supramargin- graphic manner to specific areas of cerebral
al and angular gyri, is often distinguished as cortex. Experience, or functional disuse may
the arcuate fasciculus. This fasciculus has modH)r the precise cortical areas devoted to the
considerable importance because of its role topographic representation of a given sensory
in connecting the receptive language centers area. Examples of specific nuclei and their cor-
of the temporal lobe with the expressive tical projections have been provided in chapter
motor speech centers of the inferior frontal 15.
gyrus. Such a connection must be made The densest input from the specific relay
if a sentence that has been heard is to be projection nuclei is to layer 4, but as indicated
repeated. above, pyramidal cells in layers 3 and 5 many
3. The cingulum passes within the subcortical also receive direct or indirect inputs. There is a
white matter of the cingulate gyrus; it inter- modality specific columnar arrangement.
connects the subcallosal, medial-frontal, and The nonspecific nuclei have a more diffuse
orbital-frontal with the temporal lobe, input and a more diffuse but not necessarily a
occipital areas, and cingulate cortex. generalized cortical interaction. Examples
4. The inferior longitudinal fasciculus inter- include the following: midline nuclei (massa
connects the occipital and inferior temporal intermedia), central-medial, intralaminar
areas. nuclei, and the medial dorsal (which is diffuse
5. The inferior frontal occipital fasciculus inter- to frontal areas).
connects the frontal and occipital areas. It is The nonspecific nuclei project mainly to
often difficult to clearly differentiate this layer l.
fiber system from the uncinate fasciculus. The ventral thalamus is a thin shell nucle-
us that is external to the external medullary
MAJOR AFFERENT INPUTS lamina. It does not project directly to cerebral
cortex, but receives innervation from cerebral This system is probably involved when psy-
cortex. The subnuclei grouped as the thalamic chotic behavior occurs in schizophrenia.
reticular nucleus have specific reciprocal rela- 4. cholinergic pathways from the basal fore
tionships with projection (relay) nuclei in the brain nucleus of Meynert project widely to
dorsal thalamus. As we will see below in dis- cerebral cortex. In addition cholinergic neu-
cussing the basis of the electroencephalogram rons in the septum project to the hippocam-
these nuclei have a significant effect on thalam- pus. In addition, cholinergic neurons in the
ocortical interactions. These nuclei in the brain stem tegmentum project to the thala-
rodent (but not in the primate) have a high mus and will be discussed in the chapter on
concentration of GABA-ergic neurons. The sleep (chapter 29). Electrical stimulation of
drive on the relay nuclei is therefore inhibitory. brain stem reticular formation (resulting in
The epithalamus includes the pineal body, desynchronization / arousal of the EEG)
the stria medullaris and the habenular trigone. results in an increase in rate of liberation of
These structures relate primarily to the hypo- acetylcholine from the surface of cerebral
thalamus and are not relevant to a discussion of cortex. This effect may be mediated through
thalamocortical interactions. the reticular formation projection to the
basal forebrain.
NON-THALAMIC SOURCES 5. GABAergic pathways from basal forebrain,
OF INPUT: ventral tegmental area and zona incerta to
sensory and motor cortex.
There are multiple other subcortical
6. claustrwn projects to all sensory, limbic,
sources of input including the following.
and motor areas with an excitatory input.
1. noradrenergic (norepinephrine) pathway
from the locus ceruleus of the midbrain pro-
jecting in primates predominantly to layer 6 EFFERENT PROJECTIONS:
of the motor and somatosensory cortex and Projections occur in a reciprocal manner
related frontal and parietal association cor- with many subcortical areas (thalamus, basal
tex. This pathway functions in relationship ganglia, brain stem and spinal cord). However
to arousal responses induced by sensory these projections are estimated to account for
stimuli and activity in this system is altered only 0.1 to 1% of all fibers in the white matter.
during the rapid eye movement stage of Instead most fibers are involved in intra- hemi-
sleep spheric and interhemispheric connections,
2. serotoninergic pathway from the raphe pyramidal neurons to pyramidal neurons and
nuclei in the pons and medulla and the pon- to intemeurons.
tine reticular formation. Although these
neurons project to all cortical areas, the pre- Part V: Neurophysiology Of
dominant projection in the primate is to The Cerebral Cortex: Correlates Of
layer 4 of area 17, the primary visual cortex. Cortical Cytoarchitecture And
This system may be involved in the onset of The Basis Of The Electro-Encephalogram
the slow wave stage of sleep. During rapid will be found on the CD ROM chapter 17
eye movement sleep there is decreased activ-
ity in this system. Damage to the system
Part VI: Clinical And Physiological
produces insomnia.
Correlates Of Cytoarchitectural Variation
3. dopaminergic pathways from ventral
tegmental - rostral mesencephalic nuclear will be found on the CD ROM chapter 17
groups. The strongest projection is to the
prefrontal cortex, and limbic system. The
fibers extend to all cortical layers except for
IV. The projection is primarily inhibitory.
17-20 CHAPTER 17
PART V: NEUROPHYSIOWGY OF
THE CEREBRAL CORTEX:
CORRELATES OF CORTICAL
CYTOARClllTECTURE AND
THE BASIS OF THE ELECTRO-
ENCEPHALOGRAM:
The cerebral cortex of man and of other
mammals is characterized by continuous rhyth-
mic sinusoidal electrical activity of variable fre-
quency. This electrical activity may be record-
ed through the scalp of man in the form of the
electroencephalogram (EEG) or directly from
the cerebral cortex during surgery in the form
of the electrocorticogram (ECG). The term
Figure 17-16. Isolated cerebral cortex. A) The
EEG will be used during the subsequent dis- anatomical bilateral cortical callosal preparation.
cussion to refer to the activity found in either B) The electrical activity of the preparation. The upper
the EEG or the ECG. The electroencephalo- 6 channels are bipolar recordings from the isolated
gram provides a physiologic correlate of the areas. The lower 2 channels are recorlkd from the non-
various states of consciousness. isolated cortex. From Marcus, E. M. In Reeves, A.
Epilepsy and the Corpus Callosum, New York Plenum
The normal electroencephalogram (EEG)
Press,p.158.1985.
in the awake adult who is recorded while rest-
ing with eyes lightly closed is characterized by sedative medications will produce increased
a dominant activity in the posterior (parietal- amounts of generalized beta activity and even-
occipital) recording areas of continuous 8-13 tually generalized slow wave activity. (Fig. 2-
Hz sinusoidal waves of 25-75uv (Fig.2-18). 21). The frequency of the basic background
Amplitudes recorded directly from the cortex activity is also influenced by the age and level of
are higher. This pattern is referred to as the consciousness of the patient. (Fig. 2-19, 2-20)
alpha rhythm since this was the first pattern dis- In general the activity of the two cerebral hemi-
covered. The second described pattern the beta spheres is relatively symmetrical and synchro-
rhythm is found predominantly in the frontal nous.
recording areas and consists of low amplitude The electrical activity recorded is not a
14-30Hz activities. Many sedative medications result of axon potentials and does not represent
will produce increased amounts of generalized the activity of individual neurons and synapses.
beta activity and eventually generalized slow Instead EEG rhythms represent the summated
wave activity. The frequency of the basic back- electrical activity of a large number of synapses
ground activity is also influenced by the age located in the more superficial layers of the
and level of consciousness of the patient. Any cerebral cortex. Seizure discharges do not orig-
pattern slower than alpha is referred to as com- inate in single neurons but instead are generat-
posed of slow waves (theta=4-7Hz; delta =0.5- ed in a group of neurons that manifest
3Hz) as illustrated in figures 2-24, 2-25. Many increased excitability and synchronization (the
epileptic focus). Never the less certain muta- mus was characterized by continuous sinu-
tions involving the neuronal membrane and soidal waves of 8Hz.The more recent studies
the synaptic receptor provide the basis for sev- of Steriade and Uinas (1988) have demon-
eral types of genetically determined seizure dis- strated that all thalamic reticular neurons can
orders (see chapter 29). The difference spontaneously generate rhythmic discharges at
between axonal and synaptic activity has been a rate of approximately 10Hz. Groups of such
discussed in chapter 5. cells even when deafferentate can generate syn-
chronized oscillations. These neurons have a
THE ACTIVITY OF ISOLATED strong inhibitory input to the thalamic relay
CEREBRAL CORTEX: (projection) neurons and thus could entrain
these neurons in a similar oscillation. This
In considering the basis of the electroen-
could then be reflected in a similar entrainment
cephalogram, it is of value to first consider the
of cortical neurons and synapses in a 10Hz
activity oflarge blocks of cerebral cortex isolat-
oscillation. (See below).
ed from all subcortical interactions, but retain-
In brief then the continuous rhythmic
ing pial blood supply. The basic activity of such
activity seen in the electroencephalogram must
preparations in the cat, the monkey and in the
indicate the effects of thalamic neurons on the
human is characterized by bursts of electrical
activity of cortical neurons and synapses. As we
activity composed of mixed frequency sharp
will see below, brain stem structures are also of
waves, spikes, slow waves and fast activity alter-
importance in modifYing cortical activity.
nating with periods of relative electrical silence
(Ingvar and Echlin). In the chronic studies of
Kellaway et al (1966) the bursts of activity were MODIFICATION OF CORTICAL
correlated in large part with unit discharges in ACTIVITY BY STIMULATION OF
the depths of cortex at the level of the large VARIOUS STRUCfURES: EVOKED
pyramidal cell bodies. In a related preparation POTENTIALS.
large homologous blocks of cerebral cortex The background cortical electrical activity
were isolated in each hemisphere along with may be modified by stimulation at various lev-
the interconnecting corpus callosum (Fig.17- els. These evoked responses include the super-
16A), (Swank (1949, Marcus&Watson, ficial cortical response, the direct response, the
1966). The basic pattern is composed ofbilat- transcallosal response, the primary evoked
eral relatively synchronous and symmetrical response, the recruiting response and the gen-
bursts of activity with intervening periods of eralized arousal response.
relative electrical silence (Fig.17-16B). Similar Primary evoked response. Stimulation of the
burst suppression type activity is obtained in sciatic nerve or of other specific sensory path-
preparations in which all thalamic, hypothala- ways produces a similar surface positive wave
mic and rostral mesencephalic structures have followed by a surface negative wave. (Fig.17-
been ablated. The burst suppression pattern 17) A similar response of much shorter latency
may be seen in several clinical circumstances: (1-5msec) is produced by stimulation of the
1) very deep anesthesia, 2) diffuse specific thalamic nucleus involved in the prima-
encephalopathies as in anoxic encephalopathy ry evoked response.
or encephalitis, 3) following intractable status Augmenting response: With repetitive stim-
epilepticus or 4) in the premature brain. ulation of the same nucleus at 6-12 Hz the
amplitude and latency of each successive
THE ACTIVITY OF ISOLATED response increases (Fig. 17-17).
THALAMUS Recruiting response: In contrast, repetitive 6
to 12 Hz stimulation of the nonspecific thala-
In contrast in the studies of Kellaway et al
mic nuclei such as the intralaminar, the medial
(1966), the electrical activity of isolated thala-
or midline groups or the thalamic reticular
17-22 CHAPTERl7
CORTICAL LAMINAR DISTRIBUTION OF EVOKED RESPONSES

SCH PRIMARY RCSP. AlJGMENTING RE$P RECRtltrlNG RES/?
t
• Neg.ative (-)
Positive (+)
20 mnc.
-..
Ifl"£T171111" S7111. IflP'7/71V1 'riM.
NEOCORTEX
WIll mm.
]I
0.5
:m:
1.0
1.5
2.0"1>
8= Efferents
R
• A= Specific Afferents
C= Non-Specific Afferents
C
-+
Figure 17-17. L4minar analysis of the various cortical evoked responses in terms of the type and magnitude of
response recorded with an external microelectrode at various depths. Specific afferent fibers terminate in layer IV
and are shown making synaptic contact with both granule cell interneurons and adjacent pyramidal cells.
Nonspecific afferent fibers are shown terminating in many layers including layer 1. The SCR (superficial cortical
response) is limited to the superftciallayers ofcerebral cortex. The initial surface positive component of the prima-
ry evoked response (specific stimulus, recording from specific cortical projection) originates in the deeper cortical
layers (the vertical lines represent cell discharges). The subsequent surface negative wave originates in superficial
cortical layers. The transcallosal response would have a similar form and analysis. Specific thalamic nucleus stimu-
lation results in the augmenting response. The origin of the recruiting response to stimulation of nonspecific thala-
mic nuclei is complex (see text). (Reproduced with modifications from an unpublished diagram by Purpura)
nucleus) produces a predominantly surface represents summated EPSPs (excitatory post
negative response of greater latency (15-60 synaptic potentials) generated in the more
msec) termed the recruiting response (Fig.17- superficial layers of cerebral cortex and the
17, 17-18). The response waxes and wanes and waves are therefore surface negative. At times a
is similar to the 8 to 12 Hz spindle response small initial surface positivity may be present.
that characterizes light anesthesia in the cat .In Under particular conditions of anesthesia with
the human, a similar spindle occurs at 14 - 15 stimulation of these same thalamic nuclei, a
Hz during stage 2 sleep. Although this system longer duration (100-200 msec) surface nega-
is referred to as the diffuse thalamocortical sys- tive wave may follow the initial wave of the
tem, in the monkey, the response is obtained recruiting response. This is however correlated
predominantly from the frontal and parietal with a prolonged hyperpolarization in the
association cortex. The recruiting response deeper cortical layers .In the cat preparation
tern. The response occurs with a latency of
A B c approximately 40 milliseconds and outlasts the
period of stimulation. The long latency sug-
gests a pathway involving several synapses as
opposed to the classic short latency lemniscal
sensory pathway. This system has diffuse effects
on the cerebral cortex via 2 systems: the non-
specific thalamic nuclei and the pathway from
basal diencephalon to the basal forebrain. The
intralaminar nuclei of the thalamus represent
an upward continuation of the ascending retic-
ular formation. Stimulation of these thalamic
nuclei, e.g., centrum medianum, at high fre-
quency (300 Hz) produces the same effects on
j , 4 I Ihll IIlIlIllI
cortical electrical activity as stimulation of
ascending reticular formation at a brain stem
Figure 17-18. The recruiting response. Cortical level Thus sciatic stimulation produces not only
responses in anterior sigmoid gyrus ofcat to successive
stimulation of intralaminar nuclei of thalamus (A, the short latency, localized, primary evoked
B, C) at 8 Hz characterized by long latency and a pro- response but also the long latency, generalized,
gressive increase in amplitude of the surface negative arousal response. This reflects the fact that sen-
response. The time marks indicate 10 msec. (From sory data enters the reticular formation via col-
Morison, RS., and Dempsey, E. w.: Amer. ]. Physiol., laterals from the specific sensory pathways, par-
135:288,1942) II. The similarity of the waxing and ticularly the spinothalamic system. Moreover,
waning amplitude of the recruiting response to the
multiple sensory modalities may synapse on the
spontaneous 8-12 cps spindles, which characterize seda-
tion or anesthesia with Nembutal or other barbitu- same neuron in the reticular formation. The
rates, is also demonstrated. Recordings from middle system then is in a sense nonspecific as to the
suprasylvian gyrus ofcat. A) Spontaneous spindle modality identity of the incoming stimulus.
bursts. B) Recruiting response to stimulation (stimu- The role of the reticular formation and
lus marker) or intralaminar areas of thalamus. From
Dempsey, E. w., and Morison, R S.: Amer. ]. Physiol.,
135:297, 1942 (Amer. Physiol. Soc.) Cortical Laminae I
this combination of the initial recruiting wave
(the spike) and the subsequent slow wave pro-
vides a model of the thalamic induced spike VI
wave complex and has been correlated with
behavioral changes (arrest of activity,
myoclonus) similar to the absence seizures of GLU
idiopathic epilepsy (see chapter 29).
Arousal or activation or desynchronization
Thalamic
response: Stimulation of the sciatic nerve or } Relay
other sensory pathways or eye opening or Nucleus
intense mental activity will also have a signifi-

cant generalized effect on the background Figure 17-19. The interaction of cortical pyramidal
activity of the EEG. The alpha rhythm is cell (CN), thalamic relay nucleus (TC) and thalamic
replaced by a low-voltage fast activity (Fig. 2- reticular nucleus (NRT), GLU=Glutamate, GABA=
Gamma amino butyric acid. Modified from Snead,
lSC). This response can be reproduced by
D.C. III, In Malafossa, A. Idiopathic Generalized
high frequency (50-300Hz) stimulation of the Epilepsies: Clinica~ Experimental and Genetic
brain stem ascending reticular activating sys- Aspem. London John Libbey
17-24 CHAPTERl7
other brain stem areas in sleep, consciousness,

and attention will be considered in greater
detail in chapter 29.
THE INTERACTION OF
CORTICAL NEURONS AND
THALAMIC RELAY NUCLEI:
The interaction is complex. Thalamic relay
nuclei function in two possible states: ( 1) a
transmission mode when the neuron is near fir-
A B c o E F
ing threshold in which the discharge reflects
the sensory input. (2) A burst mode when the
neuron is hyperpolarized by inhibitory input.
Im A
---- III r--
.I '-.-------- V"'-'""
The thalamic relay neurons have a special volt-

age gated calcium channel (transient or T type)
that is inactive when the membrane potential is
2m A ./'- -
• ."- v- I'.iiI! v----
.'Ii1I '-"'---
~",A
v"- \,
11 , ,,/ ~
near threshold. However when the cell is

hyperpolarized, incoming excitatory synaptic SmA ,
•..1 . . . . .- \.-1Ii '-
potentials trigger transient opening of this cal-
cium channel. The resulting calcium current
Figure 17-20. Variations in thresholds and amplitude
then brings the neuron potential above thresh-
of superficial cortical response (local cortical response)
old. The neuron then fires a burst of action as a function of locus of stimulation in the monkey.
potential until the calcium that has entered the Note the low threshold and relatively higher amplitude
cell activates potassium current that again pro- of the premotor and motor cortex responses (B, C, D)
duces a hyperpolarized state. During burst fir- compared to those obtained in area 17 (F) posterior
ing the thalamic relay neurons cannot transmit temporal (E) and prefrontal areas (A). The stimula-
sensory information to the cerebral cortex. The tion intensities were the same in all areas (0.10 msec.
single shocks). From Eidelberg, E., Konigsmark, B.,
source of the hyper polarization of the thalam- and French, ID.: Electroenceph. din. Neurophysiol.
ic relay neurons is the reticular thalamic nucle- 11:123,1959 (Elsevier).
us that is composed of GABA-ergic inhibitory
neurons. In turn the neurons of the reticular PART VI: CLINICAL AND
nucleus receiving collateral input from cortical PHYSIOLOGICAL CORRELATES OF
thalamic and thalamocortical relay neurons CYTOARCHITECTURAL VARIATION
(Fig.17-19). The thalamic reticular nucleus
I) The capacity for focal seizure discharge:
also has the property of the burst mode of dis-
charge when hyperpolarized. The burst firing Anatomical Observation: In the monkey as
of the thalamic relay cells is reflected in rhyth- in man the motor cortex (area 4) of the pre-
mic waves of excitatory postsynaptic potentials central gyrus is characterized by the presence of
in the dendrites of cortical neurons and is giant and large pyramidal cells. These giant
expressed in the surface EEG as rhythmic slow and large pyramidal cells are characterized by a
waves. This pattern of slow wave activity may long apical dendrite. Associated with these
be seen in sleep or in diffuse encephalopathies pyramidal cells, there is noted in the Golgi
During states of wakefulness, the thalamus stain, the presence of a massive tangential
remains in the transmission mode because of plexus in the molecular layer with the presence
cholinergic input from rostral pons to the thal- of many axodendritic synapses. In contrast, the
amic relay and thalamic reticular neurons. striate occipital cortex (area 17) has a dense
There are also cholinergic inputs to the thala- external line of Baillarger in layer IV but only a
mic reticular nucleus from the basal forebrain. thin tangential plexus in the molecular layer.
_ SV
~~~ IOV
15 V
Figure 17-21. Regional Differences in &izure Susceptibility in Monkey Cortex. The thresholds for electrical
seizure after discharge in response to direct stimulation of cerebral cortex are shuwn. Note the low threshold of
motor cortex ofsectors in premotor cortex and of anterior medial temporal area as contrasted to striate occipita~
(area 17) prefrontal posterior temporal, and parietal areas. Compare to Figure 17-30, note the similarity as
regards pattern of regional variation. From French, JD., Gernandt, B.E., and Livingston, R. B.: Arch. Neurol.
Psychiat., 75:270, 1956 [American Medical Association (AMA)}.
Giant pyramidal cells are absent and large pyra- cortex. On the other hand, tumors in the pre-
midal cells are sparse. frontal, posterior-temporal parietal, or occipital
Physiological Observations: The superficial areas may grow to a large size without produc-
cortical response represents the summated ing focal seizures. When focal seizures occur
postsynaptic potentials generated at superficial they may indicate a compromise oflow thresh-
axodendritic synapses. In the studies of old motor cortex with discharge originating at
Eitelberg et al. (1959) this response could be that area rather than at the primary site of
easily obtained at low threshold in the motor involvement.
cortex. On the other hand, only a feeble 2) The capacity for contralateral spread
response was produced in the striate occipital of discharge as related to callosal fiber sys-
cortex (Fig. 17-20). tem density:
French et al. (1956) studied the threshold Anatomical Observation: Using the Nauta
for generation of propagated seizure after dis- method to study degeneration ofaxons, Ebner
charge following electrical stimulation of mon- and Myers (Myers, 1965) have evaluated the
key cerebral cortex. Low thresholds were density of callosal projection approximately 10
found in the motor cortex with the ready days after section of the major interhemispher-
development of generalized seizure discharge. ic commissures. A dense callosal projection was
On the other hand, high thresholds were pre- found in the precentral, premotor and inferior
sent in the striate occipital cortex (Fig. 17-21). parietal areas. Only a sparse callosal projection
Clinical Correlation: The capacity for a was present in striate occipital and superior
clinical seizure is directly related to the capaci- temporal areas (Fig. 17-14).
ty for generation of repetitive discharge and of Physiological Observations: The original
after-discharge. Thus whether a tumor involv- studies of Curtis (1940) on the transcallosal
ing the cerebral cortex announces its location response in the monkey indicated significant
with a seizure will be related to its location. regional differences in the capacity for genera-
There is, then, an extremely high incidence of tion of this response. The response was easily
focal or generalized seizures in patients with obtained on stimulation of the premotor, pre-
parasagittal meningiomas overlying the motor central, and parietal areas but could not be
17-26 CHAPTER 17
22A found in studies of McCulloch and his associ-

ates (1944) employing a local area of seizure
discharge (strychnine neuronography) rather
than direct electrical stimulation. Both series of
studies also indicated that significant regional
differences existed as regards the diffuseness of
PC-IP L _:r",,~~:,\~Vf""""''''~''''~ callosal projection. Thus, certain cortical areas
R......'t\--~-:r, . . .........-" ,''yoo''''''.---,.......\j/'. (e.g., motor cortex) had projection only to the
IP-OC L ~l...-/t"'vl;"".N'~~'I,...,.,.;, ' I-·''"''.''',Jw.......~...\ symmetrical area of the contralateral hemi·
100u¥
'1 - - sphere. Other areas, such as the premotor area
•• e R~#,'''''\~~
22B
R..
- .......-----..w. .,-"I'"_-_.'' ' ' ...__. .
PC-IP ......,....." ••,.-.,-_•••_".- -.".....",'1.....--.,••.~~

L
R': ./ ;'./'JI.}.V.AVJv..·~-J...'J "..~\.\t
IP-OC ....,~~tI
u
Figure 17-23. Capacity for bilateral synchrony in pre-
motor area of monkey cerebral cortex. Experimental
design ofbilateral symmetrical discharging premotor
foci (1% conjugated estrogen). Recordings from superi-
Figure 17-22. Capacity for spread ofan experimental or frontal (S.E) and precentral gyri (Pre C). Note the
focal discharge. A) .Unilateral focus in the left premo- repetitive bilaterally synchronous discharges of spikes
tor area 6 of the monkey resul~ in a wide intra and and spike slow wave complexes. Compare to Figure 17-
inter hemispheric spread. B) Production of the same M. From Marcus, E. M., and Wa~on, C. w.: Arch.
unilateral focus in area17 of the right occipital area Neurol., 19:102, 1968 (AMA). &e also chapter 29.
resul~ in a restricted unilateral discharge which wen
when prolonged as in C) fails to spread. PF=pre- (area 6) had widespread projection to many
frontal, PM= premotor, PC= pre&entrRI, [Pm intrR- points in the contralateral hemisphere (areas 6,
parieta~OC=Occipital. 4, 1, 5, and 39 as regards area 6).
obtained on stimulation of the striate occipital Clinical correlation: Experimental or clini·
cortex. In general, similar differences were cal seizures originating from the premotor cor-
tex will have widespread bilateral effects where-
Pre CM
26B
"
A
Figure 17-24. Lack of capacity for bilateral synchrony L~~rwr~

in area 17 of monkey cerebral cortex. Experimental R ~~\; '~'V1' I 1 M\v1~:~IJI"" .~11~1i
design of bilateral symmetrical discharging foci as in
B
figure 17-23. Recordings from left and right occipital
area. Note independence of discharge particularly
when prolonged (A and C). Occasional bilateral dis-
charges relatively synchronous at onset could occur (B), c
particularly discharges when triggered as in D) by an
extrinsic source, e.g., photic stimulation (PS). From
Marcus, E. M, and Watson, C. w.: Arch. Neurol.,
19:107, 1968 (AMA).
...
I ,OO~.
,
CM 68-11
A
~ L--~~~~'-~~~~~ Figure 17-26: Intravenous pentylenetetrazol at thresh-
old dosage 6 days after complete section of major com-
missures in the monkey. Bipolar recordings from upper
-middle precentral gyrus. All bilateral synchrony is
lost. A) Anatomy. B) BEG recording. From Marcus,
E.M. in Reeves, A.G. Epilepsy and the Corpus
Callosum New York Plenum Press. P183.
as seizures originating from the striate occipital
Pre cu cortex will have limited focal effects. The wide
spread intra- and interhemispheric spread of
discharge from a unilateral experimental focus
in area 6 is demonstrated in Figure 17-22A.
Compare this to the limited spread of dis-
Figure 17-25.Regionalvariations in capacityfor dis-
charge from a similar focus in areas 17 of occip-
charge and bilateral synchrony following administra-
tion of a threshold dosage of an intravenous convul- ital cortex (Figure 17-22 Be).
sant agent (15mg/kg) in a monkey. Discharges begin 3) The capacity for bilateral synchronous
in a bilateral synchronous manner in the precentral discharges: Anatomical and Physiological
areas (Pre C U). Only later do discharges begin in the observations: see above
occipital area (Oc) and these are not synchronous or
symmetrical. From Marcus, E. M in Reeves, A. G. Experimental epilepsy correlation:
Epilepsy and the Corpus Callosum. New York Plenum A) Bilateral foci of epileptic discharge in
Press p.169.1985. symmetrical cortical areas of the two hemi-
17-28 CHAPTER 17
spheres: an interaction soon occurs, resulting in 27i

the synchronization of the seizure discharges in A
the two hemispheres. However in the monkey
there are significant regional variations in the
capacity for this interaction. In the premotor
B
and precentral areas a close and well-developed
interhemispheric synchrony is evident (Fig. 17-
23); in striate occipital and superior temporal
areas, bilateral synchrony is poorly sustained c
L
(Fig. 17-24). Section of major commissures
R
markedly disrupts the synchrony of discharge.
Refer to Marcus (1985).
o
B) Intravenous injection of a threshold
amount of pentylenetetrazol (Metrazol) pro-
vides an example of a diffuse toxic disease
AC - 327 ( II)
(Marcus- 1985): Following injection in the ! 400,",
I Sec:.
monkey, bilateral synchronous discharges
developed first in the premotor and precentral 27ii
areas. Discharges in the temporal and striate
occipital areas develop later and are indepen- A L~~. ~ I~
dent and multifocal (Fig 17-25). Synchrony is R~~~ ~~I
lost following section of the corpus callosum
(Fig 17-26), but is maintained in the cortical B L\II~ ~~~
callosal preparation (Fig. 17-27).
R~W~~~h~~
The role of the corpus callosum in other
generalized models of epilepsy is discussed in c
~..JIv.f'\1u~~~1iJh4~
L
chapter 28.
Clinical Correlation: Seizure discharges, as R~~
recorded in the human electroencephalogram, o
may be focal, multifocal, or generalized with L~r~~~\~
bilateral symmetry and synchrony of discharge. R~~-rwt~
When the latter category of bilateral discharges
is examined it is evident that the bilateral syn-
chrony is usually best developed in the frontal
and central and parietal parasagittal recording
Figure 17-27. Intravenous pentylenetetrRZOI at
areas. On the other hand, bilateral discharges threshold dosage (20 mg/Kg) I) Intact cat II)
in the temporal and occipital areas often appear Bilateral cortical callosal isolation. The apparent
to be independent, that is, multifocal. Section amplitude differences between the intact and the
of the corpus callosum has been employed to isolate reflect differences in the degree of
limit spread of seizure discharge or to prevent amplification.
the interaction of multiple foci of epileptic
seizure discharge when seizures could not oth-
erwise be controlled (See Reeves, 1985).
CHAPTER 18
Motor System and Movement I:
Reflex Activity, Central Pattern Generators
and Cerebral Cortical Motor Functions
INTRODUCTION presented in Table 18-1

In studying the motor system, we will con- CONCEPT OF CENTRAL PATTERN
sider reflex activity, central generators of pat- GENERATORS
terns of movement, voluntary movement and Specific neural circuits or neuronal clusters
learned movements .We will also consider two or centers may be responsible for the genera-
inter-related aspects: posture and movement. tion of simple and complex patterns of move-
Under posture we will be studying static or ment in the absence of afferent input. In actu-
tonic reactions. Under movement we will be ality' such central patterns are modified or
studying short duration phasic reactions. We modulated by afferent input, utilize many of
should keep in mind, as Sherrington has indi- the reflex components to be discussed below
cated, that the reflexes involved in posture and and are controlled and/or modified by
movement are the same. There are no reflexes descending control motor systems from higher
exclusively for the maintenance of a correct centers. Such pattern generators have been
posture, as opposed to those reflexes involved described at the level of the spinal cord and the
in . a movement, We should note that with brain stem (mesencephalic locomotor system)
more detailed microelectrode studies we may for more complex behavior related to locomo-
find that some neurons in the cerebral cortex tion. The latter system is also involved in the
or spinal cord are predominantly involved in motor components of emotional expression, as
phasic activities and other predominantly in well as chewing, licking and sucking behavior.
tonic activities. In the following discussion, we For the accurate performance of complex pat-
will examine motor function at the level of the terned movements, involving the limbs, affer-
spinal cord, the brain stem and cerebral cortex ent input and reflex activity, is essential. In the
.It is important to realize that motor functions absence of such afferent input, the movements
are represented at successively higher physio- while repetitive are not as well coordinated.
logical and anatomical levels of the neural axis. (See DeLong 1971, Harris-Warrick and
As we go higher in the neural axis, we are uti- Johnson 1989).
lizing and modifYing mechanisms that have 1. The spinal pattern generator. This is
been integrated at a lower level of the neural probably composed of bilateral clusters of
axis a concept first expressed in the modern era interneurons in the intermediate gray matter at
by Jackson. Thus pattern generators make use the base of the posterior horn. These interneu-
of the motor mechanisms involved in reflexes rons are the same interneurons involved in the
without the necessity of afferent input. In turn flexion reflex to be described below. In the
voluntary and learned movements incorporate spinal cord preparation to be discussed below
or impose a higher level of a more complex the effects of dopaminergic and adrenergic
cortical control of these reflex and central pat- agents in triggering behavior can be demon-
tern mechanisms. strated.
In subsequent chapters the role of basal 2. The mesencephalic locomotion pattern
ganglia and the cerebellum in modulating generator: this center is located in the periven-
movement will be considered. tricular tegmentum at the junction of midbrain
REFLEX ACTIVITY. and pons. Axons from this region descend to
The terms utilized in defining a reflex are the medullary medial reticular formation.
18-2 CHAPTER 18
TABLE 18·1 :DEFINITION OF A REFLEX The decerebrate preparation, involves a

transection of the brain stem a level between
TERM EXAMPLES the vestibular nuclei and the red nucleus usual-
Adequate stimulus Nociceptive, proprioceptive, ly at the intercollicular midbrain level.
tactile, visual In man the decerebrate state may reflect
Synapses involved Monosynaptic in the stretch reflex. several pathological processes such as basilar
Polysynaptic in the nexlon reflex. artery thrombosis with brain stem infarction,
temporal lobe herniation with midbrain com-
Segments involved Segmental·stretch reflex, pression, or massive destruction of both cere-
Intersegmental·infer 11mb reflexes. bral hemispheres.
Suprasegmental· brain stem-tonic
neck/labyrinthine. Cerebral cortex, Decerebrate Rigidity - A state described as
placing and long loop reflexes. decerebrate rigidity develops almost immedi-
ately. Decerebrate rigidity may be defined as
Movement or Flexion, extension, righting, the exaggerated posture of extension of the
response standing, walking, grasp, antigravity muscles due to the enhancement of
avoidance, placing
proprioceptive stretch reflexes. In four-legged
Aim or purpose Avoidance of pain, escape from animals, such as the cat and dog, the enhance-
predator, acquisition of food ment of these stretch reflexes results in exten-
sor posture in all four limbs with extension of
From this region axons descend as the medial the tail and arching of the back and neck. This
reticulospinal tract in the ventrolateral funicu- posture is also referred to as opisthotonos (Fig.
lus to the spinal locomotor system of the lum- 18-2).
bar spinal cord. In the decerebrate preparation Sherrington has described the posture of
to be discussed below, glutaminergic effects decerebrate rigidity as "an exaggerated carica-
can be demonstrated. Glutamate receptor ture of standing". This is most intense in those
antagonists will prevent the locomotion effects muscles that normally counteract the effect of
that occur on stimulation of the mesencephal- gravity. In an animal such as the sloth that nor-
ic center. mally hangs upside down, it is the flexor pos-
3. Other motor pattern centers: the premo- ture that is exaggerated.
tor cortex for visually guided movements, the It is important to realize that with transec-
subthalamic nucleus, the pontine reticular for- tion of the brain stem, the decerebrate rigidity
mation and the cerebellum will be discussed develops almost immediately. Spinal shock
below. does not result. It is important to note that
though the extensor tone is sufficient to allow
EFFECfS OF SPINAL AND the animal to stand, the animal is pillar--like.
BRAINSTEM LESIONS ON
The pillar-like limb seen in this extensor pos-
THE MOTOR SYSTEM
ture is indicative of the positive supporting
TRANSECTION OF THE reaction already seen in the "spinal" cat and
SPINAL CORD IN THE HUMAN: dog. This is the tonic form of the extensor
thrust reaction previously noted. The animal
In humans transection of the spinal cord
lacks righting reflexes and has no reactions to
reflects (1) the effects of spinal shock and (2)
sudden displacement.
the prepotency of flexion reflexes as reflex
Modification of Decerebrate Rigidity -
recovery occurs.
The posture of decerebrate rigidity may be
Transection of the spinal cord in the human
modified by several influences: tonic neck
is reviewed in Table 18-2 and in chapter 9
reflexes, tonic labyrinthine reflexes noxious
TRANSECTION OF THE stimuli, and time .
BRAIN STEM- THE DECEREBRATE Tonic Neck Reflexes (Fig.18-3). Tonic neck
PREPARATION reflexes are studied best after destruction of the
MOTOR SYSTEM AND MOVEMENT I 18-3
TABLE 18-2: COMPLETE TRANSECTION OF THE SPINAL CORD IN MAN
ONSET EVENT MANIFESTATIONS

Immediate Spinal shock Below lesion: flaccid paralysis of limbs, no OTR's,
Atonic bladder and bowel (overflow Incontinence),
Loss of autonomic control: hypotensive If erect!
Sensory loss Absence of all sensation below lesion No spontaneous
If sacflon Cl-C4 respiration (phrenic outflow -04)
1-6 weeks Recovery of flexion reflexes Sign of BabinSki, InHially dorsiflexion of greatloe and fanning
Note that flexion reflexes of small toes, later flexor withdrawal of foot, leg and thigh
usually remain prepotent
3-4 weeks Onset of detrusor &bowel function Reflex voiding and defecation begins to occur
Minimal ralum of OTR's Achilles and patellar OTR's now prasent
2-3 months Mass reflex Flexion reflexes now exaggerated without local sign with flexor
spasms, bladder emptying and profuse sweating, erection &ejaculation
AutonomiC reflexes SWeating below level of lesion retums
6 +months Local sign develops Mass reflex less prominent, flexion reflexes more speclflc
for point of stimulus (may recur with fever)
Hyperactive extensor reflexes Oeep tendon reflexes become hyperactive, spasticity develops.
Crossed extension (Fig 18-1) and allamate stepping may occur.
Occasionally positive support reaction Is sufficient for spinal standing
1Other aspecls of autonomic conlrol are also atIected including sympalhelic conIrol of blood pressure - naIed parHcular1y with
hypotenslon occurring in !he upright position (orlhostatic) and parasympalhelic conlrol of intestfnal -peristalsiS (Ileus occurs).
labyrinth or after bilateral section of nerve best after the head has been immobilized in a
VIII. These procedures eliminate various plaster cast or after section of the upper cervi-
labyrinthine influences. The afferents for the cal dorsal roots. The afferents are conveyed
tonic neck reflexes are conveyed via the upper from the otoliths via the vestibular nerves to
cervical dorsal roots from joint receptors - for the vestibular nuclei.
example, those located in the adanto-occipital
joint. The tonic neck reflexes produce several 2 s
types of modification of the decerebrate pos-
ture. Rotation of the head produces a fencer's
posture with extension of the forelimb on the
side to which chin, nose, and eyes have rotated
with flexion of the forelimb on the contralater-
al side. Correlated inter limb adjustments may
occur in the lower extremities. Extension of the
head at the neck produces extension of the
forelimbs and flexion of the hindlimbs. One
may imagine the posture of a cat that is
Figure 18-1. High spinal &lit: jIexion and crossed
attempting to look at objects upon a table. extension rejIeJces. (1) The initial posture ofthe ani-
Flexion of the head onto the chest produces mal. (2) Nocicepti:"e stimulation of the left hind foot
flexion of the forelimbs and extension of the produm jIexion of the left hindlimb and crossed
hindlimbs. One may imagine the posture of a extension ofthe right hindlimb. (3) Noci&eptin stim-
cat that is attempting to look under a shelf or ulation ofboth right and left hind limbs letuIs to flex-
door. ion of both hind limbs. FleJCion reflex then remains
prepotent. (From Sherrington, c.: The Integratin
Tonic Labyrinthine Reflexes (Fig. 18-4).
Amon of the NerJ1011S System. New Haven, Yale
These tonic labyrinthine reflexes are studied University Press, 1947, p.226).
18-4 CHAPTER 18
Figure 18-2 The posture of the decerebrate cat when

suspended. The hyperextended, rigid posture of neck,
back, limbs, and tail is to be noted (opisthotonos).
From Pollack, L]., and Dal1is, L: ].Comp.Neurol.,
50:384,1930 (Wiley).
Noxious stimulus to a limb produces the

classic inter limb reflex figure (18-4).
Time: With time (7-14 days), rigidity
decreases and righting reflexes begin to
emerge.
The anatomical basis ofdecerebrate rigidity:
Refer to chapter 11.
The Midbrain Preparation (transected
above the superior colliculus with red nucleus
and portions of subthalamic nucleus and pos-
terior hypothalamus intact). In this prepara-
tion, propriocentive reflexes are modified by
contactual stimuli.
In the dog or cat midbrain preparation, a
sequence of righting reflexes occurs. Righting
responses in the animal with intact central ner- Figure 18-3. Tonic neck reflexes modifY decerebrate
vous system are demonstarted in. Fig. 18-6, 18- rigidity (monkey preparation). Upper figures:flexion
7. Kinetic reactions such as standing and walk- of head results in flexion of upper extremities; exten-
ing may also occur. In contrast, the primate sion of head produces extension of upper extremities.
midbrain preparation is unable to stand. There linver figures - rotation of head produces extension of
upper limb on side to which face is turned and.flexion
are some fragments of and of a traction grasp
ofcontralateral upper limb. Correlated adjustments
Role of hypothalamus: The motor occur in the lower extremities. (From Twitchell, T.E.:
responses for rage are represented at a brain J.Amer.Phys. Ther.Ass., 45:413,1965).
stem level. Stimulation of the midbrain of the
decerebrate preparation will produce all of the human or primate manifests a considerable
motor components of anger. The hypothala- degree of spasticity often referred to as decorti-
mus however is essential for occurrenses of the cate rigidity. The posture of the decorticate pri-
sham rage of the decorticate animal. (Bard). mate or human involves extension of the lower
THE DECORTICATE PREPARATION extremities and flexion of the upper extremities
(Fig. 18-8). In a sense this is a double hemi-
The cat and dog preparations are similar to plegic posture.
the midbrain animal. In the primate, the tonic
grasp reflex may be present. The decorticate
REACTIONS DEPENDENT ON
CEREBRAL CORTEX
The cerebral cortex may be considered as
providing for a complex reaction to the exter-
nal environment. The cerebral cortex analyzes
afferent information from many sources and
utilizes reactions which have been integrated at
lower levels of the neural axis. Thus, the pres-
ence of the cerebral cortex allows fur the accu-
rate projection of the limb in space and for the
interaction of various reflex activities with visu-
al and tactile stimuli.
The following reflexes are associated with
the cerebral cortex:
1. The optical righting reflex. (Fig. 18-7).
This results in the righting of the head in rela-
tion to a visual stimulus. This response contin-
ues to occur after elimination of the labyrinths
and dorsal roots from the upper cervical neck.
Figure 18-4. Tonic labyrinthine reflexes modify decer-
proprioceptors. The response can still be
ebrate rigidity: Upper Figure: With the animal held
in the supine position and the head facing upwards, demonstrated after bilateral ablation of the
the limbs tWtend. LnPer Figure - With the animal motor and pre-motor areas in the primate. We
held in the prone position (face downwards) the limbs
.flex. The tonic neck influences must be eliminated by
immobilization of the neck or by section of the upper
cerviuU dorsal roots. Note that in man with neurolog-
ical disellSe, the opposite pattern may occur so that a
jlexion posture predominates when the patient is
supine and an extensor posture when prone. (From
Twitchell, T.E.: J.Amer.Phys.Ther.Ass. 45:414, 1965). 1
3
Figure 18-6. Righting reflexes in intact Cflt. Diagram
showing series of maneuvers which a cat executes in
order to turn itself in the air: (1) free ftUl; (2) head
Figure 18-5. Reflexfigures in the decerebrate cat turns, forelimbs drawn in, hindlimbs e4Ctended; (3),
preparation. Effects of nociceptive stimulation. a. (4), (5), continued turning with gradual extension of
Prior to stimulation. b. Change produced by stimula- forelimbs while hindlimbs are drawn closer to axis of
tion ofleft fore foot. c. Change produced by stimula- rotation; (6) turning completed. (Redrawn from
tion of left hindfoot. (From Sherrington, c.s.: The Many, c.R.: Auul.Sci.ParU, 1894, 119:714-717:
Integrative Action of the NerTlOUS System. New From Fulton, ].E: A Textbook of Physiology, 17th
Haven, Tale University Press, 1947, p.167). Edition. Phila-delphia, w.B. Saunders, 1955, p.221).
18-6 CHAPTER 18
Animal upside-down,
bul head r ights
NECK
RIGHTING
~ _
"- ~
' . -:.
BODY RIGHTING
ON HEAD
'-::- --, - Assyme.tric contact
- - to body, Figure 18-8 Decorticate rigidity in the human. The
" -, - ~.. head righls
differences in man between (A) decorticate rigidity
BODY ON BOOY
in neutral position (both arms are flexed) and (D)
Assymelric cOI1lacl to body, true decerebrate rigidity (legs are extended arms are
body rights rigidly extended and pronated.). (B) and (C), alter-
ations produced in the decorticate human by head
turning due to tonic neck re.f/exes. (From Fulton, J.P.,
A Textbook ofPhysiology, Philadelphia., w'B. Saundm,
1955,p.217).
OPTICAL RIGHTING the surface. This is termed the visual placing
Animal upside-down,
rights by vision reaction. On the other hand, if the animal is
blindfolded and the dorsum of the foot or
hand touches the edge of a surface, appropriate
adjustments are then made to place the plantar
BLINDFOLDED or palmar surface of the extremity on the sur-
o.' LABYRINTHECTOMIZED
face. This is termed the tactile placing reaction.
Also noted in the intact preparation is a hop-
ping response. If the animal's body is displaced
to one side, the animal abducts the leg to that
Figure 18-7. Righting reflexes in the monkey. With the
side to regain stability.
exception of the optical righting reflex (which depends
on cerebral cortex), all of the righting reflexes demon- 3. The grasp reflex, as defined by Seyffarth
strated ab011e are within the capacity of the midbrain and Denny-Brown, consists of a stereotyped
preparation. (From Twitchel~ T.E.: progressive forced closure of the subjects hand
J.Amer.Phys.Ther.ks. 45:415, 1965). on the slowly moving stimulus of the examin-
er's fingers across the palm. These authors con-
should, of course, note that righting of the sidered the tactile pressure to be the appropri-
head when the head has been turned on to the ate stimulus. This reflex had emerged following
side, is dependent not only on visual cues but frontal lobe ablation in the monkey
also on labyrinthine cues and asymmetrical (Rushworth and Denny-Brown). Local anes-
body contact stimuli. thesia infiltration of the palm abolished the
2. Placing Reactions. A number of placing reflex.
reactions are also noted in the intact animal. 4. Instinctive Grasp. A more complex and
When the animal approaches a visible edge, the variable response was also described by
forelimb is advanced to be precisely placed on Seyffarth and Denny-Brown: the instinctive
tactile grasp reaction (Fig. 18-9)2 . This
response is also triggered by a tactile (or con-
tactual) stimulus to the hand. The hand orients
so as to grasp the object. Often the hand fol-
lows a moving object making moment-to-
moment adjustments so as to grasp onto the AT BIRTH
TRACTION R£SPONSE
object. This instinctive tactile grasping reaction S1 1~ s.,.tdI.,...,..,odd\.IctofICl'fldirliPl!n
Rup:ma; All jalntl n••
allows for the exploration of space with the
hand. The grasp reflex and instinctive tactile
grasping reaction are of course, seen normally
when the intact individual attempts to grasp
onto an object or to reach for an object. It is ,-..
not surprising that intact motor and parietal
cortex is required. The movements involve dis-
tal finger and thumb movement and require
precise feedback information.
At times, however, the reaction is seen to
be released in abnormal form and degree and ,....., i , I , ! 'f .,
to occur in a context where voluntary grasping s..c.cmor;trQ4!olortAalIdII

IIlHat"ld orlMt.
1N$T1HCT1V£ GftASP IllEACTION
S Contoc1t1anO~porI)
R Haftd 0l'OI* It. HofId...,..
$. ear.toI;ttlCndWt, pori)
is inappropriate. Patients with release of the

tactile grasp reaction usually have damage to Figure 18-9. Evolution of the automatic grasping
the premotor cortex (areas 6 and 8) and the responses of infants. From Twitchell, T.E.,
adjacent supplementary motor cortex and cin- Neuropsychologia, 3: 251,1965 (ElsePier).
gulate area on the medial surface of the hemi- surface of the hand or to the dorsum of the
sphere. The instinctive tactile grasp reaction, hand. This stimulus leads to a non-tonic orien-
then, although requiring an intact motor and tation of the hand away from the stimulus. This
parietal cortex is released in an abnormal form is a more precise form of the tonic avoiding
by lesions of the premotor, supplementary response noted in a decorticate preparation.
motor, and cingulate areas. This is a form of The instinctive tactile avoiding response does
transcortical release. The same lesion, of not require the pyramidal system. The integri-
course, also acts to release various subcortical ty of the cingulate area, area 8, and the supple-
areas 3
The instinctive tactile grasp reaaion is to be 3A recent clinical review of the grasp reflex, in
compared to the instinctive tactile avoiding reac- which CT scans were used to locate lesions
tion (Fig. 18-10). The stimulus for this reaction (DeRenzi and Barbieri), indicates the strongest
is a distally moving tactile stimulus to the outer association with damage to medial frontal
(ulnar) border of the hand or to the palmar areas: predominantly, anterior cingulate gyrus
and supplementary motor cortex and a lesser
2Seyffarth and Denny-Brown (1948) also correlation with damage to the lateral premotor
described a group of behavioral responses to the areas. Usually, the release was bilatera~ unless
same stimulus, which are more variable and the damage to adjacent motor cortex had pro-
appear to be more subject to factors of attention, duced a severe paresis of the contralateral hand.
distraction, etc.: These were grouped together as In such cases, only the ipsilateral hand could be
the instinctive grasp reaction: (a) the closing tested. Considerable research data reviewed by
reaction, (b) the final grip, (c) the trap reaction, DeRenzi and Barbieri suggests that the anteri-
(d) the magnet reaction (the hand moves to fol- or cingulate area not only interconnects with the
low the object), (e) instinctive groping (if the supplementary motor cortex but also has a simi-
stimulus moves without capture, the hand pur- lar pattern ofconnection to basalganglia, corti-
sues). cal areas and spinal cord.
18-8 CHAPTER 18
Figure 18-10. Avoiding responses. A Elicitation of the avoiding response by contact stimulus to the ulnar border
of hand as a normal response in infant of 4 to 6 weeks. From Twitchel~ T.E., Neuropsychologia, 3:250, 1965
(EJsepier). B. Avoiding response as a pathological phenomenon. Over-extension and abduction offingers as hand
approaches object. (child with infantile spastic hemiparesis.) C. Avoiding response as a pathological phenomenon in
another patient with infantile spastic hemiparesis. Reaction of hand to contact stimulation of the palm. From
Twitchel~ T.E.: Neurology, 8:17, 1958 (Lippincott/Williams and Wilkins).
mentary motor cortex are required. The reac- the experimental studies, the CT scan evidence
tion is released in abnormal degree by damage suggested a medial frontal location of lesion
to the parietal lobe (and adjacent motor cor- responsible for such release.
tex). The instinctive grasp and avoidance Another variety of visually cued reaction is
responses normally are in equilibrium from an the visual instinctive avoiding reaction. This
anatomical and physiological standpoint. requires the integrity of the temporal lobe and
S. Other Reflexes Associated with the visual mechanisms. The response apparently is
Cerebral Cortex. In addition to these tactile independent of the pyramidal system. Again, in
instinctive grasp and instinctive avoiding the intact individual, equilibrium of grasp and
responses, various visual triggered responses of avoidance is to be noted.
a similar nature may be seen. One may speak: of While our discussion has focused on the
a visual instinctive grasp reaction. This requires upper extremity, similar grasp and avoiding
the integrity of the posterior parietal areas, the reactions may also be noted in the lower
visual mechanisms, and the motor cortex. As extremities. Lesions of premotor cortex also
discussed below the integrity of the lateral pre- affect gait: producing an apraxia in walking
motor cortex is undoubtedly required for visu- termed a frontal lobe gait apraxia. This will be
ally triggered reaching and grasping. Damage discussed later in this chapter.
to the temporal lobe releases this reaction in an POSTNATAL DEVELOPMENT
abnormal form. The response does occur, of OF MOTOR REFLEXES
course, in a normal form as one normally
Some reflexes are present at birth and dis-
reaches for an object, using visual stimuli. This
appear with time: the startle reflex, sucking,
type of phenomenon occurs in the Kluver-
rooting and the extensor plantar response. A
Bucy syndrome, which follows the production
sequence of reflex activities is noted in the
of bilateral lesions of the temporal lobe in the
developing human infant as regards the use of
monkey. The release of various visual automa-
hands and fingers .In addition a sequence of
tisms occurs. The animals tend to pick up all
changes occurs as regards sitting, standing and
objects that appear in their field of vision and
walking as summarized in table 18-2.
to bring these objects to their mouth. (See lim-
bic system chapter for additional discussion). OVERVIEW OF THE RELATIONSHIP
Magnani et al, studied the anatomical correla- OF PRIMARY MOTOR, PREMOTOR
tion of release of visually triggered grasping AND PREFRONTAL CORTEX.
and groping response in man. In contrast to In order to understand voluntary and
learned behavior, it is necessary to explore the TABLE 18-2: DEVELOPMENTAL CHANGES IN
relationship of primary motor, premotor MOTOR RESPONSES4
(including supplementary motor) and the pre-
frontal areas (Fig. 18-11). Voluntary and RESPONSE POSNATAL TIME
learned behaviors also reflect the motivational Sucking and rooting reflexes Present at birth.
role of limbic structures to be considered in The Moro (starlle) reflex Present at birth and
persiSllng until 2 months
subsequent chapters.
The large and giant pyramidal cells in the Tonic neck reflexes May be present af birth,
primary motor cortex discharge producing fragments af 1-2 months
movements in specific directions (flexion,
extension, abduction, adduction) resulting Traction response grasp May be present af birth
elicited by fracfion at shoulder
from the contraction of muscles at a specific
joint. Among other sources of input, the pri- Grasp reflex: all fingers flex Birth - 8 weeks
mary motor cortex receives information from briefly as unit
somatosensory cortex of the postcentral gyrus
Instinctive grasp reaction Begins af 4 - 5 months.
and the ventral lateral nucleus of the thalamus.
This input may allow the response of motor Projected grasp (pincer). Begins af 6 to 8 months
cortex to peripheral stimuli in what are termed Then thumb-flnger opposition.
long loop reflexes. Subsequenfty this is voluntary
In contrast, the premotor cortex is concerned
Plantar grasp response Present af birth disappears
with patterns of movements that are motor af 9-12 months
programs Neurons in the premotor cortex dis-
charge during the preparation phase prior to Extensor plantar response Present af birth,
movement. The premotor cortex projects in on laferal plantar stimulation disappears af 9-12 months
(due to immature
parallel pathways to motor cortex, to basal gan-
corticospinal pathway)
glia and to spinal cord. The premotor cortex
receives projections among other sources from Plantar flexion on laferal Present from 9-12 months
the unimodal sensory association cortex plantar stimulus (dorsiflexion) and normal through life
(somatosensory auditory, and visual) as well as
Sifting Intants usually sH un-
the primary somatosensory cortex and the ven- supported af 6 to 7 months,
PREFRONT~OTO_PRECENTRAL
Motor pi........ MoIDr _ . . . . PJlIMARY
AIIo MIIItImodoI SMA MOTOR Standing wHh support -At 8 to 9 months
PREMOTOR
Pulls seft to standing position -All 0-12 months
So ORSAL / \ holding onto object
~R
Walking Begins to walk wHh support
POST----+
•.AREAS_AREA 7
af 10 to 12 months.
r.um:TAL ~R
CENTRAL SIJPERIOR INFERIOR
=~ Begins to walk independenfty

. PARIETAL af 9 to 16 months
_odols..oory
/ 4We hove not considered here the prenatal motor development ot

the human feIus. WoHI and Felber (1979) review many of the ear-
lier studies (which demonslralad considerable capacHy for swim-
ming mavemenls) and discuss the use of high-resolution uHra-
Figure 18-11. Interrelation of motor, premotor, pre- sound to study In a non-Invasive manner movements intra-utero.
frontIU lind posterior JlllrietIU multimodal sensory SUch studies allow more precise establishment of actualletal mat-
IIt'e11S.The input of the somatosensory lind TlisutIl systems uration. The suck reIIex Is actually present in the prenatal stale.
to the multimodal posterior JlllrietIU llrellilre present-
ed. The input of the lIuditory system lind the relation- trallateral nucleus of the thalamus.
ship of the multimod4l sensory system to the limbic sys- The prefrontal areas have functions that
tem lire not demonstrllted. In IIgenerill sense the bRSis relate to the limbic system and the motor sys-
for rell&hing lindgrasp lire demonstrllted.
tem. While the orbital and mesial regions of the
18-10 CHAPTER 18
prefrontal cortex are related to the limbic sys- older brain stem centers, which formerly exer-
tem and will be considered in a later chapter, cised primary control, e.g., the reticular forma-
the dorsal region of the prefrontal cortex is tion and the red nucleus. Note that 70-90% of
concerned with the executive functions the fibers passing through the medullary pyra-
involved in the planning, regulation and mid will decussate and continue as the lateral
sequencing of behavior and movement over corticospinal tract. These fibers originate pri-
time. In this regard movement is simply the marily from those portions of area 4 represent-
expression of behavior. This same area of pre- ing the distal extremities and synapse directly
frontal cortex functions as the anterior multi- on alpha motor neurons in the lateral sector of
modal association cortex and receives projec- the ventral horn.
tion from the posterior multimodal association In contrast the remaining uncrossed fibers
cortex located at the intersection of the major arise from area 6 and the portions of area 4 rep-
sensory association areas. In turn this dorsal resenting the trunk and neck areas. These
prefrontal area projects to the premotor cortex. uncrossed fibers as they descend through the
PRIMARY MOTOR CORTEX (Area 4) brain stem, give off collaterals to the bilateral
medial brain stem areas of the reticular forma-
Area 4 is distinguished by the presence of tion. These uncrossed fibers continue as the
giant pyramidal cells in layer V. Occasionally anterior corticospinal tract and terminate bilat-
giant pyramidal cells may also be found more erally on interneurons, which in turn will
anteriorly in area 6. In humans, much of area synapse on neurons in the ventral medial cell
4, particularly its lower half, is found on the column of motor neurons.
anterior wall of the central sulcus. More supe- The fibers originating in the parietal cortex
riorly, area 4 appears on the lateral precentral synapse in relationship to interneurons that in
gyrus and continues onto the medial aspect of turn synapse in relationship to neurons of the
the hemisphere in the anterior half of the para- dorsal horn.
central lobule. The premotor sector of area 6 projects pri-
It is important to note that the pyramidal marily to the medial pontomedullary areas.
tract is not named because of its cells of origin The spinal projections of this area consist of the
but rather on the basis of its passage through ventromedial descending reticulospinal system
the medullary pyramid. Of the approximately and the vestibulospinal tracts.
one million fibers in the pyramidal tract, 31 per The red nucleus receives inputs from the
cent arise from area 4; 29 per cent arise from rostral (proximal) arm and leg sectors of area 4
the premotor cortex of area 6; and 40 per cent and the adjacent premotor cortex and projects
arise from areas 3, 1, 2, 5, and 7 of the parietal as the rubral-spinal system.
lobe. Fibers with a large diameter (9 to 22 u) Area 4: Stimulation. Electrical stimulation
number about 30,000 and correspond rough- of the motor cortex at threshold level produces
ly to the number of giant pyramidal cells. Most isolated movements of the contralateral por-
of these large fibers originate from area 4. It is tions of the body. The movements may be
also important to note that the same cortical described as a twitch or small jerk. With
areas that give rise to the pyramidal tract also increased strength or increased frequency of
give rise to other descending motor pathways: stimulation, repetitive jerks occur; the move-
corticoreticular, and corticorubral, (as well as ments involve a larger part of the contralateral
corticostriate and corticothalamic). From a side of the body and an orderly sequence of
phylogenetic standpoint this is a logical spread may occur. The repetitive jerks are sim-
arrangement since this relatively new control ilar to the movements of a focal motor seizure.
center, the motor cortex, has available a rela- The orderly sequence of spread is duplicated in
tively new fast conducting pathway to the ante- the "Jacksonian March" of a focal motor
rior horn cells. At the same time the motor seizure.
cortex also has available pathways to certain In the conscious patient, these movements,
which can be evoked by stimulation of the
~~
motor cortex during surgery, are not clearly the
same as consciously willed voluntary move-
SUPPL.Ef1£fIIlTAAV S.NSOAV
ments. According to Penfield, the patient rec-
ognizes that these are not voluntary move-
ments of his own and will often attribute them
to the actions of the neurosurgeon.
There was considerable controversy as to
whether muscles or movements were repre-
sented in the motor cortex. Single-unit record-
ing studies have suggested a close topographic
grouping of all the neurons for a given muscle.
Occasionally stimulation will evoke the move-
ment of a single muscle, usually a distal finger
muscle, such as an interosseous. In general,
however, stimulation produces contraction of a
group of muscles concerned with a specific
movement. Voluntary actions also involve the
integrated contraction of several muscles rather Figure 18-12. Somatic figurines. The primary motor
than the isolated contraction of a single muscle. and sensory representation and the effects produced by
supplementary motor and second sensory stimulation
It should then be apparent that the motor cor-
are demonstrated. (From Penfield, W. and Jasper, H.
tex "thinks" in terms of movements. This is, in Epilepsy and the Functional Anatomy of the Human
a sense, inherent in the intracortical connec- Brain. Boston, Little Bruwn and Company
tions between the neurons representing the 1954,p105).
various muscles related to a given movement.
Although there is considerable overlap and evolution in use of these structures as regards
plasticity in the representation of movements speech, writing, tool making and manipula-
on the surface of the motor cortex, a certain tion.
sequence is apparent (Fig. 1S-12). In the classi- It is also important to note that not all areas
cal homunculus, the representation of the pha- of the motor cortex have the same threshold
ryngeal and tongue movements is located close for discharge. As studied in the baboon
to the sylvian fissure. Unilateral stimulation of (Phillips, 1966) the thumb and index finger are
these areas results in bilateral movements. the areas oflowest threshold. Slightly stronger
Next in upward sequence are movements of shocks are required to produce a movement on
the lips, face, brow, and neck. In the middle stimulation of the great toe area; at slightly
third of the precentral gyrus, a large area is greater intensities of shock, movements of the
devoted to the representation of the contralat- face begin to occur on stimulation of the
eral thumb, fingers, and hand. In the upper appropriate area. These findings may relate in
third, the sequence of the contralateral wrist, part to the fact that those pyramidal fibers mak-
elbow, shoulder, trunk, and hip is found. The ing direct connection to anterior horn cells are
remainder of the lower extremity in the primarily those mediating cortical control of
sequence (knee, ankle, and toes) is represented the distal finger and thumb muscles.
on the medial surface of the hemisphere in the It must also be noted that at times on stim-
paracentral lobule. The representation of the ulation of the postcentral gyrus discrete move-
anal and vesicle sphincters has been located ments will be produced similar to those elicit-
lowest on the paracentral lobule. It is impor- ed from the motor cortex. There is some evi-
tant to note how large the areas devoted to the dence that such discrete movements are pro-
thumb, fingers, and face (particularly the lips duced at a higher threshold than in the pre-
and tongue) are in the human, reflecting the central cortex and that the ability to obtain
18-12 CHAPTER 18
such discrete movements is lost after ablation extensor plantar response on tactile or painful
of the primary motor cortex. However, not all stimulation of the lateral border of the foot.
of this neurosurgical data on stimulation of 2. Return of Deep Tendon Reflexes/Stretch
postcentral gyrus in the human is consistent. Reflexes. After a variable period of time, the
Modern concepts of the plasticity of the pri- deep tendon reflexes in the affected limbs
mary motor cortex: More recent studies return and become hyperactive. There is
reviewed by Sanes and Donoghue (2000) indi- increased resistance on passive motion at the
cate a considerable dynamic plasticity in the joints (when there are severe lesions even this
primate primary motor cortex. Thus although stage may not be reached). This does not
modules for the head region, upper extremity affect all movements equally but tends to have
and lower extremity can be distinguished, there its greatest effect on the flexors of the upper
is within each module, a considerable overlap extremity. A hemiplegic posture and gait is
and plasticity with less of the specific localiza- noted: the upper extremity is flexed at the
tion for each movement suggested by the ear- elbow, wrist, and fingers and the leg is extend-
lier maps. Instead a mosaic is present. The area ed at the hip, knee, and ankle and externally
devoted to specific movement representations rotated at the hip with circumduction in walk-
may be modified by trauma to peripheral ing. Walking is possible with the hemiplegic
nerves, central nervous system damage, and limb as movement of the proximal limb begins
most importantly by motor skill learning and to return. In general, recovery of function in
cognitive motor actions. the lower extremity is usually greater than in
Area 4: Ablation. The effects of ablation of the upper extremity. Following the return of
the motor cortex must be distinguished from stretch reflexes, variation in the relative degree
the more selective effects of limited section of of spasticity in the flexor and extensor muscles
the pyramidal tract in the cerebral peduncle or in relation to tonic neck reflexes may be noted.
medullary pyramid. Damage to or ablation of With the return of tonic neck reflexes one will
the motor cortex affects not only the pyramidal begin to note proximal limb movements.
tracts, but also the corticorubral, corticostriate, 3. Return of Traction Response- Abduction
corticothalamic and corticoreticular pathways. of the arm and shoulder will result in stretch of
Studies of the recovery offunction following the abductors. There will then be an adduction
motor cortex lesions in the monkey) are most use- of the arm at the shoulder. In addition, syner-
ful in illustrating many aspects of the integra- gistic flexion of the arm at the elbow, wrist, and
tion of reflex activity at successive levels of the fingers will occur, and objects may be grasped
neural axis and are reviewed on the CD ROM in this manner. This flexion synergy, however,
in table 18-3. results in a whole hand grasp; all of the fingers
Studies of recovery of function in the flex together.
human: The sequence of events in man fol- 4. Return of Selective Ability to Grasp. This
lowing partial vascular lesions (infarcts) of the stage of recovery involves a more selective
precentral cortex or of the motor pathways in grasp of the entire hand albeit a tonic grasp.
the internal capsule has been studied by There is some dissociated synergy so that the
Twitchell (1951). hand alone tends to grasp. Finger and thumb
1. Flaccid Paralysis. Particularly with a large opposition begin to return.
lesion there is a transient period of flaccid paral- 5. Return of the instinctive tactile grasp
ysis of the contralateral arm and leg and the reaction with the capacity for projectied move-
lower half of the face, with a transient depres- ment. This occurs with incomplete lesions. If a
sion of stretch reflexes. The duration of this massive lesion is present, the instinctive grasp
flaccid state (reflecting "cortical shock") is vari- reflex does not return.
able; it may be quite fleeting depending on the 6. Return of distal hand movement.
extent of the lesion (which is usually less than Eventually, depending on the extent of the
total). The sign of Babinski is present with an lesion, some return of distal hand movement
may occur but such recovery is usually less than ble reorganization of sensory and motor func-
that which occurs for movements at more tion at a cortical level that follows damage to
proximal joints, e.g., at the shoulder and hip. these systems is provided in the review ofKaas,
From a physiological and anatomical stand- 1991 and the study of Jacobs and Donoghue
point, the logic of this pattern of recovery (1991). Damage may unmask a considerable
should be evident. One sees in this sequence a degree of latent cortical plasticity as discussed
recovery of spinal reflex activities, then of brain above .The intrinsic horizontal fibers within
stem reflex activities, as noted in the decere- the primary motor cortex interconnect large
brate preparation, then those noted in the areas and could provide the substrate for this
decorticate preparation, and finally those reorganization. Some of the changes occur
reflexes integrated at a cortical level. (This within hours suggesting some degree of
analysis of recovery of function is to some prewiring. In the studies ofNudo et al (1996),
extent an oversimplification: A small hemi- experimental destruction of part of the hand
spheric lesion of the internal capsule in the area in the monkey resulted in loss of discrete
adult may produce as great a deficit as a hemi- finger movements .The monkey relied on
spherectomy performed on a hemisphere dam- proximal arm movements and the area of rep-
aged extensively early in life; Freund 1991). resentation of the shoulder and elbow expand-
More recent studies by Freund (1987) of ed into the otherwise undamaged hand and
lesions limited to the precentral gyrus in the forearm areas. However if the lesioned animals
human indicate that the essential deficit consists were trained to use the hand, the remaining
of deficits in force generation and execution of undamaged area of cortex representing the
independent finger movements. After partial hand and digits expanded into the area of rep-
recovery) force is regained and finger move- resentation of elbow and shoulder. The trained
ments) although clumsy and slow) are purposive animals regained the ability to use discrete fin-
and appropriate to the object. It should be noted ger movements in retrieving small objects in 3-
that in man, following massive lesions of the 4 weeks. The untrained animals did not achieve
motor cortex, a long delay may occur before this level of recovery. These studies certainly
spasticity develops and deep tendon reflexes indicate the potential role of rehabilitation
return. Such a long delay in the reappearance (occupational and physical therapy) in helping
of stretch reflexes usually signifies a poor prog- patients recover from the effects of cerebrovas-
nosis for complete recovery. 5 cular accidents, trauma and other pathology
The recent study ofWarabi et al, 1990 uti- involving the motor cortex. PET scan studies
lized the CT scan to predict recovery of volun- indicate increased functional activity in other
tary movement based on the degree of shrink.- areas of the same and contralateral hemisphere
age of the cerebral peduncle. When the pedun- in patients who have recovered from a hemi-
cle had shrunk to less than 60 percent of nor- paresis due to an infarct involving the internal
mal, recovery of distal limb function was capsule. This was noted in the posterior cingu-
incomplete. When cerebral peduncle was late area on the side of the lesion and the pre-
greater than 60 percent of normal, recovery of motor and caudate nucleus of the opposite
distal movement occurred. intact hemisphere. During movement there
Additional discussion regarding the possi- was increased bilateral activation of anterior
sThe studies of Patano et al (1995) utilizing insular cortex, ventral premotor, anterior cin-
CT/MRI and SPECT scan have demonstrated gulate, and inferior parietal areas (39 and 40),
that patients with a prolonged flaccid hemipare- as well as premotor cortex of the intact hemi-
sis as opposed to a spastic hemiparesis had a sphere (Weiller et al, 1992).
greater structural involvement of the lentiform The following case history illustrates the
nucleus and lower perfusion in the lentiform effects of focal disease involving the motor
nucleus) thalamus and cerebellum as well as cor- cortex.
tical motor areas. Case 18-1: Three months prior to admis-
18-14 CHAPTER 18
sion, this 29-year-old, right-handed, white

female manager developed an intermittent
"pulling sensation" over the anterior aspect of
the left thigh, lasting a few minutes which
recurred about twice a week. On the evening
of admission she again had the onset of this
same sensation, then had numbness followed
by "jerky movements" in her left foot which
progressed to involve the whole left lower
extremity. She was then observed to have tonic
extension then clonus of all four limbs with loss
of consciousness for a minute or less. She still
appeared dazed and slightly confused for the
next 5 minutes, and was subsequently amnestic
for the secondarily generalized seizure Fig. 18-13. Parasagittal meningioma. Case l8-1.CI'
Physical Examination: Normal except for scan demonstrates an enhancing lesion in the most
bite marks on the left lateral aspect of the rostral semons of the CI'scan, just anterior to the
right rolandic sulcus. See textfor details.
tongue.
Neurologic Examination: Significant or equivalent to those, which follow, in a gen-
only for a slight asymmetry of deep tendon eral sense, upper motor neuron lesions. We
reflexes, left > right. should note that the ablation of the motor cor-
Clinical Diagnosis: Focal seizures origi- tex destroys not only the origin of the pyrami-
nating right parasagittal motor cortex (foot dal tract (the corticospinal tract) but also the
area), with question of parasagittal menin- origin of the cortico-reticular, the corti-
gioma. corubral, the corticothalamic, and the corti-
Laboratory Data: Electroencephalogram costriatal fibers. The effects of such a cortical
(Fig.29-1B) demonstrated rare focal spikes, ablation are to release these various subcortical
right Rolandic parasagittal consistent with the and brain stem centers from cortical control
focal source of the secondarily generalized and also to produce the effects of damage to
seizure. the corticospinal tract. We should note that
CT scan (Fig.18-13) demonstrated an section of the pyramidal tract in the medullary
enhancing lesion in the right parasagittal pyramid or in the cerebral peduncle does not
region just anterior to the central sulcus. have the same anatomical and physiological
Arteriograms (Fig.18-14) were consistent effects as ablation of the motor cortex, which
with a right parasagittal meningioma. has been previously summarized
Subsequent Course: The patient did well Furthermore selective section of the pyra-
after removal of a well-circumscribed right midal tract or cerebral peduncle may yield dif-
parasagittal meningioma by Doctor Bernard ferent effects than section of the lateral column
Stone. The patient received diphenylhydantoin in the spinal cord. The descending rubrospinal
(Phenytoin) to prevent additional seizures. and the lateral reticulospinal tract (from the
SELECTIVE LESIONS OF THE bulbar inhibitory center of the medulla) are
PYRAMIDAL TRACT closely related to the corticospinal tract in the
lateral column. In addition the medial reticu-
We have previously indicated that the stu- lospinal tract from the pontine extensor facili-
dent should consider as the primary manifesta- tatory center descends in the anterior column
tions of an upper motor neuron lesion a spastic
and thus would be left undamaged by a lesion
paralysis with increased deep tendon reflexes of the lateral column.
and the sign of Babinski. A more detailed
The studies ofBucy suggest that both man
analysis indicates that the effects of selective
and the monkey were capable of useful move-
pyramidal tract damage are not quite the same
Fig. 18-14.Parasagittal meningioma. Case 18-1.

Arteriograms Ikmonstrate the characteristic features
of a circumscribed vascular tumor in the parasagittal
rolandic area, supplied by the riglTt anterior cerebral
artery and meningeal branches of the external carotid
artery. A. Arterial phase lateral common carotid
injection. B. Arterial phase AP view common carotid
ments after section of the pyramidal tract in the injection. C. Selective injection of the external carotid
cerebral peduncle. Thus, locomotor abilities artery. D. Common carotid injection: venous phase -
returned. The monkey could use his hand in tumor blush with large draining vein. See text for
feeding and in manipulating small objects. details.
With bilateral section, however, the hand was medullary pyramid in the monkey (A recent
used as a claw with some deficiency in inde- study by Jagiella and Sung (1989) does suggest
pendent finger movements. It should be the eventual development of spasticity in a
stressed that spasticity and increased deep ten- patient with the bilateral ischemic infarction of
don reflexes were not noted. The sign of the medullary pyramids).
Babinski was found in the human patient. In What was clearly defective after section in all
the human patient, the retention of discrete of these studies was the discrete fractionated dis-
finger movements was remarkable. Somewhat tal finger movements required for the instinctive
different results were obtained by Denny- tactile grasp reaction that normally would allow
Brown (1966) following section of the pyrami- for the precise orientation offingers to a moving
dal tract in the medul-lary pyramid. There was three-dimensional stimulus. The pyramidal tract
a moderate increase of deep tendon reflexes fibers mediating cortical control of these distal
and a mild spasticity. Schwartzman (1978) muscles make direct connection to the anterior
found no spasticity, 3 years after section of the
18-16 CHAPTER 18
horn cell. These direct fibers of the corti- ate frontal areas. These areas may also be
cospinal system elicit predominantly flexor grouped from the functional standpoint as
facilitation and extensor inhibition. In contrast, concerned with the preparation for movement
the indirect corticospinal fibers (those which and the temporal sequencing of movements
do not synapse directly on anterior horns cells) (Halsband 1993, Halsband and Freund 1990,
synapse predominantly in relation to interneu- Passingham 1987, Rizzolatti 1987, Rome
rons, which make synaptic contact with anteri- 1986, Shibasaki et al 1993, Wise 1988,
or horn cells innervating more proximal mus- Wiesendanger 1987,Wiesendanger and Wise
cles. Additional discussion will be found in 1992)
Kuypers 1987. These areas receive a polysensory input
We have not considered in our discussion from sensory association areas. These are
the possible role of the pyramidal tract in mod- widespread connections of these areas both
ifYing transmission of sensory information at within and between the hemispheres (see
the spinal cord (posterior horn) and brain stem Pandya and Kuypers, 1969, Pandya and
levels (nucleus gracilis and nucleus cuneatus). Vignolo 1971, Ward et alI946).
The various studies, which have suggested such There is considerable rationale for group-
a role, are considered in the review ofBizzi and ing these areas from the standpoint of the
Evarts (1971). results of stimulation studies. Moreover, there
CORTICORUBRAL SPINAL SYSTEM is also considerable justification for such an
approach from the cytoarchitectural stand-
In the monkey and cat, if the pyramidal
point. Histologically, area 6 is similar to area 4
tracts are intact, destruction of the rubral spinal
but lacks, in general, giant pyramidal cells.
system produces no definite motor deficit.
Area 8 has some similarity to area 6 but is also
However, in monkeys and cats that have
transitional to the granular prefrontal areas.
already had bilateral section of the pyramidal
There are considerable variations when the sev-
tract (a section which has produced very little
eral cytoarchitectural maps are compared as to
qualitative change in limb movement) a com-
plete loss of distal limb movement may occur
after additional bilateral destruction of the
rubrospinal tract. In the intact monkey, com-
plex coordinated movements may be evoked
by stimulation of the red nucleus. Flexor exci-
tation predominates with extensor inhibition.
The studies of Lawrence and Kuypers (1968)
suggested that the rubrospinal tract is mainly
concerned with steering movements of the
extremities, particularly distal segments. On
the other hand, the ventromedial brain stem Figure 18-15. The motor cortical fields of man as
reticulospinal tract is mainly concerned with determined by Foerster employing cortical stimula-
steering movements and posture of head or tion. Stimulation of the area indicated in black pro-
body and synergistic movements of the duced discrete mtJ1Iements at low threshold and was
extremities (Kuypers, 1987). designated pyramidal. Lines or cross-hatching indi-
PREMOTOR CORTEX (Areas 6 and 8): cate other areas producing mtJ1Iements and were desig-
Overview of the functions of the premotor nated in a broad sense as extrapyramidal. These
mtJ1Iements were usually more complex synergistic and
and supplementary motor cortex (Fig. 18-15).
adversive mtJ1Iements and included the adversive
Penfield grouped area 6, area 8, and the responses obtained by stimulation of area 19. Each of
supplementary motor cortex (the continuation the areas extending to the midline is continued on to
of areas 6 and 8 onto the medial surface of the the medial surface. Modified from Foerster, 0.:
hemisphere) on clinical grounds as intermedi- Brain, 59:137, 1936 (Oxford Univ. Press).
the exact boundaries of area 8 in both man and when the same movements were triggered by
monkey. Areas 44 and 45 in the inferior frontal external stimuli, there was no such readiness
convolution (Broca's motor speech or expres- potential. These non-invasive studies in man
sive aphasia centers) should also be included (as well as blood flow studies) confirm much
within this motor association or intermediate earlier experimental data derived in studies of
frontal grouping, from both the functional and the monkey (Papa et al 1991, Deeke, 1987,
cytoarchitectural standpoints. For simplicity of Wiesendanger 1987).
presentation, these areas will be considered 2. The Lateral Premotor Area. In contrast
later in relation to language function. to the SMA, the lateral PMA is concerned with
Note that clinical lesions, such as vascular the sequencing of movements that are trig-
infarcts and tumors, usually do not respect gered by external stimuli. In this regard, there
cytoarchitectural borders. Thus, vascular lesions is a close relationship of the lateral PMA to the
that involve the lateral premotor aspect of area sensory association cortex of the superior pari-
6, usually also involve the primary motor cor- etal cortex (area 5) and the posterior parietal
tex. Tumors such as parasagittal meningiomas multimodal sensory areas, which are directly
may involve both the lateral premotor and the connected, with the extra striate visual cortex.
supplementary motor cortex or may involve This relationship is complex as demonstrated in
the prefrontal and the several premotor areas. reaching for and grasping precisely an object
With increasing research, there has come presented at a particular point in visual space.
recognition that there are differential functions The lateral PMA has been divided into two
for the various sectors of these premotor areas, major functional areas: the dorsal and the
(Wise etal, 1997, Krakauer &Ghez, 2000). ventral.
An initial distinction may be made between a. The dorsal lateral PMA neurons are
the supplementary motor cortex (SMA) and the involved in reaching for that object. This area
lateral premotor areas (PMA). is also involved in learning to associate specific
1. The Supplemental Motor Area. SMA is stimuli particularly visual with the motor
concerned with the sequencing of movements response of reaching for that stimulus. As
that are initiated internally without triggering opposed to the learning of a repetitive motor
from external sensory stimuli. SMA is con- act (pressing a key) involving the supplemen-
cerned with the performance of learned tary motor cortex, this is a different type of
sequences of movement. The area just anterior learning referred to as associative learning.
to the SMA, the pre SMA is involved along Multiple bits of information must be integrat-
with other prefrontal areas such as area 46 in ed for this reaching activity, visual position of
the actual process of learning the sequences object, position of gaze, position of arm etc
(training of a motor skill). This same pre SMA and this involves information received from
area is also involved when the same complex various posterior parietal areas adjacent to the
movement sequence is imagined. Once a extrastriate cortex discussed in greater detail by
sequence has been fully and usually over Wise et al (1997.
learned, control may be centered in primary b. The ventral lateral PMA is concerned
motor cortex. with grasping. This area also must receive
The Readiness Potential (Bereitschafts information from the extrastriate cortex
Potential): In man, surface electrodes placed regarding size and shape of the object as well as
on scalp are able to record 1-2 seconds prior to other multimodal and sensory association data
voluntary movements, a significant surface so that an effective grasp of the object may
negative potential with maximum amplitude occur.
over the midline of the frontal area corre- Essentially stimulation of PMA and SMA
sponding primarily to the supplementary cor- results in a pattern of movement characterized
tex. The process of initiation of more complex by tonic abduction of the contralateral arm at
actions enhances this potential. In contrast, shoulder with flexion at elbow plus deviation of
18-18 CHAPTER 18
head and eyes to the contralateral field.. In reflexes were increased on the right at biceps
addition with SMA stimulation bilateral lower and patellar. Plantar response was extensor on
extremity movements may occur. (Fig. 21-12) the right and equivocally extensor on the left.
Ablation of these areas will result in a release of Clinical diagnosis: Seizures of focal origin
grasp reflex and an apraxia in limb movements. left premotor/supplementary motor cortex
Bilateral lesions of the SMA may result in an possibly secondary to low grade glioma. A
akinetic mute state. meningioma was less likely due to the reports
Case 18-2 provides an example of a low- of "normal CT scans."
grade glioma involving the premotor and sup- Laboratory data: CT scan (Fig.18-16)
plementary motor cortex from the standpoint demonstrated an area of calcification with sur-
of focal seizure activity. The motor effects of rounding edema in the left premotor area.
frontal lesions are presented in case histories
22-2 and 22-3, which follows the discussion of
the prefrontal areas.
Case 18-2: This 57-year-old right-handed
single nun and occupational therapist, at age
47 had the onset of observed generalized con-
vulsive seizures, which occurred without warn-
ing with sudden loss of consciousness. Shortly
after the onset of the grand mal seizures, the
patient began to have focal seizures, which
increase in frequency to one per week. She
described these as beginning with the abduc-
tion and raising of the right arm at the side,
over her head, then a jerking of the right arm,
and then she would fall to the ground. She
would remain fully conscious but she would be
unable to talk. She would have an awareness
that something strange was occurring. She had Figure 18-16. Case 18-2. Oligodendroglioma ofpre-
a sinking sensation. She denied any impair- motor and supplementary motor cortex. cr scan. The
non-contrast cr scan demonstrated an area ofcalci-
ment of memory after the episode. However,
fication with surrounding edema, involving the pre-
she would be aware that her right arm and leg motor cortex. See text.
were tingling and weak for perhaps 5 minutes
afterwards and she would be unable to speak MRl scan (Fig.18-17), demonstrated extensive
for 10-30 minutes afterwards. These focal involvement of the premotor and supplemen-
seizures occurred once a month, but for the tary areas by tumor and edema.
last 2 years, they had been occurring once a Subsequent course: Doctor Bernard
week. The patient indicated that over the last Stone performed subtotal resection of this
10 years she has had problems with her mem- tumor. Histological examination of the tissue
ory. confirmed the preoperative impression of an
She was reported to have had three "nega- infiltrating glioma - predominantly oligoden-
tive" CT scans over the years, and yearly droglioma in type. The patient received post-
EEG's, which did not reveal focal features or operative radiotherapy, 5000 rads to the left
electrical seizure discharges. hemisphere and an additional 1000 rads to area
Neurological examination: Mental of tumor. When last seen in follow-up 4 years
Status: delayed recall without assistance, was 0 after surgery, the patient was still experiencing
out of 5 and with assistance 2 out of 5. Motor infrequent (1-2 per month) short focal seizures
System: intact except for a decreased swing of of the same type involving focal movements of
the right arm in walking. Reflexes: deep tendon right arm, plus speech arrest. The neurological
examination demonstrated some decrease in
spontaneous speech some blunting of affect.
Bilateral extensor plantar responses were pre-
sent. She had a moderate frontal type apraxia
of gait and required a cane to avoid falls.
CORTICAL CONTROL OF
EYE MOVEMENT: FRONTAL
(AREA 8) AND PARIETO-OCCIPITAL
EYE FIELDS.
Overview of eye movements: In chapters
11 and 12 -the basic cranial nerve and brain
stem mechanisms for eye movement were con-
sidered. In this section, the mechanisms for
control from other centers will be considered.
This is a complex subject and has been pre-
sented in great detail in the studies of Goldberg
(2000). More specific information regarding
the frontal eye field will be found in Schall &
Thompson (1999).
Vision is sharpest at the fovea, the center of
the macular area of the retina. There are vari-
ous mechanisms for moving the eyes so that
points of interest are centered on the fovea of
the two eyes. These may be listed as follows:
saccadic eye movements, smooth eye move-
ments, vergence eye movements, fixation sys-
tem, vestibulo-ocular responses, and opticoki-
netic responses.
Definitions and anatomical localization:
1. Saccadic eye movements: Rapid move-
ments ofgaze that shift the fovea rapidly to a
point of interest are termed saccades. These
movements may be triggered by attending to a
visual point of interest, by memories or by
commands. The brain stem substrate for all
horiwntal saccades is the lateral gaze center of
the paramedian pontine reticular formation.
Several types of neurons are present in this cen-
ter, Neurons referred to as medium lead burst
cells provide direct excitation to motor neu-
rons in the ipsilateral abducens nucleus and to
the interneurons in that nucleus which give rise
Fig. 18-17 Case Hisrory 18-2. Oligodendroglioma of to the medial longitudinal fasciculus. Long lead
premotor and supplementary motor cortex, MRI non- burst cells drive the medium lead burst cells
enhanced A) Horizontal T 2 weighted study demon- and receive excitatory input from the higher
strates the wide extent of tumor and edema involving
centers to be discussed below, The medium
the premotor and frontal cortex. B) Coronal section
12 weighted demonstrates the involvement of the sup- lead burst neurons also excite inhibitory burst
plementary motor cortex. C. Reference diagram for neurons which in turn suppress the discharge
coronal section (slice 13). See text.
18-20 CHAPTER 18
of contralateral abducens neurons. In addition, directly to the pontine and mesencephalic

there are neurons located in the dorsal raphe reticular formation. Lesions of either area 8 or
nucleus of the pontomedullary area, which of the superior colliculus would produce a
cease firing during saccades (omni pause neu- defect in saccades to the contralateral field and
rons). These neurons if stimulated during a a transient visual neglect. The defect however
saccade will stop the saccadic movement. would be temporary, since the alternative sys-
Additional neurons provide tonic discharges tem would be intact. Lesions of the parietal
relevant to eye position and maintain the eyes cortex tend to produce longer lasting visual
in a position set by the saccade: the flocculus of neglect syndromes. The interaction of area 8
the old vestibular portion of the cerebellum, and the superior colliculus is even more com-
the vestibular nucleus and the nucleus preposi- plex. Area 8 projects to the caudate nucleus.
tus hypoglossi. The caudate nucleus inhibits the S. nigra pars
For vertical saccades, burst and tonic neu- reticularis, which in turn acts to inhibit the
rons are found in the rostral interstitial nucleus superior colliculus.
of the MLF in the mesencephalic reticular Other cortical areas are also involved in sac-
formation. cades: the SMA eye field and the dorsolateral
Central control of saccades: A complex sys- frontal cortex. The former area has neurons
tem with redundant features is present. that direct movement to part of a target. The
Essentially, two major cortical areas are latter contains neurons that discharge when the
involved: the contralateral frontal eye field saccade is made to a remembered target.
(area 8) and the contralateral lateral intrapari- Additional discussion of the role of the frontal
etal area of the posterior parietal area at the eye fields will be found in Pierrot-Deseilligny et
border of the extrastriate cortex. Area 8 pro- al,1995.
vides the motor input for the response to the 2. Smooth pursuit in contrast to saccades
command e.g. "look to the left or right field". keeps the image ofa moving target on the fwea.
The frontal eye field has major interconnec- Eye movement velocity must match the veloc-
tions in a topographic manner with areas that ity of the target. The medial vestibular nucleus,
participate in the streams of information that the nucleus prepositus hypoglossi and the para-
flow out of the extrastriate visual cortex. These median pontine reticular formation receive
two streams, the dorsal and ventral will be dis- information from the vermis and flocculus of
cussed in the visual system chapter. The poste- the cerebellum and project to the abducens
rior parietal area in contrast is involved with nucleus and the oculomotor nucleus. Morrow
visual attention, with representations of the & Sharpe, 1995 discuss the deficits in smooth
location of objects of interest. Beyond a simple pursuit after unilateral frontal lesions.
representation, there is a transformation of this The cortical inputs for smooth pursuit arise
information by parietal neurons into motor from area 8:the frontal eye field. In the monkey,
coordinates (Colby & Goldberg-1999). There stimulation of area 8 produces ipsilateral pur-
is a significant interconnection with area 8 with suit. Area 8 receives input from the posterior
an exchange of information. Both areas project sectors of the superior and middle temporal
to the intermediate and deep cell layers of the gyri. This area in turn receives input from the
superior colliculus. The superior colliculus in visual cortex. In man the posterior parietal area
turn projects to the mesencephalic and pontine may serve this same function. Both the frontal
reticular formation. The same areas of the and temporal (or posterior parietal) areas pro-
superior colliculus also receive inputs from the ject to the dorsolateral pontine areas.
prestriate areas of the posterior temporal gyri. 3. The fixation system holds the eyes still dur-
The superficial layers of the superior colliculi ing intentional gaze on an object. During fixa-
receive input from both the striate cortex and tion, saccades must be suppressed. The most
the retina. The frontal eye field (area 8) pro- rostral segment of the superior colliculus has a
jects not only to the superior colliculus but also representation of the fovea and neurons here
are active during fixation. These neurons act to nated all of the superior frontal gyrus between
inhibit neurons in the more caudal superior the prefrontal areas and the motor cortex as
colliculus. In addition, these neurons excite the area 6. It is clear that conscious, adversive eye
omni pause neurons in the lateral gaze center, and head movements to the contra-lateral field
which as discussed above inhibit saccades. occur most frequently in relation to stimula-
4. Vergence movements (conTJergence and tion of that portion of the middle frontal gyrus
diTJergence) and accommodation are controlled just anterior to the precentral gyrus. In actual-
by neurons within the third nerve complex of ity in the studies of Penfield and Jasper 1954
the midbrain. and confirmed more recently by Luders et al
5. Vestibulo-ocular movements hold images (1988), the eye field for gaze actuallyextend-
stable on the retina during brief head move- ed onto the motor strip between the face and
ments. In put occurs from the vestibular hand areas as demonstrated most particularly in
system. Fig. 18-10. Adversive head and eye movements
6. Opticokinetic movements hold images sta- may also occur, of course, as part of a more
ble during sustained head rotation. Visual input complex movement on stimulation of area 6 or
is required. In rabbits, retinal neurons project of the supplementary motor cortex.
to the nucleus of the optic tract in the pretec- Moreover, adversive head and eye movements,
tum which then projects to the medial vestibu- as a seizure phenomenon following loss of con-
lar nucleus. These neurons can distinguish sciousness, may occur with foci of seizure dis-
between visual and vestibular stimuli. In pri- charge more anteriorly placed in the prefrontal
mates, there is in addition, a "cortical system" areas (compare Fig. 18-18a and 18-18b) but
that includes the magnocellular layers of the these have less localizing significance. Quesney
lateral geniculate, striate cortex, and the poste- et al (1990) concluded that seizures arising in
rior portions of the middle and superior tem- parasagittal frontal area are more likely to
poral gyri. Compared to the non-cortical sys- involved conscious head turning; seizures orig-
tem, which responds to stimuli moving slowly inating in anterolateral dorsal-frontal convexity
in a temporal to nasal direction, this "cortical - unconscious head turning. In addition, stim-
system" can respond to stimuli moving with ulation in areas 18 and 19 will also produce eye
higher velocities in a nasal to temporal direc- turning. Thus, the clinical neurologist must in
tion. This evolution in the system may reflect each case weigh the localizing significance of
the changes, which have occurred in the place- seizures characterized by head and eye turning.
ment of the orbits in the skull when the pri- Such seizure components do not always have
mates are compared to the rabbit. the more specific localizing significance of the
Opticokinetic nystagmus occurs when a focal motor seizure or of the olfactory halluci-
pattern of vertical black and white lines is nation (Refer also to the paper of Ochs et al,
moved slowly in front of the eyes. A similar 1984, which discusses the variability of local-
nystagmus occurs as one sits in a moving train ization in terms of ipsilateral versus contralater-
looking out the window at the series of tele- al deviation of the eyes)
phone poles flashing by. A lesion in the cortical In addition to head and eye turning, open-
system produces defective opticokinetic nys- ing and closing of the eyelids may occur on
tagmus to visual stimuli moving towards the area 8 stimulation. At times, pupillary dilata-
side of the lesion. tion and eye movements, other than conjugate
Area 8: Stimulation: there is disagreement aversion, may occur, e.g., upward deviation of
regarding the exact boundaries of area 8 in the the eyes (Fig. 18-19).
human. Some investigators (Vogts, Foerster, Area 8: Ablation. Ablation of area 8, or (in
Penfield) (Fig.17 -10,18-10,21-15,) have lim- man) infarction of this area following occlusion
ited area 8 to those portions of middle frontal of the blood supply, results in a transient paral-
and inferior frontal gyri just anterior to the pre- ysis of voluntary conjugate gaze to the con-
central gyrus. These authors have then desig- tralateral visual field. In general, in man, this
18-22 CHAPTER 18
S. praeeentrali~
: S. eentralis
c-
d-
I
I
I
5. aTeu.at u.&
50 fTo'ntalLa
Figure 18-19. Funaiontd subdiPision ofthe frontal
eye fields in the monkey under relatively light anesthe-
sia: a) closure ofeyes; b) pupillary dilatation; c) eyelid
opening (awakening reaaion H); d) conjugMe dePia-
tUm to the opposite sUIe; and e) nystagmus to opposite
side. (From Smith, w.K., (in) Bucy, P.: The
Precentral Motor Cortex, Urbana, University of
Illinois Press, 1944.) In the studies of Crosby, RC., et
aI a.Neurol. 97:357-383,1952) oblique and vertical
movements were also observed.
and auditory stimuli. In the past, such a uni-
Figure18-18 A. Simple (conscious) (ul:persive lateral neglect has been attributed to associated
seizures at onset. The epileptogenic lesion localizes to involvement of the inferior parietal lobule. The
the middle fronttd gyrus anteriOf' to motor cortex.
studies of Kennard (1938) and of Welch and
(From Penfield, w., and Kristiansen, K.: Epileptk
Seizure Patterns, SprinBfield, IlL, Charles C. ThonuJs, Stuteville (1958), however, suggest that these
1951, p.30.) B. Unconscious Adversive Seizures at unilateral neglect syndromes may also occur as
onset. The epileptogenic focus in 16 patients whose transient phenomena following ablation of area
seizures began with unconscious aversion of head and 8 in monkeys (area within the superior limb of
eyes localizes predominantly to the anteriOf' portion of the arcuate sulcus). These animals also had
the fronttd lobe (From Penfield, w., and Kristiansen, conjugate deviation of head and eyes to the
K.: Epileptk Seizure Patterns. SprinBfield, Ill., side of the lesion and forced circling. Bilateral
Charles C. 'IbotlUlS, 1951, p.22.)
ablations within this area resulted in animals
paralysis of voluntary gaze usually does not that, in a sense, had a bilateral neglect of the
occur in isolation but is associated with a suffi- environment, remained apathetic, and neglect-
cient degree of infarction to have produced a ed visual and auditory and tactile stimuli,
severe hemiparesis. The patient then lies in bed although they could follow moving objects.
with the contralateral limbs in a hemiplegic Although some recovery occurred over a peri-
posture and with the head and eyes deviated od of weeks to months, the animals continued
towards the intact arm and leg. This deviation to have a ''wooden expression" and a fixed
may perhaps reflect the unbalanced effect of gaze. Some of these findings are seen in the
the adversive eye center of the intact hemi- human following bilateral frontal lobe damage.
sphere. The effect is usually transient, clearing In addition, however, a similar state may occur
in a matter of days or weeks. These patients at in Parkinson I s disease or in brain stem lesions
times also appear to neglect objects introduced producing akinetic mutism, which will be dis-
into the visual field contralateral to the lesion. cussed later. More recent discussions of the
The patients also neglect contralateral tactile "neglect" syndrome will be found in Watson et
al 1978 and Heilinan et al 1983. Note also renaming the phenomena as "Negative Motor
that bilateral discharge of this area may pro- Response" - an inability to perform or sustain
duce a similar state of "neglect of the environ- a voluntary movement at a stimulation intensi-
ment" and arrest of movement (Marcus et al ty that did not produce any symptoms or signs.
1970). The areas of cortex included (a) the inferior
SUPPRESSOR AREAS FOR MOTOR frontal gyrus, immediately anterior to primary
ACTIVITY (Negative Motor Response) motor area for face; (b) less often-premotor
cortex just anterior to the frontal eye field or
Dusser de Barenne and McCulloch found
the hand area; (c) The supplementary motor
in the monkey that stimulation of that portion
cortex. The authors speculate that these effects
of area 4, adjacent to area 6 (designated area
are produced because the stimulation interferes
4S), resulted in a suppression of the motor
with the preparation for movement.
response elicited by stimulation of area 4. In
PREFRONTAL CORTEX (Areas 9, 10,
addition, thresholds for obtaining responses
II, 12,46, 13, 14). Additional discussion
from area 4 were raised, and after discharge was will be found in chapter 22
aborted. Stretch reflexes and muscle tone were
The term prefrontal refers to those portions
decreased. It was soon discovered that these
of the frontal lobe anterior to the agranular
effects could be obtained by stimulation of a
motor and premotor areas (areas 9,10,11,12).
number of other cortical areas: area 8 (8S), 2S
Three surfaces or divisions are usually delineat-
and 19S. On the medial aspect of the hemi-
ed: 1) lateral - dorsal convexity, 2) medial and
sphere, similar effects could be obtained from
3) orbital or ventral .All three are concerned
the anterior sector of the cingulate gyrus: areas
with executive function and relate to the
24S and 32. These "suppressor" areas cannot
mediodorsal thalamic nuclei. In general the lat-
be distinguished on cytoarchitectural grounds
eral-dorsal relates to motor association execu-
from adjacent cortical areas. Similar effects
tive function, the orbital-ventral and the medi-
have been elicited from stimulation of the cau-
al to the limbic -emotional control executive
date nucleus and of the bulbar medullary
system. Recent studies have questioned this
inhibitory center. There has been some evi-
simplistic approach. Thus certain functions
dence that the cortical motor suppressor effects
previously considered to be associated with
are mediated via cortical reticular and corticos-
dorsolateral location have been now localized
triate connections. In subsequent studies,
to a medial location. (Stuss et al 2000). In
Fangel and Kaada, 1960 indicated that arrest of
addition, there is evidence that dorsal lateral
movement could occur from stimulation of a
lesions also alter affect and motivation.
number of distinct neocortical and rhinen-
Moreover as the clinical examples of chapter 22
cephalic points. Note must of course be made
will demonstrate, most pathological processes
that a nonspecific interference with voluntary
involve the functions associated with more
movement may occur in relation to stimulation
than one division either directly or through
of the motor cortex. Thus, the patient who is
pressure effects.
experiencing a focal motor seizure involving
Most studies of stimulation or of ablation
the hand cannot use that hand in the perfor-
lesions involving the prefrontal areas have
mance of voluntary skilled movements.
included, within the general meaning of the
Similarly, arrest of speech is frequently pro-
term prefrontal, areas beyond areas 9, 10, 11,
duced by stimulation of the various speech
and 12. Posterior orbital cortex (area 13) and
areas of the dominant hemisphere, whereas
the posteromedial orbital cortex (area 14) have
vocalization is only rarely produced.
been added to the orbital frontal group (Fig.
Recent studies by Luders et al (1988) with
18-20). These areas all share a common rela-
precise stimulation of the cerebral cortex of
tionship to the medial dorsal nucleus of the
man in preparation for epilepsy surgery have
thalamus. Areas 46 and 47, located in man on
revisited the concept of suppressor areas -
the lateral surface of the hemisphere, are also
18-24 CHAPTER 18
included. The anterior cingulate gyrus (area tests are selected, similar deficits can be demon-
24) is also included in the prefrontal area, strated in man. A more detailed discussion of
although it may be considered part of the lim- this aspect of prefrontal disorder is provided by
bic system and relates to the anterior thalamic Milner and Teuber 1968 and Stuss and Benson
nuclei. (1986). In the human, the digit span test uti-
Overview of the role of the prefrontal lizes working memory.
area in motor and cognitive function: Our Additional studies have defined three sectors
concern here is primarily with the dorsal of the dorsal subdivision, which are concerned
prefrontal subdivision. The ventral/orbital and with different aspects of working memory and
medial subdivisions also will be considered here motor planning. These areas may be specified
but also in the limbic system chapter. We are based on their relationship to the principal sulcus
concerned with the sequencing of behavior, in the monkey dorsolateral prefrontal
the planning of motor function and with a very cortex. (Fig. 18-20)
short type of memory referred to as working The area surrounding the principal sulcus
memory. WJrking memory provides for the contains neurons that begin to fire as the initial
temporary storage of information that is need- visual cue of food is presented in a particular
ed for ongoing behavior. This may be verbal, position in the contralateral visual field, and
visual or central executive. The concept of continue to fire during the delay period.
working memory is best demonstrated in the Lesions in the area of the principal sulcus will
delayed response test in the monkey. Bilateral interfere with delayed response.
removal of prefrontal areas in monkeys and Neurons in the cortex ventral to the princi-
chimpanzees produced significant effects on pal sulcus code information about what the
two separate aspects of behavior: (1) delayed object is in terms of shape and color. This area
response and delayed alternation response, (b) receives information via a ventral pathway from
emotional responses, particularly aggression the visual cortex involving the inferior tempo-
(Jacobsen 1935, Fulton and Jacobsen 1935, rallobe.
Jacobsen and Nissen 1937). In the delayed The cortex dorsal to the principal sulcus
response test, the hungry test subject observes codes information regarding the location of
food placed under one of two containers. A the object. This area receives visual information
solid opaque screen is then interposed and after via the posterior parietal area adjacent to the
a delay of at least 5 seconds, the screen is raised extrastriate cortex as discussed above.
- allowing the animal to select the appropriate There are other neurons that respond to
container. Normal primates rapidly learn this both types of stimulus information.
task and a more complex task of delayed spatial In the human, aspects of prefrontal func-
alternation in which the choices must be alter- tion are tested with a variety of tests. These
nated between the left and right containers. include more complex forms of the delayed
Both tasks, however, are difficult for the response and delayed alternation tests. The
lesioned animal to perform if delays are Luria motor sequences can be easily utilized in
imposed. Subsequent studies (see Butters and the office: the patient must reproduce a
Pandya 1969) have demonstrated that a rela- demonstrated sequence of hand movements
tively small lesion around the middle one-third (strike the thigh with the open hand then with
of the principal sulcus is sufficient to produce the ulnar aspect of the open hand and then
the deficit. Although Jacobsen initially attrib- with the ulnar aspect of the closed fist). In the
uted the disorder to a general deficit in short Wisconsin Card Sorting test, the patient must
term memory, subsequent studies have indicat- sort 60 cards based on color, or symbol or
ed that this is not necessarily the case, since number of symbols. By changing the rules
such animals can learn discriminations involv- once the patient has developed a pattern set, it
ing the selection of a specific object from is possible to also determine how readily set can
among several presented. When appropriate be changed. Failure to change set is termed
severe bilateral spastic involvement of the lower
6
extremities or a double hemiplegia. Other
types of spastic cerebral palsy include: a. quad-
riplegia, and b. infantile hemiplegia.
Arcuate In addition to the spastic varieties of cere-
Sulcus
Superior bral palsy, other types have been identified: a.
Limb double athetosis, b. ataxic c. dystonic.
As reviewed by Paneth (1986), cerebral
palsy affects at least 1 of 500 school age chil-
dren. More severely affected patients may die
in infancy. Severely affected children may have
subnormal intelligence (50%) and seizure dis-
orders (25%).
Little related the motor deficits to the cir-
INFERIOR
cumstances of birth: premature delivery,
Arcuate Sulcus Principal Sulcus breech presentations, or prolonged labor.
Inferior Limb
Often respiration was impaired at birth.
Convulsions often occurred in the neonatal
Fig. 18-20 Prefronml areas of the Monkey (Macaca period. Little's hypothesis regarding causation
Mulatta). Note location oforbiml areas 13 and 14, has had serious medical and legal implications
anterior cingulate area 28, in addition to motor pre- for the practice of obstetrics.
fronml areas 9, 10, 11, 12. Modified from Walker,
Sigmund Freud (1897) prior to his investi-
E.A: J.Comp.Neurol. 73:81, 1940 (Wiley).
gations into hysteria and the psychoneuroses
rigidity. undertook detailed clinical and neuropatho-
Fletcher & Henson (2001) have summa- logical studies of these developmental motor
rized PET scan and functional MRI studies, syndromes. Freud unified the various disorders
which suggest a role for lateral prefrontal areas into a single syndrome, and proposed the clas-
both in working memory and long-term mem- sification, which is presented above. He also
ory. Activation of the ventrolateral region (infe- proposed that the abnormalities of the birth
rior to the inferior frontal sulcus) has been cor- process - noted by little, were in actuality the
related with the updating and maintenance of consequence and not the cause of the perinatal
information. Activation of the dorsolateral pathology.
region (dorsal to the inferior frontal sulcus) has The National Collaborative Perinatal
been correlated with the selection /manipula- Project followed 54,000 pregnancies and the
tion /monitoring of that information. subsequent offspring to age 7. The conclusions
Activation of the anterior prefrontal cortex of that study (Nelson & Ellenberg 1986) tend
(anterior to a line drawn vertically from the to support Freud's hypothesis. Major prenatal
anterior edge of the inferior frontal sulcus) has malformations such as microcephaly and pre-
been correlated with the selection of process- natal rubella infection, were more common in
es/sub goals. the 189 children with cerebral palsy. Maternal
DISORDERS OF MOTOR mental retardation, and low birth weight
DEVELOPMENT. below 2000 grams were also significant predic-
tors of cerebral palsy as was breech presentation
Non-progressive disorders of motor func-
but not breech delivery. In contrast, birth
tion or control recognized at birth or shortly
asphyxia did not add predictive power in the
after birth are referred to as cerebral palsy.
analysis.
Little, in 1862, first described "spastic
rigidity". He was describing the most com- GAIT DISORDERS OF THE ELDERLY.
mon form of cerebral palsy: spastic diplegia: The older patient is frequently at risk for
18-26 CHAPTER 18
progressive disability in two areas of neurolog- It is the frequent central nervous system
ical function: (a) motor function: primarily changes resulting in falls, which concern us
manifested by disturbance of stance and gait, here. Sixteen % of these patients have a cervical
(b) higher cortical functions of cognition and myelopathy, 10% Parkinson's disease, 20% a
memory manifested by dementia. (The latter frontal gait disorder due to normal pressure
problem will be considered in Chapter 30.) hydrocephalus or to multiple strokes or to
These major problems of geriatrics - both alone involvement of white matter (Leukoaraiosis -
or in combination directly and indirectly, or Binswanger's disease, Thompson and
account for many of the prolonged admissions Marsden, 1987). Cerebellar degeneration
to acute care hospitals; and constitute the occurs in 8%, sensory imbalance in 18% and
major reason for eventual placement of the toxic metabolic in 6%.
elderly patient in chronic care facilities such as An example of a treatable cause: normal
nursing homes. The cost impact on the health pressure hydro-cephalus (NPH) will be found
care system is massive because of the increasing in case history 18-3 and Figures 18-21, 18-22
age of the population and because of the fre- presented on CD ROM. These patients pre-
quency of the disorders. sent with a triad of gait impairment (apraxia or
Sudarsky (1990) discusses the several stud- ataxia), urinary incontinence, and dementia.
ies that indicate (a) 15% ofpatients over the age The gait impairment usually predates and is
of 60 have some abnormality of gait; more severe that than the disorder of memory.
(b) 200,000 hip fractures occur annually in the In normal pressure hydrocephalus, a block is
United States - most due to falls by older indi- present in the subarachnoid space high over
viduals. (c) Accidental death is the sixth leading the convexity so that absorption of cere-
cause of death among the elderly - with the brospinal fluid (CSF) fails to occur. In such
majority of these deaths the results of falls; cases, there is no obstruction to CSF flow with-
(d) 40-50% of patients in nursing homes have in the ventricular system or within the CSF cis-
difficulty with walking; (e) surveys of older terns at the base of the brain. Such cases may
patients (of average age 78) indicate a consid- be secondary (previous head traumatic or sub-
erable fear of falling and insecurity of gait arachnoid hemorrhage with the late effects of
resulting in a self-imposed limitation of activi- blood within the subarachnoid space) or pri-
ties in 50%. [Tinettei and Speechley (1989) mary, no prior history. The designation of
estimate the annual incidence of falls in the "normal pressure" refers to the measurement
community: 25% at age 70 and 35% after age of CSF pressure at lumbar puncture in those
75. For institutionalized patients fall incidence cases. Classically, removal of 20-30 cc of CSF
is 50%.]; produces a remarkable improvement. Not all
Not all falls and not all gait disorders are cases of hydrocephalus in the elderly are of the
related solely to neurological disorders. Joint "normal pressure" communicating variety. In
and skeletal disorders may impair gait and some cases, also presenting with a similar gait
result in falls. Age-related changes in vision, disorder, there is a long-standing obstructive
hearing, and vestibular function may all impair hydrocephalus, secondary to stenosis of the
gait and postural stability. aqueduct of Sylvius, which was well compen-
In terms of the nervous system, changes in sated earlier in life, but has become sympto-
the peripheral nervous system - those related to matic late in life. Rarely, a pineal region tumor
aging and to such disorders as diabetes melli- or midline cerebellar tumor may produce
tus' and nutrition may all result in impaired obstructive hydrocephalus in the elderly. For
proprioception with resultant changes in bal- additional discussion ofNPH refer to Adams et
ance and gait. The deficits are compounded by al1965, Fisher 1982.
concurrent changes in vision, hearing and
vestibular dysfunction, (see also Tinetti et al
1988).
CHAPTER 19
Motor Systems II:
Basal Ganglia and Movement Disorders
IANATOMICAL BACKGROUND
(Fig. 19-1, 19-2)
The term "basal ganglia" originally includ-
ed the deep telencephalic nuclei: the caudate,
putamen, globus pallidus, the claustrum, and U.S/ON I
nucleus accumbens. The globus pallidus and
putamen are lens shaped and are called lentic-
ular nuclei. Collectively the putamen and cau-
date are called the corpus striatum. Additional
structures now included within this group are
the substantia nigra, the subthalamic nuclei,
the ventral tegmental area and the ventral pal-
lidum. The caudate and putamen have the
Figure 19-2 Major connections of the basal ganglia
same structure and are continuous anteriorly. with sites for surgical lesions or implantation of stim-
The globus pallidus has two sectors: a medial ulators in Parkinson's disease. Lesion 11Jlobus
or inner and a lateral or outer. The substantia pallidus. Lesion 11-Ventral lateral nucleus of the
nigra has two components: a ventral pars retic- thalamus (the sector of VL involvement is termed
ularis which is identical in structure and func- VIM= nuc. ventral inferior medial). Lesion 111- sub-
tion to the medial sector of the globus pallidus thalamic nucleus, (Modified from Lin, RH.,
Okumura, S., and Cooper, 1.S.: Electroenceph. Clin.
and a dorsal darkly staining component the
Neurophysiol. 13:633,1961)
pars compacta which contains large dopamine
and melanin containing neurons.
CEREBRAL CORTEX: PRIMARILY SMA, 6, 4, 8
The nuclei of the basal ganglia may be cat-
(+)1 GLU
egorized as (1) input nuclei (caudate, putamen
s.NIGRA DOPA S~TUM DOPA S.NIGRA
and accumbens), (2) intrinsic nuclei (lateral
COMPACTA ~1 ORS D2 EPTORS'"T-} COMPACTA
segment of the globus pallidus, subthalamic

••blta ... P
(-) GADA
•• kepbolln
nucleus, pars compacta of the substantia nigra
DIRECTP WAY INDIRECT ATHWAY and the ventral tegmental area) and (3) output
nuclei (medial segment of the globus pallidus
LATERAL GWBUS PALLIDUS
(.~ GADA ,pars reticularis of the substantia nigra and the
MEDlAL GWBUS PALLJDUS ~THALAMIC NUC. ventral pallium. The consideration of the
(Aad S. Nigra RetkaIu1s) (+)
chemical and pharmacological anatomy of
(·)1 GABA
transmitters and circuits within the system will
~LATERAL NUCLEUS THALAMUS
(Aad •••trall.tortor Nucle•• otTh.lam.a) provide an understanding of function and dys-
(+)1 GLU
function within this system.
CEREBRAL CORnYX: PRlMAR1LY SMA, 6, 4, 8
It should be noted that the nuclei of the
Figure 19-1.Diagram of the connections of the basal basal ganglia, the circuits involving the basal
ganglia with transmitters and major transmitter ganglia, the cortical areas projecting to the
action (+) excitatory or (-) inhibitory. GABA = basal ganglia, the cerebellar nuclei relating to
gamma aminobutyric acid (-); GLU = Glutamate
the basal ganglia, and the reticular formation
(+); Dopamine = Dopa (+). The action of acetylcholine
within the striatum has been omitted. &e text for (which has connections with both the cortex
details. and the basal ganglia) were once grouped
19-2 CHAPTER 19
together as an "extrapyramidal system". The thalamus ( +) to cerebral cortex. Additional cir-

term "extrapyramidal disorders" - was used to cuits involve subthalamus and s. nigra.
refer to the effects of lesions within the basal Adding greater detail to the outline indi-
ganglia system. However, the term "extrapyra- cates the following sequence:
midal" was also utilized to refer to the descend- 1. The major input into the basal ganglia is
ing pathways: corticorubral spinal and cortical- from the cerebral cortex to the striatum (cau-
reticulospinal that were alternative descending date nucleus/putamen/accumbens). This
systems to the pyramidal system. The term input is excitatory - utilizing the transmitter
extrapyramidal then becomes very non-specific glutamate and arises primarily from the supple-
and confusing and had best not be utilized. It mentary motor premotor and motor cortices
is important to note, moreover that the corti- (areas 8, 6, and 4). However, the projection
cal areas giving rise to this extrapyramidal sys- from the neocortex occurs from many other
tem are also, in part, the same areas giving rise areas. In general, frontal and parietal, lateral
to the pyramidal system. temporal and occipital areas project to the cau-
Additional discussions of the gross anatomy date nucleus, supplementary motor, premotor
will be found in chapter 1, and in Noback, et al and primary motor cortex and primary
(1991); Alexander, et al (1986); Young and somatosensory cortex project to the putamen.
Penney (1988). The hippocampal areas, medial and lateral tem-
The connections and transmitters within poral project to the nucleus accumbens.
this system are presented in the diagram of Alexander, Delong and Strick. (1986) have dis-
Figure 19-1 and are summarized below. tinguished the following segregated basal gan-
The essential pathways are the following: glia - thalamocortical circuits based on the ori-
cerebral cortex (+) to striatum (caudate / puta- gin of the initial cortical input: 1. Motor
men) (-) to globus Pallidus (-) to ventrolateral 2. Oculomotor 3. Prefrontal 4. Orbital frontal
TABLE 19-1 ANATOMICAL DIVISIONS OF 5. Cingulate-limbic. These are outlined in
CORPUS STRIATUM Table 19-2
2. There are local circuits within the stria-
Basal Ganglia - tum, which involve the excitatory transmitter
Telencephalic Nuclei Function acetylcholine.
NEOSTRIATUM 3. The striatum also receives a major
Dorsal-Caudate Iputamen Input nuclei-neocortical and dopaminergic input from the substantia nigra
s. Nigra .Nigra compacta
Venlral-Nucleus accumbens Input nucleus limbic system compacta. Based on the type of receptor, this
input may be either excitatory (D 1) or
PALEOSTRIATUM inhibitory (D2). Dopamine receptors have
(Globus pallidus) been classified based on the dopamine mediat-
-Dorsal portion: -Intrinsic nucleus
-Output nucleus ed effects on the enzyme adenylate cyclase
-Lateralsegmenl
-Medial segment -Output nucleus (which is involved in the ATP to cyclic AMP
Ventral portion transformation). D2 receptors are involved in
Ventral pallldum the inhibition of the enzyme; D 1 receptors in
stimulation of the enzyme. Note that 5
Basal Ganglia -
Associated Nuclei Function dopamine receptors have now been identified
Subthalamic nucleus Intrinsic nucleus The complex and still evolving topic has been
of diencephalon reviewed by Cooper et al, 1991, Guttman,
1992, Gerfen and Engber, 1992.
Substantia Nigra
4. Because of this differential input two
of Midbrain
- dorsal -pars compacta -Intrinsic nucleus pathways have been identified: the direct and
(dopaminergic) the indirect
- ventral- pars rellcularis -Output nucleus 5. The major direct outflow pathway arises
MOTOR SYSTEMS II: BASAL GANGLIA AND MOVEMENT DISORDERS 19-3
TABLE 19-2 CEREBRAL CORTEX TO BASAL GANGLIA TO THAlAMUS TO CEREBRAL CORTEX CIRCUITS
MODIFIED FROM ALEXANDER ET AL,)
LOOP SEQUENCE MOTOR OCULOMOTOR PREFRONTAL ORBITAL LIMBIC
1A. Major cortical Area 61 Frontal eye field! Dorsolaferal Laferal orbital Anlerlor clngulafe
input SMA Area 8 Prefrontal frontal (area 24)
1B. AddHional Areas 4, Dorsolaferal Posterior limbic I Hippocampus,

Cortical inputs 61PMA, prefrontal, parietal, Anterior parahlppocampal
l,2,3, Posterior parietal arcuafe/frontal, clngulafe amygdala
(post central) PMA See limbic entorhlnal,
temporal
neocortical
2. Striatum Putamen Caudafe (body) Caudafe (head) Caudafe(head) N. accumbans
3. Palliduml Globus Globus pallidus Globus pallidus Globus Ventral pallidum,

S. Nigra Pallidus! (caudal) (Iaf.dorsalmedlal). Pallidus , globus pallidus,
reticularis S.Nigra/ dorsomedlal), S. I S. Nigra reticularis (dorsomedial)1 (rostrallaf.)
reticularls Nigra retlcularls S. Nigra retlcularis S.N.retlcularis
4. Thalamic Ventro- Ventral anlerlor Medial dorsal Medial dorsal Medial dorsal
nuclei Laferal (magnocellularls) (palVoceliularls), (magnocellularls) (postmedial)
(pars oralls! Medial dorsal Ventral anterior Ventral Anlerior
medialis) (palVoceliularls) (palVo Cellularls) (palVo Cellularls)
5. Projection to 6/sMA Frontal eye field! Dorsolaleral Laleral Anterior

Cortical Area 8 prefrontal orbital Cingulafe
from those striatal neurons receiving excitatory systems join at a point known as the Field H2
dopaminergic input (Dl) and passes to the ofForel, then curve back towards the thalamus
medial globus pallidus - mediated by the in the Field Hi of Forel where they are known
inhibitory transmitter gamma aminobutyric as the thalamic fasciculus. This fasciculus then
acid (GABA). Substance P is also involved as a enters the ventrolateral and ventral ant-erior
transmitter or modulator in this pathway. The nuclei of the thalamus. The outflow of these
major outflow is to the inner (medial) segment thalamic nuclei is excitatory to the motor areas
of the globus pallidus. There is a lesser outflow of the cerebral cortex predominantly to the
of fibers from the striatum to the substantia premotor and supplementary motor areas.
nigra reticularis, which has the same micro- 6. The indirect outflow pathway arises from
scopic structure as the globus pallidus. The those striatal neurons receiving inhibitory
outflow of the neurons of these structures is to dopaminergic input (D2) and passes to the lat-
the ventral lateral and ventral anterior thalamic eral (or external) sector of the globus pallidus
nuclei, mediated again by the inhibitory trans- mediated by the inhibitory transmitter GABA.
mitter GABA This outflow passes via two fiber Enkephalin is also involved as a transmitter or
systems: the fasciculus lenticularis and the ansa modulator in this pathway. The neurons of the
lenticularis. The fasciculus lenticularis pene- lateral globus pallidus give rise to inhibitory
trates through the posterior limb of the inter- fibers again utilizing GABA which connect to
nal capsule; the ansa lenticularis loops around the subthalamic nucleus. This nucleus gives rise
the undersurface of the most inferior part of to excitatory fibers utilizing glutamate which
the internal capsule and then passes upward to provide additional input to medial (inner) sec-
join the fasciculus lenticularis. These two fiber tor of the globus pallidus and the substantia
19-4 CHAPTER 19
nigra reticularis. As in the direct pathway the Now let us consider the more complex
subsequent connection of these structures is nature of the microanatomy of the striatum.
inhibitory to the ventral lateral and ventral 1. From a histochemical and histological
anterior nuclei of the thalamus. The subse- standpoint, distinct areas may be noted,
quent step in the sequence as in the direct referred to as patches within the larger back-
pathway is excitatory to the motor areas of the ground matrix. The patch areas have a high
cerebral cortex utilizing the transmitter gluta- density of neurons; matrix areas are less dense.
mate. In the case of both the direct and the Patch zones contain little acetylcholine
indirect pathways a loop has been completed: esterase; matrix areas are rich in acetylcholine
cerebral cortex to striatum to globus pallidus to esterase. Patch areas are associated with bun-
ventrolateral and ventral anterior thalamus dles of dopamine fibers early in development.
back to cortical motor areas Later in development there are less dense
7. In terms of final effect of this system on dopaminergic inputs to the matrix. (Graybiel
the thalamus, if one starts the analysis at the & Ragsdale, 1978). Neurons within the stria-
striatum, the end result of the direct system on tum may be additionally categorized on the
the thalamus is excitatory. Inhibition of basis of size and morphology of the dendrite
inhibitory drive is referred to as disinhibition In and size as (a) medium-sized, spiny neurons
contrast following through the sequences of (b) large or small aspiny neurons. The different
the indirect system; one finds that the end properties of these regions and neuron types
result is inhibitory are presented in table 19-3.
If one begins at the substantia nigra com- There is considerable evidence that the
pacta and follows through the direct and indi- dopamine-containing terminals and their relat-
rect circuits, it is evident that both have the ed synapses and the cholinergic synapses in the
same end result as regards the final effect at the striatum have essentially antagonistic actions.
thalamic and the cortical level. Normally, however, they remain in a particular
8. It is then possible to analyze the eventu- balance. We will discuss the problem of an
al thalamic and cortical effects of a decrease in imbalance when we come to discuss
dopaminergic input at the level of the striatum: Parkinson's disease (Duvoisin, 1967;
the thalamus and cortex will receive less excita- Hornykiewicz, 1970). As discussed above both
tion. The results are the same whether the tend to be found in specific sites in striatum
direct or indirect pathway is considered. (striasomes). These sites exist in a larger matrix
Movement then will be decreased or slowed of the striatum.
down. The terms akinesia or bradykinesia are Several additional loops and circuits must
employed. now be considered:
On the other hand, if there is increased 1. In addition to its major input from the
dopaminergic activity, the end results at the cerebral cortex, the caudate-putamen also
thalamic or cortical level will be an increase in receives a lesser afferent input from the nucle-
motor activity irrespective of whether the us centrum medianum (C.M.) (excitatory
direct or indirect pathway are considered. The transmitter presumed to be glutamate or aspar-
terms hyperkinesia or dyskinesia are employed tate). It should be noted that the C.M. repre-
The ultimate effect of dopamine then is to sents a major interlaminar nucleus of the thala-
facilitate movement. (Cote &Crutcher, 1991 mus and is the main thalamic extension of the
and Bergman, et al, 1990).
The striatum also has GABA mediated 1 A more detailed examination of the striatum
inhibitory outflow to S.nigra compacta. in terms of microscopic neuroanatomy and neu-
Specific sites in the striatum project to the ropharmacology suggests a much more complex
S.nigra compacta (and receive afferent input story (Wexler et a~ 1991, Albin et a~ 1989,
from the S.nigra compacta)l. Martin and Gusella 1986).
reticular fonnation. The centrum medianum, TABLE 19-3: THE COMPLEX NATURE OF THE MICROANATO-
however, also receives fibers from the globus MY OF THE STRIATUM
pallidus (inhibitory transmitter: GABA). This
again completes an additional loop; relating the MATRIX REGIONS PATCH REGIONS
basal ganglia to the reticular formation. 1. Matrix areas form large 1. The patch areas are
2. It should also be noted that some fibers background regions wHh smaller and have a
a low dens/ly of neurons high dens/ly of neurons.
leave the ansa lenticularis and, rather than pass-
ing into the thalamus, descend to the pedun- 2. Receive afferent Input 2. Patch neurons receive
culopontine nucleus within the tegmentum of from superficial cortical Input from deeper
the mesencephalon. This nucleus then projects layers and muHiple cortical layers In
back to the globus pallidus. sites (motor, sensory, prefrontal and limbic
motor, premotor, frontal, cortex.
3. There is also evidence for a direct excita- parietal and occipital) and
tory input from motor and premotor areas to Intralamlnar thalamic sites
the subthalamic nucleus providing an addition- Young and Penney 1988).
al circuit for modulating motor activity.
3. Matrix areas are rich in 3.Patch zones contain
Overview of the dopaminergic systems: In acetylchOline esterase little acelylchollne
esterase. Patch neurons
addition to the dopaminergic nigral- striatal
contain GABA and
pathways, which are of major concern in our substance Pand project
discussion of motor function, there are other to the S. nigra compacta.
major dopaminergic pathways. These other Patch neurons receive a
pathways, however, are of importance when dense dopaminerglc input
from the substantia nigra
one begins to utilize L-Dopa (the precursor of
compacta.
Dopamine) in therapy of Parkinson's disease.
In addition, these pathways are of importance SPINY NEURONS ASPINY NEURONS
when agents (such as neuroleptics employed in Spiny neurons in general Aspiny neurons in general
the treatment of psychoses or other psychiatric project outside the striatum are intemeurons, form 10%
and account for 90% of of the neurons and are
syndromes) are used to block the dopamine
striatal neurons. intrinsic to the striatum.
receptor or to prevent the storage of dopamine
In addition, the overall disease state in Spiny neurons contain a Large aspiny intemeurons
Parkinson's disease may also involve these transmmer and a within the matrix contain
pathways. neuropeptide modulator the transmitter acetylcholine
Types of Spiny Neurons: Small asplny intemeurons
(a) The mesolimbic system - originating in a. Spiny matrix neurons within the matrix contain
the ventral tegmental area - medial and superi- containing GABA and the the neuropeptides
or to the S. nigra and projecting to the nucle- neuropeptide substance P Somatostatin
us accumbens (ventral striatum); the stria ter- and projecting to medial and Y.
minalis septal nuclei; the amygdala, hippocam- globus pallidus and substantia
nigra pars reticularis.
pus; mesal frontal, anterior cingulate, and b. Spiny, matrix neurons,
entorhinal cortex. A major role in emotion, containing GABA and another
memory and perception is postulated for this neuropeplide: dynorphln
system. Hallucinations are a side effect of a projecting to the medial globus
high dose of L-Dopa in the Parkinsonian pallidus and substantia nigra
pars retlcularis. c. Spiny Matrix
patient. neurons containing GABA and
(b) The mesocortical system- originating in the neuropeptide enkephalin
the ventral tegmental area and projecting to and projecting to thelateral
neocortex particularly dorsal prefrontal cortex globus pallldus. d. Patch
neurons containing GABA and
with a role in motivation, attention, & organi-
substance Pand projecting to
zation of behavior. the S. nigra compacta.
19-6 CHAPTER 19
(c) Hypothalamic (arcuate nucleus) to function as one might predict, based on the
infundibular stalk of pituitary involved in hypo- anatomical connections discussed above. An
thalamic inhibition of prolactin release. understanding of the basic anatomical interre-
lationships will aid in an understanding of the
Overlap with the cerebellar system. It is effects of the various medical and surgical
also important to remember that the major modalities of treatment in Parkinson's disease.
outflow from the cerebellum (via the superior Thus, when dysfunction develops in the circuit,
cerebellar peduncle) terminates in relation to lesions at specific critical points, such as ventro-
the same ventrolateral and ventral anterior lateral thalamic entry area or the subthalamic
nuclei of the thalamus2 . This thalamic nucleus nucleus may allow restoration of considerable
receives a projection from both the cerebellum function. The usual location of surgical lesions
(predominantly the dentate nucleus) and the for the relief of the tremor and rigidity of
globus pallidus. However, the information Parkinson's disease are shown in Fig. 19-2. It
from the cerebellum is projected in a more lim- should be evident that the lesion in the ventral
ited manner primarily via ventrolateral to the lateral nucleus of the thalamus would also be
motor areas of cerebral cortex, predominantly extremely effective in eliminating tremor origi-
the pre-motor and motor cortices. The basal nating in the cerebellum since such a lesion
ganglia differ from the cerebellum in several would prevent a disordered cerebellum from
important respects. In contrast to the more acting on the circuits passing through this
limited relationship of cerebellum to ventral nucleus and this disordered cerebellum would
lateral nucleus of thalamus (projection to no longer influence motor activities originating
motor areas of cortex - and projections from at a cortical level.
motor areas of cortex via pontine nuclei to the We must consider the circuits through the
cerebellum), the basal ganglia have widespread basal ganglia modulators of cortical function,
inputs from the cerebral cortex and via several particularly as regards movement. For volun-
thalamic nuclei back to multiple cortical areas. tary movement, these circuits clearly provide
These cortical basal ganglia relationships are complex modulation acting on the supplemen-
not diffuse or overlapping but instead, are tary motor cortex. This modulation represents
organized in parallel systems. a focused equilibrium of opposing influences.
It should be very clear then that patients When one of these influences acts to a dispro-
with disease of the basal ganglia may have sig- portionate degree, dysfunction in the main cir-
nificant manifestations not only of motor func- cuit from the cortical motor cortex to the ante-
tion but also of cognitive and emotional func- rior hom cells and to the reticular formation
tion (Cooper, et al [1991] and Starkstein, et al will result.
(1989) in relationship to Parkinson's Disease
CLINICAL SYMPTOMS AND
and Laplane, et al [1989] with regard to obses-
SIGNS OF DYSFUNCTION
sive compulsive behavior change.
There is considerable overlap with frontal General - overview Based on the anatom-
lobe, premotor and supplementary motor dys- ical circuits considered above a variety of symp-
toms and signs may occur.
2 It should be noted that the dentate nucleus of (1) A lack of movement, an inability to ini-
the cerebellum also has some outflow (via the tiate movement or a slowness of movement
superior cerebellar peduncle) to the red nucleus. because of excessive inhibition (a lack of excita-
After synapsing at the red nucleus, fibers are also tion) so that the excitatory effect ofventrallat-
conveyed to the ventrolateral nucleus ofthe thal- eral nucleus - of thalamus on supplementary
amus. The major outflow, however, apparently is motor neurons fails to occur due to a decrease
directly to these thalamic nuclei from the dentate in dopamine. This lack of movement and slow-
and, to a lesser degree, from the emboliform ness of movement is defined as akinesia and
nucleus of the cerebellum. bradykinesia as discussed above.
(2) Elimination of inhibition at a critical the ventral lateral nucleus of the thalamus
point in the system may result in a release of would also be extremely effective in eliminat-
disordered movement. The disordered move- ing tremor originating in the cerebellum since
ments are defined as dyskinesia and tremor. such a lesion would prevent a disordered cere-
(3) The relationship of muscle tone in bellum from acting on the circuits passing
antagonists and agonists may be altered so that through this nucleus and this disordered cere-
excessive tone is present, defined as rigidity. bellum would no longer influence motor activ-
Tremor superimpose on this rigidity produces ities originating at a cortical level.
cogwheel rigidity. We must consider the circuits through the
(4) A specific extreme of posture may be basal ganglia modulators of cortical function,
maintained defined as dystonia. particularly as regards movement. For volun-
(5) Problems in the sequencing of move- tary movement, these circuits clearly provide
ments as in walking or of posture as in stand- complex modulation acting on the supplemen-
ing may occur. tary motor cortex. This modulation represents
(6) Disorganization of those higher level- a focused equilibrium of opposing influences.
righting reflexes discussed in the previous When one of these influences acts to a dispro-
Chapter 18 may occur. portionate degree, dysfunction in the main cir-
Not all of these symptoms and signs occur cuit from the cortical motor cortex to the ante-
in a given disease or case. Some of these symp- rior hom cells and to the reticular formation
toms and signs occur with disease at other sites. will result. The following table lists clinical
As already discussed, akinesia or bradykinesia is symptoms base based on the anatomical con-
frequently seen in patients with disease of sideration of multiple sequential circuits involv-
frontal - premotor and supplementary motor ing inhibitory synapses, certain symptoms
areas. Refer to Delwaide&Gance (1988) for could be predicted.
additional discussion of correlation of symp- SPECIFIC SYNDROMES
toms and signs with anatomy/physiology). PARKINSON'S DISEASE AND THE
It should also be very clear then that
PARKINSONIAN SYNDROME (Recent
patients with disease of the basal ganglia might reviews are provided by Dunnett &
have significant manifestations not only of Bjorklund, 1999, Lang&Lozano,
motor function but also of cognitive and emo- 1998,Olanow &Tanner, 1999, Quinn,
tional function. (see Cooper, et al, 1991 and 1995,Riley&Lang, 2000)
Starkstein, et al, 1989 in relationship to The most common disease involving the
Parkinson's Disease and Laplane, et al (1989) basal ganglia is Parkinson's disease, first
with regard to obsessive compulsive behavior described by James Parkinson in 18173 .
change. Parkinson's disease after Alzheimer's disease is
There is considerable overlap with frontal the most common degenerative disorder of the
lobe, premotor and supplementary motor dys- central nervous system affecting approximately
function as one might predict, based on the 1 million individuals in the United States. The
anatomical connections discussed above. An basic pathology is the progressive loss of
understanding of the basic anatomical interre- dopamine producing neurons in the pars com-
lationships will aid in an understanding of the
pacta of the substantia nigra. A certain mixture
effects of the various medical and surgical
modalities of treatment in Parkinson's disease. 3 As we will discuss below, other disease entities
Thus, when dysfunction develops in the circuit, may overlap with many of the same symptoms
lesions at specific critical points, such as ventro- and signs and it is appropriate to refer to the
lateral thalamic entry area or the subthalamic lar,gergroup as the Parkinsonian Syndrome. The
nucleus may allow restoration of considerable term «Parkinsonism» has also been employed for
function. It should be evident that this lesion in this lar,ger group.
19-8 CHAPTER 19
of symptoms then develops each of which may Parkinson (Goetz, 1986). The cardinal signs
vary in severity. The essential (cardinal) signs and symptoms are summarized in table 19-4.
and symptoms consist of: tremor, rigidity, aki- Some cases, throughout their course may
nesia and defects in postural and righting continue to manifest primarily tremor as the
reflexes. Charcot essentially described this total major symptom and such cases tend to have a
picture and he named the disease after more favorable prognosis. Several types of
TABLE 19-4:CLlNCAL SIGNS IN PARKINSON'S DISEASE Parkinson's disease and syndromes may be
specified. The most common variety is the
Clinical Signs Clinical Appearance idiopathic or primary Parkinson's disease, a
Rhythmic tremor at rest: The tremor affects not only degenerative disease arising insidiously in the
AHernatlng type, inlHally fine, the extremines, but also the patient of age 40, 50 or 60. In a series of 1644
4-5 Hz, and then, as the eyelids, the tongue and patients with Parkinsonism, evaluated by
disease progresses, allen voice. The altemate Jankovic (1989) at a movement disorder clinic,
Coarse. The tremor movements of thumb
disappears on movement, against opposing index 82% were found to have idiopathic Parkinson's
but may re-emerge when finger are allen referred disease. At times, there is a family history of the
a posture Is maintained to as 'pill roiling". same disease.
1. Pathology of Parkinsonian Lesions.
Clinical rigidity which must Comparable to the
The basic pathology involves a progressive loss
be differentiated from resistance of a lead pipe
decerebrate rigidity which is bending under force in of the pigmented neuromelanin containing
primarily spasticity with the which the resistance is neurons of the pars compacta of the substantia
Jack-knife quality of spasticity relaHvely constant nigra (Fig. 19-3). (The pigmented neurons of
(a sudden resistance is throughout the range of the locus ceruleus are also affected.)4 (The stu-
encountered, which, as motion. As with spasticity,
addlHonal force is applied, rigidity may reflect increased
dent will recall that both melanin and
suddenly gives way). activity of the gamma dopamine are steps in the metabolic pathway
system. involving phenylalanine.) A long pre-clinical
period estimated at 5 years occurs in this pro-
AkInesia- lack of Seen In the fixed facies of
gressive disease. Various estimates suggest that
spontaneous movement the Parkinsonian patient,
and difficulty In lack of spontaneous when symptoms first occur, 70-80% of striatal
Ininating movement. A blinking and movement,
corollary term is loss of associated 4 Whether the Dopamine-nigral-striatal-(mesos-
bradykinesia which refers to movements (the swing of triatal) system involvement is the entire story in
a slowness of spontaneous the arms in walking).
Correlated as discussed
Parkinson's disease is unclear. The mesolimbic
movement.
above with the reducHon cortical Dopaminergic system is also affected
In dopaminergic input. (50-60% decrease). Noradrenergic and sero-
toninergic and cholinergic systems are also
Defects In posture righting Normally, as an individual
affected; e.g., 50-60% decrease in nor-adrenalin
reflexes are best noted as the tums, the eyes move Initially
panent stands, walks In the direction of the tum, concentrations in cerebral cortex, locus ccruleus,
and attempts to tum. his head moves, then limbic system, hypothalamus and cerebellum;
shoulders and arms, and 58% loss of serotonin in dorsal raphe nucleus.
the body then follows. The There is also cholinergic nerve cell loss of32-87%
paHent with Parkinson's
in nucleus basalis of Meynert. In general, none
disease, however, tums 'en
bloc", In walking at nmes, of these systems show the degree of degeneration
develops forward propul- found in the nigral-striatal-dopaminergic sys-
Sion, seems to Hit forward tem (Estimated as 80-90% depletion of striatal
and develop Increasing dopamine and 60-70% degeneration of s.
speed - producing loss of
Nigral neurons when symptoms first emerge).
balance with falls and
Injuries, and instability For extensive reviews and discussions, see Agid et
when tuming. ai, 1987, 1989.
FIGURE 19-3. Parkinson's Disease. The substantia

nigra in Parkinson's disease. A, Normal substantia
nigra. B, Similar region in case of idiopathic
Parkinson's disease. A marked loss ofpigmentation is Figure 19-5. Inry body. SUlk stained for alpha synu-
wilknt. (Courtesy Dr. Thomas Smith. Neuropathology clein.100X. (Courtesy ofDr. Thomas Smith).
University of Massachusetts) ing neurons of the substantia nigra. In many
dopamine is depleted. In terms of neurons in cases, these Lewy bodies are found in other
the pars compacta of the substantia nigra 50% neurons, e.g., cerebral cortex.
(compared to age matched controls) to 70% Immunocytochemistry has demonstrated that
(compared to young individuals) are already a small protein a-synudein is a major compo-
lost. Normally the rate of cell loss in the nigra nent of the Lewy body (Fig.19-S). Under nor-
during normal aging is 5% per decade. In mal circumstances this protein is located in
patients with Parkinson's disease the rate of cell presynaptic nerve terminals. It is therefore like-
death is subsequently 45% per decade. ly that the Lewy body represents degenerated
On histologic examination (Fig. 19-4), and aggregated neurofilaments. The Lewy
there is a characteristic, specific finding ofLewy body may also be found diffusely in cerebral
bodies: round, eosinophilic bodies surrounded cortex in Lewy body dementia.
by a dear halo within the cytoplasm of surviv- 2. Etiology of Parkinson Disease. Why
do the neurons degenerate? The majority of
cases with L-DOPA responsive Parkinson's
disease do not have a dear-cut genetic basis.
However mutations in the alpha synudein
gene have been found in several families of
Italian or Greek origin with early onset autoso-
mal dominant Parkinson's disease mapping to
locus 4Q21-25 (Goedert et al, 1998 and
Duvoisin, 1998). Other families with autoso-
mal recessive juvenile onset disease have impli-
cated the parkin gene at locus 6q25 .2-
27.0ther gene loci are discussed by Dunnett &
Bjorklund, 1999.
The major etiologic factors have involved
a genetic predisposition and possible toxic
exposures.
Figure 19-4. Inry body in a pigmented neuron of the Neuroleptic agents: The use of neurolep-
substantia Nigra. H&E stain, original at 125X. tic agents may unmask an underlying genetic
(Courtesy of DR.. Thomas Smith).
19-10 CHAPTER 19
predisposition to Parkinson's disease. A signifi- onoxypiperidine (MPPP). Meperidine is a con-

cant percentage (15-60% depending on age), trolled narcotic; MPPP is not controlled, has
of patients who receive neuroleptic tranquiliz- narcotic action, and can be produced in clan-
ers also will develop symptoms of destine labora-tories. MPTP had been recog-
Parkinsonism. These agents include pheno thi- nized shortly after its legitimate synthesis in
azides such as chlorpromazine, and haloperidol 1947 to produce a severe rigid - akinetic state
and reserpine. Reserpine interferes with the in monkeys. However, it was not until the
storage of dopamine within the nerve cells and, summer of 1982, when MPPP was produced
thus, depletes the brain of this neurotransmit- on a large scale in Northern California, for illic-
ter. Pheno thiazides and related compounds, it mass distribution, that significant numbers of
on the other hand, block. the post-synaptic young drug abusers began appearing at emer-
receptors at dopaminergic synapses. In general, gency rooms with an acute ParkinsOnian syn-
of the symptoms produced by these agents, the drome. The investigation of these cases has
akinesia, rigidity and tremor will disappear been presented in a series of papers by
when the agent has been cleared from the (Langston et al, 1983; 1992; and Ballard et al,
body. However, in some cases, the 1985). Essentially, the compound MPTP has
Parkinsonian features appear to remain as a selective toxicity on the dopaminergic neurons
permanent deficit. In such patients, one may of the pars compacta of the s. Nigra, not only
find evidence in the family history of other in human but also in subhuman primates, such
cases of Parkinson's disease (Schmidt and as the Rhesus monkey, Macaca mulatta, and
Jarcho, 1966). As discussed by Koller (1992), the squirrel monkey. Both in the human and
there is then a clear indication that neuroleptic the monkey, MPTP reproduces the clinical dis-
induced Parkinsonism represents early or latent ease, the pathological findings and the effects
Parkinson's disease made evident by anti- of pharmacological therapy of Parkinson's dis-
dopaminergic medications. ease to a relatively complete degree, including
Toxic Agents. The major impetus for the in older animals, the presence of Lewy bodies.
study of possible toxic exposure has come from With such an animal model, experimental
the study of cases of Parkinson's disease devel- medical and surgical therapy can be studied
oping in miners exposed to manganese and with a clear-cut correlation with the human
more recently in cases exposed to the agent disease (for example, see Aziz et al, 1991;
MPTP. Langston, et al, 1984,Kopin 1988). Moreover,
Manganese Poisoning. A relatively rare since there were many patients exposed to the
cause of a Parkinsonian syndrome is man- agent but not all exposed patients and not all
ganese poisoning. Manganese apparently accu- acute cases developed the chronic Parkinsonian
mulates in the melanin containing neurons of state, prospective studies can be performed as
the substantia nigra and interferes with the to the natural history and factors influencing
enzyme systems involved in the production of the onset of the disease (Stone, 1992). In part
dopamine (Mena et al, 1970), because of MPTP, increased attention has been
MPTP Toxicity. Another form of focused on other environmental exposures that
Parkinson's disease induced by the drug may be involved in producing neurotoxic
MPTP, has provided major insights in the pos- effects culminating in Parkinson's disease
sible etiology of the degeneration of the (Tanner&Langston, 1990,Olanow &Tatton,
dopamine containing neurons in the substantia 1999).
nigra. (MPTP is the abbreviated term for 1- Other pathological processes These dis-
Methyl- 4 phenyl-I, 2,3,6, tetrahydropyri- orders also will produce some of the symptoms
dine). This agent is a by-product of the chem- of Parkinson's disease without the presence of
ical process for the production of a reverse ester Lewy bodies (Gibbs, 1988).
of meperidine (demerol): I-methyl-4 propi- 1. Bilateral necrosis of the globus pallidus
may produce akinesia. Such a necrosis could encephalitic Parkinsonism and its treatment is
occur in carbon monoxide poisoning, or anox- presented in the movie "Awakenings", based
ia, or in relation to infarction. Rigidity in flex- on the book by Oliver Sacks.
ion may also follow bilateral necrosis of the Management (Refer to Lang & Lozano,
putamen or the globus pallidus. 1998 and Riley &Lang, 2000).
2. A tremor at rest may occur with destruc- When one considers that the basic patholo-
tive lesions involving the ventro-medial gy in Parkinson's disease represents a marked
tegmentum of the midbrain. Such lesions, loss of Dopamine containing neurons in the
apparendy, interrupt the pathway from the S.Nigra and a marked decrease in Dopamine
substantia nigra to the striatum. A degenera- concen-tration in the striatum whereas, other
tion of neurons in the substantia nigra and a transmitters and neurons are affected to a
decrease in dopamine in the corpus striatum much lesser degree (e.g., cholinergic system
occurs. within corpus striatum now has a relatively
3. "Arteriosclerotic or vascular (multi unopposed action) then the possible types of
infarct)" variety in which bilateral infarcts occur treatment are very evident.
in the putamen Usually this is the accompani- 1. Early medical treatment: For many years,
ment of a lacunar state in which multiple small the standard treatment involved the use of anti-
infarcts occur in the basal ganglia and internal cholinergic compounds such as belladonna and
capsule. The resultant syndrome of rigidity and atropine or of synthetic analogues.
akinesia affects the lower half of the body and Trihexyphenidyl (Artane) and benztropine
thus can be clearly distinguished from the clas- (Cogentin) are examples of such agents. The
sical idiopathic I-dopa responsive Parkinson's anticholinergic compounds affect primarily the
disease. tremor and to some extent the rigidity of
4. Von Economo's Encephalitis. A certain Parkinson's disease and in many cases may pro-
proportion of cases may be termed post- duce limited improvement.
encephalitic. These cases had a clear onset in 2. Early approaches to surgical intervention.
relation to the epidemic of Von Economo's Various surgical procedures were attempted in
encephalitis lethargica in the years 1916-1926. the 1940s and 1950s, involving limited abla-
Approximately 50% of the survivors of this tions of area 4 or area 6 or section of the cere-
devastating disease developed a Parkinson's bral peduncle. In 1952, while attempting to
syndrome due to severe loss of neurons in the section the cerebral peduncle, Cooper acciden-
substantia nigra. In such cases, Lewy bodies are tally occluded, the anterior choroidal artery,
not found but neurofibrillary tangles are pre- and the Parkinsonian patient showed a signifi-
sent in surviving cells (see Alzheimer's disease cant improvement in contralateral symptoms,
in Chapter 30 for a discussion of neurofibrillary presumably as a result of infarction of the inner
tangles). In addition to the aforementioned section of the globus pallidus. Cooper soon
Parkinsonian symptoms and signs, these came to employ stereotaxic techniques for the
patients presented other evidence of involve- direct production of lesions in the globus pal-
ment of the central nervous system, including lidus (Fig. 19-2 lesion 1). The procedure pro-
oculogyric crises (tonic vertical gaze), chorea, duced a significant reduction in contralateral
dystonia and sleep disorders. The symptoms tremor and to a lesser extent, a decrease in the
and signs indicated the involvement not only of contralateral rigidity. Cooper was able to
the substantia nigra, but also of multiple other demonstrate later that lesions in the ventrolat-
sites including the midbrain, hypothalamus eral thalamus were much more effective
and hippocampus (see Gibb, 1988). The (Fig.19-2, lesion 2). Initially, the stereotaxic
essential distribution of the pathology was in lesions were produced by the injection of alco-
the periventricular areas about the aqueduct hol or coagulation. In later procedures, a freez-
and third ventricle A dramatic example of post ing cannula was employed.
19-12 CHAPTER 19
3. Transmitter replacement: With the tures such as the globus pallidus, thalamus and
increasing knowledge of the neurotransmitters subthalamic nucleus have also been developed.
involved in the substantia nigra and corpus Transplantation of fetal mesencephalic cells
striatum and with reports of deficits of into the striatum has benefit in younger
dopamine in these structures in patients with patients but may increase dyskinesias. The
Parkinson's disease, the use of replacement problems of management are reviewed in the
therapy with L-Dopa (dihydroxyphenylala- following patient who was followed for 19
nine) subsequently developed (Cotzias et al, years.
1967, 1969). As we have indicated, the anti- Case 19-1: This 48-year-old married left-
cholinergic drugs had a limited effect handed white male schoolteacher and adminis-
primarily on the tremor and rigidity; surgery trator, 3 months prior to evaluation in 1982
affected primarily the tremor; the use of L- developed a sense of fatigue, stiffuess and lack
Dopa, which was more a physiological tech- of control in the left arm. After a period of
nique, improved the severe akinesia in addition prolonged writing, he would have to make a
to decreasing the tremor and rigidity. The use conscious effort to continue wntmg
of L-Dopa required large amounts of medica- Approximately one month prior to the
tion since much of the administered dosage evaluation; he first noted a slowing down in
was decarboxylated to dopamine at peripheral movements of the left leg. "I have to remem-
systemic sites and never crossed the blood ber to lift it."
brain barrier to be converted to dopamine Neurological examination: Cranial
(note that L-Dopa-crosses the blood brain bar- Nerves: He had a tremor of the closed eyelids
rier; dopamine does not). There were signifi- and a positive glabellar sign (he was unable to
cant side effects due to the peripheral actions of suppress eyelid blinking on tap of forehead).
the drug. By combining L-Dopa with a periph- Motor System: In walking there was a tendency
eral Dopa decarboxylase inhibitor, Carbidopa to turn en bloc and a decreased swing of the
(in the form of Sinemet) a much lower dosage left arm. There was a slight increase in resis-
of L-Dopa was required with fewer gastroin- tance to passive motion at the left elbow, wrist
testinal and blood pressure side effects. Central and knee (rigidity without definite cogwheel
side effects continued to occur, e.g., peak dose component). Although the patient was left-
related dyskinesias such as chorea and handed, there was a slowness of alternating fin-
myoclonus. The short duration of action also ger movements of the left hand. No tremor
continued to provide problems in terms of was present. Handwriting was intact with no
wearing off of dose. Other sudden on-off evidence of micrographia.
effects with sudden arrests of movement that Clinical diagnosis: Early Parkinson's dis-
were not entirely related to time of dose also ease, predominantly unilateral.
occurred as the disease progressed. Individual Laboratory data: All studies were normal
titration of dosage, specific to the particular including CT Scan of the brain, and thyroid
patient is often required. The basic problem is studies.
that Parkinson's disease is progressive. Once Subsequent course: The patient did not
the neurons in the s. Nigra have all died off or
have become dysfunctional, there is no capabil- 6 This is a combination of 10 mg. of carbidopa
ity to convert L dopa to dopamine. (Dopa decarboxylase inhibitor) and 100 mg. of
4. Other therapeutic maneuvers have been L-Dopa. Higher dosage combinations are a) 25
developed for such patients. Various dopamine mg. ofcarbidopa with 100 mg L-Dopa, and b)
agonists have been developed to bypass the 25 mg. carbidopa with 250 mg. L-Dopa. A sus-
problem of conversion of L-dopa to dopamine. tained release form is also available (50 mg. of
Additional surgical procedures involving the carbidopa with 200 mg. of L-Dopa), and is
implantation of stimulators in deep brain struc- marketed as Sinemet CR.
mg. tablets, 7 or 8 x/day, more resting pill-
rolling tremor of the left hand had emerged.
(In actuality 75-100mg of carbidopa is proba-
bly sufficient to saturate the peripheral dopa
'Ii.. ~ L i - ~--.L,'" I<.tlw decarboxylase system). Moreover, choreiform
11...- .. st... ~:.:;, ........... -movements of the left arm occurred 60 to 90
minutes after each dose of Sinemet. The chor-
eiform movements disappeared when the
dosage of Sinemet was reduced to 25/1 OOmg
6/day. The increased rigidity and tremor
responded to the addition of a DOPA agonist
Bromocriptine (Parlodel). Over the subse-
quent years other agents were employed but
the disease continued to progress with all of
Figure 19-6. Parkinson's disease. Case 19-1. See text. the problems in management discussed above.
Handwring sample: on 05/03/83 before therapy with Eventually, in 1997 he underwent mesen-
L-iUJpa/Carbidopa and 05/10/83-one week after cephalic fetal cell transplantation. Evaluation 3
starting therapy. In each example, the larger circles years after the transplant demonstrated a little
have been drawn by the examiner. improvement but a marked increase in the
wish to begin any treatment at that point in dyskinesias. Some improvement in dyskinesias
time. Re-evaluation at 3 months indicated pro- occurred after dopaminergic medications again
were reduced.
gression. One year after onset of symptoms
there was significant micrographia (Fig. 19- DIFFERENTIAL DIAGNOSIS OF
6A) and cogwheel rigidity at left shoulder, PARKINSON'S DISEASE:
elbow and wrist. Therapy with Sinemet (10- 1. In considering the akinesia and bradyki-
100 mg, 3 times per day.)6 was begun. Re- nesia of Parkinson's disease, the major differen-
evaluation one week later demonstrated a tial diagnosis in the older population are the syn-
marked improvement in handwriting (Fig.19- dromes ofgait apraxia related to Jrontallobe, as
6B) and decreased cogwheel rigidity. discussed in Chapter 18. These may be out-
As the dose of Sinemet was increased to lined as follows:
(10/100) mg 5x/day over the next week, a. Normal pressure hydrocephalus
occasional choreiform movements of the fin- b. Other types of hydrocephalus: late
gers of the left hand and occasional backward decompensation of aqueductal stenosis
flinging (hemi ballistic) movements of the left c. Multiple lacunar infarcts (the lacunar
arm occurred at 60-90minutes after later doses state)
of Sinemet. As the dose reached 10-100 mg. d. Leukoariosis - or Binswanger's Disease
6x/day, the patient reported that his handwrit- involving the periventricular white matter and
ing now was back to normal. Examination con- seen in elderly hypertensive patients
firmed the significant improvement in all find- e. Alzheimer's disease: Note, however that
ings. The patient did experience 90 minutes Mayeux et al, 1985, found that 34% of patients
after a Sinemet dose - a tremor of the left with Alzheimer's disease had some extrapyra-
shoulder and an exaggerated grasp of the left midal signs. To confound the picture, 44% of
foot toes on lifting the leg (possible form of patients with Parkinson's disease have demen-
dyskinetic or dystonic reaction). He was aware tia, with 29% found to have Alzheimer's disease
that some symptoms of his underlying disease and 10 % Lewy body dementia.
would emerge 3-4 hours after a dose of f. Frontal lobe tumors, e.g., subfrontal or
Sinemet. Five years after onset of symptoms, parasagittal meningiomas.
despite a higher dosage of Sinemet of 25/100 g. Myxedema with hypothyroid state.
19-14 CHAPTER 19
h. General paresis of neurosyphilis, now b. From a clinical and pathological stand-

uncommon but refer to case 30-S. point, the pathology of primary neuronal
In general, frontal lobe syndromes do not degeneration is much more widespread than in
have a prominent tremor (unless a coincident idiopathic Parkinson's disease. The term multi-
essential or senile tremor is present). Rigidity system atrophy is often applied to some of
may be present but this variable rigidity is of these cases?
the frontal lobe type referred to as gegenhal- c. Lewy bodies are not found.
ten. A cogwheel component (to this frontal d. In general, the patients are all poorly
lobe rigidity) is usually not present unless there responsive to Levodopa. (Since the pathology
is a superimposed tremor of other cause. The extends far beyond the Dopaminergic produc-
rigidity and akinesia predominantly affect the ing neurons of the S. Nigra.)
lower extremities. e. Some of the patients have a familial
2. In considering the tremor of Parkinson's disorder.
disease - the major differential diagnosis is essen- The more frequent types may be briefly
tial (or senile or familial tremor.) In general, noted (excellent, more detailed discussions are
this is a tremor of the outstretched hand with found in Jankovic, 1989, Riley &Lang, 2000).
some increase as termination of movement or S. Other neurological syndromes with rigidity
when a sustained posture is maintained. The and akinesia:
tremor is not present at rest and there is no pill a) Early onset Huntington's Disease and
rolling quality. Rigidity is not present, and gait WIlson's disease (see below).
is normal with a good swing of the arm. The b) Hallervorden Spatz Disease: A rare
tremor is usually long-standing without major familial (autosomal recessive disorder with link-
disability. Note that there is a small group of age to chromosome 20P) in which prominent
Parkinson's disease patients with favorable out- iron deposits and neuronal degeneration in
come who have a resting tremor as a predomi- globus pallidus and substantia nigra are associ-
nant symptom over many years. They will, ated with childhood onset of Parkinsonian syn-
however, have to a minor degree, on careful drome, dementia, spasticity, dystonia and
examination, many of the other cardinal symp- chorea.
toms of Parkinson's disease. c) Parkinsonism - dementia - ALS complex
3. Secondary Parkinsonism: Neuroleptic, found in the Chamorros of Guam (and several
toxic or vascular induced. In the series of other Pacific groups)- a probable toxic disease
Jankovic (1989), and Siemer and Reddy involving an excitatory amino-acid (beta N
(1991), these cases accounted for 10% of all methyl-amino L - alanine) - derived from the
cases of Parkinsonism. cycad seed once used in the production of
4. Parkinsonism plus syndromes. (Table 19- floor.
S) In the same series these cases accounted for d) Creutzfeldt -Jakob Disease: See discus-
10% of all cases of Parkinsonism. These latter sion of dementia (chapter 30)
patients all share the following characteristics:
a. A progressive disorder is present. CHOREA, HEMICHOREA AND
HEMIBALLISMUS:
7 Many patients with Parkinson's Disease have Chorea8 may be defined (Committee
some symptoms, usually minor, that suggest some 1981) as "excessive spontaneous movements
degree of involvement beyond the S.Nigra and irregularly repeated randomly distributed and
beyond the Dopaminergic nigral - striatal sys- abrupt in character". These movements,
tem, e.g., orthostatic hypotension which is present
in the untreated patient. Idiopathic Parkinson's 8 At times the adjective choreiform is used to
patients also may have some minor degree of describe the movement rather than employing the
upward gaze impairment. noun: chorea
TABLE 19-5 PARKINSONISM PLUS SYNDROMES
Name Abbreviation Pathology-type Location Clinical syndrome

1. Progressive PSP Neuron loss and Midbrain tegmentum and Parkinsonism plus
supranuclear abnormal tau protein ectum, substantia nigra, supranuclear impairment
palsy In neurofiMllary tangles globus pallidus, of gaze particula~y In
(the most common) In neurons and glia subthalamic nuc. basal vertical plane
Cortex and subcortex nuc., cortex Imaging=atrophy of midbrain
2. Corticobasal CBD Ballooned and Asymmefrlcallnvolvement Akinetic-rigid Parkinsonism

degeneration achromatic neurons of frontal -pa~etal cortex plus, dementia plus
plus abnormal (superior frontal), S. nigra, laterallzed apraxia, useless
neurofibrillary tangles caudate, thalamus hand, and laterallzed
with tau protein. myoclonus Ove~ap with
Linked to chromosome PiCk's, Frontal dementia and
17 in familial cases PSP.
Imaglng= focal atrophy of
frontal- parietal cortex.
3. Multiple system MSA Neuronal loss, gliosis, S.nlgra, striatum, Akinetic -rigid Parkinsonism
atrophy Incorporates and inclusions in olivopontocerebellar- (predominates in 80%)
3 previously oligodendroglia lar pathways plus plus cerebellar ataxia
separate disorders neuronal cytoplasm, Intermediolateral cell (predominates In 20%)
a. striatal nigral nuclei and gila column of spinal cord plus dysautonomia (with
degeneration containing filaments neurogenic orthostatic
b.ollvopontocerebellar derived from cytoskeletal hypotension)
atrophy profelns: tau, ubiqultin Imaging = atrophy of striatum
c. Shy-Drager Syndrome and alpha synnucleln or ponslcerebellum
depending on
predominant symptoms
although involuntary, consist of fragments or contralateral subthalamic nucleus (see

sequences of normal, coordinated movements. Carpenter, et al, 1950; Whittier and Meller,
Face, mouth, head, proximal or distal limbs 1947; Whittier, et al, 1949). It was recognized
may be involved. that the underlying lesion could be a small
Two types of processes must be distin- infarct due to posterior cerebral penetrating
guished - (1) lateralized hemichorea and (2) branch involvement, often on a lacunar basis,
generalized chorea. The lateralized hemichorea in a patient with hypertension or diabetes mel-
merges into a remarkable disorder hemiballis- litus. At times, the adjacent thalamic areas were
mus characterized by sudden flinging or ballis- involved, as well, e.g., the ventral posterior lat-
tic movements at the proximal joints such as. eral or ventral lateral nucleus. At times, the
throwing or sudden swinging movements at responsible lesion was a small hemorrhage in
the shoulder joint. Patients may start with the subthalamic nucleus (Fig.19-10) and,
hemichorea and evolve into hemiballismus. In rarely, a small metastatic tumor.
discussing this topic, we will deal first with the As regards the explanation for such con-
focal problem and then with the generalized tralateral excessive movement, hemichorea or
type. We will see in both varieties abnormalities hemiballismus, one needs only to consult
of the anatomic sequences discussed earlier in Figure 19-1. Decreasing the excitatory drive
this chapter. from the subthalamic nucleus actingoin the
HEMICHOREA AND HEMIBALLISM: medial globus pallidus and the substantia nigra
Initial clinical and experimental studies, reticularis would decrease the inhibitory drive
correlated these disorders with lesions of the from those structures acting in the thalamus.
19-16 CHAPTER 19
Therefore the thalamic/premotor-SMA circuit rhage into those structures.

would be more active and more movement Case 19-2: This 88-year-old, right-hand-
would result. ed, widowed white female with a past medical
There were other clinical studies that did history of profound hearing impairment, adult
suggest other possible localization in the stria- onset diabetes, euthyroid goiter, coronary
tum (Cooper, 1969; Goldblatt, et al, 1974; artery disease, and hypertension, 5 days prior
Martin, 1957; Meyers, 1947; Schwarz and to admission, developed the insidious onset of
Barrows, 1949). In experimental studies involuntary rotary movement in the left foot
Crossman, et al, 1988 demonstrated that local which increased in intensity and progressed to
injection of a GABA antagonist into the border involve the left shoulder. The movements were
of the lateral segment of the globus pallidus constantly present, even during sleep and with
and the adjacent medial segment of the puta- progression; her ability to ambulate with a
men would produce hemichorea in the mon- walker was impaired. She also had a dull
key. Such lesions interrupt the inhibitory affer- headache greater on the left side than on the
ent input to the lateral globus pallidus from the right during the last few days.
putamen. The lateral globus pallidus would Neurological examination: Cranial
then have greater inhibitory drive on the sub- Nerves: Intact except: for left eye blindness
thalamic nucleus. The overall effect then would (cataracts), and gross impairment of hearing
be equivalent to producing a lesion of the sub- such that shouting was necessary to communi-
thalamic nucleus; hemichorea or hemiballis- cate. Motor System: There was minimal weak-
mus would result. (See Mitchell et al, 1989). ness in the left upper extremity (5-/5). There
The responsible lesion in these cases would was a persistent hemichorea: involuntary twist-
be in the territory of the lenticulo striate pene- ing movements of her left foot and upward and
trating branches of the middle cerebral artery. rotary movements of her left shoulder. The
Another factor to be considered in chorea movement was exacerbated by motor-- tasks
and other induced dyskinesias is the possible but did dissipate with sleep. Gait was slightly
unopposed action of the nigral striatal unsteady due to hesitant placement of the left
Dopaminergic circuits as discussed earlier in foot. She did quite well with minimal assis-
this chapter. L-Dopa will exacerbate chor- tance. Reflexes: Deep tendon reflexes were
eiform disorders9 . Agents that block dopamine symmetrical, and physiologic except for
receptors, e.g., the butyrophenones (such as decreased Achilles secondary to diabetes. the
haloperidol) are often very effective in alleviat- left plantar response was extensor. Sensation:
ing hemichorea, hemiballismus and chorea (see Symmetrically diminished vibration sense in
Crossman, 1990; Klawans, et al, Albin Young toes ..
and Penney, 1989) for additional discussion. Clinical diagnosis: hemichorea
Hemichorea: Case history 19-2 presented Laboratory data: MRI scan 3 days after
below provides an example of hemichorea with admission, revealed mild cortical atrophy and a
MRI correlation of lesion location in the stria- hyperdense area the right basal ganglia (partic-
tum (caudate/putamen) following a hemor- ularly the head of caudate and putamen) and
external capsule consistent with subacute hem-
9 L-Dopa induced dyskinesias are not observed in orrhage (Fig. 19-7).
intact monkeys and humans who have normal Hospital course: The patient was begun
dopamine1lJic and normal basal ganglia func- on haloperidol 0.5 mg by mouth every morn-
tion. Parkinsonian patients, monkeys with ing and advanced to 1 mg., by mouth three
MYTP lesions and patients with a predisposition times per day with improvement in the hemi-
to Huntington disease will develop dyskinesias chorea, particularly in the upper extremity over
after receiving L-Dopa (see discussion below and the next two weeks
Luquin et aI, 1992). Hemiballism: As we have previously indi-
cated, the movements of hemi-chorea may improvement. The ataxia on finger--to-nose
evolve or merge into more violent, uncoordi- testing disappeared.
nated, rotatory, flinging movements at the GENERALIZED CHOREA: Bilateral
shoulder joint and other proximal joints; generalized chorea may occur under the fol-
termed hemi ballistic. The responsible lesion lowing circumstances:
was located in the subthalamic nucleus (FiR. (1). Acute onset with an immunological
19-8) or in the putamen or at the border oflat- basis (a) one aspect of rheumatic fever (plus or
eral pallidum - putamen, as discussed above. minus carditis and arthritis). (b) In relationship
The following case history illustrates this to various autoimmune disease such as lupus
movement disorder in a patient seen prior to erythematosus.
the era of CT and MRI scans in which the (2). As an acute complication of L-dopa
localization is relatively clear. therapy in patients with compromise of the
Case 19-3: This 79-year-old, right-hand- dopaminergic system or with disease of the
ed, white housewife had the abrupt onset in basal ganglia - as discussed above.
the early morning hours, 2 days prior to admis- (3). As an acute or chronic complication of
sion, of almost constant flinging movements of various metabolic disorders: hepatic, renal,
the right arm over which she had no control. hypocalcemia, etc. rarely occurring in pregnan-
At the same time, she noted that her right arm cy. In acute hepatic encephalopathy, a number
felt numb and heavy. Over the next 2 days, the of toxic substances that would normally be
movements decreased markedly and she removed from the portal venous system on
regained more control of the arm. passage through the liver are not removed.
Past history: The patient had been a Instead, in patients with liver disease, portal
known diabetic for 21 years, receiving insulin - hypertension may develop, portal - systemic
most recently, lente insulin, 25 units each shunting develops and toxic substances such as
morning. ammonia may accumulate in blood and brain.
Neurological examination: Motor system: In addition to depression of consciousness
Minimal weakness was present in the right (hepatic coma), a hepatic "flap" or "asterixis"
upper extremity at the elbow, wrist and fingers. may develop. With the arms outstretched,
Alternating movements and finger-to-nose extended at the elbows, and the hands extend-
testing in the right hand were markedly ed at wrist, an irregular flexion extension
impaired. Occasional involuntary flinging movement will develop at the wrists and at the
movements occurred at the right shoulder. metacarpal - phalangeal joints. A similar "aster-
Sensory System: Pain, touch, vibration and posi- ixis" may also be noted in other metabolic dis-
tion sense were all absent in the right upper eases such as uremia and pulmonary disease
extremity to the elbow and decreased in this with C02 retention. In all of these disorders:
extremity above the elbow. ataxia, dysarthria and action tremor of hands
Clinical diagnosis: hemiballismus due to a may also occur. With uremia and hypocal-
lesion of penetrating branches of the posterior cemia, myoclonus (sudden jerks of the extrem-
cerebral artery, which involved the subthalam- ities) or generalized convulsions may occur.
ic nucleus and ventral posterior lateral nucleus With repeated episodes or prolonged peri-
of thalamus. ods of hepatic encephalopathy, more profound
Laboratory data: Chest and skull X-rays and lasting changes in neurological function
EEG, and cerebrospinal fluid studies were all occur producing a syndrome characterized by
normal. chorea and athetosis, ataxia, dysarthria, tremor
Subsequent course: The flinging move- and dementia. Neuro pathological examina-
ments of the right arm subsided spontane- tion of the brain demonstrates cavities within
ously, shortly after admission. Position sense the basal ganglia, cerebellum, and cerebral cor-
returned and pain sensation showed a mild tex. Swollen astrocytes are found, particularly
19-18 CHAPTER 19
Figure 19-7. Hemichorea. Case 19-2 See Text. MRI

demonstrates a hyperdense area of the head of the right
caudate, adjacent pummen and external capsule -
within basal ganglia. This chronic irreversible consistent with a hemorrhage. A, B, C - sequential
syndrome was initially described as the horizonml sections at 5 mm. intervals - Tl; weighted D
acquired non-Wilsonian type ofhepatocerebral - Sagitml section 12.5 mm to right of midline.
degeneration. (Victor et al, 1965).
(4) As a chronic progressive disorder - indi- ing on Long Island in New York state. The
cating a degenerative disease - affecting the syndrome was characterized by the develop-
striatum and other sectors of basal ganglia and ment in mid life of a progressive psychological
cerebral cortex. change (depression, paranoia, psychoses),
The most frequent disease in this category dementia and involuntary choreiform move-
is Huntington's disease. Huntington's disease ments. The disease often affected multiple
is of importance beyond its frequency in the members of a family over a number of genera-
population of 5-10/100,000. The disease was tions. Genetic studies have confirmed that the
originally described in 1872 by George pattern of inheritance follows an autosomal
Huntington, based on clinical observations dominant pattern with extremely high pene-
made by his grandfather, his father and himself trance. In large series, 50% of offipring will
of an apparent autosomal dominant syndrome manifest the disease that is all who carry the
of high penetrance that occurred in families liv- affected gene will manifest the trait. The
Figure 19-8. Hemiballismus. Myelin stain of bnsal

ganglia demonstrating a discrete hemorrhage into the Figure 19-9. Huntington's disease. Marked atrophy of
right subthalamic nucleus. The arrow points to the the caudate and putamen with secondary dilatation of
subthalamic nucleus of the normal left hemisphere. the lateral ventricles is evident. Cortical atrophy wns
(From Luhan, J.A.: Neurology, Baltimore, Williams less prominent in this CIISC. (Courtesy ofDoaor
& Wilkins, 1968,p.334).
Emanuel Ross, Chicago.)
expression of the gene may vary. Mean age of
onset in a large sample as defined by chor- locus on this chromosome. Normal individuals
eiform movements was 42 years. However, have 6-34 repeats; patients with Huntington's
behavioral changes, including depression and disease have 36-121, (Zoghi &Orr, 2000)10.
suicide attempts may precede the movement The gene product is huntingtin. Patients with
disorder by ten years or more. Earlier onset of onset at an early age or with a more severe
disease is associated with a more rapid course form of the disease have a greater number of
and with the earlier development of features of repeats. As we have already discussed in chap-
rigidity. Such patients, for unknown reasons , ter 9 on the spinal cord, similar mutations
are more likely to have inherited the gene from involving an excessive number of CAG repeats
the father. Late onset cases (onset between 50 have also been found in a number of other
and 70 years of life) have a much more pro- neurological disorders including several of the
longed course and choreiform movements are spinocerebellar degenerations and spinobulbar
often the predominant feature (see Sax and muscular atrophy. Other disorders such as
Vonsattel, 1992). At times the term senile myotonic dystrophy and Friedreich's ataxia
chorea has been utilized for these late onset have an excessive number of repeats in other
cases, which are more likely to have involved trinucleotide sequences. Presymptomatic
cases in the maternal line. detection is possible but this should be done
Modern genetic analysis using recombinant under circumstances where a full gamut of
DNA techniques and studying families with genetic counseling is available. The underlying
large numbers of affected individuals or large gross pathology has been well established
numbers at risk have allowed the localization of (Fig.19-9). Marked atrophy of caudate nucleus
the marker site for the gene on the short arm and putamen are the pathologic and neu-
of chromosome 4. (See Gusella et al, 1983; roimaging hallmarks. This gross pathological
Martin and Gusella, 1986; Penny and Young, feature allows for diagnosis and subsequent
1988; Roberts, 1990; Wexler, et al, 1991). The monitoring of progression by means of CT
specific mutation has now been identified as an scan and MRl scan (Fig.19-9) (Vonsattel et al,
unstable trinucleotide repeat in the CAG series 1985; and Myers et al, 1985). In addition sig-
coding for poly glutamine tracts at the 4p16.3 nificant cortical atrophy also occurs as the dis-
llThese neurons are located in the matrix. Matrix
10 The Huntington Disease ffilrking Group1996 neurons that appear late in development are the
however has set the affected range as greater earliest affected, it is not until very late in the dis-
than 38 repeats ease that patch neurons are affected.
19-20 CHAPTER 19
ease progresses. The gene product huntingtin circuit. Abnonnal excessive movements due to
is expressed widely throughout the brain. increased activity of SMA then results as dis-
There are high levels in large striatal interneu- cussed above under hemichorea
rons and medium spiny neurons, as well as cor- The following case history provides an
tical pyramidal cells and cerebellar Purkinje example of Huntington's disease.
cells. Case 19-4: This 54-year-old right-handed
Additional analysis has indicated that not all white female was referred for evaluation of a
cells and transmitters in the caudate and puta- movement disorder. The patient lived alone
men are involved in the process of degenera- and it was difficult to obtain much of any his-
tion. The extensive studies have been reviewed' tory from the patient. She denied any neuro-
by Albin et al, 1990; Martin and Gusella, logical or psychiatric disorders except for a
1986; Penney and Young, 1988; Young et al problem with memory during the last year. She
1988; and Wexler et al, 1991. The cells affect- did indicate that she had worked for 10 years as
ed are classified as medium sized, spiny neu- a secretary/computer operator but had been
rons that project to sites outside the striatum fired 10 years ago because "she did not work
and which constitute approximately 90% of all fast enough". She had a past history of hyper-
striatal neurons. All contain the transmitter tension but had not been reliable in taking her
GABAll. However, different subtypes are dis- prescribed medication. The patient's son was
tinguished based on the specific associated aware that changes in emotion, personality,
neuropeptide that they contain e.g., speech, gait and a movement disorder had
enkephalin, substance P. and/or dynorphin been present for at least 3 years.
and based on the projection destinations. On Family history: The patient denied any
the other hand other cells with interneuron neurological family history except for a mater-
functions are not affected: (a) The large, spiny nal uncle who had the "shakes" (actually a
acetylcholine containing interneurons and (b) maternal aunt with essential tremor), addition-
the small aspiny interneurons containing the al investigation revealed that her father clearly
neuropeptides somatostatin and substance Y. had Huntington's disease with onset of chor-
Refer to Table 2 above. eifonn movements at age 30, and of irritability,
Early in the course of the disease there is a paranoia and gait disturbance in his early 50s.
loss of those spiny neurons which contain the The patient's eldest daughter age 34 had been
GABA and enkephalin transmitters and which depressed for 5 years and had problems with
project to the lateral globus pallidus. At this speech and walking for a number of years.
point in the disease, the loss of these striatal Neurological examination: Mental status:
inhibitory inputs to the lateral globus pallidus the patient often avoided eye contact. Affect
results in increased activity (inhibitory) of the was usually inappropriate with laughter as the
lateral globus pallidus neurons. Since the later- response to many questions. The overall mini-
al globus pallidus is the main input to the submental status score was 27/30.The only deficit
thalamic nucleus and this input is inhibitory, an related to delayed recall portion of the test 0/3
increased inhibition of the subthalamic nucleus objects. Cranial nerves: the patient had a
results. As a result, the excitatory output from hyperactive jaw jerk. She had frequent facial
the subthalamic nucleus to the medial globus grimacing. Motor system: the patient had
pallidus (MGP) and S. nigra reticularis (SNR) decreased tone at wrists and elbows. As she sat
is reduced. The output of neurons in MGP and she had frequent restless and at times chor-
SNR is reduced. This output is inhibitory and eiform movements of hands and feet. Gait was
destined for ventrolateral thalamus. The out- often "bizarre" in terms of occasional sudden
put of ventrolateral thalamus is no longer movements of a leg as moved down the hall
inhibited - and increased activity occurs in the and came to a stop. These same movements
ventrolateral to supplementary motor cortex occurred, as she remained standing. In addi-
tion in standing or walking, there were inter- described as instability of posture, a relatively
mittent dystonic postures of either left or right continuous alternation or swing between two
arm. Reflexes: Deep tendon stretch reflexes positions. For example, in the hand, this would
were everywhere hyperactive but plantar involve a swing from hyperextension of the fin-
responses were flexor. gers and thumb with pronation at the wrist to
Clinical diagnosis: Huntington's disease. full flexion of the fingers with flexion and
Laboratory data: MRI scans of head supination of the wrist. In a sense, there is an
(Fig. 19-1 0): The heads of the caudate nuclei alternation between grasp and avoidance.
were very atrophic. Cortical sulci were wide Occasionally, following cerebral infarction at
consistent with cortical atrophy. The lateral and various age's athetosis may occur as a unilater-
third ventricles were secondarily dilated. PCR al phenomenon admixed with hemichorea. In
testing for the CAG trinucleotide repeats of the general athetosis occurs as a bilateral congeni-
huntingtin gene indicated one allele normal at tal phenomenon with involvement not only of
17; and the second excessive at 42 repeats. the upper extremities but also of the lips,
Subsequent course: The patient refused tongue and lower extremities. Double atheto-
any treatment for the movement disorder. sis is one of the varieties of cerebral palsy dis-
According to the son, the patient's neurologi- cussed in chapter 18. The pathology of double
cal status worsened to a moderate degree over athetosis is found in the putamen that may
the subsequent 3 years as regards speech, have a marbled or mottled appearance as a
unsteadiness of gait, and mood swings. result of the presence of excessive numbers of
abnormally situated myelin sheaths. To a lesser
degree, the thalamus may also be involved. The
etiology is not certain: anoxia at birth or other
perinatal or prenatal pathology is considered
the likely cause. Some of the cases can be relat-
ed to kernicterus. A rise in bilirubin has
occured in the perinatal period owing to
hemolysis of red blood cells when an Rh factor
or other incompatibility of blood type has been
present.
2. Hepatolenticu1ar Degeneration
(WIlson'S Disease): This is a familial disorder
Figure19-10. Huntington's disease. Case 19-4. MRI. (recessive inheritance), which affects, to a vari-
(1'2) Refer to text. Marked atrophy of cerebral cortex
able degree, the liver and the central nervous
and of caudate nucleus is evident in this patient with
a familial history of the disorder and a significant system and in many cases, the kidney and
increase in the GAG trinucleotide repeats. bones. In the central nervous system, the most
severe involvement occurs in the basal ganglia:
Case 19-5 presented on CD ROM pro- the putamen and globus pallidus (cavitation,
vides an example of a patient with loss of neurons and an increased number of
Huntington's disease followed over a longer swollen astrocytes). To a lesser extent, the cere-
period of time. Onset occurred at age 32 with bellum and cerebral cortex are involved.
definite diagnosis of the disorder in both the The basic etiology has now been clearly
father and paternal grandfather. established as a metabolic defect. There is a
deficient plasma level of the circulating copper-
OTHER MOVEMENT DISORDERS binding globulin, ceruloplasmin12. As a result,
ASSOCIATED WITH DISEASES OF there is an excessive serum level of unbound
THE BASAL GANGLIA: copper. Normally, the binding of copper to
1. Double Athetosis: Athetosis may be ceruloplasmin prevents the passage of copper
19-22 CHAPTER 19
out of the serum. In WIlson's disease, howev- aminoaciduria. Diagnosis can be based on the
er, the increased amount of unbound copper clinical findings, ceruloplasmin levels, (normal
results in passage of this metal into the brain13, levels are 200t0400 mg/liter), serum copper
liver, and kidney (The total combined level of (normal total levels are 11 to 24 umol/liter
both bound and unbound serum copper is less versus 3 to 10 in WIlson's disease). The most
than normal). In some cases, usually of early definitive study involves analysis of copper con-
onset, the symptoms of liver involvement pre- tent in a liver biopsy. The CT scan and MRI
dominate. WIlson's disease should always be may demonstrate the lesions in the putamen
suspected when hepatocellular disease develops and globus pallidus.
in a child or adolescent. In other cases, the cen- The treatment ofWIlson's disease is depen-
tral nervous symptoms predominate and dent on a reduction of copper in the diet or the
hepatic disease may be only minor. Deposition administration of an agent that will bind cop-
of copper also occurs in the cornea at the scle- per. Penicillamine (B.B-dimethyl- cysteine) is
ral junction. The resultant greenish brown pig- an effective chelator of copper. It is well
mentation is referred to as the Kaiser-Fleischer absorbed on oral administration and promotes
ring. This ring is almost always present when the urinary excretion of copper, resulting in a
central nervous system involvement is present. decreased level of copper in the serum, central
Overall, 54% of cases present with neurological nervous system, and liver.
onset, 31% with hepatic dysfunction, 14% with The following Case 19-6 presented on CD
psychiatric symptoms, 2% with eye symptoms, ROM illustrates the clinical problem of hepa-
1 to 2% with hemolytic anemia and 1% with tolenticu1ar degeneration in a 21 year old
heart disease (see Patten, 1988). In patients female who developed progressive neurologic
with hypersplenism as a complication of the syndrome characterized by mood swings, a
hepatic disease, thrombocytopenia may wing beating tremor, choreoathetosis,
develop. dysarthria, ataxia and a Kayser Fleischer ring.
The actual symptoms referable to the neu- Her brother had died at age 16 with hepatic
rological involvement depend on the age of the disease, a Kayser Fleischer ring and choreoa-
patient. In early onset cases (late childhood and thetosis. The patient had serum elevation of
early adolescence) rigidity predominates. When free copper and a decrease in protein bound
cases begin in early adult life, movement disor- copper and an abnormal liver biopsy. She was
ders predominate (tremor and choreoatheto- successfully treated with penicillamine.
sis). The tremor is coarse and best described as 3. Dystonia:
sustained postural. The term "wing beating" is Dystonia is a hyperkinetic disorder domi-
often used. The copper also produces damage nated by sustained muscle contractions fre-
to the renal tubules, resulting in glycosuria and quently causing twisting and repetitive move-
ments or abnormal postures. (Jankovic &
12 In a few cases, ceruloplasmin levels are just Fahn, 1988) Dystonia may be focal (43%), seg-
within normal limits, but biliary excretion of mental (30%), generalized (22%)or unilateral
copper is low. Absorption of copper is normal in (5%). Focal dystonias are more common than
all cases. the relatively rare generalized form.
13 The distribution of copper in the normal Focal and segmental idiopathic dystonias:
brain corresponds in general to the distribution Focal dystonia affect predominantly a single
of catecholamine contammg neurons. body part primarily cranial and cervical mus-
Dopamine B hydro»ylase is a copper containing cles. Involvement of limbs is less common.
enzyme with considerable localization to the Segmental refers to dystonia involving multiple
basal ganglia. However, copper is also found in segments usually cranial and cervical. Included
cytochrome C-oxidase that is found throughout within this category of cervical dystonia is the
the brain. relatively common entity of spasmodic torticol-
lis in which sudden movements of the head to able response to low dosage of L-Dopa
one side occur. The movement may be inter- (termed the L Dopa responsive variant .of pro-
mittent or sustained. Focal or segmental dysto- gressive generalized dystonia). This is an auto-
nia involving the cranial nerves is termed somal dominant disorder coding to chromo-
Meige's syndrome. some 14 and involving guanosine triphosphate
The most frequent of the cranial dystonias cyclohydrolase It has therefore been recom-
is blepharospasm in which there is forced eye mended that all juvenile onset cases receive a
closure. Other aspects of cranial dystonia may trial of the L-Dopa/carbidopa combination.
involve the tongue and jaw termed lingual and Hemidystonia: Approximately 75% of
oromandibular. Other overlapping variants patients in this group do have the history, find-
may involve the larynx-spasmodic dysphonia, ings or CT or MRI evidence of a contralateral
or the pharynx with the latter producing diffi- neuropathology involving the striatum, usually
culty in swallowing. Other focal dystonias the putamen or striato-pallido-thalamic path-
known as occupational dystonias involve the way. The corticospinal pathways are not usual-
more specific muscles of the hand and arm uti- ly involved. There is then presumably an exces-
lized in specific actions: writers, typists, violin- sive input into premotor/ supplementary
ists and pianists. The underlying neuropathol- motor cortex resulting in the excessive con-
ogy has never been clearly established in idio- tralateral movement.
pathic cases. However, blepharospasm, or dys- 4. Movement Disorders Induced By
tonia of the foot does occur in Parkinson's dis- Dopamine Blocking Agents (Sethi, 2001)
ease; retrocollis and oculogyric crises occur in has provided a comprehensive review of this
post encephalitis Parkinson's disease. L-dopa topic).
and neuroleptic agents may both induce focal These agents produce frequent acute and
dystonias. The most effective treatment of focal chronic complications in psychiatric patients
/segmental dystonia is botulinum toxin injec- 1) Acute dystonic reactions-which occur in
tions that must be repeated every 3-4 months. 2-5% of patients within hours or days after
Generalized dystonia: The terms "primary onset of therapy. Note that this complication
generalized idiopathic dystonia" and "idio- occurs not only in psychiatric patients but also
pathic torsion dystonia" have replaced the in patients receiving agents of this class as
older term "Dystonia musculorum defor- antiemetics.
mans". Most cases begin in childhood or ado- 2) Acute akathisia: acute restlessness and an
lescence and are familial. Autosomal dominant inability to sit still, occurs in 20% of patients
inheritance is now considered predominant in receiving dopamine-blocking agents
both Ashkenazi Jewish and non-Jewish fumi- 3) Acute drug induced Parkinsonian syn-
lies. A mutation in a gene on chromosome 9 drome discussed above. Although symptoms
that codes for a protein torsin A has been iden- may appear in any patient given sufficient
tified for the majority of cases of juvenile limb amount of dopamine blocking agents to block
onset cases. Other cases which predominantly 80% of receptors, there does appear to be a pre-
involve the cervical and cranial muscles have a disposition to develop symptoms at lower
different genetic background. No specific more therapeutic range in patients with a fam-
structural neuropathological abnormality has ily history of Parkinsonism.
been found. However neurochemical analysis 4). Tardive dyskinesia and other tardive
of the brain does suggest abnormalities. reactions. In this context, tardive has been
Anticholinergic drugs at high dosage levels defined as 3 months of exposure to the agent
may improve the symptoms of generalized dys- (1 month for patients over the age of 60 years).
tonia in some patients. Approximately 10% of
juvenile onset cases beginning in the lower 14 In younger individuals, the limbs and trunk
extremities described by Segawa have a remark- are more often involved.
19-24 CHAPTER 19
There may be a genetic predisposition decrease in the clinical symptoms. In contrast,

Tardive dyskinesias are hyperkinetic chor- dopaminergic agents (L-dopa. bromocriptine)
eiform movements. Usually these are seen in and amphetamines may produce an exacerba-
the older patient involving the mouth. tongue, tion of symptoms (Jankovic, 1987, Singer,
lips and face 14: (oral buccolingual facial masti- 2000).
catory syndrome). Symptoms usually develop 6: Familial Paroxysmal Dyskinesias:
after 6-24 months of drug therapy and in many These disorders although not common are of
patients the symptoms decrease after drug significance because they undoubtedly occur
withdrawal. on the basis of channelopathies. The specific
In another group of patients, symptoms genetic mutation has not yet been identified.
develop only after neuroleptic drugs have been In this regard, they are similar to the episodic
withdrawn or dosage has been reduced again ataxias discussed in chapter 20, periodic paraly-
after prolonged use. In one series, such with- sis, and familial hemiplegic migraine in which
drawal or dose reduction resulted in tardive the specific ion channel mutation has been
dyskinesia in 40% of patients receiving chronic identified. (See Bhatia, 2001 and Bhatia eta!,
neuroleptic therapy. The presumed pathophys- 2000). In all of the syndromes, the neurologi-
iology is not entirely clear, cal examination is normal between attacks. In
5. Tics: Motor tics are sudden, brief invol- the majority autosomal dominance occurs and
untary movements resembling jerks or ges- males predominate. Two major entities may be
tures. The patient may experience a poorly identified (1) paroxysmal kinesigenic choreoa-
defined sensation of an irresistible urge to thetosis/dyskinesias (PKC/PKD) and (2)
move prior to the movement. These move- paroxysmal dystonic choreoathetosis/ non-
ments may be simple: an eye blink, a head jerk, kinesigenic dyskinesias (PDC/PNKD). The
or a facial grimace. In some cases, the move- first type (PKC/PKD) is the most common.
ment is more complex and patterned. resem- Attacks lasting less than 5 minutes begin in
bling a compulsive act. In some cases (syn- childhood with multiple attacks per day
drome of Gilles de la Tourette which has auto- induced by movement of chorea, dystonia, and
somal dominant transmission), multiple tics ballism. The attacks are significantly reduced
occur accompanied by vocalizations. The by the administration of low doses of the anti-
vocalization may consist of a simple sound or convulsant, carbamazepine that has action on
may involve the use of obscene 4 letter words the sodium/potassium channel. Several fami-
referring to defecation, genitalia, or sexual acts lies have mapped to the peri centromeric
(coprolalia). In contrast to other movement region of chromosome 16, where a group of
disorders, voluntary effort accompanied by ion channel genes are present. The second type
anxiety may serve to inhibit the occurrence of (PDC/PNKD) begins in infancy or childhood
the tic or tics. Then a flurry of tics may occur with infrequent attacks that last from 10 min-
after the suppression. Tics may continue to utes to 6 hours and are predominantly dyston-
occur in sleep. ic. The attacks are induced by stress, fatigue,
The usual idiopathic tics are common in alcohol and caffein. In a number of families
children and may persist into adult life. Lees (Jarman, eta!, 1997) the genetic defect has
and Tolosa (1988), indicate one of 10 school- been mapped to chromosome locus 2q33-q35,
boys will have idiopathic tics. Males are affect- an area where a number of ion channel genes
ed three times as often as females both in idio- are located. Paroxysmal exercise induced dysk-
pathic tics and in Tourette's syndrome. No inesia (PED) is a third less common variety.
specific neuropathology has been established.
Use of dopaminergic receptor blocking agents
such as haloperidol or pimozide or
fluphenazine may often produce a significant
CHAPTER 20
Motor System III:
Cerebellum and Movement
ANATOMIC CONSIDERATIONS TABLE 20-1 LONGITUDINAL SUBDIVISIONS OF THE

CEREBELLUM
Subdivisions of the Cerebellum
A number of schemes for dividing the cere-
bellum into various lobes and lobules have Median Paramedian Lateral
(Verma I Cortex) (Paravermal) (Remainder of
been devised. From a functional standpoint, it
cerebellar
is perhaps best for the student to visualize the hemisphere)
cerebellum as composed of various longitudi-
nal and transverse divisions. In order to visual- Projects to: Projects to: Projects to:
ize these subdivisions, it is necessary to unfold
Fasligial nucleus InterposHus nuclei Dentate nucleus
and to flatten the cerebellum as shown in (globus and lateral
Figure 20-1. emboliform)
Longitudinal Divisions
The major longitudinal divisions are the
Role in: Role in: Role in:
median (vermal cortex), the paramedian (par- Posture & Discrete ipsilateral Discrete ipsilateral
avermal), and lateral (remainder of the cerebel- move- extremity extremity pattems
lar hemispheres). movements of movements of movement.
The major projections and functional cor- body (axial) (appendicular) Coordinated with
cerebral cortex,
relations are outline in Table 20-1. In general, thalamus, and red
the median (vermal) region is concerned with nucleus. Initiating,
the medial descending systems and with axial planning and timing
control. The lateral and paramedian regions of movements.
are concerned with the lateral descending sys-
tems and with the appendages (the limbs) The transverse subdivisions are essentially
(midline to axis; lateral to appendages). phylogenetic divisions.
Transverse Divisions (1) The archicerebellum is composed of a
Anteroor lobe
Paleocerebellum
Middle (postenor) lobe

\l(eocerebellum
Flocculo·nodular lobe
Flocculus Archicerebellum
ChorOid plexus
01 IVth ventricle
Figure 20-1. Major transverse and longitudinal subdivisions of the cerebellum. The sUrface has been unfolded
and laid out flat. (From NobRCk, c.R. et al: 1991. The Human Nervous System. 4th edition, Philtuklphia. Lea
& Femger p. 282.
20-2 CHAPTER 20
flocculus and nodulus and is related primarily tural pattern, consisting of an outer molecular
to the vestibular nerve and vestibular nuclei. layer, a Purkinje cell layer and an inner granule
Reflecting this anatomical relation, the cell layer with an underlying medullary layer of
archicerebellum has a role in control of equi- white matter. The arrangement of cells and the
librium (balance), axial posture, and eye move- basic synaptic connections are indicated in
ment. Figure 20-2. The arrangement of cells and the
(2) The paleocerebellum, or anterior lobe, basic synaptic connections are indicated in
relates primarily to the spinocerebellar system Figure 20-3. Afferent fibers enter the cerebel-
and to its analogue for the upper extremities, lar cortex as mossy fibers. These fibers are so
the cuneocerebellar pathway (the lateral named because each terminates in a series of
cuneate nucleus is the analogue of the dorsal moss-like glomeruli, where axodendritic synap-
nucleus of Clarke). Its major function, howev- tic contacts are made with granule cells. The
er, appears more related to the lower extremi- mossy fibers have already been encountered as
ties than to the upper extremities. The primary spinocerebellar, cuneocerebellar, corticoponto-
fissure separates the anterior lobe from the cerebellar, vestibulocerebellar, or reticulocere-
middle posterior lobe. bellar pathways.
(3) The middle, or posterior, lobe, the neo- The granule-cell axon is sent into the mol-
cerebellum, relates primarily to the neocortex. ecular layer where it divides into two long
The function of the neocerebellum is primarily branches. These branches travel parallel to the
the coordination of discrete movements of the long axis of the cerebellar folium and are des-
upper and lower extremities (see Table 20-2) ignated as parallel fibers. These fibers make
Transverse Divisions of the Cerebellum excitatory synaptic contact with the extensive
CYTOARCIllTECfURE OF THE dendritic arborizations ofPurkinje cells, as well
CEREBELLUM as with stellate cells, Golgi cells, and basket
In contrast to the cerebral cortex, all areas cells. The basket cells inhibit the Purkinje cells
of the cerebellar cortex are relatively thin and via axosomatic synapses as these projections are
have the same basic three-layered cytoarchitec- inhibitory in nature The outflow of the
Purkinje cells is inhibitory in nature The tar-
TABLE 20-2 TRANSVERSE DIVISIONS OF THE
CEREBELLUM Molecular Layer Pf (+)
(+)
Archicerebellum Paleocerebellum Neocerebellum Purkinje Cell Layer Purk C
(Floccular Anterior Lobe (Middle, or Granule Cell layer Gran C ~
nodular lobe) ~osterior, lobe) (-) '\
CONNECTIONS: CONNECTIONS: CONNECTIONS: Deep WhHe Matter (+) Goigi C
Vesllbular Spinocerebellar & Neocortex
Cuneocerebellar & MI (-)
spino-olivary Deep Cerebellar Nuclei
(Inferior olive) Deep Cerebellar
(+) Nucleus neuron
ROLE: ROLE: ROLE: Brain Stem
Axial equilibrium Equilibrium Limb coordlnaHon Afferent fibers Efferent libersl
(Trunk primarily) Posture Muscle in phasic posture (+)
Posture, Muscle tone In lower movements
Inferior
Olivary
tone, Vesllbular extremities (upper and lower Nucleus
reflexes, Eye Coordinated extremities)
movements movements lower Possible role in Figure 20-2. The most signifoant cells, connections,
extremities ego higher executive the IIfferent lind effirent fibers in the cerebellllr c0r-
heel to shin functions and tex. • Arrows shuw direction of IIJIXJMl conduction.
emoHon (+) =ex&itlltory ;(-) =inhibitory. C.f= climbingfibers;
PI =ptlrllllel fiber; mf=mossyfiber· Reftr to text.
MOTOR SYSTEM III: CEREBELLUM AND MOVEMENT 20-3
get of the axons of the Purkinje cells is the cuneocerebellar
neurons of the deep cerebellar nuclei. The 2. Crossed olivocerebellar
axons of the neurons in these deep cerebellar 3. Uncrossed reticulocerebellar (from later-
nuclei are the major outflow from the cerebel- al reticular and paramedian nuclei)
lum to the brain stem and thalamus. B. Via the juxta-restiform body
Several additional systems must be consid- 1. Uncrossed from vestibular nuclei are
ered. The climbing fibers are excitatory to the predominantly to the floccular nodular lobe,
Purkinje-cell dendrites. These fibers originate the archicerebellum, and the midline vermis.
in the contralateral inferior olivary nuclei and 2. Uncrossed from vestibular nerve (note
represent a long-term latency pathway from that some fibers from the vestibular nerve
the spinal cord or cerebral cortex to the cere- bypass the vestibular nuclei and enter the cere-
bellum (olivocerebellar). These fibers are so bellum directly)
named because they climb and wrap around C. Via the middle cerebellar peduncle
the dendrites and body of the Purkinje-cell (brachium pontis):
neurons, making several hundred synaptic con- 1. The corticopontocerebellar input (via
tacts. Stimulation of a single climbing fiber the pontine nuclei) is primarily to the neocere-
results in large postsynaptic potentials and in bellum of the lateral hemisphere.This is crossed
large high-frequency bursts of discharges. from the opposite cerebral hemisphere.
The parallel fibers also have excitatory D. Via the superior cerebellar peduncle
synapses in the molecular layer, but they (brachium conjunctivum):
synapse with the dendrites of the Golgi cells. 1. Crossed ventral spinocerebellar is pri-
The Golgi cell, in turn, is inhibitory to the marily to the anterior lobe (paleocerebellum)
granule cell with a synapse within areas of the and the intermediate area of the paraflocculus.
molecular layer referred to as glomeruli. The 2. Tectal cerebellar
parallel fibers also excite other interneurons The superior cerebellar peduncle, then,
(small stellate cells) in the molecular layer, serves only a minor role as afferent to the
which, in turn, are inhibitory to the dendrites cerebellum. Its major role is as the efferent
of Purkinje cells. pathway.
GABA (gamma aminobutyric acid) is the EFFERENTS
inhibitory transmitter for the Purkinje, basket, A. Superior Cerebellar Peduncle (Brachium
stellate, and Golgi cells. Since the outflow from Conjunctivum ).
the cerebellar cortex occurs via the axons of 1. Dentate nuclei and interpositus (globus
Purkinje cells and since this outflow is inhibito- and emboliform) nuclei, there is a major pro-
ry to the deep cerebellar nuclei, it is logical to jection via the crossed brachium conjunctivum
ask what excitatory influences drive the neu- (superior cerebellar peduncle) to the ventral
rons of these deep nuclei. The answer is that lateral (and ventral anterior) nucleus of the
collaterals of the mossy fibers and climbing thalamus and to the red nucleus (denta-
fibers serve this function.l torubral-thalamic pathway).
AFFERENTS 2. Descending division of the brachium
The inputs to the cerebellum may be sum- conjunctivum conveys impulses to the parame-
marized as follow: dian reticular nuclei.
A. Via the inferior cerebellar peduncle (res- B. Inferior Cerebellar Peduncle.
tiform body): 1. The archicerebellum projects directly
1. Uncrossed dorsal spinocerebellar and from the floccular nodular lobe and via the
fastigial nuclei to the vestibular (lateral vestibu-
1However, the mossy fibers from the pontine and lar nucleus) and reticular areas of the brain
brain stem reticular nuclei apparently do not serve stem.
this collateral excitatory function.
20-4 CHAPTER 20
2. The fastigioreticular and fastigiovestibu- We have already discussed the functional

lar pathways hook around the superior cerebel- relation of the longitudinal and transverse sub-
lar peduncle as the uncinate fasciculus. In addi- divisions of the cerebellum. It is evident that
tion, impulses are also conveyed via the these two classifications overlap from a func-
juxtarestiform body. tional correlation standpoint.
C. Middle Cerebellar Peduncle. This con- From a functional standpoint, we may spec-
tains only afferent connections from the cere- ifY the following correlations:
brum via the pons into the neocerebellum. 1. Vestibular Reflexes and Eye
TOPOGRAPlllC PATTERNS OF Movement
REPRESENTATION IN CEREBELLAR a. Anatomic Correlation: Floccular nodular
CORTEX lobe
Stimulation of tactile receptors or of pro- b. Major Input: Vestibular labyrinth (semi-
prioceptors results in an evoked response in the circular canals and otolith organs)
cerebellar cortex. There is a topographic pat-
tern of representation. Visual and auditory
stimuli evoke responses primarily in the midline
vermis. Stimulation of the specific areas of the
cerebral cortex also evokes responses from the
cerebellar cortex in an appropriate topographic
manner. Moreover, direct stimulation of the
cerebellar cortex in the decerebrate animal will
produce, in a topographic manner, movement
or changes in tone of flexors or extensors. The
general pattern of representation is consistent
with the patterns of sensory and cortical repre-
sentation previously noted.
A possible pattern of somatotrophic repre-
sentation in the primate cerebellum is shown in
Figure 20-3. It is important to recall that there
is no conscious perception of stimuli arriving at
the cerebellar level.
Vestibular stimulation evokes responses not
only in the floccular nodular regions but also in
the superior and inferior midline vermis.
FUNCTIONS OF THE CEREBELLUM
AND CORRELATIONS
The cerebellum acts as a servomechanism,
that is, as a feedback loop that dampens move-
ments and motor power to prevent overshoot Figure 20-3: Topographic localization in cerebellum.
and oscillation (that is, tremor). In short, it A, Summary ofprojections from the sensory area and
acts to maintain stability of movement and pos- the motor area in the monkey; B, Summary ofcortico-
cerebellar projections in the monkey. Note that there is
ture. More recently, a role in higher motor a unilateral representation on the dorsal surface and
function, such as the initiation of planning, the a representation within each paramedian lobule on the
timing of movement, and motor learning, has ventral surface. At the lateral margin the division
been suggested for the cerebellum. between crus I and crus II is essentially the border
REGIONAL FUNCTIONAL between the dorsal and ventral surface. See Figure 20-
l.for terminology in human cerebellum. From Snider.
CORRELATIONS RS.: 1950. Arch.Neurol.Psych. 64:204 (AMA).
c. Major Deep Nucleus: Vestibular nuclei ventral lateral nucleus of thalamus and from the
(lateral) thalamus to primary motor area and area 6 of
d. Major Connections: Medial descending supplementary motor cortex (origins of the
systems, vestibulospinal and mediallongitudi- crossed lateral corticospinal system)
nal fasciculus and extraocular motor nuclei 3A. Speech
2. Posture and Equilibrium of the a. Anatomic Correlation: Superior paraver-
Trunk mal area (more often left than right). Damage
A a. Anatomic Correlation: Floccular produces cerebellar dysarthria which affects
nodular lobe (vestibulocerebellum) prosody, harmony, and rhythm of speech
b. Major Input: Vestibular labyrinth as rather than sequential or semantic aspects (see
above Amarenco et al, 1991; Lechtenberg and
c. Major Deep Nucleus: Vestibular nuclei Gilman, 1978 for additional discussion).
(lateral) 4. Initiation, Planning and Timing of
d. Major Connection: Medial descending Movement
systems - vestibulospinal systems (medial and a. Anatomic Correlation: Lateral cerebellar
lateral) hemisphere (cerebrocerebellum)
B. a. Anatomic Correlation: Midline vermis b. Major Input: Motor and premotor cere-
(spinocerebellum ) bral cortex (areas 4 and 6) and parietal cortex
b. Major Inputs: (areas 1, 2, 3, 5) to pontine nuclei to lateral
1. Vestibular labyrinth neocerebellum (after decussation) via the mid-
2. Dorsal spinocerebellar and cuneocere- dle cerebellar peduncle
bellar from body and proximal limbs c. Deep Nucleus: dentate
3. Trigeminal d. Major Connection: VIa decussation of
4. VIsual and auditory superior cerebellar peduncle to
c. Major Deep Nucleus: Fastigial 1. Red nucleus (parvocellular) with subse-
d. Major Connections: Medial descending quent rubro-olivary fibers
motor systems: 2. Ventral lateral nucleus of thalamus, then
1. VIa juxtarestiform body and central projecting to motor and premotor cerebral
tegmental system to pontine and cortex. From these areas, as already discussed,
medullary reticular nuclei (origin of medial and originate the lateral descending systems lateral
lateral reticulospinal tracts) and to vestibular corticospinal and corticorubrospinal and later-
nuclei (origin of vestibulospinal tracts). al reticulospinal and the anterior corticospinal
2. Via superior cerebellar peduncle (decus- systems.
sated) to ventral nucleus of thalamus to motor
EFFECTS OF DISEASE ON THE
cortex to anterior corticospinal tract
CEREBELLUM
3. Distal Motor Control and Speech/
Voice Control The cerebellum, may be viewed as a
a. Anatomic Correlation: Intermediate machine processing information from many
lobe (paravermal or paramedian zone-spin- sources (sensory receptors, vestibular nuclei,
ocerebellum ) reticular formation, and cerebral cortex) and
b. Major Input: Dorsal spinocerebellar and then acting to smooth out the resultant move-
cuneocerebellar ments or postures. Sudden displacements or
c. Major Deep Nuclei: Interpositus (glo- lurches are prevented. The large number of
bose and emboliform) inhibitory feedback circuits in the cerebellum
d. Major Connections: Lateral descending (the major influence of Purkinje cells on deep
motor system, superior cerebellar peduncle via cerebellar nuclei being inhibitory) qualifies the
cerebellum for this role. Lesions may then
decussation to magnocellular sector of the red
nucleus (origin of rubrospinal system) and to result in undamped oscillation. As a result,
20-6 CHAPTER 20
tremor perpendicular to the line of movement MAJOR SYNDROMES:

may occur, called intention or action tremor. While we will discuss three anatomically
Lesions may also impair the ability to respond distinct syndromes of cerebellar disease (the
to sudden displacements, resulting in instabili- floccular nodular lobe, the anterior lobe, and
ty of posture and gait (ataxia). Release offunc- the lateral hemisphere) it should be pointed
tion of ventral lateral nucleus of thalamus may out that these strict anatomic borders do not
also occur. confine many diseases that affect the cerebel-
The cerebellum is not designed for the lum. Moreover, the cerebellum is positioned
direct, fast-conduction control of movements. in a relatively tight compartment with bony
Thus, it is not surprising that, in the monkey, walls and a relatively rigid tentorium cere belli
total ablation may produce little effect, above. An expanding lesion in the posterior
although some deficit in contact placing may fossa, then, may produce a generalized com-
be evident. In humans, extensive destruction pression of the cerebellum. In such clinical sit-
of cerebellum may be present with little obvi- uations, it may be possible to differentiate only
ous deficit. Moreover, cerebellar symptoms, if between midline (vermal) involvement and lat-
present in a "static" disease process (such as eral (cerebellar hemisphere) involvement.
cerebrovascular accidents), often disappear Midline lesions produce disorders of equilibri-
with time. However, more specific tests may um and axial ataxia; lateral and lateralized para-
still reveal a minor deficit in speed and coordi- median lesions produce appendicular ataxia
nation. and tremor.
More recent studies suggest a role for the SYNDROME OF THE FWCCULAR
cerebellum in classical conditioning and in NODULAR LOBE AND OTHER
motor learning particularly as regards the MIDLINE CEREBELLAR TUMORS
memory aspect for the timing of movements
The major findings in the human, monkey,
(Raymond et al, 1996). In addition, a role of
cat and dog are a loss of equilibrium and an
the cerebellum in higher order cognitive and
ataxia (unsteadiness) of trunk, gait, and station.
emotional functions has been suggested by the
Thus, the patient, when standing on a narrow
studies of Schmahmann&Sherman, 1998,
base with eyes open, has a tendency to fall for-
Levinsohn et al, 2000,Riva&Giogi, 2000.In
ward, backward, or to one side. The patient
patients with lesions of the posterior lobe and
may be unable to sit or stand. The patient
vermis, there was an impairment of executive
walks on a broad base, often reeling from side
functions such as planning, set shifting, verbal
to side, and often falling. Despite the loss of
fluency, abstract reasoning, working memory
equilibrium, the patient usually does not com-
as well as visual spatial organization and mem-
plain of a rotational vertigo. When recumbent
ory. Higher language disturbances also
in bed, the patient often fails to show any atax-
occurred. In addition these patients had a per-
ia or tremor of limbs. Thus, the finger-to-nose
sonality change characterized by blunting of
and heel-to-shin tests are performed without
affect or disinhibition and inappropriate behav-
difficulty. With unilateral disease of the floccu-
ior. This cognitive and affective syndrome sug-
lar nodular lobe, a head tilt may be present. In
gested a disruption of the modulatory effects
addition, spontaneous horizontal nystagmus
of cerebellum on the prefrontal, posterior pari-
may be present as a transitory phenomenon.
etal and limbic circuits discussed in Chapter 18.
In humans, the most common cause of this
These changes did not occur with lesions of the
syndrome is neoplastic. The type of neoplasm
anterior lobe. The effects on cognitive and
depends on the age of the patient. The most
emotional function in patients with prenatal
likely cause in an infant or child2 is a medul-
cerebellar hypoplasia may be even more serious
loblastoma, a tumor arising in nests of external
and may include autism (Courchesne, et al,
granular cells in the nodulus forming the roof
1994,Allin et, al2001)
of the 4th ventricle. In older children and
young adults, the ependymoma, a tumor aris- confirmed the presence of a medulloblastoma
ing from ependymal cells in the floor of the with many malignant cells present in the cere-
fuurth ventricle, may cause this syndrome by brospinal fluid obtained at surgery. Radiation
pressing upward against the nodulus. In adults therapy to the entire central nervous axis was
it is more appropriate to speak. of midline begun one week after surgery. There was initial
tumors of the vermis since the tumors do not improvement but the patient deteriorated
selectively involve the floccular nodular region. three months after the surgery and expired one
In middle-aged adults, the most common month later despite chemotherapy .The find-
cause is probably the midline hemangioblas- ings at autopsy are demonstrated in Fig. 20-4.
toma. In older adults, metastatic tumors may At present, recommended therapy includes
produce this syndrome. At all ages, rare arteri- wide resection followed by radiotherapy to the
ovenous malformations may produce the syn- entire CNS axis. Dissemination of tumor cells
drome} throughout the cerebrospinal fluid is frequent,
The course of a medulloblastoma is indicat- because of the friable, cellular, non-stromal
ed in the following case history: nature of the lesion. At present, 5-year sur-
Case 20-1: This 27-month old white vival has been increased to 60%. Recurrences
female had been unsteady in gait, with poor may be treated with chemotherapy although
balance, falling frequently since the age of 13 the combination of radiotherapy and
months, when she began to walle Three chemotherapy may produce significant patho-
months prior to admission, in relation to a viral logic alterations in white matter. Refer to
infection manifested by fever and diarrhea, the Chapter 13 and 27 for additional discussion.
patient developed increasing anorexia and Mid line cerebellar tumor in the adult:
lethargy. One-month prior to admission, vom- the following case 20-2 presents an example of
iting increased, and the patient also became a midline cerebellar tumor metastatic from
more irritable. Perinatal history had been nor- breast with primary symptoms of gait ataxia,
mal, and head circumference had remained headache, vertigo and vomiting.
normal. Case 20-2: This 67-year-old white female
Neurologic examination: Mental Status: 6 weeks prior to admission developed intermit-
The child was irritable but cooperative. tent vertigo and then two weeks prior to
Cranial Nerves: The fundi could not be visual- admission a progressive ataxia of gait followed
ized. Bobbing of the head was present in the by headaches and vomiting. Past history: This
sitting position. Motor System: A significant patient had a poorly differentiated highly
ataxia of the trunk was present when sitting or malignant infiltrating ductal adenocarcinoma
standing. Gait was broad-based and ataxic, of the left breast for which she had undergone
requiring assistance. No ataxia or tremor of lumpectomy 6 years; and a radical mastectomy
the extremities was present. fullowed by radiation therapy, 3 years prior to
Clinical diagnosis: Probable midline cere- admission.
bellar tumor, most likely based on age a medul-
2 Medulloblastomas may occasionally occur in
loblastoma
adolescents and young adults.
Laboratory Data: Air-contrast ventriculo-
gram demonstrated the fourth ventricle was 3 Progressive multiple sclerosis may produce in
deformed by a mass arising from the nodulus the young or middle-aged adult severe involve-
of the cerebellum. There was secondary ment of white matter in the cerebellum and
enlargement of the lateral and third ventricles brain stem, resulting in severe truncal ataxia,
and marked forward displacement of the cere- in which the patient is ataxic in both the sitting
bral aqueduct. and standing positions. Such cases almost always
Hospital Course: Doctor Peter Carney also manifest severe appendicular involvement,
performed a suboccipital craniotomy, which that is, the cerebellar syndrome is not selective.
20-8 CHAPTER 20
Neurological examination (in the emer- changes in muscle tone. Thus, stimulation of
gency room): Cranial Nerves: There was an the middle anterior lobe results in a decrease in
absence of venous pulsations on funduscopic spindle discharge and inhibits gamma rigidity
examination suggesting a mild increase in of the decerebrate preparation. Stimulation of
intracranial pressure. Motor System: She had dif- the intermediate area of the anterior lobe pro-
ficulty standing tending to fall to the right. She duces an increased spindle discharge and facili-
was unable to walk because of severe ataxia. tates gamma rigidity in the decerebrate prepa-
There was no limb dysmetria. Reflexes: The ration. Actual ablation of the anterior lobe in
right plantar response was equivocal. these animals or functional ablation (cooling)
Clinical diagnosis: Midline cerebellar produces an increase in decerebrate rigidity
tumor metastatic from breast. without a change in the gamma system (alpha
Laboratory data: CT scan demonstrated a rigidity). However, in humans, ablation of the
large (3-4 cm) enhancing tumor was present anterior lobe does not change tone. 4 The
involving the midline vermis and right parame- major symptoms are an ataxia of gait with a
dian cerebellum and compressing the fourth marked side-to-side ataxia of the lower extrem-
ventricle subsequently confirmed by MRI scans ities as tested in the heel-to-shin test. The
of the brain (Fig.20-S). CT scan of abdomen upper extremities, in contrast, are affected to
demonstrated two possible metastatic lesions in only a minor degree.
the liver. This area corresponds to the representation
Subsequent course: The patient received of the lower extremities and to the area of pro-
dexamethasone with significant improvement jection of the spinocerebellar pathways.
within 12 hours. At the insistence of the Typical of this syndrome are cases of alco-
patient, Dr. Gerald McGullicuddy resected the holic cerebellar degeneration (Figure 20-6),
solitary central nervous system metastatic where a severe loss of Purkinje cells occurs in
lesion. Following surgery she received the anterior lobe. Although this degeneration
3000cGy( rads) whole brain radiation and was occurs primarily in alcoholics, the basic etiolo-
begun on the antitumor agent tamoxifen. She gy may be a nutritional deficiency (the specific
expired at home, four months after surgery of factor is most likely thiamine).
systemic complications of the malignancy. The major findings of a broad-based, stag-
SYNDROME OF THE gering gait with truncal ataxia and heel-to-shin
ANTERIOR LOBE: ataxia can be related to the anterior lobe of the
Stimulation or ablation of the anterior lobe cerebellum. Since symptoms improve or do
in the cat or dog may produce significant not progress after the discontinuation of alco-
hol, and the administration of multiple B vita-
mins, a toxic or nutritional factor may be pos-
tulated. (The reliability of the history of alco-
hol intake is always open to question. The
amount stated by the patient is usually assumed
to be the minimum amount.) Note that a sim-
ilar acute cerebellar syndrome occurs as one
aspect of the Wernicke-Korsakoff's syndrome
(refer to Chapter 30). At the present time, the
diagnosis of cerebellar atrophy may be con-
firmed by MRI (midline sagittal section) or by
Figure 20-4. Medulloblastoma: Syndrome of the floccu- CT scan. As a result, evidence of cerebellar
lar nodular lobe: Case 20-1. Vomiting and truncal atrophy is now found in many patients pre-
ataxia were present without tremor or ataxia of the senting with other aspects of chronic alco-
extremities. (Courtesy of Dr. John Hills). &for to text. holism or other nutritional disease who do not
necessarily present with initial symptoms of lowing case history, the major involvement was
ataxia. primarily of the anterior lobe. There was defi-
Case 20-3 presented on the CD-ROM nite family history, including evidence of con-
illustrates alcoholic cerebellar degeneration. sanguinity.
In other cases, this syndrome is the result of Case 20-4: A 45-year-old single white male
a chronic degenerative disease with a genetic carpenter presented with a 4-year history of
basis. As in alcoholic cerebellar degeneration, progressive unsteadiness in walking, present
the predominant histologic change is the loss during the daytime as well as at night and a
of Purkinje cells in the anterior lobe. In con- minimal loss of coordinated movements in his
trast to alcoholic cerebellar degeneration, the hands. He felt that his greatest deficit was
pathology is usually more widespread and not unsteadiness. He had some numbness at the
strictly limited to the anterior lobe. In the fol- toes and minor difficulty in swallowing. His
mother and father were second cousins.
Several aunts and uncles had "trouble with
their legs" in later life, resulting in a difficulty
in walking.
Neurologic examination: Cranial Nerves:
Intact except for minimal dysarthria.
Horizontal nystagmus was present on lateral
gaze, vertical nystagmus on upward gaze.
Motor System: The patient walked on a broad
base with an ataxia of trunk, as though intoxi-
cated, reeling from side to side, with marked
unsteadiness on turns. He was unable to walk
a tandem gait with eyes open. A mild intention
tremor was present, and there was minimal dis-
organization of alternating movements. In
contrast a marked ataxia and tremor were evi-
dent on heel-to-shin test. Reflexes: There was a
relative decrease in ankle jerks compared to
knee jerks. Sensory System: There was a minimal
decrease in vibration sensation at the toes.
Clinical diagnosis: Hereditary cerebellar
degeneration involving predominantly anterior
lobe
Laboratory Data: Pneumoencephalogram
performed at the University of Virginia
Hospital (Doctor Stewart) confirmed the sig-
nificant atrophy of cerebellum.
OTHER CAUSES OF
CEREBELLAR ATROPHY:
Prolonged high fever, meningitis, a post-
4 In general chronic lesions of cerebellum in
humans do not alter tone or tendon reflexes.
Figure 20-5. Metastatic midline cerebellar tumor: Acute lesions of cerebellum resulting from hem-
Case 2(J..2 .MRl (TI) a) sagittal section b) coronal orrhage or sU'lJery may produce transient hypo-
section. Refer to text. tonia (Diener and Dichgans, 1992).
20-10 CHAPTER 20
Mononuclear cells may be present in cere-

6A brospinal fluid. Whether this is a direct viral
infection or a post-infectious entity remains
unclear. . The major involvement is of the
trunk although tremors of the head, trunk and
limbs are also present. Recovery usually occurs
over 6 months but occasionally recovery is
incomplete.
Diener and Dichgans (1992) discuss the
localization of ataxia of standing body posture.
Their conclusions are as follows:
1. Lesions of the spinocerebellar portion of
the anterior lobe (mainly observed in chronic
alcoholics) result in body sway along the ante-
rior/posterior axis with a frequency of 3 per
second. This sway, or tremor, is provoked by
eye closure. Visual stabilization of posture
occurs. Since the direction of sway of the trunk
is opposite that of the head and legs, the cen-
ter of gravity is only minimally shifted and the
patient does not fall.
2. In contrast, the lesions of the vestibulo-
Figure 20-.6 Akoholic cerebellar degeneration: The
anterior lobe syndrome. There is a loss of Purkinje cells cerebellum (floccular nodular lobe and lower
with atrophy of the cerebellar folia with relatil'ely vermis), which are primarily mass lesions, pro-
selectil'e inl'oll'ement of the anterior lobe: A) schematic duce a postural instability of head and trunk
representation of the neuronal loss, B) Atrophy of the during sitting, standing, and walking. Postural
anterior superior l'ermis in sagittal section. From sway occurs in all directions often at a frequen-
Vutor, M., R.D.Adams, and E.L.Mancall: 1959. cy ofless than 1 per second. Visual stabilization
Arch.Neurol. 1:579, 599, 600 (AMA).
is limited; falls, therefore, are more frequent.
infectious syndrome, and repeated grand mal 3. Spinal ataxia (as in tabes dorsalis and
seizures may all be associated with the devel- combined system disease) results predominant-
opment of an ataxia that suggests major ly in lateral body sway. Visual stabilization is
involvement of the anterior superior vermis. In prominent (positive Romberg test).
some of these cases, there is found on CT or SYNDROME OF THE LATERAL
MRI more widespread atrophy. At times, as in CEREBELLAR HEMISPHERES
the case presented in Figure 20-7, other resid- (NEOCEREBELLAR OR MIDDLE-
ual neurologic findings may also be present. POSTERIORWBE SYNDROME):
The topography of cerebellar atrophy, particu- A number of disease entities may produce
larly as regards midline structures, can best be symptoms that can be related to the lateral
studied with MRI. Figure 20-8 demonstrates hemisphere. Some of these disease entities are
the findings in a patient with gait ataxia follow- mass lesions such as metastatic tumors (Fig.
ing high fever and meningitis, in which atro- 20-9) or intrinsic tumors (Figure 20-10). The
phy, although widespread, was most promi- diagnostic problem, moreover, is complicated
nent in the anterior superior vermis. by the fact that involvement of the cerebellar
When the ataxia is of acute or subacute peduncles may produce many of the same
onset in childhood, the possibility of a cerebel-
symptoms that result from direct involvement
litis must be considered. A varicella or other of the cerebellar hemisphere. The student will
viral infection often precedes this entity.
recall that the lateral medullary infarct pro- quently in civilian practice. Diener and
duces an ipsilateral intention tremor and an Dichgans (1992) provide a more detailed
impairment of alternating movements of the physiologic analysis of lateral cerebellar lesions
ipsilateral upper extremity. Occlusion of the affecting the limbs.
posterior inferior cerebellar artery may produce The major findings in lateral hemisphere
an infarct of the lateral medulla and/or of the lesions, are the following signs and symptoms
posterior inferior cerebellum as demonstrated in the ipsilateral extremities: intention tremor,
in Figure 13-12. disorganization of alternating movements
Demyelinating disease, that is multiple scle- (dysdiadochokinesia), dysmetria, ataxia, and
rosis, may involve in a specific case, both the overshoot on rebound. The intention tremor
brain stem and cerebellum in a multifocal man- may be described as a tremor perpendicular to
ner. the line of motion; often becoming more
Cases presenting relatively pure focal prominent on slower movements and as the
involvement of the lateral hemisphere are those target is approached.5 This intention tremor
patients surviving after gunshot or shrapnel may be noted in the finger-to-nose test. One
wounds. Such cases have been studied by may also demonstrate a similar tremor in the
Holmes (1939); they are not encountered fre- lower extremities as the patient attempts to
Figure 20-7: Generalized cerebellar atrophy tmJft severe in the anterior superior permis: cr scan. This 48-year-old
female following an acute febrile illness and 3 weeks of coma at age 3 years, delleloped severe ataxia ofSUlnce and
gait, with dysmetria on heel-to-shin testing, distal weakness in lower extremities and bilateral Babinski's signs.
20-12 CHAPTER 20
Figure 20-9. Lateral cerebellar syndrome. This

patient with bronchiogenic carcinoma had nysmgmus
and appendicular ataxia .He had this major tumor
in the lateral cerebellum and minor metastatic lesions
in the cerebral hemispheres. (Courtesy of Dr. John
Hills and Dr. Jose Segarra).
Figure 20-8:Cerebellar atrophy most prominent in
anterior superior vermis with predominant anterior
lobe syndrome: MRI. This 70-year-old female 23 years
previously had prolonged markedly elevated tempera-
ture related to meningitis, coma and convulsions with
a residual ataxia ofstance and gait.
raise the foot off the bed to touch the examin-
er's finger or in the heel-to-shin test. As with
the other signs of cerebellar disease, intention
tremor is usually ipsilateral to the hemisphere
involved.
At times, in addition to an intention
tremor, a sustained postural "tremor" may be
Figure 20-10. Syndrome of the lateral hemisphere:
evident, more particularly if the superior cere- hemangioblastoma ofcerebellum. This 72-year-old
bellar peduncle or its midbrain connections are male had a 2-year history of vertex headache (worse on
involved. Brief jerks at the onset of movement coughing), blurring of vision, diplopia, papilledema
(intention myoclonus) may occur when the and a lateralized ipsilateral tremor on finger-to-nose
dentate nucleus or superior cerebellar peduncle testing. (Courtesy of Doctor Jose Segarra).
is involved. repetitive movement in the lower extremities
The intention tremor represents a defect in by having the patient tap toes or heel on the
the ability to dampen oscillations and to damp- floor. Alternating movements are tested by
en overshoot. In the monkey, cerebellar having the patient slap the hand on the thigh
tremor occurs despite deafferentation (section or on the opposite hand, alternating between
of the dorsal roots), a finding consistent with the palmar and dorsal surface of the hand. In
the concept that there is a central generator of disease of the cerebellar hemisphere a marked
oscillations. (However, other theories disorganization of repetitive and alternating
reviewed by Diener and Dichgans (1992) sug- movement occurs. This is almost always ipsi-
gest the oscillations arise from dysfunction in lateral to the hemisphere involved.
long-latency transcortical reflexes.) These patients are also said to demonstrate
Having the patient slap the thigh above the dysmetria. This may be defined as a defect in
knee with the hand at particular rhythm tests the estimation of the force and rate of move-
repetitive movements. One can also test for ment necessary for an extremity to reach a tar-
get. The result in the finger-to-nose test is that hemangioblastoma of the right lateral hemi-
the patient fails to accurately touch the finger sphere with headache, latera1ized ataxia, inten-
to the nose. The finger may overshoot its goal tion tremor and dysmetria of the right upper
or fail to reach the goal. Note that in disease and lower extremities. At the present time, the
involving the older regions of cerebellum, eye diagnosis of these tumors may be readily made
movements may also be described as dysmetric. by means of MRI and CT scan (Fig. 20-11).
In addition, there is often a failure to properly Arteriograms may still be of value in defining
adjust force when pulling with the arm against the vascularity and blood supply of the tumor.
an opposing force. As this opposing force sud- Case 20-6 presented later in this chapter
denly gives way, the patient fails to apply a demonstrates a cerebellar infarct with many lat-
brake to the action of the arm and tends to eralized appendicular features. A cerebellar
have a rebound overshoot. The arm may even hemisphere hemorrhage illustrated later in the
strike the body or face. chapter also demonstrates many of these later-
Finally, patients with cerebellar hemisphere alized features.
disease are said to have a dyssynergia or distur- LESIONS OF THE CEREBELLAR
bance in the synergy of movements, that is a PEDUNCLES: ( METTLER & ORIOLI,
defect of the coordination of multiple sets of 1958; CARRERA & METTLER, 1947.)
agonists and antagonistic muscles when reach- Some patients demonstrating cerebellar
ing for an object. The result is a decomposi- symptoms and findings actually have damage
tion of movement. to the cerebellar peduncle rather than direct
Cerebellar Dysarthria may also be present involvement of the cerebellum.
and is characterized by scanning (hesitation) Lesions of the inferior cerebellar peduncle
that affects the pattern and intonation of result in an ataxia of the extremities on the side
speech. Prosody (rhythm and harmony) is of the lesion, with falling toward the side of the
affected rather than word sequence. At times, lesion and nystagmus.
a tremor of speech is also apparent. Dysarthria Lesions of the superior cerebellar peduncle,
may occur in cerebellar atrophy or in focal the brachium conjunctivum, produce a unilat-
processes involving the hemisphere or the eral ataxia of the limbs, with intention tremor
superior vermis. The crucial area of involve- and hypotonia. The symptoms are essentially
ment is the superior paravermal area, as dis- those of hemisphere lesions. The clinical symp-
cussed by Amarenco et ai, 1991 and tomatology is ipsilateral if the lesion occurs
Lechtenberg and Gilman, 1978. Theleft hemi- between the dentate nucleus and the decussa-
sphere is more often involved than the right. tion of the brachium conjunctivum. If the
The patient with disease of the cerebellar lesion is above this decussation, the tremor is
hemisphere also has a disturbance of gait. This usually contralateral and often is more than a
tends to be an ipsilateral disturbance of gait, pure intention tremor. These are components
with a tendency to fall toward the side of the of a sustained postural type of tremor. At
lesion. As discussed above, in lesions of the times, with involvement of this area within the
hemisphere, balance is often well maintained, midbrain, a resting tremor results as well, as
in contrast to lesions of the floccular nodular discussed in relation to the basal ganglia. It is
lobe, where a disturbance of gait and of sitting not unusual to have the tremor evolve from an
balance also occurs. The following case histo- initial relatively pure intention tremor to a later
ry 20-5 presented on CD ROM illustrates a resting tremor. At times, a minor degree of
hemichorea is also present. This is not remark-
5 Diener and Dichgans (1992) suggest that the able when one considers that these areas of the
terms kinetic, goal-directed or terminal better midbrain, the subthalamus and the ventrolater-
describe the actual tremor. Deftct in movement al nucleus of thalamus are close together and all
termination is thus referred to as dysmetria. supplied by penetrating branches of the poste-
20-14 CHAPTER 20
rior cerebral artery. Intention myoclonus may

also occur at the onset of movement and may
merge with hemichorea.
The effects of isolated lesions of the middle
cerebellar peduncles are not certain. There is
some evidence that an incoordination of fine
limb movements and an ataxia of gait may
result. In experimental lesions, circling may
result.
VASCULAR SYNDROMES OF
THE CEREBELLUM
The development of CT and MRI scan has
resulted in an increased recognition of infarcts,
hemorrhages, and arteriovenous malforma-
tions involving the cerebellum. Many have
been clinically silent or previously attributed to Figure 20-11. Hemangioblastoma of superficial
brain stem or labyrinthine pathology. We have superior and posterior right cerebellar hemisphere.
already considered the blood supply of the cr scan indicated a densely enhancing mass
cerebellum in Chapter 13, which covers vascu- (arrow) with considerable surrounding edema and
lar syndromes of the brain stem. Essentially, cyst formation extending into the opposite cerebellar
three circumferential arteries of the vertebral hemisphere and hydrocephalus. This 60-year-old
white female had a several month history of increas-
basilar circulation supply the several surfaces of ing headaches, exacerbated by straining at stoo~
the cerebellum, the arteries being named for laughing or any head movement, a sense of dizziness,
the surface they supply: a sense of instability in walking and a normal neu-
1. The posterior inferior cerebellar artery rologic examination. Angiogram demonstrated a
(PICA), usually originating from the vertebral vascular mass supplied by the posterior inferior cere-
artery: an initial medial branch of this vessel bellar and superior cerebellar arteries, as well as
meningeal branches. Dr Bernard Stone removed the
supplies the lateral tegmental area of the
tumor with relief of symptoms.
medulla, and the medial and lateral branches
supply the cerebellum. occur. On the other hand, embolic occlusion
2. The anterior inferior cerebellar artery is frequently implicated in cerebellar vascular
(AlCA), originating from the lower third basi- syndromes.
lar artery: the initial branches of this vessel sup- SYNDROMES OF OCCLUSION
ply the lateral tegmental area of the lower pons. AND INFARCTION:
3. The superior cerebellar artery, originat-
This topic has been well reviewed by
ing from the rostral basilar artery: proximal Amarenco (1991), in an article that summa-
branches supply the lateral tegmental area of
rizes the detailed studies of his group
the rostral pons and caudal mesencephalon.
(Amarenco et al, 1989; Amarenco et al, 1991;
All three vessels have extensive lep-
Amarenco&Hauw, 1990a and 1990b). The
tomeningeal anastomoses over the surface of
discussion presented here is in large part based
the cerebellum that are similar to the lep-
on their studies. Refer also to the detailed
tomeningeal anastomoses of the arteries sup- reviews of Chaves et.al., 1994 and Kase et al,
plying the cortical surface of the cerebral hemi-
1993.
spheres. As a consequence, vertebral artery
Although autopsy series localized only
occlusion may result in a lateral medullary
between 1.5 and 4.2% of all infarcts to the cere-
infarct and syndrome but infarction of cerebel-
bellum, in a CT scan series (Shenkin and
lum may be absent or limited. As in the cere- Zavala, 1982) cerebellar infarcts accounted for
bral hemispheres border zone infarctions may
15% of all intracranial infarcts. Cerebellar event. The superior cerebellar artery territory
infurcts account fur 85% of all cerebellar strokes or the posterior inferior cerebellar artery terri-
and hemorrhages for 15%; therefore, our tory are most frequently involved. In our own
emphasis will be on infurcts. experience, the symptomatic cerebellar infurct
The symptoms of infurcts and hemorrhages is often in the territory of the posterior inferior
may be similar, particularly if the infurct is large cerebellar artery (see case history below and
and associated with considerable edema. The Caplan, 1986,and Chaves et. al., 1996). The
large infurct may have what is referred to as a anterior inferior cerebellar artery is rarely
Itpseudotumor lt presentation. Essentially, the involved in isolation; the posterior inferior
patient has the acute onset of headaches (usu- cerebellar territory is often also infurcted. One
ally localized to the occipital or cervical occipi- third of patients with superior cerebellar artery
tal area), severe vertigo, nausea, vomiting and infurcts, also have infurcts within the territory
ataxia of gait (often so severe that the patient is of the posterior inferior cerebellar artery sug-
unwilling or unable to sit or stand). On exam- gesting a possible embolus from the vertebral
ination, nystagmus and ipsilateral dysmetria on artery to the more distal basilar artery branch-
finger-to-nose and heel-to-shin tests will be es. Although some patients with infurcts in the
present. Cerebellar type dysarthria is frequent distribution of the posterior inferior cerebellar
(particularly when the superior cerebellar artery will also infarct the associated brain stem
artery is involved). Coma at the onset or territory and present a lateral medullary infurct
shortly after onset usually indicates severe syndrome as in case 13-2, the majority have
edema with probable compromise of the isolated cerebellar infurcts. In contrast most
fuurth ventricle and/or aqueduct of Sylvius or patients with cerebellar infurcts of the anterior
brain stem. Evolving extraocular palsies are cerebellar artery territory also have infarcts of
also usually indicative of compromise of the the caudal lateral tegmental pontine territory.
brain stem. MRI scan or CT scan allows the Most patients with cerebellar infarcts of the ter-
following: ritory of the superior cerebellar artery have
a. distinction between infarct and associated infarcts in the brainstem territory of
hemorrhage the rostral basilar artery. It is therefure easy to
b. determination of whether hydrocephalus see that prior to the era ofCT/MRI, the clin-
is present ical features of the associated brain stem infarc-
c. determination of the vascular territory of tion (that included involvement of the cerebel-
the cerebellum and brain stem involved. lar peduncles) dominated the picture and
Patients presenting in coma or evolving obscured the infarct of the cerebellum. More
into coma due to hydrocephalus and/or brain limited infarcts of parts of the superior cerebel-
stem compression require immediate shunting lar (lateral and medial) and posterior inferior
to reduce the hydrocephalus and sometimes cerebellar artery (dorsomedial and lateral) or of
require evacuation of the hemorrhage or the cerebellar border zones are discussed in the
infurct (Shenkin and Zavala, 1982; Heros, various papers of Amarenco. The etiology for
1982). most infurcts involving the superior cerebellar
This acute presentation has long been rec- artery is embolism of cardiac source. Posterior
ognized, although occasional patients are still inferior cerebellar artery infarcts are either
initially misdiagnosed as suffering from acute embolic of cardiac source or due to atheroscle-
labyrinthine vertigo, as in the example present- rotic occlusion of the vertebral (or less often)
ed below. The majority (80 to 90%) of cere- the posterior inferior cerebellar artery.
bellar infurcts have a more benign course not The following case history presents a typi-
requiring surgical therapy. Many are recog- cal example of posterior inferior cerebellar
nized only in retrospect when a CT scan or artery infarct, the territory most frequently
MRI is obtained to analyze another CNS affected selectively.
20-16 CHAPTER 20
Case 20-6: This 64-year-old right-handed somewhat vague with some difficulty in mem-
married white male postmaster, on the morn- ory during the subsequent 8-day hospital
ing prior to admission, awoke at 3:00 a.m. with course and remained ataxic. He had three
severe posterior headache and severe vertigo, weeks of intensive rehabilitation with continu-
which was exacerbated by any head movement ous subsequent improvement. Evaluation 6
,nausea, projectile vomiting and slurred speech. months after onset of symptoms demonstrated
Shortly afterwards, he noted left facial pares- only a slight slowness of alternating move-
thesias, clumsiness of the left upper extremity, ments of the left hand.
and diplopia. Two weeks previously, the patient A final note should be made regarding the
had been seen for a transient episode of diffi- considerable ability of the human nervous sys-
culty controlling the right arm, a hissing sensa- tem to recover from extensive cerebellar
tion, and impairment of speech Past historywas lesions. Considerable recovery is possible
significant for hypertension, coronary artery because the cerebellum does not have a direct
bypass surgery, and six years previously line role in the control of motor activity but
episodes of. transient weakness and numbness instead, acts as a modulator of the motor con-
of the right arm with transient aphasia for trol and motor planning circuits.
which he had been placed on long term anti- Causes of Hemorrhage into
coagulation. At that time he had normal aortic the Cerebellum.
arch and carotid angiographic studies but EEG 1. Hypertensive Hemorrhage Into the
had demonstrated focal left frontal/temporal Cerebellum. The cerebellum is the site of
slow wave activity hypertensive hemorrhage in 8 to 10% of all
Neurologic examination: Cranial Nerves: cases. In the era before CT scan and MRI,
Conjugate lateral gaze to the left was impaired. only large hemorrhages or fatal hemorrhages
Motor System: Lateralized cerebellar findings were recognized (see Figure 20-13a). Smaller
were present with marked dysmetria of left lesions were not well localized. These are now
upper extremity on finger-to-nose testing and clearly seen (Fig.20-13b). Either the hemi-
impairment of alternating hand movements. In sphere (the hemorrhage often originates in the
attempting to stand, the patient was markedly region of dentate nucleus) or vermis may be
ataxic. Reflexes: Deep tendon stretch reflexes involved (Kase and Caplan, 1986).
were decreased in both lower extremities. 2. Arteriovenous Malformations. The cere-
Plantar response was extensor on the right and bellum is also the site of various types
flexor on the left. Before the era of CT and MRI, the precise
Clinical diagnosis: The acute onset of diagnosis was often not established. Small
headache, vertigo, vomiting, ataxia of gait, and hemorrhages might have only nonspecific
dysmetria of the left arm were consistent with symptoms of headache and dizziness, as in case
a left cerebellar hemisphere infarct or hemor- 20-7, and Fig. 20-14 presented on CD-ROM.
rhage with possible minor involvement of
SPINOCEREBELLAR
brainstem secondary to mass effect.
DEGENERATIONS
Laboratory data: CT scan demonstrated a
In addition to those nutritional and sys-
large left cerebellar infarct pressing the fourth
temic processes that involve primarily the cere-
ventricle to the right. Magnetic resonance
bellar cortex, other diseases, usually genetic,
angiography demonstrated occlusion of the left
involve the cerebellum as part of a degenera-
vertebral artery. MRI (2months after onset of
tion .Other systems may be involved in addi-
symptoms): Infarction of the total cerebellar
tion to the cerebellum We can only briefly out-
territory of the left posterior inferior cerebellar
line this very extensive topic which has been an
artery with no actual infarct of the brain stem
area of rapid research advances.
(Fig.20-12).
In classifying these disorders ,we will follow
Subsequent course: The patient was
the approach of Wood and Harding (2000), This disorder which has a prevalence of 1-2 per
adding more recent genetic information of 100,000, maps to chromosome 9q13. The
Klockgether et al (2000) and Fujigasaki et al mutation involves the trinucleotide repeat
(2001) . GAA. The normal number of repeats is 7-22,
The first step in classification is to sepa- but in patients with Friedreich's ataxia there are
rate all of these ataxic disorders into two 100-2000 repeats. The marked multiplication
main categories. undoubtedly explains the early onset and
I. The autosomal recessive cerebellar severity of the disease. The gene product is a
ataxias are usually of early onset, « 20 years protein, frataxin. Refer to Chapter 9 for addi-
of age). tional discussion.
II. The autosomal dominant cerebellar Other rare disorders in this category
ataxias (ADCA) are usually of late onset, include the following.
(>20 years). a) cerebellar ataxia with retained deep ten-
I. Autosomal recessive disorders: The don reflexes reflexes,in which a mutation in the
most common disorder in this category is frataxin gene also occurs. The cases are less
Freidreich's ataxia which accounts for at least severe than Freidreich's ataxia, but with greater
50% of all cases of hereditary ataxia reported in cerebellar atrophy on imaging studies.
large series from the United States and Europe. b) cerebellar ataxia with hypogonadism in
which there is predominant involvement of
cerebellum and inferior olivary nuclei.
c) cerebellar ataxia with myoclonus(former-
ly called the Ramsay Hunt syndrome or
dyssynergia cerebellaris myoclonica) but now
recognized to be a heterogeneous syndrome.
Included in this category are such entities as 1)
the mitochondrial disorder ,myoclonus epilep-
Figure 20-12: Cerebellar infara in posterior inferior

cerebellar artery territory. Case 20-6. Refer to text.
MRI: A) T1 weighted sagittal seaion 10 mm to left
of midline. B) 12 weighted posterior coronal seaion.
C) 12 weighted axial seaions at level of upper medul-
la inferior olive.
20-18 CHAPTER 20
sy with ragged red fibers (MERRF) and

2)myoclonic epilepsy of Unverricht&
Lundborg (Baltic myoclonus or EPM1) .The
gene locus which maps to chromosome 21
encodes a small protein cystatin B whose role
in the neurological disease is unclear.
d) other rare disorders in which cerebellar
ataxia is associated in various combinations
with deafuess, or optic atrophy or mental retar-
dation or cataracts or retinopathy.
e) There are also a whole host of relatively
rare inherited usually autosomal recessive
metabolic disorders in which progressive cere-
bellar ataxia may be a prominent feature. One
group of disorders involves deficiencies in vita-
min E due to genetic mutations or to malab-
sorption syndromes such as cystic fibrosis.
Some of these disorders might be treatable
with administration of vitamin E.
An additional disorder carries the desig-
nation ataxia telangiectasia. This is an auto-
somal recessive disorder, with onset of a pro-
gressive cerebellar ataxia beginning in the first
1 to 2 years of life followed by the development
of choreoathetosis. One in 40,000-1000,000
live births is affected. An associated finding in
all cases, usually appearing by age 6, is the pres-
ence of telangiectasis or capillary dilatation of
severe and progressive degree, initially involv-
ing the conjunctiva but then appearing over
the face and neck. and the flexor surfaces of the Figure 20-13: A) Large midline-paramedian cerebel-
limbs (antecubital and popliteal areas). The lar hemorrhage with rupture into the ventricle. This
neuropathology primarily affects the Purkinje hypertensive (240/110) 61-year-old male had sudden
and granule cells of cerebellar cortex. These onset of headache, vomiting dizziness, ataxia ofgait
and trunk, nystagmus on left lateral gaze and minor
patients have severe medical problems related
incoordination of the left hand. (Courtesy of DrJohn
to the immune system, affecting both cellular Hills and Dr. Jose &garra.) B) Large hypertensive
and humoral immunity. The thymus remains in hemorrhage into right cerebellar hemisphere with
a fetal state. The patients have a marked sensi- hydrocephalus. CI'scan (non-enhanced). This 65-
tivity to ionizing radiation and to radiomimet- year-old white male who had hypertension, diabetes,
ic chemicals, as studied in cultured fibroblasts. congestive heart failure and alcoholism, developed
over one hour, vomiting, and a marked ataxia of
The mutation which has been linked in some
gait. Examination indicated severe ataxia ofgait,
cases to chromosome llq results in a defect in marked horizontal nystagmus on gaze to the right,
repair of DNA. The defective immune state dysmetria on right finger-to-nose and heel-to-shin
results in a susceptibility to infectious diseases. tests, plus a mild right Horner's syndrome and a mild
There is a marked increase in malignancies, dysarthria, and bilateral Babinski signs. Symptoms
particularly leukemia and lymphomas, with resolved over several weeks.
rates which are 61 to 184 times normal. More constitute 1% of the general population but do
recently, studies of the heterozygotes (who not have neurologic symptoms) have demon-
and in many of these the molecular mechanism
strated a significant increase in cancer rates, has been identified (SCA I-SCAl2)*. The
with an overall rate approximately 3.5 times gene products of the SCA genes are termed
that in the general population and breast can- ataxins and are assigned a similar number .In
cer rates in females 5 times those in the control addition 2 channelopathies causing episodic
population. Diagnostic or occupational expo- ataxias have been identified as EA 1 and 2.
sure to ionizing radiation increases the cancer Gene mechanisms:
risk of the heterozygotes compared to the con- 1) CAG trinucleotide expansion: SCA
trols (Swift et al, 1991). 1,2,3,6 ,7, and 12 all involve an expansion of
II. Autosomal dominant disorders: the CAG trinucleotide repeat as in Huntington
These disorders were a problem in classifica- disease (chromosome 4p16.3) but the chro-
tion.The names of the authors of the various mosome loci are different (SCA 1 @6p, SCA 2
papers describing the clinical features and neu- @ 12q, SCA 3 @ 14q, SCA 6@19p, SCA 7 @
ropathology of each of the groups of cases or 3P, SCA 12 @5). This expansion is translated
families were attached as labels and included into proteins with expanded polyglutamine
many of the famous neurologists of the late tracts. At the ultra structural level, these
1800s and early 1900s such as Holmes, Andre expanded proteins are found in neuronal
Thomas, Marie, Foix and Alajounine intranuclear inclusions.
(Greenfield, 1954).Holmes separated these 2) CTG trinucleotide expansion: SCA 8
disorders into spinocerebellar degeneration, is a CTG expansion on 13q, the same type of
relatively pure degeneration of the cerebellar trinucleotide expansion found in myotonic
cortex and olivopontocerebellar degeneration. dystrophy.
More recently Harding (1982), proposed a 3) Channe1opathy: In EA 1 there is a
clinical classification into three major categories point mutation in a potassium channel on
of which the first type is the most common chromosome 12. In EA 2 there is a point
ADCA I: cerebellar ataxia is accompanied mutation in a calcium channel on chromosome
at some point in evolution by supranuclear 19q.
ophthalmoplegia, optic atrophy, basal ganglia Patients with EA 1 have frequent brief
symptoms, dementia and amyotrophy. attacks lasting minutes of ataxia plus myokymia
ADCA II: in addition to the above has (a muscle rippling due to peripheral motor
retinal degeneration. nerve hyperexcitability). The patients are nor-
ADCA ill: presents a relatively pure mal between attacks. Some cases benefit from
cerebellar syndrome. acetazolamide or phenytoin. Patients with EA
ADCA IV: is a recent addition to the 2, have longer attacks lasting hours to days
classification cerebellar ataxia is combined with involving severe truncal ataxia plus vertigo and
epilepsy. vomiting. The patients respond well to aceta-
The problem with all of these classifications zolamide. However nystagmus is noted
from a clinical diagnostic standpoint was that between attacks and over the years a slowly
early in the disease, all three groups might have progressive ataxia develops. The MRI study at
predominantly cerebellar features. With the that point will confirm the cerebellar atrophy.
unraveling of the molecular genetic basis of the SCA 6 also has features of a channelopathy
diseases, the term ADCA has been replaced in that the CAG expansion occurs in a gene
by the term spinocerebellar ataxia (SCA). that encodes a voltage dependent calcium
To date, 12 different loci have been identified channel. The chromosome location19 is simi-
larto EA2.
"" As of April, 2002, the number of identified
4). Unknown: The mechanisms involved
loci has grown to 17. SCA 17 involves a CAG
in SCA 4, SCA 5, SCA 10** and SCA 11 are
trinucleotide expansion. There is an overlap with
basalganglia disorders for a binding protein. ** SCA 10 has now been associated with a
pentaneuclotide expansion.
20-20 CHAPTER 20
at the present time unknown. The chromo- TIL Later onset (50 to 60 years). Cases are
some locations are SCA 4@16q, SCA 5 @11 characterized by cerebellar deficits and periph-
centromere, SCA 10 @22q and SCA 11 @15q. eral neuropathy.
Relationship to the clinical classification: IV. Possible late onset case may have a
SCA 1, 2, 3, and 12 correspond in general to peripheral neuropathy plus Parkinsonism.
ADCA I. Whether, SCA 2 or SCA 3 is the Since the molecular basis of the disorder is
most frequent mutation depends on the series now clear, the more specific molecular diagnosis
reviewed (Giunti et al, 1998 and Klockether et should be utilized when possible: most families
alI998)* carry the SGA 3 mutation. Occasionally the
SCA 7 corresponds to ADCA II. SGA 1 or the SGA 2 mutations have been found.
SCA 5,6,8 and 11 correspond to ADCA In contrast to OPCA to be discussed below,
TIL SCA 5 however has some posterior column the cerebellar cortex and the inferior olivary
features .SCA 6 has some sensory and pyrami- nucleus are not involved. The ataxia instead
dal features and thus could be placed in the correlates with a degeneration of the afferent
ADCA I group. and efferent cerebellar systems (spinocerebellar
SCA 4 has cerebellar features plus a senso- tracts and Clarke's column dorsal nucleus) and
ry neuropathy and probably would have been the lid retraction and other extraocular features
classified as ADCA I. reflect involvement of the periaqueductal and
SCA 10** combines cerebellar ataxia with third nerve nuclear areas.
epilepsy (ADCA IV). Olivopontocerebe1lar Atrophy (OPCA):
Azorean Disease: Machado-Joseph Disease: This diagnosis once included many of the
Refer to the reviews of Rosenberg (1992) and cases subsequently described as ADCA or SCA.
Sudarsky et al (1992). When cases ofprogressive adult onset ataxia are
This autosomal dominant spinocerebellar familial, they should be assigned a diagnosis
degeneration is clustered among families who based on the genetic classification described
originated in the Portuguese Azorean Islands. above. This entity also has been considered in
This is the region of origin for many families chapter 19 on the basal ganglia and is one of
residing in Southeastern Massachusetts and the the multisystem atrophies considered in the
adjacent area of Rhode Island, and the initial general category of Parkinsonism plus syn-
cases were described in this area in 1972. dromes. In contrast to the data presented in
Subsequently, other cases have been described that chapter, Berciano(1988),when consider-
in many areas of the world reached by ing both familial and sporadic cases of OPCA.;
Portuguese seafarers, explorers, whalers, and found cerebellar symptoms (predominantly
fishermen (many of whom were recruited in gait ataxia) to be the most common initial
the Azores). The manifestations depend in symptom (73%) and the most frequent symp-
part on the age of onset. tom throughout the course of the disease (88-
I. Early onset (childhood or young adult) 97%). Parkinsonian symptoms occurred as the
cases have predominantly pyramidal and fea- initial feature in 8% but eventually in 35-57%.
tures and basal ganglia dysfunction. The neuropathology involved in all cases the
II. Intermediate age of onset (20 to 40 cerebellar cortex, the pontine nuclei and the
years) Cases have cerebellar deficits and inferior olivary nuclei with associated changes
extraocular disturbances as well as the pyrami- in the white matter of cerebellar peduncles
dal features and basal ganglia dysfunction. (particularly the middle) and of the cerebellar
white matter. The substantia nigra is involved
*A recent addition to this GAG expansiongroup in 50% of cases.
is DRPLA- (rubro pallido luysian atrophy) a Non familial cases of ADGA: Wood and
basalganglia disorder. Harding (2000)estimate that approximately
** andSGA 17 two thirds of cases of degenerative ataxia
beginning after age 20 are single cases without 2000) The paraneoplastic syndromes may
a family history, and suggest that the term idio- improve with control of the primary malignan-
pathic late onset cerebellar ataxia be utilized cy. Note, however, that the late cases have evi-
rather than the old term OPCA. The majority dence. on CT or MRI of cerebellar
of cases do demonstrate the pathological find- atrophy.
ings ofOPCA. Some will go on to develop the AN OVERVIEW OF TREMORS
autonomic features of multisystem atrophy.
Before concluding our discussion of the
Some of the patients with onset after age 55
cerebellum and basal ganglia, we will briefly
years will demonstrate a relatively pure midline
outline the various types of tremor. This is nec-
cerebellar syndrome with primarily gait ataxia
essary because many common postural tremors
related to cerebellar atrophy which is most
(physiologic and essential) are mistakenly
marked in the vermis. With tests for the mol-
attributed to more serious disease of the basal
ecular basis of the disease now available (par-
ganglia or cerebellum.
ticularly as regards the trinucletide expan-
Tremor is defined as an involuntary move-
sions ),the number of such sporadic unclassified
ment characterized by rhythmic oscillation of a
cases should be reduced. Note that families
body part (or parts) that develops when there
have become smaller, full family historical
is a synchronized discharge of many motor
information is not always available. There are
units. Many peripheral and central factors
however other entities to be considered when
enter into this synchronization. Hallett, 1998,
faced with a sporadic case.
Elble, 1998, and Hua discuss the physiology of
Alcoholic nutritional cerebellar degen-
tremor and the role of mechanical factors and
eration: refer to discussion above in relation to
central oscillators, 1998.
anterior lobe.
Tremor is best classified on the basis of the
Paraneoplastic subacute cerebellar
behavioral situation in which the tremor is
degeneration: This degeneration is associated
observed (Findley, 1988; Hallet, 1991,
particularly with cancer of the ovary , breast,
Deuschl, 1998): 1. tremor at rest 2. action
small-cell cancer of the lung and Hodgkin's
tremor. Within this second category, pos-
disease. The neurologic symptoms may pre-
tural, kinetic, or intention, and task-specific
cede the discovery of the primary malignancy
tremors are distinguished.
in the majority of these patients except in those
1. Rest Tremor: This is a tremor that
with Hodgkin's disease where the diagnosis of
occurs in a body part that is not voluntarily
the malignancy usually has already been estab-
activated and is completely supported against
lished. In general, these patients present with
gravity. This tremor particularly when a pill-
subacute onset of cerebellar symptoms affect-
rolling component is present, is almost always
ing stance, gait, limbs and voice (dysarthria).
indicative of Parkinson's disease or of related
The neuropathology involves a widespread loss
disease of the basal ganglia.
of Purkinje cells and evidence of inflammation.
2. Action tremors: This is a tremor that is
The brain stem and dorsal root ganglia and
produced by voluntary contraction of muscle.
possibly the limbic system may also show
Within this category several subtypes may be
inflammatory changes, as part of a wider
specified:
"encephalitis". Anti-Purkinje cell antibodies
a. Postural tremors: These are by far the
can be identified in many of these patients.
most common types of tremor and include:
Anti-yo antibodies which involve the Purkinje
1. Physiologic Tremor - usually fine and rapid
cell cytoplasm are found in patients with ovar-
(6 to 12 Hz), occurs when attempting to sus-
ian cancer, breast cancer or other gynecological
tain a posture. This tremor is significantly
malignancies. Patients with Hodgkin's disease
increased or "enhanced" by anxiety, excessive
who develop the cerebellar syndrome may have
caffeine intake, exercise, fatigue. It is also
antibodies to a glutamate receptor (Smitt,et al
20-22 CHAPTER 20
increased by thyrotoxicosis, hypoglycemia, tremor, Parkinsonian and cerebellar features

alcohol withdrawal and beta adrenergic drugs, are absent: thus, the patient is able to walk with
such as those used in the treatment of asthma a good swing of the arms and does not turn en
and by drugs commonly employed in psychia- bloc. No pill rolling tremor emerges as the
try, such as lithium, neuroleptic, or tricyclic patient sits at rest or walks. No ataxia of gait or
medications. Beta adrenergic blockers such as stance is present. These distinctions are of
propranolol are often effective against this importance because postural tremors (of the
tremor if specific etiologic factors cannot be outstretched hands) can also occur in patients
corrected (use in asthmatics, however, is con- with clear-cut evidence of akinetic rigid variants
traindicated). of Parkinson's disease, Wilson's disease, dysto-
2. Essential Tremor: also called familial, nia and cerebellar disease. A postural tremor
benign, or senile tremor: Aside from physio- may also occur in some forms of peripheral
logic tremor, essential tremor is the most com- neuropathy or in post traumatic syndromes.
mon tremor encountered by the physician. b. Kinetic tremors (usually approximately
Prevalence studies suggest a high frequency, 5 Hz).These are tremors occurring during any
particularly in older age groups. In the over 40 voluntary movement. Several types have been
age group, 5% of the population may be affect- specified:
ed. When familial, the genetic pattern appears 1. Tremor during ta1lJet directed movements:
to be autosomal dominant. Onset of familial intention tremor. Amplitude increases during
cases may begin in childhood, adolescence, in visually guide movements towards a target par-
mid life, or later in life. The hands are most ticularly at the termination of movement. This
commonly affected, but in some patients, the tremor usually is characteristic of cerebellar dis-
head is primarily involved (side-to-side move- ease and is described in detail above. Intention
ment). Some also have involvement of the tremor is an oscillation perpendicular to the
voice or lips. The frequency of tremor ranges line of movement. Findley (1988), distinguish-
from 4 to 12 Hz. The tremor may remain sta- es the tremor from dysmetria, defining the lat-
ble or may slowly progress. Although in some ter as "the inability to attain the target or nor-
patients the tremor is of relatively small ampli- mal performance level in a guided, goal-seek-
tude, in other patients it may become relative- ing movement. The more severe and violent
ly coarse, significantly interfering with fine kinetic tremors are seen in patients with severe
motor activities. Orthostatic tremor is a variant multiple sclerosis involving both the brain stem
in which a tremor of trunk and legs and to a and cerebellum. In these cases, the head and
lesser degree of arms occurs on prolonged trunk may have a to-and-fro, anterior-to-poste-
standing and is associated with a high frequen- rior sway, or tremor, to which the term "titu-
cy of contractions alternating between antago- bation" has been applied (Findley, 1988).
nist muscles. Cerebellar intention tremor may be decreased
The underlying pathology of essential by lesions of the contralateral ventral lateral
tremor is unknown. Functional imaging stud- thalamic nucleus as discussed in chapter 19 .
ies at rest and on action suggest an abnormal 2. Task specific kinetic tremor: Kinetic tremor
bilateral overactivity of cerebellar connections which appears or becomes exacerbated during
Infarcts (homolateral) of the cerebellum or of specific activities related to occupation or writ-
contralateral motor cortex or of ventrolateral ing. It is uncertain whether primary writing
thalamus may result in the disappearance of tremor and some of the occupational tremors
the tremor (Dupuis et al,1989). Typical of of musicians etc, represent a variant of essential
essential tremor is the temporary reduction in tremor or of dystonia as discussed by Hallet
the tremor by ingestion of alcohol. The tremor (1991)
usually responds to beta adrenergic blockers,
such as propranolol. Note that in essential
CHAPTER 21
Somatosensory Function and
The Parietal Lobe
Introduction There is in the postcentral gyrus a sequence

The parietal lobe is composed of- post cen- of sensory representation which, in general, is
tral gyrus, superior and inferior parietal lobules. similar to that noted in the precentral gyrus for
Each area will be considered in terms of cytoar- motor function (Fig. 21-1). The representa-
chitecture and functions. For the superior and tion of the face occupies the lower 40 percent;
inferior parietal lobules, the different effects of the representation of the hand, the middle-
disease processes in the dominant compared to upper 40 percent; and the representation of the
nondominant hemispheres will be considered. foot, the paracentral lobule. As in the precen-
The major sensory pathways have already been tral gyrus, certain areas of the body have a dis-
covered in chapters' 7 -spinal cord, 11- brain proportionate area of representation, ie, the
stem and 15- diencephalon. The student may thumb, fingers, lips and tongue. Those areas
wish to review that material at this time. of the skin surface that are most sensitive to
touch have not only the greatest area of corti-
POSTCENTRAL GYRUS: SOMATIC cal representation but also the greatest number
SENSORY CORTEX [PRIMARY and density of receptors projecting to the post-
SENSORY S-I] central gyrusl. The peripheral field of each of
The postcentral gyrus is not, from a histo- these receptors is also very small (compared,
logical standpoint homogeneous. Four sub- e.g. to the less sensitive skin areas of the trunk.
types may be distinguished: In addition, at the lower end of the postcentral
1) Area 3a at the base of central sulcus, and gyrus, extending into the sylvian fissure (the
2) Area 3b along the posterior wall of the cen- parietal operculum), there is found a represen-
tral sulcus (anterior surface of the gyrus) both tation of the alimentary tract, including taste.
of which are relatively typical granular konio- Gustatory hallucinations may arise from
cortex and receive the major projection from seizure foci in this area (Hausser-Hauw
the ventral posterior nuclei of the thalamus. &Bancaud, 1987). There is also a representa-
3) Area 1 on the crest of the gyrus and 4) tion of the genitalia in the paracentral lobule
Area 2 on the posterior surface of the postcen- and rare patient with seizures beginning in this
tral gyrus are modified homotypical cortex. area have reported paroxysmal sexual emotions
While some of the neurons in areas 1 and 2 including orgasm and nymphomania (Calleuja
receive direct input from the ventral posterior et al1989).
thalamic nuclei, other neurons are dependent Microelectrode techniques for recording
on collaterals from area 3. from single cells in the cerebral cortex of the
Postcentral Gyrus Stimulation: Stimulation monkey and cat have allowed a considerable
of the postcentral gyrus produces a sensation elaboration of the functional localization with-
over the contralateral side of the face, arm, in the sensory cortex. The studies of
hand, leg, or trunk described by the patient as Mountcastle (1957) indicated a vertical colum-
a tingling or numbness and labeled paresthe-
sias. Less often, a sense of movement is expe- 1We will discuss in Chapter 30 the more recent
rienced. The patient does not describe the sen- observations that indicate a considerable degree
sation as painful. These various phenomena, ofplasticity may be present in sensory cortex. The
occurring at the onset of a focal seizure, may be maps here illustrated then for an individual
described as a somatic sensory aura. human or monkey may be subject to some degree
of variability. See also Kass et al) 1983.
21-2 CHAPTER 21
labeled complex cells.

Studies of cortical potentials evoked by tac-
tile stimulation in the monkey have suggested
that there is a secondary somatic sensory pro-
jection area (S-II) in addition to the classic
postcentral contralateral projection area. This
second area has a bilateral representation and is
found partially buried in the sylvian fissure at
the lower end of the central sulcus). A similar
second area of representation has been report-
ed by Penfield & Jasper (1954) Luders et al
(1985) and Blume et al (1992) in those seizure
patients in whom an abdominal sensation
1
..
l
, (aura) was followed by a sensation of paresthe-
sias in both sides of the mouth and in both
hands (Fig. 18-11). Note also that at times
stimulation of the precentral gyrus by the neu-
rosurgeon during surgery has at times pro-
Figure. 21-1 Sensory representation as deR:rmined by duced contralateral tingling or numbness, in
stimulation studies on the human cerebral cortex at addition to the more frequent motor respons-
sU1l/ery: Note the relati1lely la1l/e area dnoted tv lips,
thumb, and fingers. (From Penfield, w., and es (Penfield and Jasper, 1954). Additional dis-
Rasmussen, T.: The Cerebral Cortex of Man. New cussion of seizures originating in parietal lobe
York, Macmillan, 1955, p.214.) will be found in Williamson et al (1992) and
Tuxhorn & Kerdar (2001).
nar organization from cortical surface to white
matter. While each column is modality specif- Postcentral Gyrus Ablation: Immediately
ic, each neuron in a particular column is acti- following complete destruction of the postcen-
vated by that specific sensory modality, e.g., tral gyrus, there will often be found an almost
touch, movement of a hair, deep pressure, joint total loss of awareness of all sensory modalities
position. Jones et al 1982, Jones and Powell, on the contralateral side of the body. Within a
1970, and Killackey and Ebner, 1973, discuss short time there is usually a return of some
the specific thalamocortical relationships. The appreciation of painful stimuli. The patient
studies ofKass and his associates (1979, 1981, will, however, often continue to note that the
1983) provide additional elaboration. Within quality of the painful stimulus differs from that
the post central gyrus - four representations of on the intact side. An awareness of gross pres-
the body and limb surfaces are present in a par- sure, touch, and temperature also returns.
allel manner - with each representation rela- Vibratory sensation may return to a certain
tively modality specific. The cells in area 3a degree. Certain modalities of sensation, how-
respond primarily to muscle stretch receptors; ever, never return or return only to a minor
area 3b to rapidly and slowly adapting skin degree. (In partial lesions of the postcentral
receptors (as in movement of a hair or skin gyrus, however, these various modalities often
indentation); area 1 to rapidly adapting skin return to a variable degree). These modalities
receptors and area 2 to deep pressures and joint are often referred to as the cortical modalities of
position. sensation or as discriminative modalities ofsen-
Within areas 1 and 2, there are additional sation. The following types of sensory aware-
neurons that do not receive direct thalamic ness usually included in this category are sum-
input. These neurons respond instead to more marized in table 21-1
complex properties of the stimulus such as the In contrast, the sensory modalities of pain)
specific direction of movement and have been gross touch) pressure, temperature) and vibration
SOMATOSENSORY FUNCTION AND THE PARIETAL LOBE 21-3
TABLE 21-1:MODALITIES OF SENSATION LOCATED IN (hand region) produce deficits in discrimina-
POSTCENTRAL GYRUS tion of texture, size and shape. Lesions in area
1 interfere with the ability to discriminate tex-
Cortical Type of Stimulus ture only; lesions in area 2 - size and shape only.
Discriminative The following case histories demonstrate the
Sensory
Modalities type of sensory phenomena found in disease
1. Position sense Ability to perceive movement and the involving the postcentral gyrus.
direction of movement when the
ftnger or toe Is moved passively at the Case 21 -1: One week prior to evaluation, this
Interphalangeal joint, the hand at the 40-year old right-handed married white male
wrist or the foot at the ankle had the onset of repeated 15-21 minute
2. Tactile Ability to accurately localize the duration episodes of focal numbness (tingling
localization: specitic point on the body or extremity or paresthesias) involving the left side of the
which has been stimulated. face, head, ear, and posterior neck and
occasionally spreading into the left hand and
3. Two-point Ability to perceive that a double
discrimination stimulus with a small separation in fingers, and rarely subsequently spreading into
space has touched a given area on the left leg. Biting or eating would trigger the
the body or Limb or hand. episodes. There was no associated pain or
headache or weakness or associated focal
4. Stereognosis Ability to distinguish the shape of an
object and thus to recognize objects motor phenomena.
based on their three-dimensional Initial neurologicalexamination: Totally
tactile form. intact as regards mental status, cranial nerves,
motor system, reflexes, and sensory system.
5. Graphesthesla Ability to recognize numbers or leiters
which have been drawn on the Clinical diagnosis: Focal seizures originat-
fingers, hand, hand face, or leg. ing lower third post central gyrus, of uncertain
etiology.
6. Weight Ability to recognize differences in Laboratory data: EEG: no focal abnor-
discrimination: weight placed on the hand or foot.
malities were present. CT Scan (Fig. 21-2);
7. Perception of Ability to perceive that both sides of The non-enhanced study was normal. The
simultaneous the body have been simultaneously enhanced study demonstrated a small enhanc-
stimuli stimulated. When bilateral stimuli are ing lesion just above the right Sylvian fissure.
presented but only a unilateral MRI (Fig.21-3):Demonstrated the more
stimulus is perceived, 'extinction'
is said to have occurred. extensive nature of this process involving the
operculum - above the right sylvian fissure
8. Perception Ability to perceive the patlem of including the lower end of the post central
of texture surface stimuli encountered by the gyrus, the area of representation of the face. A
moving taelile receptors.
probable infiltrating tumor was suggested as
the most likely diagnosis. Arteriogram -
are referred to as primary modalities of sensa-
demonstrated a tumor blush at the right sylvian
tion. Perception of these modalities continues
area, consistent with a glioblastoma, a rapidly
to occur after ablation of the postcentral gyrus
growing infiltrating tumor - originating from
although some alteration in quality of sensation
astrocytic glia.
is noted. It has been assumed that the anatom-
Subsequent Course: Treatment with an
ical substrate for such awareness must exist at
anticonvulsant reduced the frequency of the
the thalamic level.
episodes. Neurosurgical consultation suggest-
In terms of more specific localization of spe-
ed an additional observation period and peri-
cific modalities of cortical sensation, the studies
odic CT scans. Three months after onset of
of Randolph and Semmes 1974 suggest that in
symptoms, the patient developed a numbness
the monkey small lesions restricted to area 3b
21-4 CHAPTER 21
of the left arm and difficulty in coordination of

left arm. Exam now demonstrated left central
facial weakness, mild weakness of the left hand,
and in the left hand a loss of stereognosis and
graphesthesia with a relative alteration in pin-
prick perception. The CT scan showed signifi-
cant enlargement of the previous lesion. EEG
now indicated focal (2-3 Hz delta slow waves
in the right frontal central Rolandic area.
Doctor Bernard Stone performed a subtotal
resection of a glioblastoma - in the right tem-
poral parietal area. Radiation therapy was
administered following surgery, 4000 rads total
whole brain and 5210 rad total to the tumor
area. Reevaluation 3 months after surgery
indicated only rare focal seizures involving the
face. The neurological examination was nor-
mal. Repeat CT scans, however, continued to
demonstrate a large area of enhancing tumor in
the right temporal-frontal-parietal area.
Despite the use of dexamethasone and arterial
chemotherapy with cis-Platinum, he continued
to progress with the development of a left field
defect, left hemiparesis and a loss of all modal-
ities of sensation on the left side. Subsequently
he developed significant changes in memory
and cognition. CT scan demonstrated progres-
sion with extensive involvement of the right
side of the brain and spread to the left hemi-
sphere. Death occurred 33 months after onset
of symptoms. At postmortem examination of Figure. 21-2. Glioblastoma somatic sensory cortex:
focal sensory seizure with onset in left face. Case 21-
the brain, almost the entire right hemisphere
1. cr scan with contrast tkmonstrated a small focal
was replaced by necrotic infiltrating tumor. enhancing lesion in the right post-centralgyrus just
The tumor now had spread into the corpus cal- above the Sylvian fissure. Upper - reference diagram
losum and temporal and occipital lobes. The for plane of section. Lower scan 9 - the enhancing
internal capsule, thalamus, hypothalamus and lesion is marked with a white square. (See text).
basal ganglia were destroyed. oped progressive "weakness" and difficulty in
Case 21-2: This 62-year-old white, right- control of the right lower extremity. Several
handed housewife, six years prior to admission weeks later, the patient now experienced,
had undergone a left radical mastectomy for aching pain in the right index finger in addition
carcinoma of the breast. Five months prior to to a progressive deficit in the use of the right
admission, the patient developed a persistent hand. This was more a "stiffuess and incoordi-
cough, left pleuritic pain and a collection of nation" than any actual weakness. One month
fluid in the left pleural space (pleural effusion). prior to admission the patient noted episodes
She now had the onset of daily headaches in of pain in the toes of the right foot and numb-
the right orbit, occasionally awakening her ness of right foot occurred, lasting 2 to 3 days
from sleep. Four months prior to admission, at a time. She subsequently developed, difficul-
over a 3 to 4 week period, the patient devel- ty in memory and some minor language
weakness was present in the lower limb (most
marked distally). Spasticity was present at the
right elbow and knee. In walking, the right leg
was circumducted; the right arm was held in a
flexed posture. Reflexes: Deep tendon reflexes
were increased on the right. A right Babinski
response was present. Sensation: An ill-defined
alteration in pain perception was present in the
right arm and leg - more of a relative difference
in quality of the pain than any actual deficit.
Repeated stimulation of the right lower
extremity (pain or touch) produced dysesthe-
sias (painful sensation). Position sense was
markedly defective in the right fingers with
errors in perception of fine and medium ampli-
tude movement in the right toes.
Simultaneous stimulation resulted in
extinction in the right lower extremity.
Graphesthesia (identification of numbers,
e.g., 8, 5,4 drawn on cutaneous surface) was
absent in the right hand and fingers and poor
in the right leg. Tactile localization and two-
point discrimination were decreased on the
right side.
Clinical diagnosis: Metastatic tumor to
the left post central and precentral gyri with a
cortical pain syndrome (pseudo thalamic pain
syndrome).
Laboratory data: Chest x-ray: Several
metastatic nodules were present in the left
Figure.21-3. Glioblastoma, somatosensory cortex- lung. EEG: almost continuous focal 4 to 7 Hz
focal sensory left fllCial seizures. Case 21-1. (See text). slow wave activity was present in the posterior
MR1 scans demonstrating the more extensive involve- frontal central and parietal areas. Imaging
ment ofcortex and white matter: A) coronal section;
B) horizontal section.
studies were consistent with a focal metastatic
lesion in the parasagittal upper left parietal area.
deficit, suggesting a nominal aphasia, prompt- Subsequent course:: Because there was
ing hospital admission. evidence in this case that the disease had spread
Neurological examination: Mental status: to multiple organs, radiation and hormonal
slowness in naming objects was present therapy were, therefore, administered rather
although she missed only one item of 6. than any attempt at surgical removal of the left
Delayed recall was slightly reduced to 3-out-ofparietal metastatic lesion. Temporary improve-
five in 5 minutes. Cranial nerves: early ment occurred in motor function in the arm
papilledema was noted: absence of venous pul- but the patient eventually expired five months
sations, indistinctness of disc margins, and min- after admission. Autopsy performed by Dr.
imal elevation of vessels as they passed over the Humphrey lloyd of the Beverly Hospital dis-
disc margin. A right central facial weakness was closed extensive metastatic disease in the lungs,
present. Motor rystem: Mild weakness of the liver, and lymph nodes and a single necrotic
right upper limb was present. A more marked metastatic brain lesion in the upper postcentral
21-6 CHAPTER 21
gyrus of the left parietal area, 1.0 cm. below the cut gross homologue of areas 40 and 39 in the
pial surface and measuring 1.2 x 1.0 x 0.6 cm. monkey cerebral cortex.
The occurrence of episodic pain in the involved All of these areas may be classified as
arms and legs along with the production of an varieties of homotypical cerebral cortex. The
experienced painful sensation on repetitive tac- major afferent input of the superior parietal
tile stimulation (dysesthesias) in patients with lobule area 5 in the monkey is from the prima-
sensory pathway lesions is sometimes referred ry sensory areas of the post central gyrus. Area
to as a "thalamic" or "pseudo thalamic" syn- 7 of the monkey cortex receives indirect corti-
drome. (Refer to discussion of WIlkins and co-cortical connections. The superior parietal
Brody, 1969). In this case, the anatomical lobule receives projections from the posterior
locus for the pseudo thalamic syndrome is lateral nuclei of the thalamus; the inferior pari-
apparent. etallobule from the pulvinar (see Chapter IS).
The effects of deficits in cortical sensation on These secondary sensory areas project to an
the total sensory motor function of a limb are adjacent tertiary sensory area and then to a
apparent in this case. The actual disability and multimodal sensory association area at the
disuse of the right arm and leg were far out of temporal parietal junctional area. This latter
proportion to any actual weakness. Such an area in the posterior parietal cortex then pro-
extremity is often referred to as a "useless jects to another multimodal sensory association
limb." The actual weakness that was present area in the frontal - peri arcuate - principal sul-
undoubtedly reflected pressure effects on the cus area, to the premotor and frontal eye fields.
precentral gyrus and the descending motor (Discussed earlier in relationship to premotor
fibers in adjacent white matter. and prefrontal motor function). Area 7 has
Destructive lesions of the postcentral gyrus connections to the limbic cortex: cingulate
during infancy or early childhood often pro- gyrus (Mesulum et al, 1977).
duce a retardation of skeletal growth on the The implications of these connections
contralateral side of the body. Such a patient for the integration of complex movements are
examined as an adolescent or adult will be clear. It is not surprising then that single cell
found to have not only cortical sensory deficits studies as reviewed by Darian-Smith et al
in the contralateral arm and leg but also a rela- (1979) demonstrate responses of neurons in
tive smallness of these extremities (shorter arm area 5 to manipulation of joints; hand manipu-
or leg, smaller hand and glove size, smaller lation as in grasping and manipulation objects,
shoe size). or in projecting the hand to obtain a specific
object associate with reward. Neurons in area
SUPERIOR AND INFERIOR
7 discharged in relationship to complex, eye
PARIETAL AREAS
and limb movements (Lynch et alI977). The
In the monkey these areas are collec-
reviews of Andersen et al, 1997 and Colby &
tively designated the posterior parietal cortex. Goldberg, 1999 discuss the multiple represen-
In both the human and the monkey, superior
tations of space in the posterior parietal cortex,
and inferior parietal lobules can be distin-
particularly the intraparietal sulcus area. When
guished divided by the intraparietal sulcus. In damage to parietal cortex occurs, the patient
man, the superior parietal lobule is composed manifests a variety of spatial deficits. A neglect
ofBrodmann's cytoarchitectural areas 5 and 7,
occurs in relation to multiple sensory modali-
the inferior parietal lobule of areas 40 and 39, ties but is most prominent with regard to con-
(the supra marginal and angular gyri). In the tralateral visual space as we will discuss below.
monkey the superior parietal lobule is desig- There are corresponding deficits in the genera-
nated as area 5; the inferior parietal area as pri- tion of spatially directed actions.
marily area 7. This results in some confusion as Stimulation. The threshold of the superior
correlations are attempted. There is no clear- and inferior parietal lobules for discharge is rel-
atively high. Although Foerster reported the not explained by any sensory deficit. There was
occurrence of some contralateral paresthesias a deficit in the conception and execution in the
on stimulation in man, Penfield did not con- spatial and temporal patterns of movement.
firm these results. Stimulation in the inferior The end result is an impairment of purposive
parietal areas of the dominant hemisphere did movement as discussed above. The response to
produce arrest of speech, but this is a nonspe- visual stimuli in terms of attending to and
cific effect, occurring on stimulation of any of reaching for objects is impaired (see Baynes et
the speech areas of the dominant hemisphere. al1986, Nagel-Leiby et al1990, Perenin et al
It must, of course, be noted that space-occu- 1988, and Pierrott Deseilligny et al 1986).
pying lesions in the parietal lobules may pro- Lesions involving the white matter deep to the
duce sensory or motor seizures by virtue of inferior parietal lobule may damage the superi-
their pressure effects on the lower threshold or portion of the optic (geniculocalcarine) radi-
post and precentral gyri. ation, producing a defect in the inferior half of
Ablation: Darian-Smith et al (1979) have the contralateral visual field, an inferior quad-
summarized the effects of selective lesions of rantanopsia.
area 5 and or area 7 in the monkey. The most
DOMINANT HEMISPHERE
selective studies were those of Stein (1977)
PARIETAL LOBULES
using reversible cooling lesions. Cooling of
Destructive lesions of the parietal lobules
area 5 resulted in a clumsiness of the contralat-
produce additional effects on more complex
eral arm and hand so that the animal was
cortical functions. Those lesions involving par-
unable to search for a small object. Cooling of
ticularly the supramarginal and angular gyri of
area 7 produced a much more complex clum-
the dominant (usually the left hemisphere)
siness which was apparent only when the arm
was moved into the contralateral visual field. inferior parietal lobule may produce one or
more of a complex of symptoms and signs
Movements of the hand to the mouth were
known as Gerstmann's Syndrome. These
intact. (Refer to discussion of Colby &
include:
Goldberg, 1999, Wise et al, 1997, for a more
(a) Dysgraphia (a deficit in writing in the
recent discussion of the topic.)
presence of intact motor and sensory function
Earlier clinical studies in humans had sug-
in the upper extremities),
gested possible sensory deficits in relation to
ablation of the inferior or superior parietal b) Dyscalculia (deficits in the performance of
areas. The detailed studies of Corkin et al, calculations ),
(1964) on patients subjected to limited cortical c) Left-right confusion, and
ablations of the inferior or superior parietal d) Errors in finger recognition, for example,
middle finger, index finger, ring finger, in the
areas (in the treatment of focal epilepsy) clear-
presence of intact sensation (finger agnosia).
ly indicated that no significant sensory deficits
occurred. The postcentral gyrus rather than e) In addition, disturbances in the capacity
for reading may be present. Some patients may
the parietal lobules is critical for somatic senso-
ry discrimination. The more recent studies of also manifest problems in performing skilled
Pause et al (1989) confirmed that anterior pari- movements on command (an apraxia) at a time
when strength, sensation and coordination are
etal (post central lesions) resulted in
intact.
somatosensory disturbances including surface
Usually only partial forms of the syndrome
sensibility, 2 point discrimination, position
sense as well as more complex tactile recogni- are present. The problem of the dominant
parietal lobe in language function will be con-
tion. In contrast, in posterior parietal lesions,
there was a preferential impairment of complex sidered in greater detail and illustrated in the
somatosensory and motor functions involving section on language and aphasia. The reader
exploration and manipulation by the fingers - should refer to chapter 24 for an illustrative
21-8 CHAPTER 21
case history. and New Orleans may be placed on the Pacific

NONDOMINANT HEMISPHERE Ocean', Boston on the Florida peninsula; and
PARIETAL LOBULES New York City somewhere west of the Great
Lakes.
Patients with involvement of the nondomi-
The disturbance in capacity for the construc-
nant parietal lobe, particularly the inferior pari-
tion of drawings has been termed a construc-
etal lobule, often demonstrate additional
tional apraxia or dyspraxia. An apraxia may be
abnormalities in their concepts of body image,
defined as an inability to perform a previously
in their perception of external space, and in
well-performed act at a time when voluntary
their capacity to construct drawings.
movement, sensation, coordination, and
The disturbance in concept of body image
understand are otherwise all intact. The fol-
may include the following (a) a lack of aware-
lowing deficits may be present: the patient may
ness of the left side of the body, with a neglect
be unable to draw a house or the face of a
of the left side of the body in dressing, undress-
clock; or to copy a complex figure such as a
ing and washing. (b) Despite relatively intact
three-dimensional cube, a locomotive, and so
cortical and primary sensation, the patient may
forth; in severe disturbances the patient may be
fail to recognize his arm or leg when this is pas-
unable to copy even a simple square, circle or
sively brought into his field of vision. (c) The
triangle. The following case demonstrates
patient may have a lack of awareness of a he~
many of these features.
paresis despite a relative preservation of cortIcal
sensation (anosognosia) or may have a total
Case 21-3: This 70-year-old, single, white
denial of illness. At times, this may be carried
female , right-handed, retired candy maker .
to the point of attempting to leave the hospital
underwent a left radical mastectomy for carCI-
since as far as the patient is concerned; there is
noma of the breast, three years prior to admis-
no justification for hospitalization. The denial
sion. Four months prior to evaluation, the
of illness undoubtedly involves more than per-
patient became unsteady with a sensation of
ception of body image.
rocking as though on a boat. She no longer
The disturbance in perception of external
attended to her housekeeping and to dressing.
space may take several forms: (a) neglect of the
Over a three-week period, prior to evaluation,
left visual field and of objects, writing, or pic-
a relatively rapid progression occurred with
tures in the left visual field. At times, this is
deterioration of recent memory. A persevera-
associated with a dense defect in vision in the
tion occurred in motor activities and speech.
left visual field; at other times, there may be no
The patient was incontinent but was no longer
definite defect for single objects in the left visu-
concerned with urinary and fecal incontinence.
al field , but extinction occurs when objects are
For 2 weeks, right temporal headaches had
presented simultaneously in both visual fields.
been present. During this time, her sister
Again, the problem of possible involvement of
noted the patient to be neglecting the left side
occipital cortex or of subcortical optic radiation
of her body. She would fail to put on the left
should be considered as previously noted.
shoe when dressing. In undressing, the stock-
(b) An inability to interpret drawings such as a
ing on the left would be only half removed.
map or to pick out objects from a complex fig-
Family History: The patient's mother died
ure. The patient is confused as to figure back-
of metastatic carcinoma of the breast.
ground relationship and is disoriented in
Neurological examination: Mental status:
attempting to locate objects in a room. When
Intact except for the following features: The
asked to locate cities on an outline map of the
patient often wandered in her conversation.
United States, the patient manifests disorienta-
She often asked irrelevant questions and was
tion as the west and east coasts and as to the
often impersistent in motor activities. There
relationship of one city to the next. Chicago
was marked disorganization in the drawing of a
house or of a clock. A similar marked disorga-
nization was noted in attempts at copying the
picture of a railroad engine (Fig 21-4). There
was a marked neglect of the left side of space
and of the left side of the body. The patient
failed to read the left half of a page. When she
put her glasses on, she did not put the left bow
over the ear. When getting into bed, she did
not move the left leg into bed. She had slipped
off her dress on the right side, but was lying in
bed with the dress still covering the left side.
The patient had been reluctant to come for
neurological consultation. Although she com-
plained of headache and nausea, she denied any o ('} '"
other deficits. Her relatives provided infor- ?J 0' 0
mation concerning these problems. Much
additional persuasion over a two-week period Figure. 21-4. Nondominant parietal constructional
was required before the patient would agree to apraxia. Case 21-3. The patient's attempts to draw a
be hospitalized. Cranial nerves: A dense left house are shown on the upper half of the page. Her
homonymous hemianopsia was present. When attempts to copy a drawing ofa railroad engine are
shown on the lower half of the page (B & C).
reading, the patient left off the left side of a
The examiner's (Dr. Leon Menzer) original is
page. She bisected a line markedly off center. designated (A).
Disc margins were blurred and venous pulsa-
tions were absent, indicating papilledema. (Brain scan radioisotope Hg197 and arteri-
The right pupil was slightly larger than the left. ograms) were consistent with a large well-
A minimal left central facial weakness was pre- defined lesion in the posterior section of the
sent. Motor system: Although strength was right temporal inferior parietal area (Fig. 21-6).
intact, there was little spontaneous movement Subsequent course: Treatment with
of the left arm and leg. The patient was ataxic steroids (dexamethasone and estrogens) result-
on a narrow base with eyes open with a tened in temporary improvement. The patient
dency to fall to the left, and was unable to stand refused surgery. Her condition soon deterio-
with eyes closed even on a broad base. rated with increasing obtundation of con-
Sensation: Although pain, touch and vibration sciousness. She expired two months following
were intact, there was at times a decreased her initial neurological consultation.
awareness of stimuli on the left side. Errors A CT scan from a more recent case demon-
were made in position sense at toes and fingers strating many aspects of this syndrome is illus-
on the left. Tactile localization was poor over trated in Figure 21-7. In many cases, the loca-
the left arm and leg. With double simultaneous tion of lesion may appear to be predominantly
stimulation, the patient neglected stimuli on posterior temporal. Such large posterior tem-
the left face, arm and leg. poral lesions would certainly compromise the
Clinical diagnosis:: Metastatic breast cortex and subcortical white matter of the adja-
tumor to right non-dominant parietal cortex. cent inferior parietal area.
Laboratory data: Chest X -ray indicated a In this case, marked deficits in perception
possible metastatic lesion at the right hilum. of the cortical modalities of sensation were pre-
EEG was abnormal because of frequent focal 3 sent. In other cases, as in the case demonstrat-
to 4 cps slow waves in the right temporal and ed in Fig 21-7, such involvement is much less
parietal areas, suggesting focal damage in these marked.
areas (Fig 21-5 on CD atlas). Imaging studies In some cases, involvement of the motor
21-10 CHAPTER 21
Figure. 21-6 Non dominant parietal lesion. Que 21-3. Brain scanHg197. A large uptake of radioisotope is
demonstrated in the right parietal and adjacent posterior temporal area. (Courtesy of Dr. Bertram Selvmtone.)
cortex is evident with an actual left hemiparesis - with right frontal lesions leading to left hemi
accompanied by an increase in deep tendon spatial neglect only for tasks that emphasize
reflexes and an extensor plantar response. At exploratory-motor components of directed
times in patients with neglect syndromes, there attention whereas parietal lesions emphasize
may be several indications in the clinical exam- the perceptual-sensory aspects of neglect.
ination and in the laboratory studies that the With lesions of the non-dominant hemi-
involvement of the frontal lobe areas is more sphere, there is a significant alteration of the
prominent than the parietal involvement. We patient's awareness of his environment. The
have already indicated that the neglect compo- behavior of an individual is in part determined
nents of this syndrome may also be noted in by his own particular perception of the envi-
lesions of the anterior premotor area (area 8). ronment. If that perception is altered or disor-
The prefrontal and premotor areas as discussed ganized, the behavioral responses of the patient
above and in chapter 18, receive projection may appear inappropriate to others.
fibers from the multimodal area of the posteri- Obviously, not all individuals will respond in
or parietal area. It is possible that in some cases the same manner to a given environmental sit-
the posterior temporal - inferior parietalloca- uation; part of the response will be determined
tion of the lesion may also be critical in inter- by the past experience and personality of the
rupring these association fibers. For these sev- individual. Thus, given the same lesion, one
era! reasons, it is perhaps more appropriate to individual may be unaware of a hemiparesis,
use the term, syndrome of the non-dominant another may deny the hemiparesis but agree an
hemisphere, rather than the more localized illness is present, a third may claim to be
designation, non-dominant inferior parietal healthy and claim that people are conspiring to
syndrome. Duffuer et al, 1990 have presented keep him in the hospital.
the concept of a network for directed attention
Figure. 21-7 Nondominant parietal lobe syndrome. cr scans. This 68-year-old left-handed male with diabetes
mellitus and hypertension had the sudden onset of left arm paralysis, loss ofspeech and ability to read and write all
of which recovered rapidly. On examination 9 months after the acute episode he continued to have the following
selective defoiu: (1) he was vague in recalling his left hemiparesis (2) in dressing, he reversed trousers and failed
to cover himself on the left side. (3) He had extinction in the left visual field on bilateral simultaneous visual
stimulation and over the left arm and leg on bilateral simultaneous tactile stimulation. (4) A left Babinski sign
was present. cr scan now demonstrated an old cystic area of infarction in the right posterior temporal-parietal
(territory of the inferior division of the right middle cerebral artery).
CHAPTER 22
Limbic System
INTRODUCTION Emotional Brain

Since the initial observations of Kluver and
Rhinencephalon Bucy (1937) and Papez (1937), which local-
The neurologist Paul Broca in the later half ized emotions in the telencephalon, many
of the 19th century initially designated all of other investigators have added information
the structures on the medial surface of the concerning the localization of behavior. We
cerebral hemisphere the "great limbic lobe." now know that many cortical and subcortical
This region, due to its strong olfactory input, regions are incorporated in the "emotional
was also designated the rhinencephalon. brain."
The olfactory portion of the brain (rhinen- Different investigators have coined differ-
cephalon, or archipallium) comprises much of ent terms to succinctly describe the limbic sys-
the telencephalon in fish, amphibians, and tem, particularly the visceral, vital, or emotion-
most mammals. In mammals the presence of al brain. The term "visceral brain" would
a large olfactory lobe adjacent to the hip- seem appropriate since much of our emotion-
pocampus was once considered to be evidence al response is characterized by specific respons-
of the important olfactory functions of these es in the viscera (Fulton, 1953). On the other
regions. However, when a comparative neu- hand, the importance of the emotional
roanatomist examined the brains of sea mam- response for the self-preservation of the indi-
mals that had rudimentary olfactory apparatus, vidual and the perpetuation of the species has
e.g., dolphins and whales, the presence of a
large hippocampus suggested other than olfac-
tory functions for this region.
In 1937, Papez proposed that olfactory
input was not the prime input for this region,
and the experiments of Kluver and Bucy
(1937, 1939) and Kluver (1952 and 1958)
demonstrated the behavioral deficits seen after
lesions in this zone. More recently, it has been
shown that in primates only a small portion of
the limbic lobe is purely olfactory: the olfacto-
ry bulb, olfactory tract, olfactory tubercle,
pyriform cortex of the uncus, and corti-
coamygdaloid nuclei (Fig. 22-1). The other
portions--hippocampal formation, fornix,
parahippocampal gyrus, and cingulate gyrus--
are now known to be the cortical regions of
the limbic system (Fulton, 1953; Green,
1958; Papez, 1958; Scheer, 1963; Isaaccson,
1982). Figure 22-1 Gross view of ventral surface of brain
tkmonstrating olfactory bulb and olfaaory tract.
22-2 CHAPTER 22
led other investigators to call this region the macrosmatic, while those with a poorly devel-
''vital brain" (MacLean, 1955). The term oped sense of smell are called microsmatic.
used most commonly by investigators and the Dogs and cats are macrosmatic animals, while
one used in this chapter is limbic lobe (limbus humans and all of the great apes are micros-
= margin) because the involved region is locat- matic (Fig 22-2). In the dog, 15% of the brain
ed on the medial margin of the cerebrum and Relates to olfaction while in the human
surrounds the brain stem as it enters the dien- brain, the portion devoted to olfaction is
cephalon. minute. Most dogs and cats have an olfactory
We can separate the entire central nervous system that is infinitely superior to ours both in
system into a "somatic brain," which controls sensitivity and the ability to discriminate
the external environment through the skeletal among odors. Nevertheless, we can still distin-
muscles, and a "visceral brain," which controls guish thousands of different odors, and a mul-
the internal environment through the control timillion-dollar industry has developed to
of smooth muscles and glands. Our discussion stimulate our olfactory system. In fact, many
of this region begins with the olfactory system people have built careers on their olfactory
and continues into the Limbic System acuity (wine and coffee sniffers and per-
fumers). Many blind or deaf people have such
I. OLFACTORY SYSTEM a refined sense of smell that they can detect
subtle changes in their environment.
The olfactory system must be included in
The olfactory information is distributed
any discussion of the emotional brain as it
from the olfactory bulb through three olfacto-
sends fibers directly into the medial temporal
ry stria:
lobe, and this olfactory information is especial-
1. Intermediate stria -- olfactory tubercle.
ly important to the emotional brain.
2. Medial olfactory stria -- septal region
Olfactory Nerve. The olfactory nerve
and via the anterior commissure into the
(cranial nerve I) originates from the upper-
opposite olfactory bulb and,
most portions of both nasal fossae, which
3. Lateral olfactory stria -- olfactory cortex
occupy the mucous membrane covering the
of the uncus and corticomedial amygdaloid.
superior nasal conchae and adjacent septum.
The terminations in the amygdala produce a
The mucous membrane is attached to the
strong response in the emotional brain to sub-
walls of the nasal septum that in this region is
stances that stimulate the olfactory systems
formed by the ethmoid bone.
especially smoke, food and pheromones.
Olfactory Receptors. The 100 million or
Details on the structure of the olfactory
more bipolar receptor cells are embedded in
bulb, the olfactory connections and the trans-
sustentacular cells. The dendrites of the recep-
duction of odors into neuronal signals are
tor cells are short and ciliated. The cilia are
included in the CD-ROM section on special
embedded in the odor-absorbing secretion
senses.
secreted by the Bowman glands that forms the
mucosa. New cells from the basal layer are
constantly replacing the olfactory receptor ll. LIMBIC REGIONS IN THE BRAIN
cells. All of the axons from the olfactory neu- The limbic/emotional brain is divided into
roreceptor cells are unmyelinated. They gath- cortical and subcortical regions.
er together into about 20 bundles (fila olfac- Cortical Areas are located in: Frontal Lobe,
toria), which then pass through openings in Temporal Lobe and Cingulate Gyrus while
the cribriform plate of the ethmoid bone to Subcortical areas are found in the brain stem,
synapse in the olfactory bulb. diencephalon and septum.
Olfactory Discrimination. Vertebrates Table 22-1 identifies the cortical and sub-
with a well-developed sense of smell are called cortical limbic structures
LIMBIC SYSTEM 22-3
SUBCORTICAL STRUCTURES TABLE 22-1. THE SUBCORTICAL AND CORTICAL NUCLEI
REFER TO CHAPTER 11) OF THE L1M~IC SYSTEM
Reticular Formation of the Brain Stem SUBCORTICAL NUCLEI CORTICAL STRUCTURES

and Spinal Cord. The spinal and cranial nerve OF THE LIMBIC SYSTEM: OF THE LIMBIC SYSTEM:
roots are the first-order neurons for sensory 1. Reticular formation of the l.Temporal Lobe:
information to reach the somatic and visceral brain stem and spinal cord --Amygdala
brain. These peripheral nerves send much sen- --Midbrain limbic nuclei --Hippocampal fonnatlon-
sory information via axon collaterals into the (Interpeduncular nucleus, --Parahippocampal cortex
Paramedian nucleus, --Rostral portion of
reticular formation of the spinal cord, medul- ventrallegmental area, temporal lobes
la, pons, and midbrain. The reticular forma- Ventral half of the 2. Frontal Lobe
tion is organized longitudinally, with the later- periaqueductal gray. --Frontal association areas
al area being the receptor zone and the medi- 2. Hypothalamus (preoptic, --Supracallosal gyrus and
al area being the effector. In the medial zone lateral, Lateral mammillary longitudinal stria
nuclei) --Subcallosal gyrus
are the ascending and descending multisynap- 3. Thalamus (midline, -Orbital frontal cortex
tic fiber tracts of the reticular formation: the intralaminar, anterior,and 3. Cingulate gyrus and
central tegmental tract. dorsal medial nuclei) cingulate isthmus
4. Epithalamus
Throughout the levels of the brain stem
5. Septum
there are also certain important limbic nuclear 6. Nucleus accumbens
groupings in the reticular formation:
1. The mesencephalic portion of the reticular and septum.
formation seems to be especially important, 2. From the locus caeruleus of the upper pons
since this zone provides a direct reciprocal
and the raphe of the midbrain the ascending
pathway to the hypothalamus, thalamus,
Olfactory Bulb
Lateral (llt::art,nrv
briform Plate
(Ethmoid)
!9,,11~~- Olfactory Mucosa of
Glomerulus Nasal Cavity
Amygdaloid Nucleus
(Basolateral Region)
Figure 22-2 Diagrammatic representation of the olfactory system and its conneaions
22-4 CHAPTER 22
serotoninergic and adrenergic systems run
-_
release of glycogen stores from the liver, pro-
into the diencephalon and telencephalon viding energy for muscular contractions that
and provide direct input into these regions.
Interpeduncular Nucleus. The interpe-
...........
duncular nucleus (posterior perforated sub-
stance) is found on the anterior surface of the
midbrain in the interpeduncular fossa extend-
ing from the posterior end of the mammillary
body to the anterior end of the pons. It
receives fibers from the habenular nuclei
(habenulopeduncular tract) and has reciprocal
connections with the hypothalamus and the
midbrain limbic region. Amygdaloid informa-
tion reaches this region through connections
via the stria terminalis to the septum and then •
_ _ CeNIc:o<
from the septum to the interpeduncular nucle- Ccwd
us. Hypothalamic input and septal input are

also important parts of the autonomic infor- Figure 22-3. Medial surface of a cerebral hemisphere
mation to the brain stem passing through this including entire brain stem and cerebellum.
nucleus.
Hypothalamus (Figs. 22-3, 22-4, and
chapter 16). The hypothalamus is the highest
subcortical center of the visceral brain. The
basic function of this region is to maintain
internal homeostasis (body temperature,
appetite, water balance, and pituitary fimc-
tions) and to establish emotional content. It is
a most potent subcortical center due to its
control of the autonomic nervous system.
The hypothalamus receives input from all
portions of the limbic system, as well as from Figure 22-4. Medial surface of a cerebral hemisphere
the reticular formation, basal ganglia, and with medulla, pons, and cerebellum retno1Jed.
frontal association cortex. The hypothalamus
connects to the thalamus, midbrain, pons, and
medulla via the medial forebrain bundle and
the dorsal longitudinal fasciculus (Nauta,
1963). Autonomic fibers from the hypothala-
mus run in the lateral portion of the reticular
formation and descend to the cranial nerves
and the thoracolumbar (sympathetic) and
sacral levels (parasympathetic). The most
potent effects result from hypothalamic con-
trol of the pituitary gland and the adrenal
medulla. The adrenal medulla releases epi-
nephrine and norepinephrine, which produce
a decrease in peripheral blood flow, an increase Figure 22-5. Medial surface of a cerebral hemisphere
in central blood flow, and an increase in heart with thalamus re1tWfled, demonstrating relationship
rate and force. These agents also stimulate between fornix and hippocampus.
LIMBIC SYSTEM 22-5
Clngulate CorIeJC
listed in Table 22-2.
Stimulation of the hypothalamus can pro-
duce the flight-or-fight response (fear or rage),
as well as several visceral responses--sweating,
salivation, defecation, and retching. These can
be produced in adjacent regions or by moving
the electrode site or changing the stimulation
parameters (e.g., by varying the current).
Another interesting result has been noted in
cats made docile with amygdaloid lesions;
these animals become savage when a lesion is
placed in the ventromedial hypothalamic
nuclei. The effects of hypothalamic stimula-
Figure 22-6. Coronal section through diencephRlon Rt tion and ablation on sleep will be considered in
level ofMRSSR intermediR showing mRmmillothRlR- chapter 29.
mit trRCt feRPing mRmillary body. Weil myelin stRin.
Thalamus (Fig. 22-3, 22-4). The anterior,
accompany the response. medial, midline, and intralaminar dorsal thala-
The mammillary nuclei (Figs. 22-3, 22-4, mic nuclei receive input from the ascending
22-6) of the hypothalamus connect to the nociceptive pathways, hypothalamus, reticular
anterior thalamic nuclei and habenula, via the system (especially the midbrain reticular for-
mammillothalamic tract, and to nuclei in the mation), cingulate, and frontal association cor-
brain-stem tegmentum via the mammil- tex. The intralaminar and midline nuclei con-
lotegmental tract. The lateral mammillary nect to the medial and other specific dorsal
nucleus receives axons via the fornix from the thalamic nuclei, which then project to the
hippocampus, axons from other portions of cerebral cortex.
the hypothalamus and septum through the Epithalamus (see chapter 16). The habe-
medial forebrain bundle, and input from the nular nuclei (epithalamus) give origin to the
midbrain tegmentum and substantia nigra via habenulopeduncular tract, which projects to
the mammillary peduncle. Effects ofhypothal- the midbrain tegmentum and interpeduncular
amic stimulation on the autonomic system are nucleus. The habenular nuclei receive afferents
TABLE 22-2 EFFECTS OF HYPOTHALAMIC STIMULATION from the septum and preoptic region via the
ON THE AUTONOMIC NERVOUS SYSTEM stria medullaris and connect to the intralami-
nar nuclei.
STIMULATION OF STIMULATION OF Septum (Fig. 22-5). The septum forms
ANTERIOR POSTERIOR the medial wall of the frontal horn of the lat-
HYPOTHALAMUS= HYPOTHALAMUS =
PARASYMPATHETIC SYMPATHETIC RESPONSE eral ventricle. The septum consists of two
RESPONSE OR ANXIETY RESPONSE parts: the septum pellucidum containing the
Decrease in - heart rate, Increase in- heart rate, septal nuclei (dorsal, lateral and medial) and
respiration, and blood respiration, blood pressure, the caudal velum interpositum. The septum
pressure; Increase in Decrease in peristalsis and pellucidum is rostral to the interventricular
peristalsis and In gastriC In gastric and duodenal
and duodenal secrelions; secretions, Decreased
foramen. The septum pellucidum consists of
Increased salivation; and salivation with sweating, glial membrane and some pia arachnoid
depending on the inlernal and piloerection. (velum interpositum), with the bulk consisting
milieu, even evacuation of Dilation of Pupils of the column of the fornix. This paired glial
the bowels and bladder. Concomitant with membrane, along with the fornix, separates
Constriction of the pupils; sympatheHc excitation
the bodies of the lateral ventricles.
Concomitant with the there is parasympathetic
parasympathetic excitation inhibition. The lower part of the septum pellucidum
is sympathetic Inhibition. (septal area) consists of many neurons and glia.
22-6 CHAPTER 22
This zone receives strong input from the

amygdala via the stria terminalis and hypothal-
amus. The septum connects with the:
1. Hypothalamus, interpeduncular nucle-
us, and the midbrain tegmentum via the medi-
al forebrain bundle,
2. Habenula via the stria medullaris, and
3. Basolateral amygdaloid nuclei through
the diagonal band.
Destruction of the septum in cats causes
docile animals to become fearful or aggressive,
Figure 22-7. Coronal Section through amygdala and
but only for a short time. Complete destruc- hypothalamus. MRI-T1. Hippocampal gyrus =
tion of the septum may produce coma, proba- parahippocampal gyrus
bly because it destroys the strong connections
and the sublenticular substantia innominata.
between the septum and hypothalamus.
The amygdala receives extensive projections
Nucleus Acumbens (see chapter 19. This
from many cortical areas and in turn sends
nucleus lies below the caudate, and receives
projections to these areas. In primates as one
fibers from the amygdala via the ventral amyg-
expects in comparison to rodents, there has
dalofugal pathway and from the basal ganglia
been a significant increase in the projections
and thus provides a major link. between the
from and to isocortex (neocortex) as opposed
limbic and basal nuclei. This nucleus has a high
to allocortex and mesocortex. These projec-
content of acetylcholine. In Alzheimer's dis-
tions originate from: 1) the multimodality sen-
ease, there is a significant loss of cholinergic
sory areas, 2) tertiary unimodal sensory associ-
neurons in this nucleus.
ation areas, 3) visual association areas which
ROLE OF CORTICAL are particularly prominent in the primates, 4)
STRUCTURES IN EMOTIONS first and second order central sensory neurons
of the olfuctory system.
From the standpoint of the role of the
TEMPORAL LOBE
amygdala in emotion and instinctive behavior,
Parahippcampal Gyrus. The uncus (a there are important connections with the basal
hook in Latin) forms the anteriormost region forebrain, medial thalamus (medial dorsal
in the parahippocampal gyrus on the medial nucleus), hypothalamus (preoptic, anterior
surface of the temporal lobe. Its surface is the and ventromedial and lateral areas), and the
olfactory cortex and the principal nucleus of tegmentum of the midbrain, pons and medul-
the amygdala lies internally (Fig 22-4,22-5). la (to various nuclei concerned with visceral
Amygdaloid Nuclei (Figs. 22-6, 22-1, 22- function such as chewing, licking and the
8). The amygdala is uniquely located to pro- motor components of emotional expression).
vide the intersection between the primary The more specific connections of the
motivational drives of the hypothalamus and amygdaloid nuclei are listed below
septum and the associative learning that occurs (1) Olfactory Nuclei. The corticomedial
at the hippocampal and neocortical group receives olfactory information from the
levels. lateral olfactory stria and interconnects with
The amygdala (Fig. 22-9) consists of three the contralateral corticomedial nuclei (via
main groupings of nuclei: corticomedial, baso- anterior commissure) and ipsilateral basolater-
lateral, and central. In addition to these prin- al nuclei. The primary efferent pathway of the
cipal nuclei there are extratemporal neurons corticomedial nucleus is the stria terminalis,
including the nucleus of the stria terminalis which projects to the septum, medial hypo-
LIMBIC SYSTEM 22-7
Figure 22-8. Coronal Section through mammillary bodies and amygdala. MRJ- 12.
thalamus including preoptic nucleus of the frontal lobe, orbital frontal gyri, cingulate
hypothalamus, and to the corticomedial nucle- lobe, thalamus (especially dorsomedial nucle-
us in the opposite hemisphere. us), catecholamine containing nuclei of the
(2). Limbic Nuclei. The central and baso- reticular formation, and substantia nigra.
lateral nuclear grouping is associated with the (3). The ventral amygdalofugal pathway
limbic brain, and has connections with the projects from the central nucleus to the brain
parahippocampal cortex, temporal pole, stem and to the septum, the preoptic, lateral,
Figure 22-9 A) Sagittal Section. Temporal lobe with amygdala and hippocampus. MRJ-Tl. B) Sagittal section
Weil myelin stain. Inferior horn LV is the junction ofposterior and inferior horns of lateral ventricle.
22-8 CHAPTER 22
and ventral hypothalamus, and--in the dorsal amygdala have been produced for control of
thalamus--to the dorsomedial, intralaminar, aggression. In patients with bilateral lesions of
and midline thalamus. the amygdala there is an impairment of the
Stimulation of the amygdaloid region. In ability to interpret the emotional aspects of
monkeys, cats, and rats stimulation produces facial expression. (Young et al1995, Adolph,
aggressive behavior. The stimulated cats have et al 1998, Anderson et al, 2000). Patients
a sympathetic response of dilated pupils, with high functioning autism have a similar
increased heartbeat, extension of claws, pilo- disorder (Adolphs et al2001). On functional
erection, and attack behavior. When the stim- MRI studies, these patients failed to activate
ulus stops, they become friendly. Animals will the left amygdala, as well as the cortical face
even fight when the amygdala is stimulated area or the left cerebellum when implicitly pro-
and stop fighting if the stimulus is off. Eating, cessing facial expressions (Baron-Cohen et al,
sniffing, licking, biting, chewing, and gagging 2000 Critchleyet al2000). When quantitative
may also be stimulated here. In contrast stud- MRI is performed in such autistic patients,
ies in the cat indicate that stimulation of the there is significant enlargement of the volume
prefrontal areas will prevent aggressive behav- of the amygdala. Howard et al (2000) suggest
ior. In humans, stimulation of the amygdala that these results may indicate that a develop-
produces feelings of fear or anger (Cendes et mental malformation of the amygdala (possi-
al-1994). A role in sexual behavior has also bly an incomplete neuronal pruning) may
been postulated, although this may be more underlie the social-cognitive impairments of
prominent in the female. the autistic patient.
Ablation of Amygdala. In the studies of
Amaral selective bilateral lesions of the amyg- HIPPOCAMPAL FORMATION
dala 1 in the adult monkey significantly (22-9,22-10,22-13)
decreased the fear response to inanimate This region of the limbic system has been
objects such as an artificial toy snake. This of critical importance in our understanding of
object was now picked up whereas previously, both the clinical aspects and underlying bio-
such an object had triggered intense fear logical substrate of memory and of complex
responses. The social interactions of the partial epilepsy.
lesioned monkey with other members of a
colony were significantly altered. The lesioned Anatomical Correlates:
animals were more sociable with more sexual From an anatomical standpoint, compared
and nonsexual friendly contacts with other to other lobes of the brain, the temporal lobe
members of the colony. They were described
as socially uninhibited. In the male, aggression
was decreased, but occasional females had an
increase in aggressive behavior. When the
bilateral lesions were produced at two weeks of
age, there was a decrease in fear responses to
inanimate objects but an increase in fear
responses to other monkeys. This latter effect
interfered with their social integration into the
colony.
In the human, bilateral lesions of the
1 These selective lesions were produced by injec- Figure 22-10. The sectors or fields of the hippocampus.
tion ofibotenic acid which damages neurons but The dentate gyrus ,subiculum and related structures
does not affect fibers ofpassage are demonstrated. Nissl stain.
LIMBIC SYSTEM 22-9
is a complex structure. It contains four diverse Entorhinal Region: The entorhinal/
components: parahippocampal gyrus forms the large poste-
Neocorte» 6 layers: superior, middle and rior segment of the piriform region. This is
inferior temporal gyri (see chapter 17) Brodmann's area 28 and constitutes the bulk
Allocortex - 3-layers: the olfactory cortex, of the parahippocampal gyrus. This area has
hippocampal formation and subiculum. extensive interconnection with the higher
Mesocortex- a transitional type of 6-layer association cortex throughout the neocortex
cortex (transitional between neocortex & allo- and also receives olfactory information from
cortex): entorhinal/parahippocampal gyrus the olfactory stria. This is the major pathway
(the large posterior segment of the pyriform for relating neocortex to the limbic cortex of
region), presubiculum and para subiculum. the hippocampus. 3
Older classifications have used the terms
Cortical Nucleus - the amygdala (discussed archicortex for the hippocampus, paleocortex
above). for the piriform area and neocortex for lateral
The hippocampus is phylogenetically the temporal areas based on presumed phyloge-
older part of the cerebral cortex termed allo- netic considerations. Here we will follow in
cortex and consists of three layers: polymor- general the terminology as above, employed in
phic, pyramidal, and molecular. The dentate the recent monumental work of Gloor (1997).
gyrus2 fits inside the hippocampus and, like The hippocampus is divided into sectors
the hippocampus, has three layers: molecular, (referred to as fields) based on cytoarchitectur-
granular, and polymorphic. The most primi- al differences (Fig.22-10) CAl-CA4, (or fields
tive cortex is the paleocortex of the olfactory of Rose hl-h5). (Note that an older term for
bulb. the hippocampus is Ammon's {the ram} hom,
The fibers of the dentate gyrus are con- thus-Comu Ammonis = CA). CA4, the end
fined to the hippocampal formation while the folium or end blade merges with the hilus of
hippocampal fibers leave the hippocampal for- the dentate gyrus. CAl, the sector closest to
mation through the fornix and project to the subiculum is referred to as the Sommer's
either septum or to the mammillary bodies sector. This sector is most severely affected by
and mesencephalic tegmentum. The cortex cell loss following hypoglycemia, anoxia, and
adjacent to the hippocampus changes from status epilepticus (Fig.22-11). However this
three layers to six layers and is classified as tran- selective vulnerability may also involve CA3
sitional mesocOrtex and includes the parahip- and CA4 with relative sparing of CA2 and the
pocampal gyrus (medial to the collateral sul- dentate granule cells. The subsequent gliosis
cus), including entorhinal cortex. The pyri- (mesial sclerosis) of the hippocampus is the
form lobe consists of the lateral olfactory stria, pathology found at surgery or autopsy in 75%
uncus and the anterior part of the parahip- of cases of complex partial seizures arising in
pocampal gyrus. the hippocampus.
The hippocampal regions are interconnect-
2In the dentate gyrus in common with the olfac- ed by a commissure, the hippocampal com-
tory epithelium and cerebellum, new neurons missure. In the primate, the dorsal commissure
are formed throughout life. In the vast remain- originates in the entorhinal cortex and pre-
der of the brain there is no differentiation of subiculum. The ventral commissure originates
nerve cells after birth, and when these nerve cells
die they are not replaced (Altman 1962, Gage 3Note that the «entorhinal gyrus» of lower
1994). One must expect considerable research in mammals corresponds in humans to a much
the future to focus on just whichgenes permit the larger region that includes the middle, inferior,
continued replacement of nerve cells in these and parahippocampal gyri and the temporal
regions. portion of the fusiform gyrus.
22-10 CHAPTER 22
in the CA3 sector and the dentate hilus pri- dentate gyrus. There are also mossy cells in the
marily in their more rostral areas e.g. in rela- polymorph layer probably excitatory interneu-
tion to the uncus rons. There are also scattered interneurons in
Cytoarchitecture of the Hippocampus: the molecular layers. The connections of the
In the hippocampus, the three layers are as fol- hippocampal formation are summarized in
lows: Table 22-3.
1. Molecular in which the apical dendrites of The Selective Vulnerability of
the pyramidal cells arborize. This layer is Hippocampus (Fig.2-11) occurs in diseases
usually divided into a more external stratum such as anoxia and hypoglycemia. In addition
lacunosum-moleculare and a more internal the hippocampus appears to be significantly
stratum radiatum. It is continuous with involved in most seizures of temporal lobe ori-
molecular layer of dentate gyrus and adja- gIll.
cent temporal neocortex. 1. Why does this selective vulnerability occur?
2. Pyramidal cell layer (stratum pyramidalis) The CA 1 region is rich in NMDA recep-
contains pyramidal cells that are the princi- tors. The dentate hilus and the CA3 sector
pal cells of the hippocampus. Dendrites are rich in kainate receptors. Activation of
extend into molecular layer and Schaffer these receptors by glutamate would allow a
axon collaterals arise from pyramidal neu- considerable entry of calcium ions into the
rons and synapse in the molecular layer on pyramidal neurons beginning a cascade that
dendrites of other pyramidal cells.
3. Polymorphic layer (stratum oriens)-in, which
the basilar dendrites of the pyramidal cells
are found. Contains axons, dendrites and
interneurons. This layer in CA3 is continu-
ous with hilus of the dentates gyrus. Only
the hippocampus sends axons outside the
hippocampal formation.
Cytoarchitecture of the Dentate Gyrus:
In the dentate gyrus, the following three layers
are found:
1. Molecular layer contains dendrites of gran-
ule cells
2. Granule cell layer. These small neurons
replace the pyramidal cell layer of hip-
pocampus. The granule cells are unipolar;
all of the dendrites emerge from the apical
end of the cell into the molecular layer.
Efferent neurons from the granule cells are
c
mossy fibers that synapse only with cells of
hippocampal areas CA2 and CA 3. Figure 22-11. Selective vulnerability of the hippocam-
3. Polymorphic cell. Also referred to as the pus demonstrated in Nissl stains. A, Normal
hilus, this layer is continuous with CA3 of Ammon's horn with labels for fields hl-h5 of Rose
hippocampus. inserted. B, Anesthetic death: recent necrosis in
Sommer sector (hi) and partial loss of neurons in h3
The pyramidal and granule cell neurons are
and the end plate (h4, h5). C, Hypoglycemic coma:
excitatory utilizing glutamine as the transmit- there has been significant loss ofpyramidal cells in
ter. In addition there are inhibitory interneu- section hi. (From Meyer, A. (in) Greenfield,J., et al.,
rons (GABA-ergic), basket cells, in the poly- Neuropathology 2nd Edition. Baltimore, Williams &
morphic layer of both the hippocampus and Wilkins, 196 p.256).
LIMBIC SYSTEM 22-11
TABLE 22-3 • CONNECTIONS OF HIPPOCAMPAL (stereotyped movements) involving face,
FORMATION limb, and trunk.
3. Why do not all of the various pathological
AFFERENT INPUT: processes in the hippocampus produce seizures?
1. Perforant palhway from adjacentlaleral entorhinal There appears to be a critical age during
cortex onto granule cells of dentale gyrus and the
infancy and early childhood for the acquisi-
alvear pathway from the medial entorhinal cortex. The
entorhinal areas, in turn, receive their inpulfrom many tion of the pathology that is associated with
of the highesllevel of associational cortex in the seizures originating in mesial temporal lobe.
frontal, orbital, temporal (amygdala), parietal, and There may be an age related remodeling of
cingulale cortex through the cingulum bundle. intnnslC hippocampal connections.
2. Septum through the slria terminalis. Whether a single episode of epileptic status
during infancy is sufficient to produce these
3. Contralaleral hippocampus, via the hippocampal changes or whether, multiple episodes may
commissure. be required is still under discussion.
EFFERENT PROJECTIONS: 4. Is the hippocampal pathology alone sufficient
These fibers, the axons of hippocampal and subiculum to explain the complex partial seizures oftem-
pyramidal neurons form the fornix and have connections poral lobe origin? As reviewed by Gloor
with the following structures. (1997), many of the specimens examined
after surgery or at autopsy also demonstrate
1. Laleral mammillary nuclei, habenulae nuclei, anterior
midline and intra laminar thalamic nuclei, lateral hypo· extensive changes in the amygdala as well as
thalamic nuclei, midbrain tegmentum, and perlaque· mesial and lateral isocortex. (Overall how-
ductal grey via a column of the fornix ever, in the autopsy studies of Margerison
and Corsellis (1966) the most frequent site
2. Septum, preoptic region, parollactory and cingulale
cortex via the precommissural fornix and supracallosal of damage and cell loss was in the hip-
fornix pocampus.) Rather than using the more
restrictive term of hippocampal sclerosis, it
is more appropriate to use the term mesial
could result in cell death. Moreover the
temporal sclerosis. Even this term fails to
pyramidal neurons of these sectors as com-
include the involvement of more laterally
pared to CA 2 and the granular cells of the
placed neocortex in some of the symptoms
dentate gyrus contain very little calcium
in seizures originating in temporal lobe. (see
buffering protein calbinden.
below)
2. Seizure Activity. Most seizures beginning
after age 15 are classified as partial, and the
majority of these are classified as complex HIPPOCAMPAL SYSTEM & MEMORY
partial. Approximately 75% of the complex (see also Chapter 30 on Learning and
partial seizures arise in the temporal lobe, Memory).
the remainder in the frontal lobe. While The studies of Milner (1972) have shown
these seizures may arise in temporal neocor- that bilateral removal or damage of the hip-
tex, the majority arise in the mesial tempo- pocampus produces great difficulty in learning
ral structures particularly the hippocampus. new information, a condition called antero-
The hippocampus has a low threshold for grade amnesia. The excitatory amino acids, 1-
seizure discharge; consequently, stimulation glutamate and I-aspartate are important in
of any region that supplies hippocampal learning and memory through the mechanism
afferents or stimulation of the hippocampus of long-term potentiation. Long-term poten-
itself may produce seizures. Hippocampal tiation is a long lasting facilitation after repeat-
stimulation produces respiratory and car- ed activation of excitatory amino acid path-
diovascular changes, as well as automatisms ways and is most pronounced in the hip-
22-12 CHAPTER 22
pocampus and may be related to the initiation eN II 12A

of the memory trace
The amygdala and its connections are asso-
ciated with the conditioning of the emotional
response of fear (Refer to review of LeDoux,
2000) and above.
OTHER CORTICAL REGIONS

OF THE LIMBIC SYSTEM
1~ _ _ _ CollorttoJ*""'tu"
Cingulate Cortex. This region (Fig. 22-5)
receives reciprocal innervation from the anteri-
or thalamic nuclei, contralateral and ipsilateral
cingulate cortex, and temporal lobe via the
cingulum bundle, as well as projecting to the
corpus striatum and most of the subcortical
limbic nuclei. The cingulate cortex is continu-
ous with the parahippocampal gyrus at the
isthmus behind the splenium of the corpus
callosum.
Stimulation of cingulate cortex also pro-
duces respiratory, vascular, and visceral
changes, but these, changes are less than those
produced by hypothalamic stimulation.
Interruption of the cingulum bundle, which
lies deep to the cingulate cortex and the
parahippocampal gyrus, has been proposed as
a less devastating way to produce the effects of
prefrontal lobotomy without a major reduc-
tion in intellectual capacity. (For additional dis-
cussion of the effects of stimulation and of
lesions of the anterior cingulate area on auto-
nomic function and behavior refer to Devinsky
et al, 1995)
PRINCIPAL PATHWAYS OF
THE LIMBIC SYSTEM
1. Entorhinal Reverberating Circuit (Fig.
22-12A). This fiber system is an adjunct to the
circuit described by Papez (see below). The
entorhinal reverberating circuit functions as Figure 22-12. A) The perforant pat:bway modified.
follows: From Carpenter MB Core Text of Neuroanatomy,
a. Entorhinal cortex receives input from Baltimore William and Wilkins B) The Papez
polysensory (multi-model sensory association circuit C) Sagittal section showing medial surface of
cortex) cerebral cortex and amygdala cerebrum demonstrating the limbic structures which
surround the brain stem and are on the medial sur-
b. Entorhinal fibers project via the perforant face of the cerebrum. Portions of Papez Circuit are
pathway to the granule cells of the dentate shown ineluding- fornix, anterior nuclei, mammil-
gyrus via the perforant pathway. There are lary bodies, eingulate cortex and cingulum. MR/-12.
LIMBIC SYSTEM 22-13
also direct projections to CAl, CA3 and to of the hypothalamus at the level of the inter-
subiculum ventricular foramen. Different portions of the
c. The major projection of the dentate gyrus fornix have specific names:
is to the proximal dendrites of the CA3 hip- - Portio fimbria (fringe) of the fornix
pocampal pyramidal cells. There are also found on the medial surface of the hippocam-
synapses on the neurons of the polymorphic pus and consists of fibers from the fornix and
layer. hippocampal commissure.
d. The CA3 pyramidal cells project via - Portio alveus, band of fornix fibers cover-
Schaffer collaterals to CAl pyramidal cells. ing ventricular surface of the hippocampus.
e. CAl pyramidal cells collaterals project to - Portio tenia, connecting the hippocam-
the subiculum and entorhinal cortex. pus to the corpus callosum.
f. The entorhinal cortex projects back to - Portio corpus, located underneath the
each of the neocortical polysensory projection corpus callosum and entering the hypothala-
areas completing a reverberating system. mus
2. Papez Circuit - Portio columnaris, found in the sub-
a. Many hippocampal pyramidal cells stance of the hypothalamus.
synapse on the pyramidal cells of the adjacent The fornix is also divided into a precom-
subiculum. The pyramidal cells of the subicu- missural portion (in front of the anterior com-
lum constitute the origin of most of the fibers missure), that enters the septum (from the
in the fornix, hippocampus), and the postcommissural por-
b. Fornix projects primarily to the mammil- tion (behind the anterior commissure), that
lary bodies of the hypothalamus and septum, distributes in the mammillary bodies and mid-
c. Mammillary bodies then project via the brain (from subiculum). These relationships
mammillothalamic tract to the anterior nuclei should be traced out in the atlas section.
of the thalamus, 4. Stria Terminalis. The pathway of the stria
d. Anterior thalamic nuclei project to cingu- terminalis (the efferent fiber tract of the
late gyrus, amygdala) parallels the fornix but it is found
e. Cingulate gyrus then projects via the cin- adjacent to the body and tail of the caudate
gulum bundle of fibers to the parahippocam- nucleus on its medial surface (refer to atlas
pal/entorhinal cortex, which subsequently and chapter 16) The stria terminalis inter-
projects to the hippocampus as outlined above connects the medial corticoamygdaloid
completing the circuit. nuclei, as well as connecting the amygdala
to the hypothalamus and septum. There is
3.Fornix (Figs. 22-5, 22-6, 22-7 and chap-
also a strong termination in the red nucleus
ter 16). Note that the fornix is the efferent
of the stria terminalis, which is found above
pathway from the hippocampus and subicu-
the anterior commissure and lateral to the
lum and is connected to the hypothalamus,
column of the fornix.
septum, and midbrain. This tract takes a
5. Ventral Amygdalofugal Pathway. This fiber
rather circuitous pathway to reach the hypo-
pathway originates primarily from the baso-
thalamus. The fornix originates from the
lateral amygdaloid nuclei and to a lesser
medial surface of the temporal lobe and runs
degree from the olfactory cortex, spreads
in the medial wall of the inferior horn of the
beneath the lentiform nuclei and enters the
lateral ventricle, passing onto the undersurface
lateral hypothalamus and peoptic region,
of the corpus callosum at the junction of the
the septum and the diagonal band nucleus,
inferior horn and body of the ventricles, and
Some of these fibers bypass the hypothala-
running in the medial wall of the body of the
mus and terminate on the magnocellular
lateral ventricle suspended from the corpus cal-
portions of the dorsomedial thalamic
losum. The fornix finally enters the substance
nuclei.
22-14 CHAPTER 22
6. Cingulum. This fiber bundle is found on in pseudobulbar palsy. Such patients exhibit
the medial surface of the hemisphere and inappropriate response to situations because
interconnects primarily the medial cortical the interrupted corticonuclear/ corticobul-
limbic areas, especially the parahippocampal bar pathway no longer dampens the strong
formation, with one another. descending autonomicjlimbic input to the
7. The Intracortical Association Fiber System. brain-stem cranial nuclei. The resultant
The superior and inferior longitudinal fasci- inappropriate behavior is termed emotional
culus, and uncinate fasciculus. The limbic lability. A sad story may trigger excessive
regions on the lateral surface of the hemi- crying, a funny story excessive laughter.
sphere have strong interconnections with
polysensory and third order sensory cortical m. THE NEOCORTEX OF
regions throughout the cerebral cortex THE TEMPORAL LOBE
through this system
Lateral Neocortical Areas. As regards the
8. Limbic System and the Corticospinal and
neocortical areas, (area 41) the primary audi-
Corticobulbar Pathway. The bulk of the
tory projection area, is located on the more
pyramidal pathway originates in the
anterior of the transverse gyri of Heschl (Fig.
motor/sensory strip. However, most move-
22-13). This area is a primary special sensory
ments begin with a "thought" in the frontal
region and has a pronounced layer IV (granu-
association areas. A possible example of
lar or koniocortex) similar to but considerably
release of the bulbar areas for emotional
thicker than areas 17 and 3. Area 41 receives
expression from frontal-lobe control is seen
C1rcul r
sulcus
Roof of ventricle
Fig. 22-13 The superior and medial sUrfaces of the temporal lobe. The transverse gyrus of Heschl and the relation-
ships of the temporal lobe to the gyri of other structures surrounding the syll1ian fissure are demonstrated. The tem-
poral stem refers to the core of white matter relating the temporal lobe to the remainder of the cerebral hemisphere.
The hippocampalgyrus of the figure is now termed the parahippocampalgyrus. (From Penfield, w., and Jasper,
H.: Epilepsy and the Functional Anatomy of the Human Brain. &ston, Little, Brown and Company, 1954, p.52).
LIMBIC SYSTEM 22-15
the main projection from the medial genicu-
late nucleus of the thalamus. Our understand-
ing of the tonal organization in this region
comes from studies in the monkey and chim-
panzee where the lowest frequencies project to
the more rostral areas. Some investigators limit
the term "Heschl's gyrus" to the more anteri-
or of the transverse gyri and localize the pri-
mary auditory cortex to the posterior aspects
of that gyrus (Liegeois-Chauvel et al., 1991).
The remaining neocortical areas of the
temporal lobe have a well-defined six cortical Fig. 22-14 Ejfeas offocal discharge in superior tem-
layers and are classified as homotypical. poral gyrus. The location of the discharging lesion at
Auditory and Auditory Association. Area surgery in nine patients with focal seizures begin-
42 surrounds area 41 and receives association ning with a sensation of vertigo is tkmonstrated to be
fibers from this area. Area 22, in turn, sur- primarily superior temporal gyrus (From Penfield,
rounds area 42 and communicates with areas
w., and Kristiansen, K.: Epileptic Seizure Patterns.
Springfield, Ill., Charles C. Thomas, 1951, p.49.)
41 and 42. Both areas 42 and 22 are often
designated as auditory association areas, and in I NTERPR(1IV( I Lt.US'ONS
the dominant hemisphere they are important

in understanding speech as Wernicke's area.
Visual Perceptions. The inferior temporal
areas have significant connections with area
18, providing a pathway by which visual per-
ceptions, processed at the cortical level, may
then be related to the limbic areas.
Fig. 22-15. Interpretive illusions (disturbances of
perception) produced by stimulation at surgery of
SYMPTOMS OF DISEASE temporal lobe cortex in patients with temporal lobe
INVOLVING THE TEMPORAL LOBE seizures. VISual illusions were produced pretromi-
In considering the functions of the tempo- nantly in the minor (that is, non-trominant) hemi-
sphere. Auditory illusions were produced from both
ral lobe and the effects of temporal lobe
sides chiefly in the superior temporal gyrus. Illusions
lesions, one must bear in mind as discussed offamiliarity (deja-vu) were produced predomi-
above that the temporal lobe has several struc- nantly from the non-tkJminant hemisphere.
tural, phylogenetic, and functional subdivi- Sensations offear, unreality, loneliness, or of detach-
sions. Thus, one may distinguish as discussed ment were produced from stimulation in either tem-
above: poral region. From Penfield, w., and Perot, P.:
1 - the allocortex of the hippocampal Brain, 86:599, 1963 (Oxford Univ. Press). After
Mullan and Penfield: Archives of Neurology &
formation, Psychiatry, 81:269, 1959.)
2 - the transitional mesocortex bordering
this area, reasons for this:
3 - the neocortex that occupies all of the 1. The basic lesion (such as a glioma) often
lateral surface and the inferior temporal areas. involves both neocortical and non-neocortical
4 - the amygdala already considered above areas of the temporal lobe.
When one considers disease processes 2. The threshold of the hippocampus for
affecting the temporal lobe, signs and symp- seizure discharge is relatively low, whereas that
toms obviously do not follow the precise sub- of the neocortical areas on the lateral surface is
divisions outlined above. There are several relatively high. Since connections from the
22-16 CHAPTER 22
TABLE 22-4 CORRELATION OF TEMPORAL LOBE SEIZURE

/LIMITED STIMULATION SYMPTOMS WITH ANATOMY
SYMPTOMS ANATOMICAL CORRELATION

Autonomic Amygdala. Less often cingulate
phenomena gyrus or orbital frontal
Fear, less often Amygdala
anger or other
emoHon
Fig. 22-16 Experiental responses (hallucinations) to
stimulation at surgery of temporal lobe and adjacent Crude auditory Heschl's transverse gyrus
inferior parietal area in pamn" with temporal lobe sensation: Hnnltus (primary auditory projection)
seizures. Auditory responses occur from stimulation Visual and auditory Higher order visual and audHory
in either dominant or nontUJminant hemisphere, illusions: perceptual association cortex. Superior
(primarily superior temporal gyri). VISual responses distortions (22-15) temporal gyrus In studies of
occur primarily from stimulation of the nondomi- Penfield. For visual predomlnanlly
nant hemisphere. The stippled area within the inter- non dominant hemisphere In
rupted lines indicates the posterior speech area of the studies of Penfield
dominant hemisphere. No experiential responses Vestibular sensations: Superior temporal gyrus
occur on stimulation of this speech area in the domi- dlzzinessJvertigo posterior to audHory cortex
nant hemisphere. From Penfield, w., and Perot, P., (22-14)
Brain, 86:676, 1963 (Oxford Uni1'. Press). Arrest of speech Wernicke's area and posterior
lateral temporal and inferior temporal area to speech area (posterior temporaV
parietal (angular-supramarginal)-
the hippocampus exist, seizure discharges
dominant hemisphere
beginning in the lateral temporal neocortex
Olfactory Olfactory cortex of the uncus
often activate discharge in the hippocampus. (terrninafion of lateral ollactory
hallucinations
3. Lesions in the more posterior temporal stria):Uncinate epilepsy of Jackson'
areas often involve the adjacent posterior pari- Experiential Lateral temporal cortex: primarily
etal areas, that is, the inferior parietal lobule. phenomena/dreamy superior temporal gyrus.
In contrast anteriorly placed lesions of the states: More complex Controversial. However ictal
temporal lobe often involve the adjacent infe- illusions such as phenomena Is abolished by
rior frontal gyrus. Lesions spreading into the deja vU*, deja vecu*, ablation limited to lateral temporal
jamals vu*, other neocortex (Blume et a11993,
deeper white matter of the temporal lobe (par- illusions of Mullan &Penfield, 1959)
ticularly in its middle and posterior thirds) recogniHons, visual Refer to CD ROM
often involve part or all of the optic radiation. and auditory
hallucinations (often
of past experience)
Symptoms following Stimulation of the (22-15, 22-16)
Temporal Lobe.:
Automafisms= Primary or secondary bilateral
Seizures involving the temporal lobe are repetiHve simple or involvement of amygdala I
frequent and produce a variety of symptoms. complex often hippocampus. Invariably
These may be classified as simple partial if stereotyped motor accompanied by contusion
acts, most commonly and amnesia for the acts
awareness is retained or complex partial if involving mouth,
awareness is not retained and the patient is lips etc. Speech or
amnestic for the symptoms. A simple partial limbs may be Involved.
seizure may progress to a complex partial Defects In memory Hippocampus
seizure and may subsequently generalize. recording followed by
These symptoms are outlined in Table 22-4 amnesia for the event
with the most likely anatomical correlate. 'Deja vu=Sensafion of famillartly, d* vew =Sensation of strangeness,
A detailed discussion of the correlation jamals vu =perceplion is dream like
between symptoms in simple and complex
LIMBIC SYSTEM 22-17
partial epilepsy with temporal structures is the hospital. Cranial nerves: A possible deficit
included on the CD for this chapter. in the periphery of the right visual field and a
In general, as we have indicated, there is minor right central facial weakness were pre-
mixed symptomatology during partial seizures sent. Reflexes: A right Babinski sign was pre-
of temporal lobe origin. The following case sent
history illustrates many of the points just dis- Clinical diagnosis: Simple and complex
cussed regarding seizures of temporal lobe ori- partial seizures originating left temporal lobe
gin. probably involving at various times left lateral
Case 22-1: Three months before admis- superior temporal gyrus, uncus, amygdala and
sion, this 56-year-old right-handed male baker hippocampus, with tumor the most likely eti-
had the onset of 4-minute episodes of vertigo ology in view of age and the focal neurological
and tinnitus, unrelated to position, followed findings.
by increasing forgetfulness. Later that month Laboratory data: EEG: Frequent focal
he had a generalized convulsive seizure that spike discharge was present throughout the
occurred without any warning. The patient left temporal and parietal areas consistent with
then developed episodes of confusion and a focal seizure disorder (Fig. 29-1 and CD
unresponsiveness, followed by a left frontal atlas). A recording 6 days later indicated
headache. Several studies; EEG, pneumoen- almost continuous 3 to 5 (Hz) focal slow-
cephalogram, and carotid arteriogram were all wave activity (focal damage) in the left tempo-
negative. One month before admission, the ral area (fig. 29-1 and CD Atlas). Imaging
patient began to have minor episodes, charac- studies: Left carotid arteriogram indicated a
terized by lip smacking and a vertiginous sen- possible avascular mass lesion left posterior lat-
sation, during which he reported seeing sever- eral frontal.
al well-formed, colorful scenes. At times, he Subsequent course: These episodes were
had hallucinations of "loaves of bread being eventually controlled with anticonvulsant
laid out on the wall." In addition, he would medication. Seizures recurred 7 months after
have a perceptual disturbance (e.g., objects onset of symptoms. An aura of unpleasant
would appear larger than normal). He also had odor was followed by a generalized convulsion
colorful visions and terrifYing nightmares "ter- followed by four or five subsequent seizures of
rifYing dreams, crazy things". a somewhat different character (deviation of
Neurological examination: Seizures the head and eyes to the right, then tonic and
observed: The patient had frequent transient clonic movements of the right hand spreading
episodes of distress characterized by saying, to the arm, foot, and leg lasting approximate-
"Oh, oh, oh, my" and at times accompanied ly 1 to 2 minutes, followed by a post-ictal right
by automatisms: fluttering of the eyelids, hemiparesis). He also experienced minor
smacking of the lips, and repetitive picking at seizures characterized by sensory phenomena
bedclothes with his right hand. Consciousness on the right side of the body. Neurologic
was not completely impaired during these examination now indicated progression with a
episodes, which lasted from 30 seconds to 3 marked expressive aphasia, with little sponta-
minutes. The patient reported afterward that neous speech and difficulty in naming objects.
at the onset of the seizure he had seen loaves There was a dense right homonymous hemi-
of bread on the wall and smelled a poorly anopia, a flattening of the right nasolabial fold,
described unpleasant odor. At other times, the and a right hemiparesis, with a right Babinski
olfactory hallucination was described as pleas- sign. The symptoms and findings suggested
ant, resembling the aroma of freshly baked that the basic disease process might well have
bread. Mental status: The patient was disori- spread to involve the adjacent areas across the
ented to time, could not recall his street sylvian fissure--the speech areas of the inferior
address and could not pronounce the name of frontal convolution, premotor areas, and sen-
22-18 CHAPTER 22
Figure. 22-17. Complex and simple partial seizures:

cystic-mixedglial tumor and cortical dysplasia right
temporal lobe. Case 22-2.CI' scan demonstrated an
area of atrophy or cyst right anterior temporal lobe
with possible minimum enhancement at the border.
This 17-year-old right-handed male, at age 4 years
began to have "staring spells and bizarre behavior"
with some proceeded by the "sound a musical rhythm".
An EEG spike discharge was present in the right
anterior-middle temporal area. (&for to text).
sory motor cortex. An arteriogram indicated a
large space-occupying tumor of the left tem-
poral lobe, and with additional progression,
craniotomy was performed by Dr. Robert Figure. 22-18.Glioblastoma left temporal lobe.
Yuan 16 months after the onset of symptoms. Complex partial seizures with secondary generaliza-
A necrotic glioblastoma was found involving tion in a 47 year old. Case 22-3. MRI 12 non-
the superior temporal gyrus, the deeper tem- enhanced. A) Horizontal section; B) coronal section.
(Refer to text.)
poral and extending superficially under the
Sylvian fissure to involve the adjacent posteri- occurring several times per day.
or portion of the inferior frontal gyrus. A tem- Neurological examination: Observed 3-
poral lobectomy was performed (from the minute seizure: The seizure began with loss of
anterior temporal pole posteriorly for a dis- contact and a stare and then automatisms of
tance of 6 cm). the hands. He stood up, walked around the
Today, CT scan and MRI would be room, went to the physician's desk and
employed for early diagnosis in patients with attempted to pull open a nonexistent middle
this type of seizure disorder as in the following drawer. He answered questions vaguely with
cases and surgery might be limited to a stereo- one or two word answers. Confusion was pre-
taxic biopsy. sent for 1-2 minutes after the end of the
Case 22-2. This 17-year-old right-handed episode. Cranial nerves: a left central facial
male, at age 4 years began to have "staring weakness was present.
spells and bizarre behavior." Some episodes Clinical diagnosis: Focal seizures origi-
had been preceded by the "sound of a musical nating right temporal lobe. Observed seizure
rhythm". EEG at that time indicated a right was complex partial. The seizures beginning
temporal spike discharge Seizures were con- with the musical sound might be classified as
trolled for ten years with anticonvulsants but simple partial with secondary complex partial.
then recurred and were poorly controlled Laboratory data: EEG: Intermittent focal
LIMBIC SYSTEM 22-19
spike discharge anterior-middle temporal area. Symptoms from Ablation of or damage to
CT scan (Fig.22-17): An area offocal atrophy the Temporal Lobe.
was present in the right anterior temporal lobe 1. Efftcts on Hearing. Unilateral lesion of
with possible enhancement at the border. auditory projection areaway result in an
MRI: AT the Yale Epilepsy Center was more inability to localize a sound. Bilateral lesions
consistent with a tumor in the right anterior may produce cortical deafuess.
temporal lobe. 2. Aphasia. Destruction of area 22 in the
Subsequent course: Dr. Dennis Spencer dominant hemisphere produces a
at the Yale Epilepsy Center performed a tem- Wernicke's receptive aphasia. Such a patient
poral lobectomy. This demonstrated a cystic not only has difficulty in interpreting speech
glial tumor with components of astrocytes and but also, in a sense, has lost the ability to use
oligodendrocytes. Cerebral cortex also previous auditory associations. Lesions that
demonstrated abnormal lamination and dys- deprive the receptive aphasia area of
plastic features. Seizures were fully controlled Wernicke in the dominant temporal lobe
over the next three years. (area 22) of information from the auditory
Case 22-3. This 47-year-old ambidextrous projection areas of the right and left hemi-
male experienced his first seizure one month spheres result in pure word deafuess. Such
prior to admission. He felt light-headed and a patient can hear sounds and words but is
warm. Then he was observed to walk 100 feet unable to interpret them.
down a hallway, appearing "dazed" and not 3. Visual Defects. U nilaterallesions of the tem-
recognizing people. He fell to the floor, with porallobe that involve the subcortical white
a loss of consciousness, bit his tongue and was matter often produce damage to the
confused afterwards for several minutes. geniculocalcarine radiations. Since the most
Neurological examination at 2, 16 and inferior fibers of the radiation that swing
48 hours after the episode a persistent right forward around the temporal horn (repre-
Babinski sign, and slight right hyperreflexia senting the inferior parts of the retina and
were present. referred to as "Meyer's loop") are often the
Clinical diagnosis: Complex partial first to be involved, the initial field defect
seizures. In view of age of onset and persistent may be a contralateral superior field quad-
focal signs a brain tumor should be suspected rantanopia.
as the etiology. 4. Kliiver-Bucy Syndrome. This syndrome
Laboratory diagnosis: Sleep deprived results from bilateral ablation of the tempo-
EEG: normal. CT and MRI scans (Fig. 22-18) ral pole, amygdaloid nuclei, and hippocam-
demonstrated an extensive infiltrating tumor pus in the monkey (Kluver and Bucy 1937).
of the left temporal lobe most likely a glioblas- The animals could see and find objects, but
toma. they could not identify objects (visual
Subsequent course: Despite agnosia). The animal showed marked
Anticonvulsant therapy (phenytoin) additional deficits in visual discrimination, particularly
episodes occurred over the next month: loss of in regard to visual stimuli related to various
train of thought while talking and several min- motivations. They also had a release of very
utes ofloss of memory. A subtotal resection by strong oral automatisms and compulsively
Dr. Bernard Stone (St. Vincent Hospital) placed objects in their mouths, which, if not
demonstrated a Grade III-IV astrocytoma edible, were dropped. They had a tendency
(glioblastoma). Despite radiotherapy and to mouth and touch all visible objects and
chemotherapy, the disease pursued a relentless manifested indiscriminate sexual practice.
course producing early and severe disability They willingly ate food not normally a part
prior to death, approximately one year after of their diet (such as corn-beef sandwiches).
onset of symptoms. They showed a lack of response to aversive
22-20 CHAPTER 22
stimuli and had no recollection or judg- IV. FRONTAL WBE: PREFRONTAL

ment. The animals also lost their fear CORTEX AND EMOTIONS (Areas 9,
(release phenomenon) and, in the case of 10,11,12,46,13,14)
wild monkeys, became tame and docile The term prefrontal refers to those por-
creatures. They had a marked absence of the tions of the frontal lobe anterior to the agran-
fight-or-flight response and also lost fears of ular motor and premotor areas. The prefrontal
unknown objects or objects that previously region is in a unique position in the brain as it
had frightened them. (See amygdala receives a vast stream of information from pol-
above). The problems in visual discrimina- ysensory, third order sensory and from cortical
tion may reflect a disconnection of the visu- and subcortical limbic areas including especial-
al association areas from the amygdala/ ly dorsomedial nucleus, hypothalamus and
hippocampal areas. indirectly the amygdala.
5. Memory: Bilateral damage to the hip- In the prefrontal cortex three regions are
pocampus produces a marked impairment usually delineated:
of the ability to form new associations, an 1) Lateral - dorsal convexity,
inability to establish new memories at a time 2) Medial, and
when remote memory is well preserved. 3) Orbital.
6. Unilateral effects on memory: Patients with All three are concerned with executive
resection of the left temporal lobe may lose function and relate to the dorsomedial thalam-
the ability to retain verbally related material ic nuclei. In general the lateral-dorsal relates to
but gain the ability to retain visually related motor association executive function, the
material relevant to the right hemisphere. orbital -ventral and the medial to the limbic
The reverse is true for right temporallobec- -emotional control executive system. Recent
tomy patients. studies have questioned this simplistic
7. Psychiatric disturbances: Waxman and approach. Thus certain functions previously
Geschwind (1975) have described an inter- considered to be associated with dorsolateral
ictal personality disorder characterized by location have been now localized to a medial
hypo sexuality, hyper religiosity, hyper- location (Stuss et al 2000). In addition, there
graphia, and a so-called stickiness or viscos- is evidence that dorsal lateral lesions also alter
ity in interpersonal relationships. In some affect and motivation. Moreover as the clinical
patients a psychosis may be apparent in peri- examples will demonstrate, most pathological
ods between seizures (the interictal period) processes involve the functions associated with
that is often most severe during periods more than one division either directly or
when the seizure disorder is well under con- through pressure effects.
trol. In other patients a transient psychosis Although the term prefrontal traditionally
may be related to the actual seizure dis- included areas 9, 10, 11 and 12,most studies
charge or the postictal period. There is con- of stimulation or of ablative lesions involving
troversy regarding this issue. the prefrontal areas have included, within the
8. Aggressive behavior: aggressive behavior and general meaning of the term prefrontal, areas
episodic dyscontrol may be related to dys- beyond these Brodmann designations. Thus
function of the amygdala or to damage to the posterior orbital cortex (area 13) and the
prefrontal areas, which inhibit the amyg- posteromedial orbital cortex (area 14) have
dala. This remains an area of considerable been added to the orbital frontal group (Fig.
controversy (Mark and Ervin, 1970; 18-28). These areas all share a common rela-
Geschwind, 1983 Ferguson et al, 1986). tionship to the medial dorsal nucleus of the
9. Complex partial seizures as discussed above thalamus. Areas 46 and 47, located in man on
may follow mesial temporal sclerosis. the lateral surface of the hemisphere, are also
often grouped with areas 9, 10, 11, and 12.
LIMBIC SYSTEM 22-21
Another area, the anterior cingulate gyrus and visceral contractions. These responses
(area 24) is also included in the prefrontal area, are believed to be the somatic basis of the
although it relates to the anterior thalamic emotional changes that originate in the
nuclei. Some authors (particularly in dis- limbic cortex.
cussing frontal epilepsy) also include area 8 (2) Frontal Association Areas/Lateral
and the supplementary motor cortex already Prefrontal Granular Frontal Cortex. This
discussed above in relationship to premotor region that is important in controlling
cortex. behavior lays rostral to the premotor cor-
The multiple connections of the prefrontal tex, area 6 & 8 and has already been dis-
areas are discussed by Damasio 1985, cussed in chapter 18. The frontal associa-
Goldman-Rakic 1987, Jacobson and tion areas (areas 9, 10, 11, and 12) receive
Trojanowski 1977, Nauta 1964, Pandya et al their input from the cingulate regions and
1971 and Stuss and Benson 1986. Essentially, cortical association areas in the temporal,
all sensory association and polysensory (multi- parietal and occipital lobes. They also have
modal) areas and the olfactory cortex project a strong reciprocal connection with the
to the prefrontal areas. The prefrontal areas in parvicellular portions of the dorsal medial
turn have reciprocal connections to the pre- thalamic nucleus via the anterior thalamic
motor, temporal, inferior parietal and limbic radiation. The dorsal medial thalamic
cortex. The connections to the limbic system nucleus, in turn, receives most of its input
include (a) cingulate gyrus and then via cin- from the hypothalamus and the midbrain
gulum to hippocampus and (b) uncinate fasci- limbic nuclei. The frontal association
culus. Subcortical bidirectional connections region has strong projections to the hypo-
are prominent in relationship to the medial thalamus and thalamus.
dorsal nucleus of the thalamus, amygdala, and Overview of the role of the prefrontal
hippocampus. Significant projections to the area in motor and cognitive function: this
caudate nucleus - putamen and the premotor topic has already been discussed in chapter 18.
areas provide the anatomical substrate for Stimulation complex partial seizures.
influencing motor function. Projections to the These seizures, partial seizures with impair-
superior colliculus provide the substrate for ment of consciousness, were formerly consid-
modifYing eye movements - e.g., "look to the ered to be entirely temporal lobe in origin. It
direction opposite to the target." is now recognized that 20-30% of such
Here we will briefly outline the major con- seizures are extratemporal in origin - predom-
nections of the major subdivisions inantly frontal lobe (Schwartz et al 1989,
( 1) Orbitofrontal Cortex. The orbitofrontal Williamson et al1988). Compared to complex
cortex (areas 11 and 12) receives input partial seizures of temporal lobe origin, com-
from the cingulate regions, other sections plex partial seizures of frontal lobe origin are
of the prefrontal cortex, the magnoceUular usually briefer, occur more frequently and tend
division of the dorsomedial nucleus, the to have a much shorter post ictal period of
amygdala and temporal areas. The confusion. Recent studies of St.Hi1aire at ali
orbitofrontal cortex in turn has strong Wada and Weiser (see Chauvel et al1992) sug-
projections to the autonomic regions of gest that these automatisms of orbital or medi-
the hypothalamus and magnocellular dor- al parasagittal origin are often complex involv-
somedial nucleus of the thalamus in addi- ing both arms or both legs or trunk or pelvis,
tion to the amygdala and temporal struc- at times in organized kicking, struggling, run-
tures. Stimulation of the posterior orbital ning or screaming. In contrast, automatisms of
surface, like stimulation of the cingulate, temporal lobe origin are more often oral or ali-
parahippocampal gyrus, and amygdala mentary (licking, chewing, swallowing, etc).
changes the respiration, cardiac rhythm, Such frontal lobe seizures must also be differ-
22-22 CHAPTER 22
TABLE 22-5: SUMMARY OF THE LOCALIZATION general, most studies of prefrontal function
TYPES OF FRONTAL EPILEPSY
have dealt with bilateral damage or with a uni-
lateral lesion which, because of its parasagittal
LOCATION OF SEIZURE BEHAVIORAL EFFECTS location in relation to the medial aspect of the
Supplementary motor Tonic, postural and
speech arrest; prefrontal area, has produced essentially bilat-
eral effects.
Clngulate Complex partial The first well-authenticated case of the
Anterior frontal polar Forced thinking or initial loss frontal lobe syndrome is the crowbar case of
of consciousness plus Mr. Phineas P. Gage reported by Harlow in
adversive components 1868. In an explosion in 1848, a pointed
tamping iron shot through the skull of the
Orbital frontal Complex partial plus
patient, an efficient, well-balanced, shrewd,
olfactory hallucinations
plus Illusions; and energetic railroad foreman. The bar, 3.5
feet in length and 1.25 inches in greatest diam-
Dorsolateral Tonic plus or minus aversion eter, entered below the left orbit and merged
Opercular Mastication, salivation, in the midline vertex, anterior to the coronal
swallowing plus speech suture, lacerating the superior sagittal sinus in
arrest plus or minus the process. Following the injury, a marked
epigastric and gustatory personality change was noted. The balance
symptoms (see under "between his intellectual faculties and animal
parietal) plus or minus
secondary spread to propensities" had been destroyed. He was
other simple partial. "impatient of restraint or advice which con-
flicts with his desires; at times - obstinate yet
capricious and vacillating, devising many plans
entiated from seizures of psychogenic origin of future operations which are no sooner
and from the "petit" absence seizures of gen- arranged than they are abandoned in turn for
eralized epilepsy (see Chapter 29). Thus, others appearing more feasible."
orbital frontal seizures present many features Additional studies of such patients with
previously associated with pseudo or psy- bilateral damage to prefrontal areas have been
chogenic seizures. Frontal polar seizures or reviewed by Damasio (1985), Damasio et aI,
dorsolateral convexity may present as forced 1994 and by Stuss and Benson, (1986). In
thinking or apparent absence seizures. humans, gross correlation of location of
Quesney et aI, 1990 make a distinction pathology (trauma and mass lesions) with
between discharges originating in the dorso- major behavioral syndromes has been suggest-
lateral convexity, which are more likely to pre- ed.
sent with automatisms and affective compo- (1) A syndrome of «jrontal retardation» or
nents compared to parasagittal discharges that «pseudo depression» (abulia) manifested by
are more likely to present with motor or apathy, non-concern, lack of motivational
somatosensory components. drive and a lack of motivational drive and a
The present International Classification lack of emotional reactivity has been asso-
(see Commission - 1989) provides a summary ciated with lesions involving the frontal
of the localization types of frontal epilepsy that poles and/or the medial aspects ofboth hemi-
includes more than the prefrontal areas and is spheres. In its most severe form a syn-
presented in Table 22-5: drome of akinetic mutism occurs. Some
Additional information concerning frontal have also noted aspects of this syndrome
lobe seizures/epilepsy will be found on the with dorsolateral frontal lesions.
CD ROM. (2) In contrast, the «pseudopsychopathic» syn-
Prefrontal cortex damage in humans: In drome is distinguished by a lack of inhibi-
LIMBIC SYSTEM 22-23
tion including: facetiousness
("Witzelsucht"), sexual and personal
hedonism, and lack of concern for others
has been associated with orbital frontal
pathology. Some of these patients with
ventromedial orbital lesions have been
described as manifesting confabulation, a
particular disorder of memory found in
patients with the Korsakoff syndrome; (a
syndrome in which lesions of the dorsal
medial nucleus of the thalamus have been
Figure 22-19. Prefrontal leukotomy. A surgical sec-
implicated (chapter 30». Patients with
tion has separated the prefrontal connections with the
lesions of lateral orbital and lateral convex- thalamus. Courtesy ofDr. Thomas Sabin and Dr.
ity have been described as restless, hyperki- Thomas Kemper.
netic, explosive and impulsive. As indicat-
response of patient with chronic pain previ-
ed above, damage in the dorsolateral sec-
ously requiring large doses of narcotics. Such
tor appears to result in impairment of that
studies must be interpreted with a certain
high level cognitive ability which allows for
abstraction, and creative activities. A rigid- degree of caution. In the psychiatric patients,
the lesions are produced in individuals with
ity or concreteness of response often is pre-
preoperative abnormalities of personality func-
sent. Additional discussion of the effects
of frontal lobe lesions on emotional regu- tion. The effects are not necessarily those that
the same lesion would produce in otherwise
lation will be found in Grafrnan et al
normal individuals. There is, however, a con-
1986.Most patients do not fall into these
siderable resemblance in these cases to the
discrete groups as regards the effects on
effects produced by trauma (to the prefrontal
emotion and personality and the correla-
tion with tumor location is often not pre- areas) in relatively normal individuals.
The early results did suggest that these
cise. Large prefrontal tumors often involve
procedures did produce an alteration in the
several prefrontal regions.
Prefrontal Lobotomy. Based on the initial emotional response with a reduction of anxiety
reports of Jacobsen regarding the effects of generated in conflict and painful situations.
prefrontal lobotomy on the emotional Emotional response was often detached from
responses of the Chimpanzee, Moniz, a neu- the pain and conflicts.
ropsychiatrist and Lima a neurosurgeon intro- However, these effects on emotion can
duced in 1936 the surgical procedures of pre- now be produced by the use of the tranquiliz-
frontal lobotomy to modifY the behavior and ing drugs that were developed beginning in
affect of psychotic patients. Subsequently, the middle 1950s. The development of these
Moniz introduced the procedure of prefrontal drugs, in addition to the frequent postopera-
leukotomy: bilateral disconnection of pre- tive complications including seizures and per-
frontal areas from subcortical (thalamic and sonality alterations, led to the discontinuation
basal ganglia) and other cortical areas (Fig. 22- of the procedure. (Valenstein, 1986). The
19). A more specific approach to problems of personality changes are those that have been
severe anxiety, manic behavior, and chronic elaborated above. The personality change
results from the isolation of the limbic subcor-
pain was the procedure of stereotaxic anterior
cingulotomy introduced by Ballantine et al, tical structures from input provided by the
1967. A number of lobotomies were per- prefrontal areas. Following prefrontalloboto-
formed in the 1940s and early 1950s for psy- my or leukotomy, these patients were often
chiatric reasons or to modifY the emotional impulsive and distractible. Their emotional
22-24 CHAPTER 22
responses were often uninhibited with an

apparent lack of concern over the conse-
quences of their actions. A related finding was
an inability to plan ahead for future goals; at
times, the patients were unable to postpone
gratification, responding to their motivations
of the moment. (In a sense, a loss of the real-
ity principle had occurred). Although dis-
tractible, a certain perseveration of response
was noted with an inability to shift responses
to meet a change in environmental stimuli or
cues. A rigidity and concreteness of response
was apparent with deficits in abstract reason-
ing. A somewhat similar but less drastic per-
sonality change can be produced by bilateral
severance of the anterior thalamic radiation Figure 22-21. Frontal parasagittal meningioma.
from the medial nucleus or by direct destruc- Case 22-4 refer to text. RJulioaaille brain Scan
tion of the medial nuclei or orbital cortex. (Hg197) demonstrates dense uptake in riglrt frontal
This less massive resection of cortex lessens parasagittal area.
anxiety with fewer personality changes.
this 69-year-old right handed white housewife;
Destruction of the anterior cingulate regions
visited a relative (a physician) in Israel whom
also produces this less drastic change. Current
she had not seen in a number of years. He
psychosurgical or functional neurosurgical
noted a change in the patient's personality.
procedures have been reviewed by Diering and
The patient was described as apathetic with
Bell(1991).
silly immature reactions. In retrospect, the
The results of partial or complete pre-
patient's husband felt that these alternatio~s
frontal lobotomy have shown that this region
had begun insidiously a number of years preVi-
is important in motivation, intellect, judg-
ously. Her letters became incoherent .Ten
ment, abstract reasoning, and emotional con-
months prior to evaluation, a left central facial
trol.
weakness was first noted followed two months
Parasagittal Lesions. It must be noted that
later by a decreased left arm swing. Six months
lesions (e.g., meningiomas) which were initial-
prior to evaluation, her husband noted, she
ly parasagittal or subfrontal in relation to the
was purchasing items for which she had no
prefrontal areas may, as they progress, com-
need: 24 pairs of shoes, 15 brassieres.
promise the function of adjacent premotor
Subsequently she became careless in her
areas (8 and 6 and the supplementary motor
housework. On occasions she lost her purse.
cortex). The resultant clinical picture may
Her ability to play bridge had decreased over
then include not only the changes in personal-
the last year, although her golf game was
ity but also the release of an instinctive tactile
unchanged.
grasp and of a suck reflex. An incontinence of
Neurological examination: Mental sta-
urine and feces may be present in addition to
tus: There was a marked impersistence in
an apraxia of gait - an unsteadiness of gait,
motor activities. She was often inattentive.
which is apparent as the patient attempts to
There was inappropriate joking. Her answers
stand and begins to walk but clears up once
were often irrelevant. (According to her hus-
the act has been initiated. The following case
band this had been present for many years).
histories illustrate many of the features of focal
Digit span was decreased to 5 forward and 3
disease involving the prefrontal areas.
in reverses. There were marked deficits in seri-
Case 22-4: Two years before admission,
LIMBIC SYSTEM 22-25
al 7 substractions. At times she began to sub- uted to Alzheimer's type senile dementia.
tract other numbers, at times she added rather When increased intracranial pressure and coma
than subtracted. There was a significant spatial suddenly developed, neurological and neuro-
disorientation. There was a marked impair- surgical intervention occurred.
ment in the ability to copy a cube and deficits Limbic Brain as a Functional System.
in drawing a house. There was disorientation The emotional brain is organized into a
in locating cities on a map. Cranial nerves: hierarchy of function proceeding from the
There was a significant neglect of single stim- reticular formation, including mesencephalic
ulus objects in the left visual field and a greater midbrain nuclei to the hypothalamus and thal-
neglect when bilateral simultaneous stimuli amus to the limbic and neocortical regions.
were utilized. At times there was a limitation Reticular Formation. The reticular forma-
of voluntary gaze to the left. A left central tion is the site where information is received
facial weakness was present. Motor system: from the peripheral nerves. This system is so
There was minimal weakness of the left arm organized that only certain stimuli trigger it to
and leg. Variable resistance was present on pas- alert the brain. If it were possible for any
sive motion at left wrist and elbow suggesting response to trigger this system, then the indi-
the "gegenhalten"of frontal lobe disease. vidual's survival would be threatened. The
There was a decreased swing of the left arm in response, however, is selective because
walking. The gait was initially apraxic but throughout our lives we have evolved a set of
improved as the patient picked up speed. emotional responses that determine whether
Reflexes Deep tendon stretch reflexes were we will respond to situations calmly or with
increased on the left, with a left Babinski sign rage or fear. What happens is that the reticu-
and a bilateral release of the grasp reflex. lar system, based on the sensory information
Clinical diagnosis: Right frontal lobe with probably some subconscious cortical
tumor: probably a meningioma based on the assistance, focuses the attention by sorting out
long history. the relevant information, thus enabling the
Laboratory data: EEG (Fig 22-20 on CD central nervous system to continue function-
Atlas), and imaging studies (Fig. 22-21) all ing efficiently throughout a crisis.
indicated a right frontal parasagittal lesion. A Hypothalamus. By the time the data reach-
meningioma was considered most likely since es the hypothalamus there are already distinct,
vascular supply was derived from the left and well-organized emotional responses. The
right middle meningeal and left anterior hypothalamus, with some assistance from the
meningeal arteries. thalamus, sets the level of arousal needed for
Hospital course: At craniotomy, Dr. the emotional state and organizes and mobi-
Samuel Brendler found a large right posterior lizes the cortical and subcortical centers (espe-
parasagittal frontal fibrous, meningothelial cially the autonomic nervous system).
meningioma measuring 8x8cm attached to the Pleasure/punishment Areas. Throughout
right side of the superior sagittal sinus. the limbic brain are found pleasure or punish-
Case history 22-5 presented on CD ROM ment centers. These were located by implanti-
provides an example of a patient with a slowly ng electrodes at various subcortical sites in an
progressive subfrontal meningioma manifested animal and training it to press a bar that con-
by symptoms of apathy, loss of ambition, nects the electrode to an electrical current
"depression" of mood, emotional lability, with (Olds, 1958). If the electrode is in certain
a tendency to introspection and a slowness of pleasure centers, the animal will self-stimulate
mental processes. All of these symptoms were until it is exhausted. In fact, the animal would
initially attributed to depression and a rather press the lever than eat. The pleasure
hypothyroid state. As gait and memory prob- centers are located throughout the limbic sys-
lems developed, these symptoms were attrib- tem, but especially in the septum and preoptic
22-26 CHAPTER 22
TABLE 22-6:THE NEUROLOGICAL SUBSTRATES OF PSYCHIATRIC DISORDERS
DISORDER DEFINING FEATURES NEUROLOGIC CORRELATE

SChizophrenia Progressive psychotic* disturbance Based on neuropathology, MRI, PET
with deterioraHon
-Positive symptoms: thought disorder: -Decreased gray matter in temporal areas- left
delusions and hallucinations posterior superior temporal and mesial temporal
-Negative symptoms: poverty of speech,
decreased movements poverty of affect, -Prefrontal, left parietal and bilateral temporal
withdrawal from interpersonal relations
Rx
Respond to neuroleptics**
Affective disorders Majority is not psychotic. Disorder is not In post stroke depression, variable location of
progressive and no deterioration occurs. infarct: Iefllateral frontal &basal ganglia, or right
-Bipolar frontal or right temporal/parietal
-Unipolar-manic - Metabolites norepinephrine (+) in csI
-Unipolar depression *** - Norepinephrine &serotonin (-),
Also Hypothalamic with (+) ACTH
Anxiety/panic Autonomic acHvation Is similar to Brain stem adrenergic and serotonergic centers
pattern with fear responses are implicated in anxiety. In panic attack patients
blood now to right limbic system increased
between attacks
Obsessive/compulsive Recurring thoughts trigger Increased metabolic activity in dorsolateral

repetitive motor acts. prefrontal, anterior cingulate and caudate nucleus
Personality disorders Various types: hysterical, passive Pseudopsychopathic syndrome may follow
aggressive, antisocial (overlaps with prefrontal damage. Studies of violent antisocial
criminal), passive dependent, schizoid, individuals indicate smaller prefrontal areas
obsessive/compulsive, paranoid
Autism Retarded development of social/emotional Cerebellar hypoplasia plus alterations in many

interactions with development of limbic structures Including amygdala,
stereotyped motor automatisms hippocampus, entorhinal cortex, septal nuclei,
mammillary
Asperger's Milder form of autism Neocortical migration disorders
* Psychosls::gross Impainnenlln realHy testing atIecIing perception, thought and insight.

** Neuroleptics=dopamlne antagoniSis
*** AntI depressants such as tricyclic agents and monoamine oxidase inhibitors increase norepinephrine and serotonin at seleclive recep-
tor sites in hypothalamus and the limbic system by inhibition 01 reuptoke 01 biogenic amlnes. Seleclive serotonin reuptoke Inhibitors
(SSRrs) are elleclive for less severe cases 01 depression. For mania and bipolar disorder, IHhium carbonate is alleclive. Neurolepllcs may
decrease manic behavior. For severe atIecIive disorders electroshock theropy may be utilized.
region of the hypothalamus. ations of the viscera continue. In a mildly

Other brain centers when stimulated pro- stressful situation, such as one involving anger
duce fear responses: pupil dilation, piloerec- or heavy work, some of the digestive processes
tion, and sweating. In these "punishment slow down, and the heart rate and blood flow
regions," located in the amygdala, hypothala- increase. If the situation is threatening--trig-
mus, thalamus, and midbrain tegmentum, the gering the reactions of fear, pain, intense
animal quickly stops pressing the bar. If the hunger or thirst, or sexual arousal--most of the
situation is non-threatening, the normal oper- digestive processes slow down and heart rate,
LIMBIC SYSTEM 22-27
blood flow, and respiration increase. Once the Various types of dysfunction in this system
threatening situation passes, conditions quick- will produce those significant alterations in
ly return to a normal balance between the behavior that represent the spectrum of psy-
sympathetic and parasympathetic nervous sys- chiatric disease, briefly summarized in the next
tems. section
Limbic Cortical Regions. The limbic corti-
cal regions are strongly influenced by the emo- The Role Of The Limbic System
tional patterns set by the hypothalamus and In Psychiatric Disorders
amygdala which are then transmitted with
The involvement of the limbic system
only a very few synaptic interruptions into the
either from a structural or functional stand-
limbic cortex where the emotional pattern is
point is central to the psychiatric disorders
elaborated and efficiently organized. The neo-
which affect large numbers of patients. These
cortex (prefrontal cortex and, to a lesser
disorders may affect perception, cognition and
degree, the temporal lobe), based on past
affect.
experience, examines the situation, sorts out
The neurological substrate is presented in
the emotional responses from the intellectual,
Table 22-6. The epidemiology and genetics of
and inhibits or controls the situation based on
the major disorders are presented in Table 22-
what past experience has proven to be expedi-
7. Additional information will be found on
ent for individual survival.
the CD ROM.
Consider the following examples: a moth-
er responds to her baby's crying, while the
father sleeps on; in the middle of the night a
jet airplane thundering overhead causes no
response, while a whiff of smoke or breaking
glass quickly arouses the central nervous sys-
tem and keeps it focused.
TABLE 22-7: EPIDEMIOLOGY AND GENETIC ASPECTS

OF THE MAJOR PSYCHIATRIC DISORDERS·
Disorder Population Concordance in Concordance in Dizygotic

Frequency % Monozygotic Twins % twins, Siblings, Parents %
Schizophrenia 0.5-1 68** 11
Affective disorders 10-20 14-25**
-Unipolar 18-19 40 11
-Bipolar 1-2 72 14
* Anxiely disorders and personality disorders aIfecIlarge numbers of Ihe population

** Risk is unchanged when adopted at birth and removed from biologic family
CHAPTER 23
Visual System
INTRODUCTION 1. The outer fibrous tunic - cornea and

Of all our senses, vision is the most impor- sclera.
tant: we perceive the world mostly through 2. The middle vascular and pigmented
our eyes. Even though light intensity varies by tunic - choroid, ciliary body, iris and pupil.
a factor of 10 million between the brightest 3. The inner neural tunic - retina with pig-
snowy day and a starlit night, our eyes and mented epithelium and neuronal layers.
visual system adapt to these intensity changes. The outer fibrous tunic consists of two
We can discriminate between thousands of parts: the anterior transparent cornea and the
hues and shades of color. Our eyes are set in posterior fibrous white sclera.
our heads in such a way that each eye sees The cornea, the window to the world,
almost the same visual field, making depth per- allows light rays to enter the eye. Most of the
ception possible. refraction needed to focus light rays on the
In the visual system the primary, secondary, retina occurs at the air-cornea junction. The
and tertiary neurons are in the retinae and are sclera forms the white of the eye and the rest
all part of the central nervous system. The of the outer covering.
right field of vision projects to the left cerebral Middle Tunic- the choroid, the ciliary
hemisphere; the left field of vision projects to body, and the iris. The middle tunic is richly
the right cerebral hemisphere. vascular and provides oxygen and nutrients to
the inner, photoreceptor layer, and the retina.
STRUCTURE OF THE EYE
The choroid is vascular and pigmented and
The anatomy of the receptor organ, the forms the posterior portion of this tunic. Its
eye is shown in Figure 23-1. It has three layers, inner portion is attached to the pigmented
or tunics: layer of the retina. The ciliary body is found in
the anterior portion of the middle tunic and
consists of a vascular tunic and the ciliary mus-
cle. The ciliary body surrounds the lens and
consists of a vascular tunic (the ciliary muscle)
_0
0..0
and the suspensory ligaments (the zonule),
which suspend the lens (Fig 23-1BJ. The cil-
iary muscles consist of meridional and circular
\.OfO<ol
Nchl, .. fibers. The meridional fibers are external to the
circular fibers. The ciliary muscles are the mus-
cles used in accommodation, focusing on near
objects.
Lens. The lens separates the anterior
chamber from the vitreous body and com-
pletes the refraction of the entering light. A
fibrous network, the zonule, suspends the
lens. For distance vision the fibers are taut and
Figure 23-lA. Horizontal meridional section of the the anterior surface of the lens is pulled flat.
eye. (From Iason and Usson. 1970. Histology, For close vision the ciliary muscle contracts,
Philadelphia, W.B.Saunders.)
23-2 CHAPTER 23
and the dilator pupillae. When the circular

muscles, the sphincter pupillae contract, the
iris is drawn together and the pupil constricts,
such as purse strings close the mouth of the
purse. The second set of muscles, the dilator
pupillae, are radial and draw the iris back
toward the sclera.
The sphincter pupillae are supplied by the
parasympathetic nervous system via the ciliary
nerves, the fibers of which run together with
nerve III. Transmission by this pathway is
cholinergic, the dilator pupilla are supplied by
the sympathetic nervous system via the superi-
or cervical ganglion. Neurotransmission in this
pathway is alpha-adrenergic.
Pupillary Reflexes. When light is flashed
into either eye, the pupil dilates, the light
reflex. When the eye focuses on close objects,
Figure 23-1B.Enlargement of a potion of the merid- accommodation occurs
ional section ro shuw the angle of the eye. The letter P 1. Light Reflex. In dim light the aperture of
indicates the pectinate ligament or the trabecular the pupil increases (dilator muscle) while in
meshwork. The arruws indicate the course of circula- bright light the aperture of the pupil
tion of aqueous fluid. (From Leeson and ueson,
decreases (sphincter muscle). The afferent
Histology, Philadelphia, WB Saunders, 1970.)
fibers arise in the retina and travel with the
the fibers go slack, and the anterior surface optic nerve and tract, these fibers pass
becomes more convex; the eye accommo- through the lateral geniculate and synapse
dates. A decreased ability to focus on close in the pretectal region of the midbrain.
objects is a normal consequence of aging. The Neurons of the pretectal nuclei project
term ''visual acuity" refers to the resolving bilaterally to the Edinger-Westphal nucleus.
power of the eye in terms of the ability to focus 2. Accommodation. This reflex changes the
on near or distant objects. For example, refractive power of the lens by the ciliary
23/40 means the patient's eye sees at 23 feet muscle contracting and decreasing the force
what the normal eye sees at 40 feet. on the suspensory ligament of the lens; the
The pigmented iris on the anterior portion lens assumes a more rounded appearance
of the vascular tunic divides the space between with a shorter focal length. The neural path-
the lens and the cornea into an anterior cham- way arises in the occipital lobe and the final
ber (between the lens and the cornea) and a efferent fibers run together with nerve III.
narrow posterior chamber (between the sus- In looking at distant objects the pupil
pensory ligaments of the lens and the iris). The dilates while in focusing on nearby objects
iris is a circular structure that acts as a the pupil constricts.
diaphragm to control the amount of light 3. Fixed Pupil. In the absence of trauma to the
falling on the retina. The opening is analogous eye, a dilated pupil that does not respond to
to the f-stop of a camera. The eye has a range light, fixed, is usually a sign of pressure on
equivalent to the range from £2 to £22. the third nerve. This is typically from supra-
PUPILLARY REFLEXES tentorial mass lesions that have produced
Pupillary Muscles. Two sets of muscles in herniation of the mesial segments of the
temporal lobe through the tentorium.
the iris control the size of the pupil, sphincter
Compression of the third nerve and of the
VISUAL SYSTEM 23-3
midbrain occurs. Progressive rostral- caudal
damage to the brain stem then evolves. This
problem when first detected must be treat-
ed as a neurosurgical emergency.
Inner Tunic, Retina - pars optica, pars cil-
iaris, and pars iridica. The inner tunic contains
photoreceptor cells and nerve cells. They are
organized so that photoreceptor cells contain-
ing the photopigments are closet to the sclera
and the nerve cells are above them. The nerve
cells send fibers to the optic nerve through a
pigment-free area, the optic disc. Light must
traverse the nerve network to reach the pho-
toreceptors.
The pars ciliaris and iridica are primarily a
pigmented region on respectively the ciliary
body and iris. The pars optica contains the GanglIOn c:ell1aver
photoreceptor cells and will be the focus of

our discussion.
The pars optica contains:
- outer pigmented layer,
- inner photoreceptor cells closest to the sclera, Figure 23-2 A. Schematic diagram of the ultrastruc-
- nerve cells that are internal to photorecep- tural o19anization of the retina. Rods and cones are
composed of outer (OS) and inner segments (IS), cell
tors and form the optic nerve that leaves the
bodies, and synaptic bases. Photopigments are present
retinae through a pigment-free area, the optic in laminated discs in the outer segments. The synaptic
disk. Light must traverse the nerve network to base of a rod is called a spherule; the synaptic base of a
reach the photoreceptors. cone is called a pedicle. Abbrwiations: RB =bipolar
The pars optica of the retina consists of the cells, MB=midget bipolar cell, FB a flat bipolar cel~
following layers (Fig.23-2A): AM =amacrine cel~ MG =midgetganglion cell, DG
= diffuse ganglion cell. (From Carpenter, M.BA Core
1. Pigmented epithelium (most external),
Text of Neuroanaromy Baltimore, Williams and
2. Receptor cell layer - rods and cones, Wilkins).
3. External limiting membrane,
4 . Outer nuclear layer containing the nuclei There are two types of photoreceptor cells:
of rods and cones, rods and cones.
5.0uter plexiform layer- containing the The rods are sensitive in dim light as they
synapses of rods and cones with the dendrites contain more of the photosensitive pigment
of bipolar and horizontal cells, and the cell rhodopsin than the cones. This system has
bodies of horizontal cells, poor resolution; newspaper headlines are the
6. Inner nuclear layer- containing the cell smallest letters that can be recognized.
bodies of bipolar, and amacrine cells, The cones are sensitive to color. There are
7. Inner plexiform layer- containing the there separate groups of cones each of which
synapses of bipolar and amacrine cells with contains photopigments that are primarily sen-
ganglion cells, sitive 1) to blue - short wave lengths, 2) to
8. Ganglion cell layer, green - middle wave lengths, or 3) to red
9. Optic nerve layer, and longer wave lengths. Color vision requires
10. Internal limiting membrane. light levels greater than bright moonlight and
Photoreceptors - Rods and Cones. has high resolution-fine detail can be seen.
The rods and cones are not uniformly distrib-
23-4 CHAPTER 23
• CONES
o RODS
uted in the retina. Most of the 6 million cone Figure 23-2B. The densitiet ofcones and rods on or
cells are located in an area 2 mm in diameter, near the horizontal meridian through a human reti-
the macula lutea (Fig. 23-1,), which can be na. The insert is a schematic map of the retina showing
the fwea (F) and the blind spot (B). The striped area
seen through the ophthalmoscope. In the
represents the regions of the retina, which were SIImpled
center of the macula lutea lies a zone of pure in obtaining the counts plotted here. From Chapanis
cones, the fovea (Fig. 23-2B). The rest of the aftn' 0sterberg,.Aaa Opth, 1935, Suppl.6 (Bltukwell).
macula lutea is composed of both rods and
cones, and most of the peripheral retina con-
1.0
tains only rods. There are about 123 million
.9
rods.
.8
Rods - VISion in Dim Light
and Night VISion
... .1
CI)
3·&
The rods permit vision, scotopic (dark vision), ~.5
in the dark-adapted eye. Rods contain a single
pigment, rhodopsin, which is related to vitamin
Al (retinol). The spectral sensitivity of night or
.1
scotopic vision is identical to the absOlption
spectra of rhodopsin (Fig 23-3) light that can 400 SOO 600
be absorbed by rhodopsin is seen; light that
WAVELENGTH IN mlt.
cannot be absorbed such as red light is not Figure 23-3. Comparison ofthe absorption CUYJ1e of
seen at these low light intensities. Scotopic pure visual purple (interrupted line) with the intensi-
vision has quite poor definition; two light ~ of light just risible in a dark-adapted human subject
sources must be quite far apart to be distin- (continuous cUYJ1e). From Luthigh, Arch.Ophtha1.2O:
713.1938 (AMA).
guished as two sources rather than one.
Peripheral vision has progressively poor defin- such as night goggles with infrared sensors, are
ition. The modem human uses this system designed to compensate for these limitations.
very little since we have bright, portable light The visual pigment, rhodopsin absorbs
sources or radar. Several modem inventions, photons. Each rhodopsin molecule consists of
VISUAL SYSTEM 23-5
retinal and opsin. Retinal absorbs the light 1. Blue -423 nm (short wavelengths),
while opsin is the protein in the plasma mem- 2. Green -530 nm (middle wave lengths),
brane of the rods. The photon converts retinal and
from the II-cis form to the all-trans form. The 3. Red - 560 nm (longer wavelengths).
all-trans retinal has to be re isomerized to 11- Color vision requires light levels greater than
cis retinal to reform rhodopsin and to begin bright moonlight and has high resolution so
the process again. The photons result in hyper- that fine detail can be seen. Any color that
polarization of the plasma membrane that is does not excite two pigments, such as deep
the light dependent part of visual excitation. purple (400 nm) and deep red (650 nm) will
The photoreceptors are depolarized in the be hard to discriminate. For this reason, a
dark due to the sodium channels remaining color of 660 nm in bright light can mimic a
open, called the dark currents. The dark cur- color of 640 nm in weaker light. To distin-
rent is turned off in light. Daylight prevents guish the color orange, 600 nm, the visual sys-
the regeneration of rhodopsin in the rods. tem compares the relative absorption by two
After 5-10 minutes in the dark, scotopic visual pigments, in this case red and green.
vision begins to return as the rhodopsin is Comparing the absorption by one visual
regenerated, and reaches maximal sensitivity pigment to the overall brightness apparently
after 15 to 23 minutes. Since rhodopsin does makes these color discriminations. For this rea-
not absorb red light, using red goggles can son a color of 660nm, in bright light, mimics
preserve night vision. a color of 640 nm in weaker light. Only when
Cones - Color VISion the two types of cones are excited can color
and brightness be determined independently.
Color vision requires much higher light inten-
sities and occurs primarily when the image is Electrophysiology of Retinal
focused upon the macula. Each cone contains Photoreceptors and Neurons.
one of the three-color pigments whose Synaptic Organization of the Rods,
absorption spectra are shown in Fieure 23-4. Cones and Neurons in the Retinae (Figure
The visual pigment of the cones consists of 23-2A)
opsin and retinal. 1. Rods and cones synapse on the den-
The cones are divided into three separate drites of bipolar cells and horizontal
groups that contain photopigments primarily cells. In the peripheral portion of the retina,
sensitive to a different part of the visible spec- 60 degrees from the center, as many as 600
trum as follows: rods may converge on single bipolar cell, while
in the fovea, only one or two cones may do so.
BI.LE GHEEN HED In the macula lutea both rods and cones may
" ....
I
" '110\
,
.....",.............. innervate a single bipolar cell.
,. \/1 \':. 2. Axons of bipolar cells and amacrine cells
:\
... synapse on dendrites of ganglion cells. Once
\
\
./ \
./ \ \
again, the degree of convergence on the gan-
/' \ ... glion cell depends on the region of the retina.
" \ "\
\ ........... Ganglion cells in the fovea connect with only
one bipolar cell.
~ O+---,---~--~---r---r--~
380 440 500 560 620 680 740 3. Axons of ganglion cells leave the retina;
form the II cranial nerve that synapses in the
WAVELENGTH (MILLIMICRONS) lateral geniculate, hypothalamus, and mid-
Figure 23-4. The absorption spectra of three types of brain. There are about a million optic nerve
cones. (Drawn from records in Marks, Dobelle, and fibers. Clearly, considerable data reduction has
MRcNiehol. 1964. Science 143:1181; and Brown and occurred between the 100 million rods and
Wald.1964. Science 144:45.)
23-6 CHAPTER 23
cones and the one million optic nerve fibers. a hyperpolarizing response to light. This very
Two other types of neurons are found in surprising result has been obtained in all verte-
the retina: horizontal and amacrine cells. brate visual receptors studied to date.
Horizontal cells are found in the outer plexi- Contrary to what one would expect, they act
form layer (next to the rods and cones); their as if dark were the stimulus. During darkness,
dendrites make contact with numerous rods high concentrations of cyclic GMP increase
and cones over a 230 to 400-pM field. Their membrane conductance and give rise to a dark
axons run transversely along the retina and current that flows from the outer to inner seg-
branch to make contact with many other rods ment, depolarizing the cell. After absorbing a
or cones at the bipolar-cell junction. The hor- photon, rhodopsin activates cyclic-GMP-
izontal cells connect groups of visual receptors phosphodiesterase, which cleaves cyclic GMP,
in one area with groups in another area. lowers cyclic GMP levels, and by reducing the
Amacrine cells lie in the inner plexiform layer membrane conductance, hyperpolarizes the
(next to the ganglion cells). The dendrites rod. Also contrary to expectation, the rod and
form postsynaptic contacts with bipolar cells cone cells release transmitter when it is dark,
and presynaptic contacts with ganglion cells; but this release ceases when it is light.
no axon has been described. Horizontal Cell of retinae - hyperpolarizes
Response of the cells to light (Fig. 23-5) in response to light, but it has a large receptive
field. Even when the light is shining on recep-
Rods and Cones. Both rods and cones show tor cells 250pm away, there is a strong hyper-
..... polarizing response. Potential spread through
the horizontal layer is by slow potentials; no
. .CIPTO. ClLL
action potentials have been observed.
Bipolar Cell: Both the direct hyperpolariz-
ing receptor response and the horizontal-cell
Imll~$'
output impinge on the bipolar cell. Here we
mQ:iEEE5 see the first type of data reduction carried out
.$'
Hp.'ZONT... L CILL
in the retina: center surround contrast

enhancement. The bipolar cell has one type of
output--hyperpolarization--for a bright spot
.'POL .... CILL
on a dark field and another type of output--
depolarization--for a large bright field.
Amacrine Cell. Recordings from the
ffilHHffE . . M ... C.'Na ClU
amacrine cell show that it responds primarily
to sudden changes in light intensity. Note that
it is active primarily when the light turns on or
off. This is the second type of processing, or
+. ~TI data reduction, that takes place in the retina:
. '
t O... NOL'ON CILI.I
dynamic detection.
Ganglion Cells. There are two types of gan-
glion-cell responses -amacrine or bipolar cell .
i- r-' rr I- ..L-
-;;r::-____
.. Amacrine Cell Response. This response is,
primarily a dynamic response to turning the
,~- ~-:~
light on or off. Some cells react more strong-
ly to the light coming on than off; others have
Figure 23-5. Responses of the cell types in the Necturus the opposite response. These cells are inhibit-
retina. From ES. Werblin and ].Dowling. 1969.]. ed by illumination of both a spot and the sur-
Neurophysiol. 32:339 (Amer. Physiol. Soc.) rounding area.
VISUAL SYSTEM 23-7
Bipolar Cell Response. The second type of receive much more attention in the optic
ganglion-cell response reflects bipolar-cell nerve bandwidth if it is moved around because
activity. When only the central portion of its each tiny movement will set of a new set of
receptive fields is illuminated, the ganglion cell dynamic or movement receptors and these
responds with an intense train of action poten- receptors make up about half the total optic
tials during the illumination that abruptly nerve fibers. For example the rotating flashing
stops when the light ceases. The frequency of lights of emergency vehicles attracts more
the action potentials during illumination is attention than a fixed light.
proportional to the logarithm of the bright- VISUAL PATHWAY (Fig.23-6)
ness of the light. When both the spot and the
1. Origin of Cranial Nerve II from gan-
surrounding area are illuminated, there is less
activity than occurs in the dark (the back-
ground level). When only the surround is illu-
minated, there is no specific response.
A third type of ganglion cell response (not
shown in figure 23 -5)- is a center off type.
When the center of the receptive field is illu-
minated, action potentials frequency decreas-
es. When the surround is illuminated activity is
greater than the background level, but not as
intense as in the second type of response to a
spot noted above.
To summarizeganglion cells signal the onset
and cessation of light flashes and are effectively
stimulated only by edges or abrupt transitions
between light and darkness in their fields.
Diffuse illumination does not stimulate gan-
glion cells very well. Vhual (Otfo
The axons from the ganglion cells traverse (Gr,o 17)
the inner surface of the retina to the optic disk,

where they turn and form the optic nerve, Ltft oct.lpital cortu
which runs for about 1 inch before entering Figure 23-6. The lIisual pathways lIiewed from the lIen-
the optic foramen on its way toward the dien- tral surface of the brain. Ligl1t from the upper half of
cephalon. the lIisual field falls on the inferior half of the retina.
Optic Nerve. Electrical recordings from Ligl1t from the temporal half of the lIisual field falls on
optic nerve fibers also show the types of data the nasal half of the retina; ligl1t from the nasal half of
the lIisual field falls on the temporal half of the retina.
reduction occurring in the retina. First there is
The lIisual pathwaysfrom the retina to the striate c0r-
convergence; many receptors must fire one tex are shown. The plane of the lIisual fields has been
bipolar cell in the fovea Consequently the rotated 90 tkgrees toward the reader. The inset (lower
"grain"of the visual image depends on the left) shows the projection of the quadrants of the rigl1t
location on the retinae. Second brightness can lIisual field on the left calcarine (striate) cortex. The
be detected. Third there is a center surround macular area of the retina is represented nearest the
contrast enhancement. Lastly there is a occipital pole. Fibers mediating the pupillary ligl1t
reflex lealle the optic tract and project to the pretectal
dynamic or motion detection. region; fibers from the pretectal olillary nucleus relay
A spot of light on the retinae will be coded signals bilaterally to the lIisceral nuclei of the oculomo-
in terms of its brightness and its edges. As it is tor complex. (Modified from Carpenter and Sutin.
turned on and off, the dynamic receptors fire 1983. Human Neuroanatomy. Courtesy of Williams
to alert higher centers. The spot of light will and Wilkins.)
23-8 CHAPTER 23
glion cell layer in the retina, By this crossing, all the information from
2. Optic nerve, the left visual field is brought to the right lat-
3. Optic chiasm, eral geniculate nucleus and subsequently to
4. Optic tract, the right calcarine cortex. The fibers of the
5. Synapse in lateral geniculate nucleus of right nasal retina also cross in the chiasm to
the thalamus, join the fibers from the left temporal retina.
6. Visual radiation from lateral geniculate Thus, the visual pathway repeats the pattern in
nucleus to the striate (visual) cortex - area 17 other sensory systems; the right side of the
of the occipital lobe, visual field is represented on the left cerebrum.
7. Visual association cortex - areas 18 and
Lesions in the Optic Pathway:
19,and
8. Multimodal associations with cortical 1. In the retina or the optic nerve before
regions in the posterior temporal-parietal, and the optic chiasm (2 in Figure 23-7) there is no
frontal lobes in both hemispheres (Fig. 18- sight in that eye - monocular blindness.
11). 2.In the chiasm, the fibers from both tem-
poral visual fields are cut; the result is bitem-
VISUAL FIELDS
poral hemianopsia (3 in Figure 23-7)
Retina. 3. Lesions behind the optic chiasm pro-
duce blindness in one visual field, a homony-
Each retina is divided into a temporal or
mous hemianopsia from injury to the optic
nasal halfby a vertical line passing through the
tract, the lateral geniculate body or the genicu-
fovea centralis. This also serves to divide the
retina of each eye into a left and right half. A
PATlEHT's JIC1\JAI..
horizontal line passing through the fovea VISUAL FlELD
would divide each half of the retina and mac-
ula into an upper and lower quadrant. Each
area of the retina corresponds to a particular
sector of the visual fields, which are named as
viewed by the patient. For each eye tested
alone, there is a left and right visual field cor-
responding to a nasal and temporal field.
Because of the effect of the lens, the patient's
left visual field projects onto the nasal retina of
the left eye and the temporal retina of the right
eye. Similarly, the upper visual quadrants pro-
ject to the inferior retinal quadrants.
Optic Nerve and Optic Chiasm.
At the chiasm, the fibers in the optic nerve
from the left nasal retina cross the midline and
join with the fibers from the right temporal
Figure 23-7. Common lesions of the optic tract.1)
retina to form the right optic tract. This dense Norma~ 2) optic ner1Ie, 3) optic chimm, 4) optic
bundle of over a million fibers runs across the tract or complete geniculate or complete geniculocal-
base of the cerebrum to the lateral geniculate carine radiation or complete cortical 5) temporal
nucleus of the thalamus. Fibers from the infe- segment ofgeniculocalcarine radiation (Meyer's
rior nasal retina (the superior, temporal visual loop) producing a superior quadrantanopia. If the
parietal segment of this radiation were involved, an
field) cross in the inferior portion of the chi-
inftrior quadrantanopia would result. 6) Calcarine
asm, which usually lies just above the dorsum or posterior cerebral artery occlusion producing a
sellae. homonymous hemianopia with macular sparing.
VISUAL SYSTEM 23-9
localcarine radiation (4 in Figure 23-7). field of the right eye; only vague outlines of
4. Partial lesions of the geniculocalcarine objects could be seen. A slight left central
radiations produce a quadrantanopsia (5 in fig- facial weakness was present. Motor System:
ure 23-7). movements on the left side were slow.
5. Macular sparing is seen with lesions in Reflexes: A release of grasp reflex was present
the visual cortex following calcarine artery on the left side.
infarcts (6 in Figure 23-7). The macula is rep- Clinical diagnosis: Subfrontal menin-
resented close to the occipital pole and this gioma rising from the inner third sphenoid
area receives anastomotic flow from the mid- wing. Alternative location would be olfactory
dle cerebral artery. groove.
The following case is an example of a lesion Laboratory data: Imaging studies demon-
in the optic nerve, anterior to the optic chiasm. strated a tumor blush in the right subfrontal
Case History 23-1: This 53-year-old region extending back to the right optic nerve
white right-handed housewife had a progres- groove consistent with a meningioma arising
sive 23-year history of right-sided supraorbital from the olfactory groove or inner third sphe-
headache with decreasing acuity and now noid wing, (Fig. 23-8)
almost total blindness in the right eye. During Hospital Course: A bifrontal craniotomy
the 3 years before admission, intermittent tin- performed by DR. Sam Brendler exposed a
gling paresthesia had been noted in the left well-encapsulated smooth tumor a menin-
face, arm, or leg. About 1 year before admis- gioma attached to the inner third of the sphe-
sion, the patient had a sudden loss of con- noid wing. Approximately 90 to 95% of the
sciousness and was amnestic for the events of tumor was removed exposing the right optic
the next 48 hours. No explanation for the nerve. Examination 4 months after surgery
episode was clearly established. The cere- indicated right anosmia and right optic atro-
brospinal fluid protein was reported to be ele-
vated (230 mg/dl). The patient and her fami-
ly reported some personality changes over a
period of several years, including a loss of
spontaneity and increasing apathy.
General Physical Examination: There
was a minor degree of proptosis (downward
protrusion of the right eye).
Neurologic Examination: Mental Status:
The patient was, in general, alert but at times
would become lethargic. Her affect was flat.
At times, she would laugh or joke in an inap-
propriate manner. Cranial Nerves: There was
anosmia for odors, such as cloves, on the right
and a reduced sensitivity on the left. Marked
papilledema (increased intracranial pressure
with elevation of the optic disk and venous
engorgement was present in the left eye. In
Figure 23-8. Sphenoid-wing meningioma producing
contrast, there was pallor of the right optic rompression of the right optic and olfactory nerves.
disk indicating optic atrophy. Visual acuity in Case 23-1 Refor to text. Right carotid arteriogram,
the right eye was markedly reduced. This com- venous phase demonstrating tumor blush in the sub-
bination of funduscopic findings is termed the frontal area of the anterior fossa, extending into the
Foster Kennedy syndrome. The patient had middle fossa. (Courtesy of Dr. Samuel Wolpert. New
only a small crescent of vision in the temporal England Medical Center Hospitals.)
23-10 CHAPTER 23
phy were present. bitemporal hemianopsia or an incomplete

Optic Chiasm: A bitemporal defect results bitemporal field defect. The usual cause is a
(Fig. 23-9, 23-10, 23-11). This may be a pituitary adenoma or a supra sellar tumor such
as a craniopharyngioma.
Case 23-2. Patient of Dr. Martha Fehr.
This 45-year-old man had an I8-month histo-
ry of a progressive alteration in vision. He was
unable to see objects in the right or left periph-
ery of vision. He was concerned that in the
process of driving he might hit pedestrians
stepping off the sidewalks in the periphery of
vision. He had also experienced over 6-8
months, progressive headaches, loss of energy
and libido.
Figure 23-9. A large pituitary adenoma with sec-

ondary hemorrhage has exrended upward out of the
sella to compress the optic chiasm and optic nerves. This
53-year-old white male 11 months before death experi-
enced difficulty reading small print, with greater
involvement of the right eye than the left. This pro-
gressed to total blindness in the right eye and shortly
thereafter-sudden loss of vision in the left eye, an
absence ofpupillary responses, and a bilateral anos-
mia. Vision improved after partial surgical removal
and irradiation, but fatal meningitis developed.
(Courtesy ofDrs. John Hills and Jose Segarra).
, •• 1' .....
os 00
Figure 23-10. Pituitary adenoma. Vuual fields

demonstrating a bitemporal hemianopia. O.s. =left
eye; O.D. = right eye. This 51-year-old obese male with
large puffy hands and a prominent jaw, declining
sexual interestfor 18 years, an 8-year history ofpro-
gressive loss of visual acuity, a 6- to 7-month history of
diplopia due to a bilateral medial rectus palsy and
headache had stopped driving because he was unable
to see the sides of the road. Urinary adrenal and Figure 23-11. A large pituitary adenoma in a 44-
gonadal steroids and thyroid functions were low, with
year-old man with a bitemporal hemianopia. Case
no follicle-stimulating hormone. Imaging studies
23-2. Significant extrasellar exrension compresses the
demonstrated a large pituitary adenoma with signif-
Tl optic chiasm. MRI scans: A) midline sagittal sec-
icant suprasellar exrent.
tion B) coronal section. (1'1 with contrast.)
VISUAL SYSTEM 23-11
Neurologic exam: Normal except for a The optic nerve fibers from the temporal
bitemporal hemianopia. visual field, the crossed fibers, end in layers 1,
Clinical diagnosis: Pituitary adenoma 4, and 6. The fibers from the temporal retina
compressing the optic chiasm. (the nasal visual field), the uncrossed fibers,
Laboratory data: Endocrine studies: all end in layers 2, 3, and 5. Each optic nerve
were normal. MRL' A large macroadenoma fiber ends in one layer on 5 or 6 cells. The
measuring 3 cm in diameter extended outside total number of cells and fibers is roughly
of the sella turcica to compress the optic chi- equal. LGN cells respond well to small spots
asm (23-11). of light and to short, narrow bars of light, as
Subsequent course: Dr. Gerald well as to on-off stimuli. Diffuse light is a very
McGuillicuddy performed a gross total trans poor stimulus.
sphenoidal resection of the tumor, with a sig- Cells in the LGN grow rapidly in the first
nificant improvement in vision. Three years 6 to 12 months after birth, under the influence
later, the patient again had visual symptoms of visual stimuli. Visual sensory deprivation
and eye pain. MRI scans indicated regrowth of during this period leads to atrophy and life-
tumor with possible impression on the right long blindness. Two major streams of visual
optic nerve. He was treated with radiotherapy. information leave the retina to the LGN (1)
Note that males are more likely to present The magnocellular stream starts in the large
with large pituitary adenoma compressing the cells of the retinal ganglion (Y-cells) that pro-
optic chiasm. Women are more likely to pre- ject to the magnocellular layers (layers 1 and 2)
sent with microadenomas or small macroade- which subsequently project to the striate cor-
nomas since they are more likely to be seen at tex. The cortical neurons of the magnocellular
an earlier stage due to an initial complaint of stream respond to movements, orientation
amenorrhea. and contrast but respond poorly to color. (2)
Lateral Geniculate Nucleus (LGN). The parvocellular stream begins with small
cells of the retinal ganglion layer (X-cells) that
The LGN is primarily a relay station in the
project to parvocellular layer of LGN layers 3
visual pathway. Some optic fibers for pupillary
and 6. These cells respond either to shape and
light reflexes bypass the LGN and descend
orientation or color red/green and blue/yel-
into the pretectal region of the midbrain.
low.
Others, for coordinating eye and head or neck
movements, descend to the superior colliculus. Optic Radiation.
Also some of the retinal fibers synapse in the The fibers to the visual cortex leave the lat-
suprachiasmatic nucleus of the hypothalamus eral geniculate nucleus and form the optic
and then project to the pineal by way of the radiation, which sweeps around the posterior
sympathetic fibers where they influence circa- horn of the lateral ventricle, through the pari-
dian rhythms and endocrine functions. etallobe to the occipital lobe and the calcarine
The lateral geniculate nucleus is a six-layer cortex (Fig. 23-6). Some fibers from the later-
horseshoe-shaped structure. Visual processing al geniculate nucleus also enter the inferior
begins in the large and small cells in the LGN. pulvinar nucleus.
The small cells are in layers 1 to 4, and the The visual radiation is so extensive that not
large cells in layers 5 and 6. Each LGN cell all the fibers can pass directly posterior to the
receives direct input from a specific area of the calcarine cortex. Only the most dorsally placed
retina, and each area of the LGN is driven fibers pass back deep into the parietal lobe.
from a specific area of the visual field. Each The more ventrally placed fibers pass forward
receptive field has a center that is either on (Myer's loop) and deep into the temporal
or off and a surround that has the opposite lobe, swing posteriorly around the anterior
polarity. portion of the inferior horn of the lateral ven-
23-12 CHAPTER 23
tricle, and continue posteriorly lateral to the third of the calcarine cortex and extends onto
ventricle wall to the calcarine cortex. In con- the occipital pole.
trast to the densely packed optic tract, the Area 17 receives fibers from and sends
optic radiation fans out widely on its passage fibers to area 18 but does not have any direct
through the parietal and temporal lobes. callosal or long-association-fiber connections
OCCIPITAL LOBE to other cortical areas. The columnar and hor-
izontal organization of the primary visual cor-
The occipital lobe in Brodmann's numeri-
tex has been discussed previously in chapter
cal scheme consists of areas 17, 18, and 19.
17. Area 17 is more mature at birth and has
From a cytoarchitectural standpoint, area 17
the most precise map. The other visual areas
represents a classic example of specialized
develop through maturation and experience,
granular cortex, or koniocortex. Areas 18 and
although experience modifies VI as well (see
19 represent progressive modifications from
Chapter 29).
koniocortex toward homotypical cortex (Refer
Area 18 has extensive connections with
to chapter 17 for a discussion of cytoarchitec-
areas 18 and 19 of the ipsilateral and con-
ture).
tralateral hemispheres, which were demon-
Area 17, the striate cortex, the principal
strated by both the earlier strychnine neu-
visual projection area in humans is found pri-
ronography studies and the more recent
marily on the medial surface of the hemi-
horseradish peroxidase studies.
sphere, occupying those portions of the
Callosal fibers enter the opposite hemi-
cuneus (above) and lingual gyrus (below) that
sphere, and association fibers communicate
border the calcarine sulcus. For this reason, it
with the premotor and inferior temporal areas
is often termed the calcarine cortex. Much of
and area 7 of the adjacent parietal cortex.
this cortex is located on the walls and in the
As discussed in greater detail below, Zeki
depths of this sulcus.
and associates (1992) studied each of these
The extrastriate visual cortex, including
visual areas to create a map of the retina.
parastriate areas 18 and 19 forms concentric Parallel pathways process various aspects of
bands about area 17 and is found on both the
visual information--color (wavelength),
medial and lateral surfaces. Area 19 in humans
motion, stereopsis, and form (line orienta-
extends onto the adjacent mid and inferior
tion)--and extend from the retina to the later-
temporal gyri.
al geniculate nucleus, striate cortex, and final-
Most of our understanding of occipital-
ly, extrastriate cortex.
lobe function comes from simian studies. In
Ocular dominance Columns. Ocular
non-human primates five visual :\l'eas have
dominance columns are seen in the striate cor-
been identified:
tex. They are seen as an alternating series of
VI - corresponding to area 17 in humans,
parallel stripes that represent a column of neu-
V2 and V3 - corresponding to area 18, and
rons in the striate cortex innervated by either
V4 and V5 - corresponding to area 19.
the ipsilateral or contralateral eye. Ocular
Area 17 is the primary visual area, and
dominance columns extend in alternating
receives the termination of the geniculocal-
bands through all cortical areas and layers, and
carine (or optic) radiation. This projection is
are absent in only the cortical region repre-
arranged in a topographic manner, with the
senting the blind spot and the cortical area
superior quadrant of the contralateral visual
representing the monocular temporal crescent
field represented on the inferior bank of the
of the visual field. The mosaic appearance of
calcarine fissure, and the inferior quadrant of
these ocular dominance columns is demon-
the contralateral visual field represented on the
strated with autoradiography using 2-
superior bank. The macula has a large area of
deoxyglucose and stimulation of only one eye.
representation, which occupies the posterior
Simple cells are driven monocularly while the
VISUAL SYSTEM 23-13
1993, and Williamson et al., 1992.
Physiology
The optic (geniculocalcarine) radiation ter-
minates on the cells in the calcarine cortex,
which respond like retinal ganglion cells.
Their receptive fields consist of an excitatory
region surrounded by an inhibitory region.
Fields with the opposite pattern are also seen
in higher mammals. These fields are excited by
an annulus (donut) of light.
Hubel and Wiesel have described three
types of higher-order cells in the visual cortex:
1.Simple cell.
Figure 23-12 Fo&IIl disclmrge in oceipittd lobe. 2.Complex cell and,
l.6cation of the lesions lit surgery in 11 patients who 3.Hypercomplex cell.
htul focal seizures beginning with visutU senstJtWns. Simple cell. This cell type responds best to
(From Penfield, w., lind Kristillnsen, K.: Epilepti& a bar of light with a critical orientation and
Seizure Plltterns, Springfield, Chllrles C. Thonuu, location. The receptive fields of several simple
1951, p.47.) cells are shown in Figure 23-13. The excita-
complex and hyper complex cells are stimulat- tory field of each simple cell is bordered on
ed from both eyes. one or both sides by an inhibitory field as
shown for simple cell a. The small portion of
Stimulation of Areas 17, 18, and 19
the visual field outlined in Figure 23-13 drives
Direct electrical stimulation of areas 17, thousands of simple cells, each with a discrete
18, and 19 in conscious people produces visu- location and orientation. Each simple cell
al sensations (Pollen, 1975) (Fig. 23-12). appears to receive input from a number of
These images are not elaborate hallucina- ganglion cells, which have their excitatory and
tions (as in complex partial temporal seizures) inhibitory fields in a straight line.
but rather are described as flickering lights, Every simple cell can be driven by input
stars, lines, spots, and so forth. Often the from either eye, but they usually show a pref-
images are described as colored or moving erence for one eye or the other. For example,
around. The images are usually localized to a simple cell may be strongly excited by a bar
the contralateral field, at times to the con- seen with the right eye and only weakly stimu-
tralateral eye. An illustrative case, 23-4, is pre- lated by the same bar seen with the left eye.
sented below. This differential sensitivity may form the basis
At times, the patient cannot determine lat- of binocular vision.
erality. In addition, stimulation of areas 18 Complex Cell. A number of simple cells
and 19 (and sometimes 17) produces conju- having the same orientation activate a complex
gate deviation of the eyes to the contralateral cell. The complex cell has a definite orienta-
field and, at times, vertical conjugate move- tional preference, but a much larger receptive
ments. Discharge of the occipital cortex may field. An example of this is complex cell alpha
be followed by transient visual defects similar in Figure 23-13. Any horizontal line of any
to the transient post-ictal hemiparesis that may length within the outlined visual field excites
follow focal seizures beginning in the motor complex cell alpha. Lines with different orien-
cortex (see Aldrich et al., 1989). More com- tations in the same visual field will drive other
plete discussion of seizures beginning in occip- complex cells.
ital cortex can be found in Salanova et al., Hyper complex cell. The final cell type is a
23-14 CHAPTER 23
HYPERCOMPLEX CELLS GANGLlON.I CELL SIMPLE CELLS COMPLEX CELLS

2 / .r '" a b c tC J1
E -E
I "'E
-.. ·O~E
~~
KEY
E· EXCITE
O. NO EFFECT
I. NtIBlT
Figure 23-13. Types of visual stimuli that excite each of the four Pypes of cells found in the calcarine cortex. The
square represents a box 2 inch by 2 inch, 5feet away from the monkey's eye. The actu41 stimuli are bright bars of
light on a dark field. (Data from Hubel and Wusel. 1968. J. Physiol. 195:215.)
hyper complex cell. It has characteristics very enced by the direction of the edge. Lastly, a
similar to the complex cell except it discrimi- hyper complex cell must have a corner, an
nates lines of different lengths. The bottom angle, or the end of the edge within its field to
light bar in Figure 23-13 will inhibit hyper be activated.
complex cell 2. If its left-hand border were When a rectangle of light is flashed upon
moved into the visual field, it would strongly the retina, the cells described are initially acti-
excite hyper complex cell 2. Once again, it is vated but adapt fairly quickly and then are
excited by lines of a critical orientation any- hardly stimulated. However, if the pattern
where within a large portion of a visual field, flashes on and off, the cells are repeatedly stim-
but they must not be too long. Corners and ulated. The cortex is also stimulated if the pat-
angles also excite these cells. tern moves a little on the retina. A different
About half a million optic-tract fibers enter group of ganglion and simple cells will react,
each occipital lobe. It should be clear that but because of their larger receptive fields,
there are many more cells processing this most of the complex and hyper complex cells
information, and indeed, the banks of the cal- continue to be stimulated. The nervous sys-
carine cortex contain many millions of cells. tem has overcome the problem of stationary
The response to a large rectangle of light images by continually producing rapid, sac-
varies with the type of cell. Only if the edge cadic eye movements that constantly shift the
falls on the center of a cell's receptive field will image on the retina. Indeed, when the image
it be excited. Ganglion cells are very sensitive is stabilized by special contact lenses, it disap-
to position, contrast, and dynamics. Ganglion pears.
cells, in turn, excite simple cells that outline In the process of data reduction, the visual
the edges of the rectangle of light. Simple cells system loses the ability to judge absolute light
have a larger receptive field than ganglion cells, intensity for the most part.
are less sensitive to position, but are sensitive Differences in intensity within a field can
to the direction of the edge. Simple cells do be determined easily but not the overall inten-
not respond to continuous light or dark stim- sity of the field; photographers who estimate
uli in their fields or to bars of light with an ori- exposures usually waste a lot of film. Only the
entation other than their preferred orientation. pupillary reflex system retains the ability to
Complex cells have much larger receptive measure absolute intensity.
fields than simple cells but are heavily influ- Different calcarine cells within a narrow
VISUAL SYSTEM 23-15
colwnn petpendicular to the surface repeat which then projects to area V5, either directly
this processing for each of the primary-color or through area V2. Each of the prestriate
receptors to give information on form, color, areas V5, V4, and V3 sends information back
motion, and contrast. Lesions as small as 1mm to VI and V2, as well as to the parietal and
result in a detectable loss of all of these modal- temporal areas. This provides for more inte-
ities in a small area of the visual field. grated visual perception. Striate
Zeki and associates (1992) demonstrated To summarize, let us consider the example
how the four identified perceptual pathways of a slowly moving colored ball. Visual infor-
(color, form with color, dynamic form, and mation is fractionated into the modalities of
motion) relate to the specific visual areas. form, color, and motion in the calcarine cor-
The neurons of area V5 (area 19) are tex. That information is reassembled elsewhere
responsive to motion and directionally selective, to give us a unitary view of the ball.
but they are nonselective for color. In con- We are just beginning to understand where
trast, the majority of cells in V4 (area 19) are and how this parallel processing is done.
selective for specific wavelengths of light (color If the object is the letter A, then further
sensitive), and many are selective for form (line processing takes place in the dominant (usual-
orientation) as well. ly left) lateral occipital cortex (Brodmann's
The cells of the adjacent areas V3 and V3A areas 18 and 19), the visual language associa-
(area 18) are selective for form (line orientation area. Letters seen in the left visual field
tion) but are indifferent to wavelength (color). and represented in the right calcarine cortex
VI (area 17) and V2 (area 18) distribute infor- must project across the posterior cotpus callo-
mation to these specialized fields. VI has col- sum before they can be recognized in the left
wnn and intercolumnar areas. The colwnns visual association cortex.
stain heavily for the energy-related enzyme Information needed to reconstruct com-
cytochrome oxidase. The neurons within the plex forms flows through the inferior occipi-
colwnns are wavelength sensitive, tend to con- tal/temporal region, primarily on the non-
centrate in layers 2 and 3, and receive input dominant side. Located here are cells that can
primarily from the parvocellular layers of the discriminate between human faces, for exam-
lateral geniculate nucleus. Information con- ple. Similarly, sheep have cells that respond
cerning color is then projected either directly only to the image of a wolf (not of a sheep),
or through thin-colwnn stripes in area V2 to and monkeys have cells that respond only to a
V4. human face but not to a snake or a banana.
By contrast, form-selective neurons are Many of these cells are sensitive to gaze, being
located in the intercolwnnar areas in VI. strongly stimulated by direct eye contact but
Form-related-to-color derives from the parvo- only weakly stimulated when the eyes are
cellular-neuron layers of the lateral geniculate averted.
nucleus, which project first to the intercolum- Extra-occipital higher-level visual process-
nar areas of VI and then to V4. ing then occurs in area 7 of the parietal lobe,
The second form system is independent of areas 23 and 21 of the temporal lobe, and area
color and depends on inputs from the magno- 8 of the frontal lobe (see Pandya and Kuypers,
cellular layers of the lateral geniculate nucleus 1969).
to layer 4B ofVI projecting to V3. Extrastriate Occipital Lobe and Eye Movements.
areas send projections back to the dorsal later-
al geniculate nucleus and the pulvinar of the Areas 18 and 19 send fibers to the tectal
thalamus. area of the superior colliculus. Such connec-
The motion-sensitive system consists of tions are necessary for visual fixation and accu-
inputs from the magnocellular layers of lateral rate following of a moving object. The slow
geniculate nucleus to layer 4B of area VI, and smooth conjugate eye movements that
23-16 CHAPTER 23
occur when the eyes are following a moving With such calcarine-cortex lesions, the field
visual stimulus (pursuit movements) should be defects are usually similar (congruous) in both
distinguished from the independent phenom- eyes. By contrast, incomplete optic-tract
enon of voluntary (saccadic) conjugate eye lesions may produce somewhat unequal (non
movements. congruous) homonymous field defects in both
Saccadic movements are rapid and shorter eyes.
in latency and duration. They do not require Vascular lesions, in particular occlusion of
a visual stimulus and do not depend on ;my the posterior cerebral artery, often result in a
connections to area 18. Rather, they are homonymous hemianopia with macular spar-
dependent on area 8, which sends fibers to the ing. That is, vision in the macular area of the
lateral gaze center of the pons. involved field remains intact. Such preserva-
This discussion of cortical control of eye tion of macular vision probably occurs because
movements is clearly simplified (see also chap- the macular area has a large representation in
ter 18). Both areas send some fibers to the the most posterior third of the calcarine cortex
superior colliculus, and ultimately, both the and is the area nearest the occipital pole. This
saccadic and pursuit movements involve the area, then, is best situated to receive lep-
pontine gaze centers. In addition, vestibular tomeningeal anastomotic blood supply from
and cerebellar influences also determine eye the middle cerebral and anterior cerebral arter-
movement. ies. Occasionally, with occipital infarcts, there
Lesion in Area 17 may be preservation of vision in a small periph-
eral unpaired portion of the visual field, called
Complete unilateral ablation of area 17
the temporal crescent (see Benton et al.,
(VI) produces a complete homonymous
1980).
hemianopia in the contralateral visual field (the
In vascular insufficiency or occlusion of the
same half field in each eye has no conscious
basilar artery, infarction may occur in the dis-
visual perception). Such patients may have
tribution of both posterior cerebral arteries,
some crude visual function such as spatial producing a bilateral homonymous hemi-
localization, presumably because of optic-tract
anopia and a syndrome of "cortical blindness."
connections to the superior colliculus. A
Such patients lose all visual sensation, but
report by Barbur and colleagues (1993) sug-
pupillary constriction in response to light is
gests that conscious perception of the type of
preserved.
visual stimulus and its direction of motion can
continue to occur after selective VI lesions Lesions of Extrastriate Areas 18 and 19
have been made, due to activation ofVS (pos- Lesions in areas 18 and 19 often referred
sibly by subcortical input to VS). Vision is to as the visual association areas, produce
clearly abnormal in this blind field. VI to VS deficits in visual association, including defects
input is the dominant input in intact in visual recognition and reading. The prob-
individuals. lem is that in humans with a unilateral lesion,
With partial lesions, a partial defect results. one is almost never dealing with disease limit-
For example, if only the superior bank of the ed to areas 18 and 19 (however, see discussion
calcarine fissure is involved, the visual field below of more recent studies).
defect is limited to the inferior quadrant of the Rather, one finds that adjacent portions of
contralateral field. A bilateral infarct of either either the inferior temporal areas or of the infe-
the upper or lower bank of the calcarine fissure rior parietal lobule (the angular and supramar-
may produce a homonymous altitudinal hemi- ginal gyri) are involved or that the lesion
anopia in which apparent blindness exists in extends into the deeper white matter of the
either the entire lower or upper field of vision lateral occipital area and involves association
(as appropriate). and callosal fibers. Such more-extensive
VISUAL SYSTEM 23-17
lesions will, of course, produce the deficits pre- developed a cough with some blood present in
viously noted in the discussion of parietal func- the sputum (hemoptysis), one month before
tion. A limited unilateral ablation might pro- admission. Five days before admission the
duce defects in visual following, as tested by patient developed a generalized headache,
evoking opticokinetic nystagmus (e.g., mov- which was precipitated by coughing or strain-
ing vertical black lines on a white background ing and which awakened him or prevented
or looking at telephone poles from a moving him from sleeping. Two days before admis-
train). sion, the patient noted blurring in the left infe-
Bilateral lesions limited to areas 18 and 19 rior quadrant of his field of vision. The day
occur only rarely in humans. In humans such before admission, he noted complete loss of
a lesion would deprive the speech areas of the vision in this quadrant. On the day of admis-
dominant hemispheres of all visual informa- sion, the headache increased, and the patient
tion. The patient would presumably see was unable to see anything in the left visual
objects but be unable to recognize them or to field. Past history was significant. The patient
place visual sensations in the context of previ- had multiple pulmonary infections, treated
ous experience. The patient would be, more- with antibiotics.
over, unable to relate these visual stimuli to Neurologic examination: Cranial nerves:
tactile and auditory stimuli. In monkeys, Early papilledema was present. A non-
restricted lesions in the "visual" areas of the congruous left homonymous hemianopia was
temporal and parietal lobes also interfere with present (Fig. 23-14A).
pattern discrimination (Mishkin, 1972). Clinical diagnosis: Mass lesion right
Horton and Hoyt (1991) have reported occipital? Tumor, abscess.
that unilateral lesions specific to the extrastriate Laboratory data: Imaging demonstrated
V2 jV3 cortex produce quadrantal visual field an enhanced lesion in the posterior and medi-
defects. As discussed by Zeki (1992), rare al aspect of the right hemisphere (occipital and
patients with restricted lesions in V4 present adjacent parietal lobes). EEG was abnormal
with achromatopia. The patients see the world because of frequent focal 3 to 4 cps, slow
only in shades of gray but perception of form, waves in the right occipital area and to a lesser
depth, and motion are intact. Rare patients degree, the right posterior parietal area.
with lesions limited to V5 have akinetopia. Cerebrospinal fluid pressure was elevated to
Stationary objects are perceived, but if they 210 mm CSF, 97 lymphocytes were present
are in motion, the objects appear to vanish. (upper limit is 5 to 7 lymphocytes). Protein
Plant and coworkers (1993) have reviewed was increased to 75 mg/dl. Glucose was 75
such impaired motion perception. Selective mg/dl (normal when compared to blood
deficits in form perception are even less fre- sugar of95 mg/dl).
quent. Destruction of both form systems and Subsequent course: The patient was treat-
therefore of V3 and V4 (areas 18 and 19) ed with antibiotics (cephalothin sodium, peni-
would be required and, as discussed above, cillin, and streptomycin), and visual fields,
such a lesion would also destroy VI (area 17), EEG, and spinal fluid findings improved.
resulting in total blindness. Within 3 weeks the field defect had resolved to
The following case illustrates the effects of a non congruous left inferior quadrantanopia
a space-occupying lesion in the occipital lobe. (Fig. 23-14B).
One should compare these findings to those Ten days later the patient was readmitted
reported earlier in Case 23-1, a lesion in the to the hospital with a three-day history of right
visual system anterior to the optic chiasm. eye pain, sweats, and chills. Neurologic exam-
Case History 23-3 (Fig 23-14) This 47-year- ination now revealed a recurrence of blurred
old white, right-handed, real estate salesman optic-disc margins, a left homonymous hemi-
23-18 CHAPTER 23
anopia and a slight increase in deep tendon

reflexes on the left. Imaging studies now
revealed a large space-occupying lesion in the
right parietal/occipital region, displacing the
right lateral ventricle forward and downward.
After 10 days treatment with antibiotics (peni-
cillin and streptomycin), a craniotomy was per-
formed by Dr. Bertram Selverstone revealing
an abscess and a large surrounding area of hard
granulomatous cortex and white matter that
were removed. The etiologic organism was
subsequently found to be a microaerophilic
streptococcus.
Follow-up examination 6 months after
surgery was normal, except for the left
homonymous hemianopia (Fig. 23-J4C).
The case that follows is another example of
the effects of a lesion in the occipital lobe with
very different consequences then those seen in
the previous case.
Case History 23-4. This IS-year-old left-

handed single white female restaurant employ-
ee had the onset of her seizures at age 14 when
she had a sequence of five seizures in less than
12 hours. Each began with flashing lights,
"like Christmas tree lights," all over her visual Figure 23-14. Case History 23-3, Brain abscess, rigltt
field, plus the sensation" that peoples' faces occipital area: Perimetric examination of visual fields.
were moving. She then would have an appar- A, Initial examination demonstrated a somewhat
asymmetrical (non congruous) left homonymous hemi-
ent generalized convulsive seizure. Neurologic
anopia less in the left eye than the right. The fields are
examination, and CT scan were all reported as shown from the patient's point of view. B, 16 days later;
normal. An electroencephalogram reported with antibiotic therapy, an improvement had occurred.
occasional focal sharp and slow waves in the A non congruous, quadrantanopia is now present. C,
left hemisphere. The patient was treated with Fields after an additional 24 days. A relatively com-
carbamazepine (Tegretol), 400 mg in the plete homonymous hemianopia, present at the time of
readmission, persisted following surgery as shown above.
morning, and 230 mg at hour of sleep with no
additional
She apparently had done quite well with for 3 years then had a recurrence of a general-
no additional grand mal seizures. She had rare ized convulsive seizure possibly related to
episodes of "fear attacks," which would last 23 omission of medication. Six weeks later, she
to 25 minutes. The last attack had occurred 2 reported two additional episodes characterized
years ago, but as recently as two months ago, by flashing lights, then movement of the lights
she had had one episode of flashing lights. A away from a center circle, then dizziness, then
recent EEG was normal. a sensation of unreality. She also had other
Neurologic examination: normal. episodes of feeling unreal accompanied by fear.
Clinical diagnosis: Seizures of focal origin The neurologic examination demonstrated
left occipital. a minor right central facial weakness not pre-
Subsequent course: The patient did well sent previously.
Laboratory data: BEG: normal. MRI
VISUAL SYSTEM 23-19
scan now revealed a small tumor at the left
occipital pole with surrounding edema (Fig.
23-15). CT scan, this tumor appeared partial-
ly calcified but did show enhancement.
Review of the CT scan obtained in Arizona at
age 14 indicated similar findings. Angiograms
suggested tumor vascularity of a type seen with
meningiomas.
Dr. Bernard Stone removed a discrete
encapsulated tumor that appeared to be a
Figure 23-16. Occlusion of right posterior cerebral
meningioma. Subsequent microscopic exami-
artery. Case 26-6 on CD ROM. Tangent screen exami-
nation, however, indicated a rare type of indo- nation of"isual fields, 3 months after the acute went.
lent follicular adenocarcinoma of the thyroid, This 75-year-old woman had the acute onset of headluhe,
which sometimes spreads as a single lesion to bilateral blindness, confusion, "omiting, mild atRxia
brain and remains quiescent for many years. and bilateral Babinski signs. All findings cleared
In the postoperative period, a non-congruous except a residual left homonymous hemianopsia with
macular sparing. O.S. =left eye; O.D. =right eye.
right-inferior-field defect was present (partial
quadrantanopia). The blood level of thyroid-
stimulating hormone (TSH) was elevated. A tebral metastasis.
thyroid nodule was found. A thyroidectomy Vascular lesions of the calcarine cortex:
was performed, and thyroid replacement med- Various types of visual field defects may occur
ication was prescribed. No additional seizures including a homonymous hemianopsia, with
were observed over the next 18 months. The (23-16) or without macular sparing, or a
patient subsequently developed a lumbar ver- quadrantanopsia. The CT scan correlations are
presented in Figures 23-17 and 23-18.
Figure 23-15 Case 23-2. Focal "isual sekures character-

ked by ".flashing lights" and the sensation of moTJement
of the "isual field with secondary generalization begin-
ning at age 14 due to metastatic (thyroid) tumor of the
left occipital lobe. MRI, T2-weighted, non-enhanced
demonstrated a small tumor at the left occipital pole
with surrounding edema. (See textfor details.)
23-20 CHAPTER 23
Figure 23-17 cr scan ofa total infarct, presumably embolic in the right posterior cerebral artery cortical territory
(occipital and posterior temporal lobes) obtained 5 days after the acute onset of confusion and possible visual hallu-
cinations in an 86-year-old right-handed male. As confusion cleared examination indicated a dense left homony-
mous hemianopia with no evidence of macular sparing. The patient would look to the right and to the midline but
would not follow objects to the left beyond the midline. Contrast to Fig. 23-18.
Figure 23-18. cr scans ofa partial infarct of the left pos-

terior cerebral artery territory (inferior calcarine) with
superior quadrantanopia probable basilar vertebral
ischemia with artery-to-artery embolic infarction of the
occipital (calcarine artery). This 71-year-old right-hand-
ed male with a history of diabetes mellitus and hyperten-
sion had acute onset of vomiting, ataxia, minor confu-
sion, and a persistent problem with peripheral vision in
the right visual field, followed by episodes of vertical
diplopia. Examination the following month demonstrat-
ed a homonymous visual field defect involving the right
superior field, minor ataxia, and a right Babinski sign.
Compare to figure 23-17.
CHAPTER 24
Speech, Language, Cerebral Dominance
and the Aphasias
INTRODUCTION TABLE 24-1 CAUSES OF DYSARTHRIA

In the preceding sections, we have alluded
LOCATION OF PATHOLOGY EXAMPLES
to various areas in the dominant hemisphere
Local diseases of the larynx, Laryngeal carcinoma
concerned with speech and language. The tongue or lips
reader may well have been confused by the
introduction of such terms as aphasia, apraxia, Disease of the muscles Oculopharyngeal
agnosia and dyslexia. It is well to warn the stu- affecHng the tongue, dystrophy
dent beginning the study of language function the lips or pharynx,
that prior to the development of modem neu- Diseases affecting the Myasthenia grovis,
roimaging this had been an area of much con- neuromuscular JuncHon In botulinum toxin
fusion, with much disagreement and multiple the muscles of the-tongue,
hypotheses. This discussion will be limited to lips and pharynx
the more practical problems of anatomical Diseases affecting the A) Hypoglossal nerve
localization. peripheral nerve supply of (caroHd endarterectomy).
DYSARTHRIA the tongue, lips, or pharynx, B) Recurrent laryngeal
nerve (thyroid surgery).
We should indicate at the onset that we are C) Metastatic or regional
not concerned here with the problem of cancer Involving the
dysarthria. Dysarthria refers to a difficulty in lymphatics In the neck.
articulation of speech from weakness or paraly- D) Diphtheritic neuropathy
sis or from mechanical difficulties. Dysarthria
Diseases of the brain stem Lateral medullary Infarcts,
may have many causes at many levels of the motor nuclei parHcula~y amyotrophic lateral
peripheral or central nervous system as indicat- nucleus amblguus. sclerosis (so called
ed in Table 24-1. progressive bulbar palsy),
or bulbar poliomyelitis.
CEREBRAL CORTEX AND
COMPLEX DISTURBANCES Bilateral damage to the Bilateral Infarcts, multiple
OF VERBAL EXPRESSION corticobulbar fibers sclerosis producing a
(cerebral cortex, Intemal pseudobulbar palsy.
There are, however, more complex distur- capsule, or upper brain stem).
bances of regards verbal expression, that occur
at a time when the basic motor and sensory sys- in the United States in reference to develop-
tems for articulation are intact. Similarly there mental language disorders as opposed to the
are complex disturbances in language function, acquired aphasias.
as regards comprehension of written and spo-
ken symbolic forms that occur at a time when CEREBRAL DOMINANCE
the basic auditory and visual receptor apparatus It is perhaps appropriate at this point to
is intact. We refer to these more complex consider the question of cerebral dominance.
acquired disturbances of language function as Most individuals are right-handed (93 per cent
aphasias. In general, it is possible to relate of the adult population), and such individuals
these language disturbances to disease of the almost always (>99%) are left-hemisphere
dominant cerebral hemisphere, involving the dominant for language functions. A minority
cerebral cortex or cortical association fiber sys- of individuals (some on a hereditary basis) is
tems. The term dysphasia, which is used in left-hand dominant. Baseball appears to have
England interchangeably with aphasias, is used collected a high percentage of these individuals
24-2 CHAPTER 24
as left-handed pitchers. Some left-handers are auditory aSSOCIation cortex, posterior to

right-hemisphere dominant (50%) but a cer- Heschl's gyrus on the superior-lateral surface
tain proportion is left-hemisphere dominant. of the temporal lobe (areas 22 and 42) border-
It has been estimated that 96 percent of the ing the Sylvian fissure and including the speech
adult population are left-hemisphere dominant reception area of Wernicke, was found to be
for speech. larger in the left hemisphere. Similar differ-
Hand, eye and foot preference occurs in ences have been found in the brain of the fetus
monkeys and limb preference occurs in cats and newborn infant (Wada et al1975). The
(Cole 1957). One might inquire as to why the studies of LeMay and her associates (1972,
majority of humans are right-handed. 1978, and 1978), Galaburda et al, (1978),
Although hand preference does not become Chui and Damasio (1980) elaborated on the
apparent until one year of age, the studies of asymmetries of the Sylvian fissure and occipital
Yakolev and Rakic (1966) would suggest that lobe demonstrated on arteriography and CT
even before this age, there is an underlying scan during life. Similar asymmetries were
anatomical basis for the dominance of the right demonstrated in the brains of the great apes,
hand. In the study of the medullae and spinal e.g., chimpanzee, but not in the Rhesus mon-
cords of a large number of human fetuses and key (LeMay and Geschwind 1978). LeMay
neonates, the fibers of the left pyramid were and Culebras (1972) studied the endocranial
found to cross to the right side in the casts of human fossil skulls in which imprints of
medullary pyramidal decussation at a higher the major fissure could be noted and demon-
level in the decussation than fibers of the right strated similar differences in Neanderthal man.
pyramid. Moreover, more fibers of the left Damasio and Geschwind (1984) provide addi-
pyramid crossed to the right side than vice tional review of this topic.
versa. Although the majority of pyramidal Development Aspects:
fibers decussated, a minority of fibers remained It is clear that from a functional standpoint
uncrossed. It was more common for fibers a considerable degree of flexibility exists in the
from the left pyramid to decussate completely child as regards dominance for language func-
to the right side of the lower medulla (and tion. Thus, in a child under the age of 5 years,
eventually spinal cord. The minority of fibers destruction of the speech areas of the domi-
that remained uncrossed was more often those nant left hemisphere during pre or postnatal
descending from the right pyramid into the life produces only a minor long-term language
right side of the lower medulla. The end disturbance (Varqha-Khademe at al1985). If
result, in the cervical region at least, was for the the damage to the speech areas in the domi-
right side of the spinal cord and presumably the nant hemisphere occurs between the ages of 5
anterior horn cells of the right side of the cer- and 12 years a more severe aphasia occurs;
vical cord to receive the greater corticospinal however some limited recovery of language
innervation. There is then an anatomical basis may occur within a year. These cases suggest an
for the preference or dominance of the right equipotentiality of the two hemispheres for
hand. Since the majority of fibers supplying language function during the early years of
the right cervical area have originated in the left development. In these cases under the age of 5
hemisphere, on this basis alone one could refer years the right hemisphere must assume a
to the dominance of the left hemisphere. dominant role in mediating those learned asso-
Study of the adult brain results in similar con- ciations important in language and in the use
clusions (Kertesz & Geschwind, 1971). of symbols either through process compensa-
The studies of Geschwind and Levitsky tion and/or reorganization. If total destruc-
(1968) established that an actual anatomical tion of the speech area of the dominant hemi-
asymmetry was present in the adult brain sphere occurs in adult life only a minor recov-
between the two hemispheres in an area signif- ery of language functions will occur. Patients
icant for language function. That area of the
SPEECH, lANGUAGE, CEREBRAL DOMINANCE AND THE APHASIAS 24-3
with left hemisphere damage sustained under of this problem are often artificial, in the sense
the age of 5, develop a strong left-hand prefer- that such discussions tend to deal with relative-
ence. Patients with damage sustained after the ly isolated pure types of language disturbance,
age of 5 have only weak: left-hand preferences which have relatively specific localization. The
or are ambidextrous. Additional discussion of actual patient with aphasia more often presents
the role of genetics in dominance and of the a mixed disturbance with damage to several
effects of early damage to the left hemisphere areas; some have damage to all major areas in a
can be found in Dellatollas et al, (1993). global aphasia. This is not unexpected when
Normal development of speech in the one realizes that all of the major speech areas of
child: There is considerable variability. the dominant hemisphere are within the corti-
Milestones may be outlined as follows: 9-12 cal vascular territory of the middle cerebral
months-babbles, "mama, dada". At 12 artery. Other areas involved in related disorders
months single words utilized and echoes are supplied by the anterior cerebral artery (the
sounds. At 15 months has several words, at 18 superior speech area) or by the posterior cere-
months has vocaulary of 6 words and possible bral artery, (those areas involved in pure dyslex-
hand dominance. At 24 months puts 2-3 ia and agnosias). Willmes and Poeck (1993)
words together into a sentence. and Kirshner (2000) provide additional
reviews.
APHASIA
Three cortical areas of the dominant hemi-
In approaching the patient with aphasia it is
sphere are of major importance in language
well to keep in mind that textbook discussions
disturbances (Fig.24-1):
MOTOR WRITING
CENTER OF
EXNER
ANTERIOR SPEECH COR rEX
Figure 24.-1. Speech areas of the dominant hemisphere, summary diagram combining the data ofpathological
lesions and stimulation studies. Precise sharp borders are not implied. The tksignations of Penfield and Roberts
1959 the terms "anterior speech area", "posterior speech area", and "superior speech cortex".
24-4 CHAPTER 24
(1) Broca's motor aphasia or expressive speech In these correlations, it is important to make a
center: The opercular and triangular portions distinction between acute and chronic effects
of the inferior frontal convolution (areas 44 It is necessary first to review those compo-
and 45). nents oflanguage function that are evaluated in
(2) Wernicke's receptive aphasia area: The the neurological examination (adapted from
auditory association area on the superior and Benson 1985).
lateral surface of the posterior portion of the (1) Conversational speech:
superior temporal gyrus (area 22 and adjacent a. Amount: Nonfluent versus fluent. Mute
parts of area 42). refers to total absence.
( 3) Inferior parietal lobule: The angular b. Articulation, rhythm and melody, defec-
and supramarginal gyri (area 39 and 40), at tive in nonfluent, normal in fluent. However
times associated with Gerstmann's syndrome note that the nonverbal aspects of language
of dysgraphia, dyscalculia, left-right confusion prosody, (the affective, intonation and melodic
and finger agnosia. aspects of speech) and gesture often involve the
Other cortical areas: the supplementary right hemisphere (refer to Ross, 1993)
motor cortex (superior speech area) may also c. Content:
play a role in language function. Stimulation 1. Grammar - (referred to as syntax):
studies by Luders et al, 1988, have also identi- Nonfluent speech is often telegraphic - lacking
fied a basal temporal speech area. the words or word parts and endings needed to
In addition to these cortical areas, the asso- express grammatical relations; whereas,
ciation fiber systems relating these areas to each patients with fluent aphasia can produce long
other and to other cortical areas are of consid- sentences of phrases with a normal grammati-
erable importance for certain types oflanguage cal structure.
disturbance, as we will indicate later. 2. Meaning and substance - (referred to as
From a practical localization standpoint we semantics): Patients with fluent aphasia often
can, in a general sense, speak of patients as pre- demonstrate a number of abnormalities in
senting an anterior or posterior type of aphasia terms of the choice of words.
(anterior or posterior to the central sulcus) a. The precise word may be replaced by a
(Fig.24-1) . nonspecific work or phrase.
1. The anterior type of aphasia relates to b. The correct word or phrase answer may
Broca's motor aphasia area. The patient's be replaced by a phrase that describes the use
speech may be generally described as nonfluent of an object (circumlocution). Because such
with little spontaneous verbalization. patients are fluent, casual examination may fail
2. The patients with the posterior types of to detect such glib features.
aphasia are fluent and do speak spontaneously. c. The correct word may be replaced by an
The lesions in such cases involve Wernicke's inappropriate word or phrase substitution (ver-
area in the posterior portion of the superior bal or semantic paraphasias), e.g., "clocks for
temporal gyrus or the inferior parietal lobule. wristwatch" .
The fluent aphasias include (a) Wernicke's d. The correct word may contain replace-
receptive aphasia, (b) disconnection syn- ment sounds or syllables, which are incorrect
dromes, (c) Gerstmann's syndrome, (d) dyslex- (literal or phonemic paraphasias) e.g., "note for
ia plus, e) dyslexia without agraphia, (f) the nose".
agnosias. However since the posterior areas are e. The correct word may be replaced by a
relatively close to one another it is not unusual totally new word (neologism), e.g.
for a single disease process to involve both "Zingbam" .
areas. (2) Repetition: the ability to repeat words
Now let us consider in greater detail lan- or phrases
guage functions and the postulated anatomical a. This may be absent in a mute individual,
correlations of these various language centers. in a severe nonfluent patient or in a patient
SPEECH, LANGUAGE, CEREBRAL DOMINANCE AND THE APHASIAS 24-5
with a severe type of Wernicke's aphasia.
b. This may be impaired as an isolated
symptom (so-called conduction aphasia)
c. This may be preserved in an individual
with other wise intact language
Or preserved in isolation (so-called Sylvian
isolation syndrome).
(3) Comprehension of spoken language
is tested by providing spoken or written com-
mands that do not require a verbal response,
such as "hold up your left hand, close your
eyes, and stick out your tongue".
4. Word finding and selection: Naming Figure 24-2. Armt ofspeeeh on stimullltion oftIomi-
of objectS or selection of the proper name of an 1UJnt hemisphere at surgery. (Fmn Penfield, w., tmd
object. Defect is defined as anomia or nominal lWmussen, T.: The Cerebml Cortex ofMan. New
York, The MR&milltln Company, 1955,p.107.)
aphasia.
5. Reading: Defect is defined as alexia or priate localization as noted below. Luders' et al
dyslexia. 1988 and Dinner and Luders (2000) have
6. Writing: Defect is defined as agraphia or recently reviewed this subject with the follow-
dysgraphia. ing conclusions:
7. Related functions: (1) Speech arrest or interference was elicit-
a. Calculations: Defect defined as acalculia or ed in five areas:
dyscalculia. a) Primary motor cortex when stimulating
b. Perception in visual, auditory or tactile the representation of muscles involved in
sphere: defects in recognition when the senso- speech of the dominant or non-dominant
ry modality and naming are otherwise intact hemisphere;
are defined as agnosia. The main sensory b) Negative motor areas (suppressor areas),
modality involved is vision and this merges that is the supplementary motor areas, and
with optic aphasia, dyslexia and nominal apha- inferior frontal gyrus of the dominant hemi-
sia. The inability to recognize faces (prosopag- sphere;
nosia) and color agnosia are special examples c) Broca's area - dominant hemisphere
(De Renzi, 2000). only; (note that Broca's area overlaps the
c. Apraxias: Defects in use of objects when motor suppressor area of the inferior frontal
motor and sensory functions are otherwise gyrus,
intact. d) Wernicke's area - dominant hemisphere
STIMULATION OF THE only;
SPEECH AREAS e) Basal temporal language area - dominant
hemisphere only. Dinner and Luders conclud-
In general, as demonstrated in Figure 24-2,
ed that any effect of stimulating the superior
stimulation of the dominant hemisphere -
speech area was related to inhibition of motor
speech areas - produces arrest of speech.
activity. This area did not appear to have speech
("Aphasic Arrest" in the terminology of
function per se. (Ablation type studies do sug-
Penfield and Rasmussen). Paroxysmal arrest of
gest possible speech functions).
speech often occurs as one aspect of seizures
(2) In stimulation of Broca's, Wernicke's
involving the dominant hemisphere. More
and the basal temporal areas at high stimulus
selective aspects of aphasia such as ictal alexia or
intensities, complete speech arrest occurred
agraphia or anomia without speech arrest have
with a global receptive and expressive aphasia;
been reported in rare patients - (Ardila and
however, the patient could still perform non-
Lopez, 1988, Warner, 1988) with the appro-
verbal tasks. At lower intensities of stimulation,
24-6 CHAPTER 24
the effects were incomplete: speech was slow, explain the problems in speech, which these
simple but not complex tasks could be per- patients manifest, since lesions involving the
formed (both motor sequences and calcula- face area of the nondominant motor cortex do
tions). Simple but not complex material could not produce the speech disturbance.
be repeated. A severe naming defect (anomia) Moreover, tongue and pharynx receive a bilat-
still occurred. eral corticobulbar supply, so that a unilateral
In children some seizures may be associat- cortical lesion involving the motor cortex in
ed with long-lasting expressive aphasia this area is not a sufficient explanation. These
(Landau-Kletfuer Syndrome) (Sawhney et al, patients appear to have lost the motor memo-
1988). ries for the sequencing of skilled coordinated
movements of tongue, lips and pharynx that
ABLATION OF SPEECH AREAS:
are required for the vocalization of under-
ANATOMICAL CORRELATION
standable single words, phrases and sentences.
OFSPEC~CSYNDROMES
They are usually able to vocalize sounds. At
The nonfluent aphasias involving times, they may be able to vocalize single
Broca's area: In 1861, Broca described words into a proper grammatical sequence for
patients with nonfluent aphasia: little sponta- telegraphic sentences.
neous speech with poor repetition but with In the patient with a relatively pure form of
considerable preservation of auditory compre- Broca's motor aphasia, the capacity to formu-
hension. The spontaneous speech that late language and to select words in a mental
remained was agrammatic and telegraphic. sense is intact. The student might logically
Based on his examination of the lateral surface inquire as to whether the patient has also lost
of the cerebral hemispheres at autopsy, he his motor memories or motor associations for
emphasized the damage to the third left frontal making a nonverbal sequence of movements of
gyrus, the frontal operculum of the inferior the tongue and lips. Frequently this is the case,
frontal gyrus. Although considerable contro- as will be demonstrated in the illustrative case
versy was generated at the time, Broca's name history. We may refer to this defect in skilled
has continued to be associated both with the sequential motor function (at a time when
disorder, nonfluent aphasia, and with the pos- motor, sensory and cerebellar function are
tulated anatomical area. As discussed by intact, and when the patient is alert and under-
Damasio and Geschwind, (1984) subsequent stands what movements are to be performed)
CT scans of the museum specimen of Broca's as a motor apraxia. There are several types of
case indicated much more extensive damage apraxia with different localization. In general,
than that described by Broca. Damasio, (1992) we may relate the more purely motor forms of
in an extensive recent review of aphasia dis- apraxia to the motor association areas of the
cusses in detail the differences between true premotor cortex. One could then refer to
chronic Broca's aphasia and the more limited patients with Broca's motor aphasia as patients
and transient effects of lesions restricted to with a motor apraxia of speech.
Broca's area alone. The following presents an example of this
Broca's area is essentially a continuation of type of aphasia. An embolus to the superior
premotor cortex and may be considered a spe- division of the left middle cerebral artery pro-
cialized motor association area with regard to duced marked weakness of the face tongue and
the tongue, lips, pharynx, and larynx. This distal right upper extremity and a severe selec-
area is adjacent to the motor cortex represen- tive nonfluent aphasia. The hand weakness
tation of the face, lips, tongue and pharyngeal rapidly disappeared, the right central facial
muscles. It is not, therefore, unusual for these weakness, an apraxia of tongue movements and
patients to have also a supranuclear type weak- some expressive difficulties persisted. Most
ness of the right side of the face and a right likely, the embolus fragmented and passed into
hemiparesis. This by itself is not sufficient to the cortical branches supplying Broca's area.
Case 24-1: This 55-year-old, right-handed weakness was present. The patient had difficul-
white housewife while working in her garden at ty in tongue protrusion and was unable to wig-
10:00 a.m. on the day of admission suddenly gle the tongue. When the tongue was protrud-
developed a weakness of the right side of face ed it deviated to the right. Motor !)Stem: there
and the right arm and was unable to speak. was a marked weakness without spasticity in
Nine years previously the patient had been the right upper extremity, most prominent dis-
hospitalized with a three-year history of pro- tally and a minor degree of weakness involving
gressive congestive heart failure secondary to the right lower extremity. Reflexes: deep ten-
rheumatic heart disease (mitral stenosis with don stretch reflexes were increased on the right
atrial fibrillation). An open cardiotomy was in the arm and leg. Plantar responses were both
performed with a mitral valvuloplasty (the valve extensor, more prominent on the right. Sensory
opening was enlarged) and removal of a !)Stem: Intact within limits of testing.
thrombus found in the left atrial appendage. Clinical diagnosis: Broca's: anterior apha-
Postoperatively, the patient was given an anti- sia embolus from heart to left middle cerebral
coagulant, bishydroxycoumarin (Dicumarol), artery, superior division.
to prevent additional emboli since atrial fibril- Laboratory data: EEG was normal (48
lation continued until the present admission. hours after admission). Electrocardiogram
She had done well in the interim. However, revealed atrial fibrillation. CSF was normal
prothrombin time at the time of admission was Subsequent course: Within 24 hours a sig-
close to normal; that is, the patient was not in nificant return of strength in the right hand
a therapeutic range for anticoagulation. had occurred; independent finger movements
General physical examination: Blood could be made. Within 48 hours after admis-
pressure was moderately elevated to 170/80. sion the patient was able to repeat single words
Pulse was lIO and irregular (atrial fibrillation). but still had almost no spontaneous speech.
Examination of the heart revealed the findings She appeared aware of her speech disability and
of mitral stenosis: a loud first sound, a diastolic would manifest some frustration. She was able
rumble and an opening snap at the apex as well to carry out two- or three-stage commands
as the atrial fibrillation. although tongue movements and persevera-
Neurological examination: Mental status tion remained a problem. Within 6 days of
and language function: She had no sponta- admission, the patient used words, phrases and
neous speech, could not use speech to answer occasional short sentences spontaneously and
questions and could not repeat words. She was was better able to repeat short sentences. At
able to indicate answers to questions by nod- this time strength in the right arm had
ding (yes) or shaking her head (no), if ques- returned to normal, but a right central facial
tions were presented in a multiple-choice for- weakness was still present. Two weeks after
mat. In this manner it was possible to deter- admission, she still had expressive disabilities
mine that she was grossly oriented for time, consisting of word-finding and apraxic compo-
place and person. She was able to carry out nents in tongue placement and alternating
spoken commands and simple written com- tongue movements. Although complete sen-
mands, such as, "hold up your hand, close your tences were used, sentence formulation in
eyes. " However, she had significant difficulty spontaneous speech was slow and labored with
in performing voluntary tongue moments word finding difficulties. Repetition was better
(such as ''wiggle your tongue"; "stick out your performed. In reading sentences aloud, substi-
tongue") on command. Cranial nerves: She tutions or word omissions were made. The
tended to neglect stimuli in the right visual patient did well in naming common pictures
field and was unable to look to the right on and in matching printed words to spoken
command although the head and eyes were words or printed words to pictures. She could
not grossly deviated to the left at rest. A write from dictation and would often respond
marked right supranuclear (central) type facial preferentially in writing when difficulty in
24-8 CHAPTER 24
speaking was encountered. A right central

facial weakness was still present.
With the passage of time, this type of
patient would continue to show some degree
of improvement (Mohr, 1973). Improvement
could continue to occur over a two-year peri-
od. Although lesions of Broca's area may pro-
duce the acute onset of a nonfluent aphasia,
rapid amelioration of the deficit occurs even
when the acute lesion involves underlying
white matter, as well as the superficial cortex.
In order to produce a more persistent
severe nonfluent aphasia with good compre-
hension but poor repetition, more extensive
lesions are required. In the CT scan correla-
tion study of Naesar, (1983), this larger lesion
extended from Broca's area to the anterior
parietal lobe usually including the deep struc-
tures such as caudate, putamen and/or internal
capsule. Ludlow et al (1986) compared persis-
tent versus nonpersistent nonfluent aphasia fif-
teen years after penetrating head injuries of the
left hemisphere in the Vietnam War. Both
groups had nonfluent aphasia still present at six
months after injury with equal involvement of
Broca's area. The group that failed to recover
at 15 years had a more extensive left hemi-
sphere lesion with posterior extension of the
CT scan lesion into Wernicke's area and some
involvement of the underlying white matter
and basal ganglia. The additional study of
Naeser et al (1989 compared severe nonfluen-
cy to less severe Broca's aphasia - 6 months to Figure. 24-3. Anterior aphasia: embolic infarct (sec-
ondary ro rheumatic atrial fibrillation. Case 24-2
9 years following an infarct of the left cerebral
(refer ro text) MRI: A) Tl weighted, coronal section.
hemisphere. Those patients with severe non- B) 12 weighted, horizontal section.
fluency had more extensive lesions of the sub-
cortical white matter involving: a) the subcal- disease and "an irregular pulse" (atrial fibrilla-
losal fasciculus deep to Broca's area containing tion) had the sudden onset of loss of speech,
projections from the cingulate and supplemen- central weakness of right face, an inability to
tary motor areas to the caudate nucleus plus b) protrude the tongue and a right hemiparesis.
the periventricular white matter near the body Although hemiparesis, face and tongue prob-
of the left ventricle deep to the lower motor- lems disappeared within a week, recovery of
sensory cortical area for the mouth. The MRI speech was slower and limited. At one week,
of a case (24-2) with chronic residuals of a she could produce some two-syllable words.
more persistent nonfluent aphasia is presented Neurological examination at 17 months:
in Figure 24-3. Language function: Spontaneous speech was
Case 24-2: On May 30, 1985, at midday, slow and relatively scanty. She could name
this 37-year-old right-handed woman with a objects slowly without difficulty, could do
past history of rheumatic fever, rheumatic heart some simple repetitions and could write from
dictation. She could carry out two and three
stage commands. She could read slowly aloud
but had little comprehension of what she read.
Reflexes: A residual right Babinski sign and
right-sided hyperreflexia were present.
Clinical diagnosis Anterior aphasia:
embolic infarct of superior division of middle
cerebral artery.
Laboratory data: Although initial CT
scans in May 1985 had been reported as nega-
tive·, the MRIs in November 1986 and June
1990 demonstrated the infarct, which included
Broca's area, as well as adjacent frontal areas
with predominant involvement of frontal oper- Figure 24-4. Penistent anterior aphasia after left
culum (inferior frontal gyrus) and adjacent carotid occlusion with old infarction, predominantly
middle frontal gyrus. In addition, a minor of left middle cerebral territory with lesser involve-
independent infarct was present in right oc~ip ment of anterior cerebral territory. Case 24-3(reftr to
ita! area (presumably embolic to the calcanne text). (Courtesy ofDr. John Hills and Dr. Jose
artery). Segarra)
Subsequent course: Similar findings were The Fluent Aphasias
present at 5 years, June 1990).
Wernicke's aphasia and Wernicke's area:
A brain section from a patient (Case 24-3)
In 1874, Wernicke described a type of aphasia
with a persistent nonfluent aphasia (is present-
that differed significantly from the nonfluent
ed in Figure 24-4.
aphasia described by Broca and that had a
Case 24-3: This 69-year-old, right-handed
more posterior localization. This type of
male expired in 1965. In 1961 and 1963, the
patient has fluent spontaneous speech with
patient, had experienced transient episodes of
poor comprehension and poor repetition. The
right hemiparesis and aphasia, both followed
patient has difficulty in understanding symbol-
by complete recovery. In 1964, a mo~e
ic sounds, i.e., words that have been heard and
persistent right hemiparesis and aphaSIa
is unable to carry out verbal commands. The
had developed.
patient is unable to use those same auditory
General physical examination: No left
associations in the formulation of speech.
carotid pulsation was present.
Moreover, the patient is essentially unable to
Neurologic examination (1965):
monitor his own spoken words as he talks,
Language functions: Speech was nonfluent
since he lacks the ability to interpret and to
with only a small verbal output. A significant
compare the sounds, which he himself is pro-
nominal aphasia with paraphasias was present.
ducing to previous auditory associations. The
Reading was limited. Comprehension of spo-
end result is a patient who is fluent but who
ken language was good. A marked apraxia was
uses words combined into sentences that lack
present for movements of tongue, lips and
any meaning to the listeners. Word substitu-
hands. Motor system: Right hemiparesis with
tion (paraphasia) is frequent. In severe cases,
associated reflex findings.
not only are phrases and words combined into
Pathologic diagnosis: Left carotid occlu-
meaningless sentences but also the patient
sion with old infarction, predominantly of left
combines syllables into words that have no
middle cerebral territory with lesser involve-
meaning (jargon aphasia). The patient, howev-
ment of anterior cerebral territory Note that
er, is usually unaware of his errors. The patient
minor cortical infarcts are also present involv-
usually fails to show the "rationale" frustration,
ing cortex of right hemisphere. (Courtesy of
which is characteristic of patients who have
Dr. John Hills,; and Dr. Jose Segarra.)
24-10 CHAPTER 24
Broca's motor aphasia and who are aware of and usually grammatical. He made use of many
their errors. At times, the patient shows some paraphasias and neologisms (nonsense words).
awareness that his verbal responses are failing He often appeared unaware of his errors. He
to deal with the environment. At times, the was unable to name single objects such as pen-
problems in communication are so severe that cil, cup, and spoon though he could recognize
the patient becomes agitated and is mistaken and demonstrate their use. He could read
for psychotic, as demonstrated in the case his- occasional individual words; for example, cat,
tory below. The anatomical localization for house. He could not comprehend or carry out,
Wernicke's aphasia based on early autopsy either spoken or written commands. His
studies has been confirmed by subsequent CT attempts at spontaneous writing produced only
scan and MRI studies: the posterior temporal- a few letters. He was unable to write words or
parietal area. In the studies ofNaeser (1983) phrases from dictation. He did significantly
the essential lesions involved Brodmann's Area better when asked to copy a printed sentence
22 (Wernicke area) of the posterior-superior or phrase. Repetition of spoken phrases or sen-
temporal gyrus and the adjacent supramarginal tences was poor. Calculations of even a simple
gyrus of the inferior parietal area. nature were poorly performed. Reflexes: A
In general, the responsible lesion is usually minor increase in deep tendon stretch reflexes
an infarct within the territory of the inferior was present on the right side. The plantar
division of the left middle cerebral artery often response on the right was equivocal. The left
embolic. There is usually very little evidence of was flexor.
a hemiparesis. In contrast, Broca's aphasia usu- Clinical diagnosis: Wernicke's type of flu-
ally reflects infarction within the territory of the ent aphasia probably secondary to an embolus
superior division of the left middle cerebral to the inferior division of the middle cerebral
artery and a right facial weakness and right artery.
hemiparesis are often present. (See Chapter 26 Pure word deafness: We have indicated
for additional discussion of vascular anatomy.) previously in discussing the auditory cortex,
Case 24-4 provides an example of a patient that this is a related relatively rare problem
with a Wernicke's type aphasia (Auerbach et al1982 and Coslett et al1984).
Case 24-4: This 40-year-old, right-handed In cases of pure word deafness, the hypotheti-
white male had experienced a series of myocar- cal center of auditory word association
dial infarctions beginning 10 months prior to (Wernicke's area) appear to be intact but audi-
consultation. Angiographic studies indicated tory information is unable to reach this center
occlusion of the right coronary artery and the from the auditory projection cortex (of either
left anterior descending coronary artery with hemisphere); in a sense disconnection has
stenosis of the circumflex artery and a coronary occurred. The auditory word association cen-
artery bypass procedure was performed using ter is intact. Previous auditory associations
extracorporeal circulation. The anesthetist may be used in the formulation of the patient's
noted that the patient was nonreactive 15min- own speech. Input of visual information to the
utes after the last administration of halothane center may also be intact. It should be evident
anesthesia. When the patient did wake up, he that the distinctions that have been made here
was quite agitated, combative and in retrospect between Wernicke's receptive aphasia and
had transient difficulty using the right arm. and word deafness are to be some extent artificial.
he continued to behave despite medications In general, lesions in this area do not respect
throughout the postoperative period, in a dis- such artificial distinctions and often destroy not
oriented and combative manner. Transfer to only the center for auditory word associations
the psychiatry service was actively planned but but also the inputs into this area from the audi-
a neurology consultation was obtained. tory projection areas.
Neurological examination: Mental status: Both Wernicke's receptive aphasia and
He was alert but agitated. Speech was fluent word deafness are often grouped under the
general term auditory agnosia. evidence of a Broca's aphasia, the patient is
Conduction or repetition type fluent unable to repeat test phrases and sentences,
aphasia: This type of aphasia is characterized e.g., "The rain in Spain falls mainly on the
by a relatively fluent spontaneous speech but plane" or "no ifS, ands or buts" and is unable
with marked deficits in repetition. Literal para- to write from dictation. Often, the syndrome
phasias are present and word-finding problems is seen in a less than pure form as in the case
may be present. The patient is usually aware of history that accompanies Figure 24-6. This is
the errors made. In contrast to the Wernicke's not surprising since the involved territory is
type of aphasia, auditory comprehension is that of the middle cerebral artery predomi-
usually relatively well preserved. The anatomi- nantly the inferior division. The essential lesion
cal location of the lesion is somewhat variable must spare Broca's and Wernicke's area to a
(Geschwind, 1965, Benson et al 1973, considerable degree but significantly damage
Damasio and Damasio 1980, Demasio 1992, the interconnection of these areas. If there is
Nausea 1983, Damasio and Geschwind 1984). significant damage to either Wernicke's or
The lesion essentially serves to disconnect Broca's areas, repetition will be defective on
Wernicke's area from Broca's area (the posteri- either the input or output side of the loop. A
or from the anterior speech areas). The essen- case demonstrating conduction aphasia will be
tial fiber system is the arcuate fasciculus presented as part of the next section.
(Fig.24-5). This fiber system arches around the Fluent aphasias associated with lesions
posterior end of the Sylvian fissure to join the of the dominant inferior parietal areas:
superior longitudinal fasciculus. In the study angular and supramarginal gyri: Geschwind
ofNaeser (1983) this system was involved deep ( 1965) indicated the critical location of the
to the supramarginal gyrus and/or deep to inferior parietal lobule in man situated between
Wernicke's area. In other cases the white mat- the visual, auditory and tactile association
ter deep to insular cortex has been involved areas. As such, it may act as a higher associa-
(Damasio and Geschwind 1984). In the resul- tion area between these adjacent sensory asso-
tant conduction aphasia, the patient under- ciation areas. In earlier chapters; we have
stands spoken commands and is usually able to already identified this area as the posterior pari-
carry out complex instructions that do not etal, multimodal sensory association area.
require a repetition of language. Although Geschwind has suggested that correlated with
able to speak spontaneously with little or no the development of this area in the human (the
angular and supramarginal gyri cannot be rec-
ognized as such in the monkey and are present
only in rudimentary form in the higher apes),
there has developed the capacity for cross
modality sensory-sensory associations without
reference to the limbic system. He contrasts
this situation with that in subhuman forms
where the only readily established sensory-sen-
sory associations are those between a non lim-
bic (visual, tactile or auditory) stimulus and a
limbic stimulus: those stimuli related to prima-
ry motivations such as hunger, thirst, sex.
Figure 24-5. The arcuate fasciculus: dissection of the
long fiber system, the superior longitudinal fasciculus (Such considerations of course do not rule out
demonstrating the arcuate fasciculus, passing beneath the establishment of limbic-non limbic stimuli
the cortex of inferior parietal, and posterior temporal associations in man, particularly during infancy
areas. A small bundle of Ufibers are also demonstrat- and childhood.) These theoretical concepts
ed incidentally at posterior, inferior margin of the would suggest the underlying basis for man's
temporal lobe interconnecting adjacentgyri. language functions . It is not surprising then
24-12 CHAPTER 24
that those aspects of language function which of information from the visual association
are most dependent on association between areas.
auditory and visual stimuli and auditory-visual- Many lesions in the inferior parietal area
tactile stimuli (reading and writing) are most extend into the subcortical white matter
disturbed by lesions of angular and supramar- involving the long association fiber system, the
ginal gyri. In the words of Geschwind, "It is a arcuate fasciculus - as discussed above.
region which turns written language into Patients with dominant inferior parietal
spoken language and vice versa." lobule lesions often demonstrate problems in
The component parts of the resultant syn- drawing (constructional drawing). Whether
drome are not constant. The patient will have this reflects damage to the cortex of the angu-
a varying degree of difficulty in writing (dys- lar and supramarginal gyri or a disconnection
graphia), particularly as regards spontaneous of these areas from the more anterior motor
writing. Often the ability to copy letters, words areas because of involvement of subcortical
and sentences will be relatively well preserved. association fibers is usually uncertain.
In contrast the patient will usually have diffi- As we have already discussed, many patients
culty writing from dictation, although at times, have involvement of all of the components of
this function may be less affected than sponta- the posterior speech areas, the inferior parietal,
neous writing. There is often an associated the arcuate fasciculus, and Wernicke's area. The
deficit in reading (dyslexia) although this is not following case history demonstrates such a
invariable. sequence of involvement in a tumor infiltrating
Significant defects in spelling and in calcu- this area with greatest difficulty in repetition as
lations (dyscalculia) may be present. There the most prominent initial feature.
may be an associated left-right confusion. Case 24-5: This 42-year-old right-handed
Errors may be made in finger identification, truck driver noted fatigue and irritability 6-8
with confusion as to index, ring and middle fin- weeks prior to admission. Three to four weeks
gers (finger agnosia). The combination of prior to admission, he noted he was using
dysgraphia, dyscalculia, finger agnosia and left words which he did not mean to use. Certain
right confusion is identified as Gerstmann's words would not come to him. During the
Syndrome. week prior to admission, he had two general-
From the standpoint oflocalization, several ized convulsive seizures; each proceeded by a
points of caution should be indicated. ringing sensation in the ears.
Dysgraphia may also result from disease involv- Neurological examination: Mental status:
ing the premotor cortex anterior to the motor The patient was alert and oriented to time,
cortex representation of the hand. It is likely place and person cooperative and able to carry
that information is conveyed from the inferior out the four-step command: "stick out your
parietal area to the premotor motor association tongue, close your eyes, hold up your hand and
cortex and then to the precentral motor cortex. touch the thumb to your ear". There was how-
This area of premotor cortex (sometimes ever evidence of a significant left-right confu-
termed the writing center of Exner) must func- sion when laterality was introduced e.g. "left
tion in a manner analogous to Broca's area. It hand to right ear". The ability to do even sim-
would be reasonable to consider dysgraphia ple calculations was markedly impaired with or
from a lesion in this premotor location as without paper e.g.lOO-9=99. There was little
essentially a motor apraxia due to destruction evidence of an expressive aphasia. Flow of
of an area concerned in the motor association speech was slow with only minor mispronunci-
memories for writing. ations. Reading was slow but with few errors.
Pure dyslexias may occur without actual The patient's did have minor difficulty in nam-
involvement of the angular supramarginal ing objects-a mild nominal aphasia. The
areas. The basic lesion as we will indicate, is a patient's greatest difficulty was in repetition of
lesion that deprives the inferior parietal cortex simple test phrases. There were moderate
defects in drawings of a house and a clock but had a significant improvement in fluency, he
few errors in copying simple figures. There was continued to have a severe posterior type of
a significant dysgraphia with marked difficulty aphasia. He was unable to carry out simple
in writing a simple sentence spontaneously or commands. His speech was incoherent, with
in writing from dictation. On the other hand, nonsense words and neologisms. He appeared
the patient was much better able to copy a sim- unaware of his errors and did not appear frus-
ple sentence. Significant errors were made in trated by his failure to follow commands. In
spelling. Memory was impaired; with immedi- addition to this Wernicke's type aphasia, the
ate recall object recall limited to 2/5 objects patient was unable to repeat words of two syl-
and delayed recall in 5 minutes limited to 0/5. lables. He could do no calculations, had severe
Digit span was limited to 2 forward and 0 in difficulties in copying drawings and was unable
reverse. Cranial nerves: A mild right central to even write his name. The patient received
facial weakness was present. Sensory system: radiotherapy but his condition continued to
Tactile localization was impaired on the right worsen with the development of a progressive
side. expressive and receptive aphasia and hemipare-
Clinical Diagnosis: Fluent posterior apha- sis all suggesting the spread of a rapidly grow-
sia, disconnection syndrome plus elements of ing glioblastoma. Coma, pupillary changes and
Gerstmann's syndrome (left right confusion, respiratory changes then intervened suggesting
dyscalculia, dysgraphia) plus seizures of focal the effects of herniation of the residual tempo-
origin (Heschl's gyrus posterior temporal lobe ) rallobe. Death occurred 7 months after onset
with secondary generalization. All suggested a of symptoms, and 5 months following surgery.
lesion in the left posterior temporal-posterior The neurosurgical approach to the man-
parietal area agement of a glioblastoma particularly those
Etiology was uncertain but tumor (glioma) involving the speech areas of the dominant
was considered most likely in view of the evolv- hemisphere has changed in the 35 years since
ing course. this patient was seen. A limited stereotaxic
Laboratory data: EEG: Focal 4-5 Hz slow biopsy under CT scan guidance would be
wave activity was present in the left parietal and undertaken and the patient would then be
posterior temporal areas. Brain scan (radioac- treated with dexamethasone and radiotherapy.
tive Hg 197): Increased up take of isotope in The end results would have been similar and
the left posterior temporal-parietal area mea- actually may even have occurred earlier. The
suring 4x5 cm. postoperative quality oflanguage function may
Left carotid arteriogram: A vascular mass have been transiently better. Unfortunately this
was present in the region of the angular gyrus patient had a very malignant and aggressive
with tumor stain in the area. tumor. The median survival of glioblastomas
Subsequent course: Papilledema soon with surgery alone is 26 weeks, with the addi-
developed. Dr.Robert Yuan performed a cran- tion of radiotherapy 52-60 weeks.
iotomy which revealed a palpable firm mass Case 24-6: This 57-year-old female, with a
slightly above and posterior to the angular long history of hypertension in the summer of
gyrus. At 2 cm below the surface, firm yellow 1985, had a brief episode of difficulty in word
tumor tissue was encountered. All visible finding and a more prolonged episode in
tumor and adjacent cortex of the angular and December 1985 with confusion, ''visual prob-
supramarginal gyri were removed and a partial lems", "inappropriate speech and difficulty
left temporal lobectomy was performed. finding the appropriate words". Following an
Histologic examination indicated a highly additional episode in March 1986, she had per-
malignant glial tumor with active mitosis and sistent problems in reading and apraxia of the
necrosis (a glioblastoma). Post operatively, the right hand.
patient had a marked expressive and receptive Neurological examination (May 1986):
aphasia. By 30 days after surgery, the patient Language function: Spontaneous speech was
24-14 CHAPTER 24
usually quite fluent. She described the room,

the environment and her friend. In contrast,
capacity for repetition was very poor both as
regards spoken and written speech.
Spontaneous writing was very poor except for
name and address Reading to herself aloud was
poor with little comprehension. She was able,
however, to follow single one stage spoken or
written commands but unable to do a
sequence of commands. Naming of objects
was well performed. Cranial nerves: Extinction
occurred in the right visual field for bilateral
simultaneous stimuli. Motor system: No hemi-
paresis was present. Reflexes: Right-sided
hyperreflexia and a right Babinski sign were
present.
Clinical diagnosis: Posterior aphasia, Figure 24-6. Posterior aphasia, infarction left posteri-
infarction left posterior temporal and parietal or temporal and parietal areas, inferior division, left
middle cerebral, (probably embolic following left
areas, probably due to embolic occlusion of
carotid occlusion) cr scan. Case 24-6 (Reftr to text).
inferior division of the left middle cerebral
artery. substitute other names, but more often will
Laboratory data: CT scan: Infarct left pos- describe the use of the object as a means of
terior temporal and parietal areas (Fig. 24-6). naming it, e.g., for a light switch - "That's the
Angiograms: Occlusion of the left internal thing that makes the light go on and off" (cir-
carotid artery. All left anterior and middle cumlocution). At times, associated findings
cerebral artery branches filled from the right suggest localization to the dominant posterior
carotid. An artery-to-artery embolus was temporal parietal area; at times, there is some
presumed. association with a Broca's area motor aphasia.
Global aphasia: These patients have little Mixed transcortical aphasia or isolation
verbal output either spontaneous or on repeti- of the speech areas: In contrast to the patient
tion, no comprehension and no ability to read with conduction aphasia and to patients with
or write. CT scans demonstrate massive infarc- Broca or Wernicke's aphasia, there are patients
tion of the entire middle cerebral artery terri- who have excellent repetition but little sponta-
tory of the dominant hemisphere involving neous speech. Broca's area, Wernicke's area
presylvian areas of the frontal, temporal and and the arcuate fasciculus are intact. The peri
parietal areas (see Naeser 1983). sylvian areas supplied by the middle cerebral
Anomie or amnesic or nominal aphasia: artery remain intact but are isolated from other
There remains a variety of aphasia - nominal cortical areas by infarction at the borders
aphasia - which is commonly encountered but between the middle and anterior cerebral arter-
which is not as readily localized to a particular ies or between the middle and posterior cere-
cortical area. The patient recognizes objects bral arteries. (See Geschwind et al 1968,
when these are present in the visual or tactile Geschwind 1971, Damasio and Geschwind
sphere but is unable to name the object or is 1984, Benson 1985 and Bogousslavsky et al
unable to access the internal dictionary to find 1988). As discussed in greater detail in chap-
the name, Nominal aphasia is often noted as ter 26, carotid artery stenosis may produce a
part of other aphasic syndromes. When perfusion defect at the border zone of the mid-
encountered in relatively pure form, speech dle and anterior cerebral artery (watershed
output is usually fluent, comprehension is nor- infarct). On the other hand, a fall in blood
mal and repetition is normal. The patient will pressure may produce perfusion-related infarc-
tion at the border zone between the middle and at the same time damaged the posterior
and posterior cerebral artery. The patient can portion or, at least, the splenium of the corpus
repeat without difficulty (fluent for repetitions) callosum (or the fibers radiating from the sple-
but has little spontaneous speech and little nium). The fibers conveying visual data from
comprehension. At times, the patient echos the right hemisphere must presumably reach
(echolalia) everything stated by the examiner. the speech areas of the dominant hemisphere
Transcortical motor aphasia: This rela- by passing through the posterior segment of
tively rare syndrome reflects isolation of the corpus callosum. The following case 24-4
Broca's area from the more anterior frontal would suggest this type of unilateral lesion pro-
areas and from the supplementary motor area. ducing a transient and partial but selective type
The lesion is within the territory of the anteriof dyslexia.
or cerebral artery. The speech pattern resem- Case 24-7: Seven days prior to admission,
bles that found in Broca's aphasia except that following a period of athletic activity, this 15-
repetition is intact. year-old, right-handed white male high school
Transcortical sensory aphasia: This rela- student had the onset of a 48-hour period of
tively rare syndrome reflects isolation of sharp pain in the left jaw and supraorbital area.
Wernicke's area from more posterior temporal The next day the patient noted blurring of
occipital areas. The lesion is within the territo- vision and the following day had the onset of
ry of the posterior cerebral artery. The resultant vomiting. Four days prior to admission, the
syndrome resembles Wernicke's aphasia except patient noted that he was unable to read and to
that repetition is intact. translate his Latin lessons. No definite aphasia
Damasio and Geschwind (1984), Benson was apparent. Two days prior to admission,
(1985) and Kirshner (2000) discuss the differ- the patient had the sudden onset of severe left
ent types of transcortical aphasia (motor senso- facial pain, accompanied by tingling paresthe-
ry, mixed) with anatomical correlation. sias of the right leg. The patient became stu-
Visual agnosia and selective dyslexia porous and then unresponsive for approxi-
(alexia without agraphia): Visual agnosia may mately 90 minutes. An examination of spinal
be defined as a failure to recognize visually pre- fluid at that time revealed pressure elevated to
sented material. Dyslexia or alexia represents a 290 mm of water with 250 fresh blood cells.
more selective deficit: a failure to recognize Neurological examination: Mental status
visually presented words (this is sometimes also and language function: Intact. Cranial nerves:
called word blindness). The student may con- small flame shaped hemorrhages were present
ceptualize the basic disturbance as a disconnec- on funduscopic examination's slight, right,
tion of the visual areas from the speech areas of supranuclear-type (central) facial weakness was
the posterior temporal and inferior parietal present. Neck: A slight degree of resistance was
areas. This disturbance could result from bilat- present on flexion of the neck (nuchal rigidity)
eral lesions or from a unilateral lesion. As we consistent with the presence of blood in the
have previously indicated, bilateral destruction subarachnoid space.
of the visual association cortex (areas 18 and Clinical diagnosis: Subarachnoid hemor-
19) would theoretically produce this effect. An rhage of uncertain etiology. In view of age and
alternate combination of lesions would involve the transient dyslexia, and the transient par-
destruction of the primary visual cortex (area erethises of the right leg, an arteriovenous mal-
17) of the dominant left hemisphere and the formation in the left parasagittal parietal-occip-
visual association cortex of the right hemi- ital area might be suspected.
sphere. Laboratory data: Arteriograms: An arteri-
A large unilateral lesion producing essen- ovenous malformation was present in the left
tially this same effect has been implicated in occipital region. The main arterial supply was
dyslexia. This lesion has usually destroyed the the posterior temporal branch of the left poste-
visual cortex of the dominant left hemisphere rior cerebral artery. The malformation drained
24-16 CHAPTER 24
into the lateral sinus. The posterior portion of ing approximately two weeks after surgery
the anterior cerebral artery was shifted across indicated that language function was intact
the midline, indicating a hematoma as well as except for reading. Oral reading was very slow
the malformation. (4 times slower than normal for a test para-
Subsequent course: On the evening after graph), halting and stumbling.
admission, the patient had the sudden onset of Comprehension of the material read was good.
a bifrontal headache and was unconscious for a Minor errors were made in the visual recogni-
2- to 3-minute period with deviation (repetition of letters. This was reflected in occasional
tive driving) of both eyes to the right, and with errors in spelling. Writing and drawing were
sweating and slowing of the pulse rate. Over intact but slow. Visual, auditory and tactile
the next two days an increase in blurring of the recognition and naming of objects was intact.
optic disc margins was noted (early papillede- Calculations were intact. No right-left confu-
ma). Four days after admission, the patient sion or finger agnosia was present. Repetition
suddenly complained of being unable to see of speech and spontaneous speech were intact.
from his right eye. He became restless and agi- Follow-up evaluation at 20 and 30 months
tated. Additional headache and neck pain with indicated that, although the patient was doing
numbness of right arm and leg were reported. well in school, receiving A's and B's with excel-
Examination now disclosed a dense right visu- lent grades in mathematics, he still was
al field defect (homonymous hemianopsia). described as slow in reading compared to his
The deep tendon reflexes were now slightly level prior to illness. No actual errors were
more active on the right. Funduscopic exami- made in reading when this was tested.
nation suggested that recent additional sub- Geschwind (1965) has reviewed many of
arachnoid bleeding had occurred since new the previously reported cases of selective
retinal hemorrhages were present. The next dyslexia. It is uncertain whether the informa-
day the patient was noted to have a significant tion from area 18 of the non-dominant hemi-
reading disability (dyslexia), although other sphere passes to the non-dominant angular
language functions were intact. Because of the gyrus and then crosses to the dominant tem-
progressive evolution of neurological findings poral parietal areas or whether these fibers pass
due to an expanding intracerebral hematoma, instead directly to area 18 of the dominant
Doctor Robert Yuan performed a craniotomy, hemisphere with information then conveyed to
which revealed blood present in the subarach- the dominant temporal parietal areas. He final-
noid space. The left lateral occipital cortical ly concludes that both pathways are probably
surface had numerous areas of bluish discol- operative. The relatively minor nature of the
oration indicating an intracerebral clot. The final residual deficit in the present case would
main arterial vessel was a lateral and inferior be consistent with such multiple pathways. It
branch of the posterior cerebral artery, bearing addition, non-fatal hemorrhages always pro-
no relationship to the calcarine region. The duce less damage than infarcts of comparable
draining vein was located in the occipital-tem- size. Finally, Coslett (2000) has reviewed vari-
poral area, close to the tentorium. At a depth ous recovered pure cases of dyslexia where the
of 1 cm, a hematoma of 50 cc of clot was right hemisphere may have played a role in
found. The clot extended down to the occipi- reading. Such patients do better with concrete
tal horn of the lateral ventricle but did not nouns than abstract nouns, verbs and functors
enter the ventricle. The malformation, (pronouns, prepositions, conjunctions and
hematoma and related cerebral tissue of the lat- interrogatives). It should be noted that a rela-
eral occipital area were removed. The calcarine tively selective dyslexia in the absence of a
area remained intact at the end of the proce- severe general visual agnosia might occur.
dure. Over a period of several days, the visual Geschwind has suggested that whether a gen-
field deficits disappeared. eral visual agnosia or dyslexia occurs may
Detailed language and psychological test- depend on the degree of disconnection of the
dominant speech areas from the parietal and tor and motor areas of the non-dominant hand
occipital areas of the non-dominant hemi- so that hand can also perform skilled move-
sphere. In the patient who already has left ments on command.
occipital cortex damage, dyslexia may require Apraxia then could result from damage at
only damage to the splenium, whereas visual any point in this series of association centers
agnosia may require more extensive damage to and their interconnections. Depending on the
the posterior body of the corpus callosum as point of disruption in the circuit, the type of
well. As noted bilateral lesions of visual associ- impairment will vary. Thus, a lesion of the
ation cortex (areas 18 and 19) would also pro- anterior one-half of the corpus callosum will
duce a visual agnosia. (See also Coslett and result in an apraxia limited to the nondominant
Saffran 1989 and Friedman and Albert 1985). hand. In contrast, a lesion of the dominant
In addition there are patients who have premotor association areas would be more like-
acquired dyslexia, which is unrelated to the ly to produce a bilateral impairment in certain
processing of the visual information input. tongue and hand movements.
These patients have a central (rather than the The concept that many varieties of apraxia
peripheral dyslexia of the pure alexia syndrome represent a disconnection between various cor-
discussed above). The central dyslexic patient tical areas, as reintroduced by Geschwind
has an impairment of the "deeper" or "higher" 1965, provides a more anatomically based
reading functions by which visual word forms approach than the use of terms such as motor
mediate access to meaning or speech produc- or limb kinetic (motor association areas) or
tion mechanisms. This problem has been ideomotor apraxia (parietal lobe apraxia).
reviewed in detail by Coslett (2000). Feinberg Heilman et al (2000) and Ochipa & Rothi
and Farah (2000) have reviewed the general (2000) have provided a more recent analysis of
topic of agnosias this topic.
The student will also encounter the term
APRAXIA ideational apraxia. This term that has received
As we have previously indicated this term multiple definitions over the years is now
may be defined as impairment in motor per- employed to indicate a defect in performing a
formance in the absence of a paralysis or senso- series of acts in their proper sequence. This
ry receptive deficit and at a time when cerebel- problem may occur in diffuse disorders such as
lar and cognitive functions are otherwise intact. Alzheimer's disease or frontal lobe disorders or
In the carrying out of a skilled movement on left parietal disorders. Some would suggest that
command there are several stages, which are, this type of dysfunction really represents not an
similar to those considered under language apraxia but a deficit in recent memory and
function. The command, if auditory, must be would require among the defining conditions
received at the cortical sensory projection area of apraxia that dementia not be present.
of the dominant hemisphere. The information (The topic of apraxia remains an area of con-
must then be relayed to the auditory associa- troversy).
tion areas for the words of the command to be
comprehended, that is, to evoke the appropri- NONDOMINANT
ate auditory associations. From these area HEMISPHERE FUNCTIONS
information must be relayed, to the multi- As we have previously indicated, certain
modal association area of the dominant inferi- symptoms appear to follow damage to the
or parietal association area. Information is then non -dominant parietal areas such as lack of
conveyed as discussed previously to the premo- awareness of hemiplegia, neglect syndrome,
tor and supplementary motor association areas defects in spatial construction and in percep-
of the dominant hemisphere. Information tion of three-dimensional space. Some have
must then be sent to the dominant motor cor- questioned whether a true dominance of these
tex and via the corpus callosum to the premo- functions actually exists in the hemisphere that
24-18 CHAPTER 24
is non-dominant for speech. Certainly, neglect out additional learning when the left visual
syndromes may also follow lesions of the dom- field and left hand are employed. Section of
inant parietal area or of either premotor area. the corpus callosum interferes with such trans-
As regards concepts of visual space, there is fer of learned information. There is evidence,
some evidence from the studies of Gazzaniga however, that some sensory information and
et al (1965), on section of the corpus callosum learned sensory discrimination is transferred
that the dominant left hemisphere is depen- between hemispheres via non-callosal path-
dent on information that must be conveyed ways. (Refer to Ettlinger 1965 and Sergent
from the right hemisphere. Moreover, the 1986)
studies of Penfield discussed in chapter 22, In considering the functions of the corpus
suggest that in patients with temporal lobe callosum based on studies of patients subjected
seizures, visual hallucinations are more likely to to callosotomy for control ofintractable epilep-
arise from stimulation of the right hemisphere sy, much caution must be exercised. (1) The
than of the left, The stimulation studies of patients also have focal multifocal or diffuse
Fried et al (1982) suggest short-term memory cortical damage sustained at variable age. At
for visuospatial functions may be localized to times, some reorganization of function has
the right superior temporal gyrus. Perception occurred. (2) The acute disconnection syn-
for visual spatial material may be localized to drome which has been described after corpus
the right parietal-occipital and to right frontal callosum surgery (see Reeves 1985, Sass 1988,
operculum. A defect in the recognition of Engel 1989) consisting of mutism, agnosia,
faces (prosopagnosia) has been related to apraxia or the non-dominant limbs, apathy,
lesions of the right parietal-occipital or inferior bilateral grasp release and gait apraxia may, in
temporal-occipital junction (see Luders et al part, relate to traction on non-dominant
1988, Fried et al1982, Sergent and Vtllemore parasagittal frontal, supplementary motor and
1989, Landis et al1988). premotor areas. (3) Ontogenetic effects and
effects of staging surgery have been noted. (4)
ROLE OF CORPUS CALLOSUM The same deficits do not necessarily occur in-
IN TRANSFER OF INFORMATION patients with agenesis of the corpus callosum.
The corpus callosum allows the non-domi-
nant hemisphere access to the special language
centers of the dominant hemisphere. Thus,
the intact right-handed individual can name an
object, such as a key; independent of whether
the object is placed in the left or right hand.
Following section of the corpus callosum, the
object can be named when placed in the right
hand but not when placed in the left hand. In
a similar manner, the corpus callosum allows
the dominant hemisphere access to those spe-
cialized areas of the non-dominant hemisphere
concerned with concepts of visual space.
There is also evidence that the corpus callo-
sum is involved in the transfer of information
concerned with learned sensory discrimina-
tions. Thus, the intact monkey or man, who
has been trained to press a key with the right
hand only when a particular visual pattern
appears in the right visual field, has no difficul-
ty in performing the same discrimination with-
CHAPTER 25
Case History Problem Solving: Part III
Cerebral Cortex: Cortical Localization
These cases represent the gamut of disease era! papilledema with venous engorge-
affecting the cerebral cortex. The pathology ment, arteriovenous nicking, and a recent
represented may be tumor, infurction, or hem- hemorrhage in relation to the right disc.
orrhage. Some of the lesions are intrinsic; oth- Visual acuity, however, was well
ers are extrinsic. The nature of the pathology preserved.
may be uncertain; the location of the patholo- c. Both pupils demonstrated a sluggish
gy, however, should be evident to you. response to light.
d. A left central (supranuclear) type of facial
CASE 2S-1A: Three months prior to admis- weakness was present with a droop of the
sion, this 39-year-old, right-handed, white, left corner of the mouth.
male mechanic had the first of repetitive 3. Motor system: Strength was intact and cere-
episodes characterized by "vertical wavy lines)) bellar tests were negative. However the
in his left visual field. The initial episode lasted patient tended to lean slightly to the left
30 minutes; subsequent episodes, 1 to 2 min- when walking.
utes. The patient had been seen by an ophthal- 4. Reflexes:
mologist during the first of these episodes and
a left visual field defect, which would disappear a. Deep tendon reflexes were asymmetrical,
at the end of the episode, was detected. An being slightly more active on the left than
on the right.
electroencephalogram revealed no definite
abnormality. Approximately 1 month later, the b. Plantar responses were flexor. Abdominal
left visual field defect remained as a permanent reflexes were present bilaterally.
deficit. At this time the patient also noted the c. No release of grasp and suck reflexes had
onset of numbness in his left hand. Two occurred.
months later the patient noted the onset of 5. Sensory system:
bitemporal and bifrontal headaches precipitat- a. Pain, touch, and vibration were intact.
ed by any motion of the head. One week prior
b. Position sense for fine amplitude move-
to admission there was an onset of vomiting
ments at the fingers and toes was
and these symptoms prompted his admission.
decreased on the left.
Past History: Not remarkable.
c. On simultaneous tactile stimulation of the
General Physical Examination: Not remark- left and right side, extinction of stimuli
able. occurred on the left.
NEUROLOGICAL EXAMINATION: d. Errors were made in object identification
1. Mental status: This was intact except for in the left hand.
some vagueness in the chronology for events e. Occasional errors were made in the identi-
in the present illness. The patient was ori- fication of numbers drawn on the fingers
ented as to time, place and person. Delayed of the left hand.
recall was intact. No aphasia was present; LABORATORY DATA:
reading and writing were intact.
The electroencephalogram and imaging studies
2. Cranial nerves: now suggested a single lesion.
a. A complete left homonymous hemianop- QUESTIONS:
sia was present.
1. Localize the initial symptoms? In your con-
b. Fundoscopic examination indicated bilat-
25-2 CHAPTER 25
sideration as the location of the lesion, you 2. Cranial nerves: No abnormalities were
will wish to consider the localizing signifi- present.
cance of the following: the initial episodes of 3. Motor system: No relevant findings were pre-
''vertical wavy lines" b. the homonymous sent. The patient had fallen during the sec-
hemianopsia. What is the nature of these ini- ondarily generalized seizure, sustaining a
tial symptoms? fracture of the left humerus and dislocation
2. Which areas were subsequently involved by at the left shoulder. Since that time he had a
the lesion? Take into account the pattern of poor swing of the left arm due to limitation
findings on sensory examination. of left shoulder movement. A slight atrophy
3. What is the pathological nature of the of the hypothenar eminence with some
lesion? Take into account the short duration weakness in the ulnar distribution had also
of symptoms and the age of the patient. been present since that injury.
4. Which diagnostic study would you perform? 4. Reflexes: Deep tendon reflexes were sym-
metrical; plantar responses were flexor.
5. How would you treat the seizures?
5. Sensory system: All modalities were intact
6. How would you manage the basic lesion?
except for errors in graphesthesia in the left
hand.
CASE 25-2: This 35-year-old, right-handed,
LABORATORY DATA:
white male had the onset of a sudden pins-and-
needles sensation which began in the left foot 1. Skull x-rays: The calcified pineal was shifted
and then spread within a few seconds to 4 to 5 mm compared to a shift of 2 mm. in
involve the entire left side of the body includ- films obtained 1 year previously.
ing the arm and the face. The total episode last- 2. Electroencephalogram: Focal slow wave
ed for 8 minutes. Similar episodes then activity of 4 to 6 Hz was present, consistent
recurred once or twice weekly beginning most with focal damage.
frequently on the left side of the face or tongue
3. Cerebrospinal fluid: Normal pressure and
and less often on the left foot or hand. Four protein (21 mg.jIOO mI.) were present.
months later the patient had a similar episode
but fell to the floor with a loss of consciousness 4. The imaging studies were consistent with a
of several minutes duration during which single focal lesion.
observers reported some clonic movements of QUESTIONS:
the left arm and leg. Neurological examination, 1. Where is the lesion in terms of the origin of
lumbar puncture, and electroencephalogram at the seizure activity?
that time were reported as normal. The
2. What are the possible pathological diag-
episodes were temporarily controlled with anti-
noses? In answering this question you
convulsant medication, phenytoin (Dilantin),
should keep in mind that the patient is of
but then recurred with increasing frequency. At
middle age (35), the seizures are clearly
the time of hospital admission, 19 months after
focal, and there is a 19-month history. These
onset of symptoms, these episodes of numb-
ness were occurring 3 to 4 times per day. facts alone, even without the confirmatory
laboratory data, should lead to the most
Past History: There was no history of signifi- likely diagnosis.
cant head trauma. There was no family history
of seizures. 3. Which diagnostic study would you perform?
4. How would you treat the seizure?
5. How would you treat the basic lesion?
1. Mental status: Orientation and memory
were normal.
PROBLEM SOLVING PART III: CORTICAL LOCALIZATION 25-3
CASE 25-3: A 66-year-old, right-handed, lower extremities described as
white widow developed changes in affect and "gegenhalten."
lack of interest in her surroundings over a 1- c. The patient was very hesitant and very
month period. Although previously she had fearful of sitting, standing, or walking.
been alert, caring for herself, doing her own There was some retropulsion (a tendency
shopping, and interested in her relatives, she to fall backward when attempting to sit or
now took to her bed and became disheveled in walk). When she walked her right foot
appearance. She would talk little if at all. She appeared to be glued to the floor.
complained of a vague weakness in her legs,
4. Reflexes:
was unwilling to walk, but was able to walk to
the bathroom without assistance. a. Deep tendon reflexes were symmetrical
and active.
Past History: A myocardial infarct had occurred
10 months previously. There was a 10-year his- b. An equivocal plantar response was present
tory of Paget's disease involving the bones of on the right; that on the left was flexor.
the lower extremities. c. Strong grasp reflexes were released at
hands and feet. Visual and tactile suck
reflexes were also released.
1. Mental status:
5. Sensory system:
a. The patient was apathetic with a dull
a. Pain, touch, and position sense were
appearance.
intact.
b. The patient was disoriented for person
b. There was a minor decrease in vibratory
and time. She knew that she was in a hos-
sensation at the toes, which may well have
pital in the state of Massachusetts but did
related to the patient's general nutritional
not know the city.
status.
c. She was unable to recall her birth date or
to name any president. She could give no LABORATORY DATA:
account of her illness. 1. Sedimentation rate elevated to 98 mm. in
d. She was unable to add 5 and 5 and could one hour.
not do multiplication or subtractions. 2. Skull x-rays: An osteolytic lesion (area of
e. She repeated 4 digits forward and none in bone destruction) was present.
reverse. 3. Lumbar spine x-ray: A suspicious, probably
f. Spontaneous speech was scanty but with- osteolytic lesion was seen in the body of the
out a definite dysarthria or aphasia. She Ll vertebra.
could name 3-out-of-6 objects, could 4. Stool Guaiac: A small amount of occult
repeat 6-out-of-6, and could read aloud 4- blood was present. Hematocrit and hemo-
out-of-6. She was able to perform slowly a globin were normal. Rectal and proctoscop-
two-step command. She was apparently ic examination revealed a firm mass at
unable to write. approximately 9 cm. above the anus.
2. Cranial nerves: II-XII were intact except 5. Electroencephalogram indicated a focal lesion
that the left disc margin was blurred on fun- having the quality of damage (continuous
duscopic examination. focal 2 to 4 Hz slow waves).
3. Motor system: 6. Imaging studies were consistent with a single
a. No focal weakness was present. focal lesion.
b. There was a variable resistance in both 7. A lumbar puncture 3 weeks prior to admis-
sion had revealed pressure increased to 220
25-4 CHAPTER 25
mm. of CSF and protein elevated to 59- Past History: Gout had been present since age
mg./IOOml. 20. He had sustained an apparent coronary
QUESTIONS: artery occlusion in the past.
1. Where is the lesion? (Assume a single central NEUROLOGICAL EXAMINATION:
nervous system lesion). 1. General: blood pressure: 130/80; pulse 85
2. What is the most likely pathology? and regular.
3. How would you manage this problem as 2. Mental status:
regards more specific diagnosis and therapy? a. The patient was oriented for time, place,
Which neuroimaging studies would you and person.
perform? b. Memory for recent and remote events was
In considering these questions you will wish to intact. Immediate and delayed recall was
keep in mind the following points: intact.
1. As regards the location of the lesion: c. The patient could do simple calculations
a. The personality change, accompanied by but had difficulty with more complex
impairment of all areas of mental function, problems.
b. The release of strong grasp reflexes in d. These results may have been influenced by
both upper and lower extremities, in addi- the fact that the patient demonstrated a
tion to suck reflexes, marked impersistence in following com-
c. The apparent inconsistent findings as mands. The patient was somewhat apa-
regards resistance to passive motion, thetic and yawned frequently during the
examination. There was a flattening of
d. The disturbance of sitting posture and of
mood.
gait.
e. The patient denied that he had any partic-
2. As regards the type of pathology: ular problems requiring hospitalization.
a. The elevation of sedimentation rate, He denied illness and stated he was as
b. The apparently rapid onset of symptoms, healthy now as he had been one week
c. The presence of occult blood in the stool, prior to hospitalization.
d. The presence of osteolytic lesions, £ Abstract reasoning was intact, as tested in
e. The mass noted on examination of the proverb interpretation (used abstract con-
rectum. cepts).
g. No aphasia was present.
3. Which diagnostic studies would you per-
form? h. A distinct deficit in the construction of
three-dimensional drawings was present.
3. Cranial nerves: All were intact except for:
CASE 25-4: On the evening prior to admis-
sion, his wife noted that this 62-year-old right- a. A significant left facial weakness of
handed, white, male civil engineer had the rel- supranuclear type.
atively sudden onset of slurred speech associat- b. An inconstant neglect of left field on
ed with a drooping of the left side of the face. simultaneous stimuli to left and right visu-
The patient denied that these symptoms were al fields.
present. The following morning he was exam- 4. Motor system: Strength and gait were intact
ined by his brother, a physician, who con- and cerebellar tests were negative.
firmed the presence of slurred speech and 5. Reflexes: Deep tendon reflexes were sym-
weakness of the lower one-half of the left side metrical, plantar responses were flexor and
of the face but also noted a weakness of the left no pathological grasp reflex was present.
arm and leg.
6. Sensory system the left eyelid and then almost immediately by
a. Pain and touch were intact. a twitching of the distal segment of the left
b. Stereognosis, two-point discrimination, thumb. This soon spread to the left forefinger,
and tactile localization were normal. then to the middle finger, and then involved
However, position sense was decreased at the hand in repetitive clonic movements.
toes and fingers on the left. There was a According to observers, the clonic movements
tendency to ignore tactile stimuli on the then spread into the left arm. The twitching
left face, arm, and leg when simultaneous about the eyelid spread to the entire face. This
left and right stimulation was carried out. initial episode lasted a total of 15 minutes;
Graphesthesia was intact in the right there was, however, a residual numbness of the
hand, but defective on the left. left thumb and index finger: "as though they
had fallen asleep." There was also a transient
LABORATORY DATA:
weakness of those areas first involved. Since the
1. Blood serological test for syphilis was nega- first episode, the patient had experienced
tive. minor recurrences of "tingling" of the left
2. Skull x-rays were normal. thumb and index finger.
3. Electroencephalogram: abnormal because of Past History: Six years prior to admission the
focal 2-5 Hz slow waves. patient underwent a right radical mastectomy
4. Brain scan (radioactive Hg 197): A diffuse for carcinoma of the breast. Regional lymph
focal uptake was present. nodes were reported as negative. The patient's
mother and sister also had carcinoma of the
SUBSEQUENT COURSE: breast.
Over the next 3 months, significant improve-
ment occurred. The patient was able to do
complex calculations. He had no difficulty in 1. Mental status: intact with no evidence of
drawing or in locating points on a map. aphasia. No deficits were noted in drawing.
Sensory examination was normal. The patient 2. Cranial nerves: A minimal left supranuclear
still had difficulty in maintaining his concentra- central facial weakness was present.
tion. Psychological testing now indicated ver- 3. Motor system: A mild weakness was present
bal IQ of 123, performance IQ of 104, with in the left upper extremity and rapid alter-
full scale IQ of 116, compared to much lower nating movements of the left hand were
scores of Ill, 87, and 101 respectively at the slowly performed
time of his acute illness. 4. Reflexes:
QUESTIONS: a. Deep tendon stretch reflexes were
1. Where is the lesion (be specific)? increased on the left.
2. What is the nature of the lesion? Ifvascular b. An equivocal plantar response was present
discuss the type of lesion and the vascular on the left; that on the right was flexor.
territory c. No grasp reflex was present.
3. Which studies should be performed (in 5. Sensory System:
terms of neuroimaging and other studies)? a. Pain, light touch, position, and vibration
were normal.
CASE 25-5: This 52-year-old housewife was b. There was a slight disturbance in graphes-
referred for evaluation of episodic "twitching thesia over the left hand and face. There
of the left thumb and forefinger" beginning 2 was minor impairment of two-point dis-
weeks prior to admission. The patient had crimination over the left thumb and fore-
noted the sudden onset of a numbness of the finger.
left thumb, followed in seconds by twitching of
25-6 CHAPTER 25
QUESTIONS: described. There was an accompanying sensa-

1. Indicate the location of the lesion in this tion of fright. During such an episode the
case. patient would be able to continue driving or
walking.
2. Indicate the most likely pathology.
3. (a) Attach a label to the twitching which A second type of episode, lasting 30 to 120
begin in the left thumb, then spread to seconds, was characterized by an inability to
the other fingers, then to left hand, arm, talk properly, a babbling of speech, and an
and face. inability to understand speech. During this
time a sensation of vague familiarity and fatigue
(b) Attach a label to the transient weakness,
and at times a sense of reincarnation would
which followed these episodes of
exist.
twitching.
4. Which diagnostic studies would you per- A third variety was characterized by the visual
form? sensation oflooking down a long dark corridor
with a light at the other end. There was no
5. Discuss management of this patient. concept of time: at times the corridor seemed
to move from right to left. At the end of such
CASE 25-6: This 19-year-old, right-handed, an episode things would not look as they
white, male pharmacy student was referred for should; objects appeared distorted, and color
evaluation of frequent minor seizures. At age altered. Objects were seen as black and white.
18 months, the patient had fallen striking his The whole scene would seem unworldly.
head against a concrete floor and within hours Sounds would be perceived but would fail to
had lapsed into coma. Later that day he be registered and would not make sense.
required emergency neurosurgical treatment at NEUROLOGICAL EXAMINATION:
the Children's Hospital for a "skull fracture
Mental status, cranial nerves, motor-system
and a bleeding vessel which the neurosurgeon
reflexes, and sensory system were all intact
had to tie." The patient apparently made an
except for a minimal lag of the left side of the
excellent recovery. However, from 3 years of
age until 5 years of age he experienced "large face in smiling. During the examination, the
patient had a minor episode; his head dropped
convulsions" (apparently generalized convul-
and he appeared out of contact for 20 to 30
sive seizures). During this time he also experi-
seconds. He did not answer questions directly
enced minor episodes characterized by the sen-
but replied by saying, "What was then, what
sation that objects were becoming smaller or
was that then, what was that then?" He was
larger. The patient recalled that at; times, he
confused for several minutes, after the episode.
had the sensation that bright geometric pat-
He was subsequently amnestic for the events of
terns were present and shrinking in size.
the episode.
Almost invariably the patient experienced the
sensation of fear with these episodes. The QUESTIONS:
patient had no seizures from age 5 years until 1. The electroencephalogram indicated a stable
age 16 years. Since age 16, the patient had fre- focus of discharge. Indicate the location of
quent minor episodes of several types occur- that focus.
ring as frequently as 15 to 30 times a day. 2. ClassifY the seizure according to the
One type of episode was accompanied by International Classification of Seizures.
dreamy sensations lasting a few seconds; at 3. What is the most likely explanation for the
times things looked unreal. At the same time acute events, which occurred at age 18
the patient would feel that the whole episode months?
was somehow very familiar, that objects looked
4. Why did seizures recur at age 16 years?
very familiar in a manner that could not be
CASE 25-7: This 20-year-old white male (Mr. particularly marked in the thumb
KB.) had been admitted to Boston City abductor.
Hospital at age 9 months with acute right b. Gait: A minimal circumduction of the
hemiplegia and acute right-sided hemi convul- right leg was noted.
sions associated with a fever. A right hemiple- 5. Reflexes:
gia was present for several days and he contin-
ued to have a mild right hemiparesis. Several a. Deep tendon reflexes were increased on
additional seizure episodes occurred between the right.
ages 1-3 years. No additional episodes b. Plantar response was equivocal on the
occurred until age 17 when the patient had a right.
focal seizure characterized by tonic posture of 6. Sensory system: Minor deficits were present in
the right arm - abducted at the shoulder and the right upper extremity characterized by
flexed at the elbow - followed by turning of errors in fine-movement perception of the
the head and eyes to the right. Consciousness right fingers and errors in graphesthesia of
was impaired but not completely lost. For sev- the right hand. Pain and touch were intact.
eral minutes the patient was unable to speak.
SUBSEQUENT COURSE:
Upon regaining speech, he was able to follow
commands. With adjustment of anticonvulsant medication,
excellent seizure control was attained. Only
Treatment with anticonvulsants (Eskabarb -
rare limited focal (partial) seizures occurred
long-release form of phenobarbital) was rela-
over the next 30 years.
tively effective in preventing seizure recur-
rence. Once a month the patient did experi- QUESTIONS:
ence a few seconds of ''weakness or limpness" 1. Locate the lesion.
of the right hand with a possible small jerk of 2. What is the origin of focal (partial) seizures
the right hand. Approximately two weeks characterized by tonic posture of the right
before his initial office visit in January 1968, arm with deviation of the head and eyes to
the patient discontinued his medications. Four the right and with arrest of speech?
days prior to this visit, at a time of sleep depri-
3. The patient has a right hemiplegia and yet
vation, the patient had a focal seizure with
he does not have aphasia. Explain.
tonic movement of the right arm and deviation
of the head and eyes to the right followed by a 4. In view of the acute onset of the hemiplegia
generalized convulsive seizure. Since age 9 at age 9 months and the subsequent lack of
months, residual weakness of the right arm had progression, speculate
been present. However language functions had Concerning the etiology.
developed and he had done well in school 5. Why was the weakness most prominent in
NEUROLOGICAL EXAMINATION: the distal muscles of the upper extremity
(particularly the thumb)?
1. General: The patient was left-handed with
long-standing smallness of the right side of 6. Why did seizures recur?
the face, arm, and leg. 7. Why has the smallness of the right side
2. Mental status: All areas were intact with no occurred?
aphasia. 8. What is the nature of the sensory deficit?
3. Cranial nerves: All were intact except for 9. How would you manage the seizure
slight lag on the right in smiling. problem?
4. Motor system: 10. Does the recurrence of seizures at age 17,
a. There was a mild weakness of the right after no seizures since age 3, indicate that a
upper extremity, most marked distally and progressive pathology is present?
25-8 CHAPTER 25
CASE 25-8: This 23-year-old, right-handed, pushing the nurses aside and ran into a wall.
white male was admitted with chief complaints He had to be restrained by several people, and
of frequent and increasing headaches and was given some injections. Psychiatric treat-
"seizures". The problem apparently began 15 ment was begun with no significant improve-
months prior to initial evaluation, when sever- ment. Two months prior to evaluation, the
al months after their marriage, the patient's patient's wife inquired ofhim whether the psy-
wife noted a change in his personality. In par- chiatrist had been able to tell him anything
ticular, the patient no longer had any desire for about the cause of his episodes. He threw a jar
sexual intercourse. He became more irritable, of mustard at her, then the plates off of the din-
at times with only minimal provocation and he ner table. He rushed at her. As she retreated,
was verbally and physically abusive. he kept coming after her. He seemed unaware
Eight months later, (7 months prior to initial of his actions, and did not seem to recognize
evaluation), he began to awake from sleep with her. He placed his hands about her throat and
numb feeling of right side of the lips which began to choke her. With difficulty, she man-
quickly spread to the right side of face; would aged to break free. She noted that he appeared
last a few minutes and resolve. When the dazed and sleepy. At this point, fearing for her
patient awoke during such episodes, he found life, the wife decided upon a divorce. The
himself sitting upright. These would occur patient denied any memory for this episode.
weekly and only as the patient was going to Intermittent bitemporal and bifrontal
sleep or after he had fullen asleep. headaches began to increase in frequency.
Occasionally, he had incontinence of urine and
After a few weeks the seizures changed in char-
tongue biting during his severe nocturnal
acter. While sleeping, the patient would sud-
seizures, which now were occurring, on a daily
denly be thrown toward his right side, his head
basis.
would arch back and he would have difficulty
breathing. He would be aware during these Fifteen days prior to admission, the patient
episodes and could understand what people became angry at a dog that was barking out-
said, but could not speak. Sometimes the side the house. He ran outside to chase the
patient would not be thrown to the side, but dog, but could not catch him and he kicked
would simply have tonic stiffening and claw- the fence gate. This is the last he remembers.
like formation of the right hand, lasting 20 to His girlfriend relates that the patient began
30 seconds. punching the brick wall of the house and then
began to bang his head forcibly against the
Two months later, (5 months prior to evalua-
wall, stopped, and fell on his back staring,
tion) he underwent a right inguinal hernior-
whereupon his girlfriend helped him walk into
rhaphy and had several attacks in the recovery
the house. The patient next recollects the trip
room. Since that time, the patient has experi-
to the hospital where lacerations of his hands
enced one or two seizures per day, some of
were sutured and he was released.
which occurred while awake.
Because of these episodes, he was admitted to NEUROLOGICAL EXAMINATION:
a local hospital for evaluation. EEG and LP On admission evaluation, this was entirely nor-
were reported to be normal. Following the mal. Bilateral paresthesias of the hands were
lumbar puncture he developed a bifrontal reproduced by hyperventilation.
headache. While sitting in a wheelchair, he SUBSEQUENT COURSE:
began to complain of headaches. A nurse
8 months later, minor findings were present:
placed her hand on his forehead and his wife
told the nurse to get her hand off. According 1. Mental status: He was anxious but affect was
to other observers, he ran down the corridor indifferent and passive.
2. Cranial nerves: A slight right central facial
weakness was present
3. Reflexes: Deep tendon reflexes were slightly
increased at right biceps, patellar and
Achilles. The right plantar response was
equivocal.
QUESTIONS
1. What is the most likely explanation and
anatomical basis for the episodes of aggres-
sion in this casd
2. How often does directed aggression occur
as an ictal event as opposed to non-directed
aggressive behavior during ictal or post ictal
confusional states?
3. From the anatomical standpoint what is the
explanation for the change in personality?
4. What is the localization for the episodes of
seizures while sleeping characterized by the
following description "the patient would
suddenly be thrown toward his right side,
his head would arch back and he would note
difficulty in breathing"?
5. What is the anatomical; localization for the
episodes of tonic stiffening and claw-like for-
mation of the right hand? What is the expla-
nation for the initial episodes of tingling of
the right side of face and lips?
6. How can you tie all of this together into a
comprehensive diagnosis?
7. Discuss the possible underlying pathology
and your diagnostic and therapeutic man-
agement.
CHAPTER 26
Cerebral Hemispheres:
Neuropathology and Clinical Correlation I.
Vascular Syndromes
The course and nature of some of the more orrhage, and (5) subarachnoid hemorrhage.
common diseases affecting the cerebral hemi- These various categories are not mutually
spheres are already familiar to the student on exclusive. Thus occlusive vascular disease usual-
the basis of those case histories presented in the ly occurs in relation to the process of athero-
previous chapter on cortical localization. We sclerosis - the deposition of fatty material (cho-
will refer back to some of those case histories. lesterol) in the walls of arteries. However,
However, we will not limit our discussion sim- emboli produce their effect essentially by
ply to the neocortex but will discuss the cere- occlusion of cerebral arteries. Such emboli
bral hemispheres in a more general sense. It generally originate in relation to clots within
will also be convenient at this point to consid- the chambers of the heart. At times, however,
er several broad categories of diseases, not pre- such embolic material has originated at an area
viously discussed, which do not necessarily of occlusive disease when atheromatous mater-
restrict themselves to the cerebral hemispheres. ial or an overlying thrombus (clot) has broken
Diseases affecting the cerebral hemispheres loose to be carried into the more distal circula-
account for the largest proportion of central tion. There is, on the other hand, an overlap
nervous system diseases encountered in med- between ischemic occlusive disease and intrac-
ical practice. These diseases may be focal or erebral hemorrhage. Thus certain areas of tis-
diffuse in nature. There is also a third or inter- sue damage resulting from ischemia may
mediate category of multifocal (that is, com- become hemorrhagic secondarily. The symp-
prised of many focal events). Our major con- toms and signs, which then evolve, may resem-
cern in this chapter will be with focal vascular ble those of intracerebral hemorrhage. The use
disease. of angiography, CT scan, and MRI have
VASCULAR DISEASES OF allowed a more precise delineation of infarct vs
THE CEREBRAL HEMISPHERE hemorrhage but have left a large group of
patients where a specific cause of the infarct
Vascular problems account for the largest
remains uncertain.
category of diseases affecting the cerebral
hemispheres. Cerebrovascular disease remains ISCHEMIC-OCCLUSIVE DISEASE:
the third leading cause of death in the United Within this category the subtypes indicated
States. The annual incidence is close to in Table 26-1 may be specified (based on
300,000. Approximately 261,000 fall into the Kistler, 2000, Sacco et al1989, and Wolf et al.
ischemic/occlusive/category and 36,000 into 1987.
the category of intracerebral and subarachnoid Earlier clinical and autopsy studies suggest-
hemorrhage. The overall mortality due to this ed a higher incidence of large or small vessel
cause has been falling due to: (1) better control disease compared to embolic disease. (See
of hypertension; (2) better control of cardiac Adams et alI997).
arrhythmias; (3) decreased incidence of Atherosclerosis involves the large- and
rheumatic heart disease; (4) decreased inci- medium-sized extracranial and intracranial por-
dence of meningovascular syphilis. Several tions of the cerebral arteries. With increasing
types must be considered: (1) atherosclerosis deposition offatty material at points ofbifurca-
with ischemia due to stenosis and occlusion (2) tion or angulation, a progressive narrowing
small infarcts (Lacunar infarcts) due to hyper- (stenosis) of the lumen occurs (Fig. 26-1).
tension, (3) embolism, (4) intracerebral hem- Eventually, at approximately 70-75% stenosis, a
26-2 CHAPTER 26
decrease in cerebral blood flow through this

point of narrowing in the vessel will occur (the
TABLE 26·1 TYPES OF ISCHEMIC·OCCLUSIVE DISEASE
Cause of Ischemic· Percent of Total Cases

Occlusive Disease
1. Large vessel 15 % (internal carotid artery
atherosclerosis: conSliMes 9% of all ischemic)
2. Small vessel (lacunar) 9%
3. Embolic Overall 60%( secondary to

atrial fibrillation conSliMes
15% of all ischemic)
4. Dissection and
other causes 3%
actual relationship may be calculated according

Figure 26-1. Atherosclerosis of arteries in the circle of
to Bernoulli's principle). The area supplied by
Willis at the base of the brain. (Courtesy ofDrs. John
this vessel may then at some point receive less Hills and Jose Segarra).
than the required amount of blood (oxygen,
glucose, and so forth). When this occurs, we in nature or it may be prolonged with actual
may speak. of cerebral ischemia. Kalimo et al tissue death (infarction) and residual neurolog-
(1997) outline the effects of decreased perfu- ical deficit. As progressive narrowing of the
sion as follows: with a blood flow>40% of the lumen occurs, eventually a point of total occlu-
normal value, normal spontaneous and evoked sion is reached. The narrowing of the lumen is
activities of nerve cells is still present. Between moreover accentuated by several additional
30-40% of normal flow, neurons are unable to processes: (a) thrombus formation - the forma-
produce sufficient energy to continue trans- tion of a clot of platelets, fibrin, and blood cells
mission of impulses. At < 30 % of perfusion, due to stasis, change in intimal surface, and so
transmission by the neuron no longer occurs forth, (b) ulceration of the intimal surface at
although the neuron is still viable. When per- the locus of the atherosclerotic surface at the
fusion falls below 15% of normal, membrane locus of the atherosclerotic plaque, and (c)
failure begins to occur. The transmembrane subintimal hemorrhage in relation to this area
ion gradients are no longer maintained and of deposition. The process of ulceration of the
extracellular potassium rises. Unless perfusion intimal wall may produce an originating site for
and energy production are restored, irre- emboli composed of the atheromatous materi-
versible nerve cell damage will occur. Note that al. Such an ulcerated intimal wall is a likely site
there is a zone adjacent to this focal area of of thrombus formation producing additional
damage referred to as the penumbra where stenosis. The study of Eliasziw et al (1994)
total failure has not yet occurred. This area confirmed that plaque ulceration more than
represents tissue that could be saved by thera- doubles the risk of stroke at higher degrees of
peutic measures. stenosis. Fragments of the clot may also travel
The clinical correlates of this sequence of as emboli into the distal circulation.
focal ischemia are as follows. A dysfunction of We have used the joint term, atherosclerot-
the involved ischemic area occurs with focal ic ischemic occlusive vascular disease , since
symptoms of weakness, numbness, and the there is no one-to-one relationship between
like. This dysfunction may be only temporary actual occlusion of a vessel and tissue death
NEUROPATHOLOGY: VASCULAR SYNDROMES 26-3
(infarction or encephalomalacia) in the region requirements when metabolic conditions have
supplied by that artery. Thus, total occlusion of changed.
a vessel may occur with or without the devel- Infarction (encephalomalacia): It is
opment of significant neurological symptoms appropriate at this point to briefly summarize
and signs. There may be at times persistent the gross and microscopic changes, which
symptoms and signs correlated with significant occur when ischemia has been of a sufficient
tissue destruction. At other times, with steno- degree to produce tissue death. The neu-
sis, there may be only episodes of transient ropathologist generally distinguishes between
symptomatology without actual tissue destruc- pale and hemorrhagic infarction. Most infarcts
tion. These transient episodes, related to vascu- following ischemia are "pale" and are not
lar insufficiency, are referred to as transient complicated by hemorrhage at a gross level.
ischemic attacks. During the first 4 to 6 hours no gross or micro-
The several factors which account for this scopic changes are apparent. Between 8 and 48
lack of close correspondence between the state hours swelling of gray and white matter is
of a particular artery and the vascular status of noted; the white matter may appear somewhat
the region supplied by that vessel have already granular. After 48 hours the infarcted area feels
been covered in the earlier discussion of basilar soft and mushy; the descriptive term necrosis
vertebral ischemic/occlusive disease. (Refer may be used. This state may be generally rec-
also to figure 26-7 below) ognized by visual inspection. Over the next 10
1. There are significant variations in the days a decrease in swelling occurs. Through
capacity of the circle of Willis to provide collat- enzymatic processes, liquefaction occurs. By 3
eral circulation. weeks, in larger lesions a gross cavity begins to
2. There are significant leptomeningeal appear. Within a period of several months, all
anastomoses over the surface of the cerebral of the necrotic tissue is replaced by a fluid-filled
cortex between the anterior, middle, and pos- cavity.
terior cerebral arteries of a given hemisphere. Advances in imaging studies have allowed
With regard to each cerebral artery one may for earlier detection of ischemia and infarction.
then speak. of its area of central supply and its Refer to Shaeblitz and Fisher, 1999. Perfusion
area of peripheral supply. This latter peripheral imaging MRI studies will demonstrate
area usually receives also the peripheral supply decreased perfusion and presumably ischemia
of adjacent vessels and is in a sense a border within 15 seconds.This ischemia may be
zone or watershed. reversible. This is similar to the older neuro-
3. To a variable degree, anastomoses are physiologic test; the electroencephalogram
present between the external and internal which when employed in the operating room
carotid arteries. during carotid endarterectomy will begin to
4. Finally, a considerable variability occurs detect the changes of ischemia within 10-15
because of certain general systemic and meta- seconds. Diffusion weighted MRI studies may
bolic factors. Thus a narrowed vessel may still demonstrated differences between normal and
deliver sufficient blood when the systemic ischemic presumably infarcted tissue within
blood pressure is 190/100 but fails to do so minutes to one hour. * Standard MRI will
when the blood pressure falls to 120/70 dur- detect the increased water content of infarcted
ing sleep, on sudden standing after a long peri- tissue at 6-12 hours. CT scans may also begin
od of recumbency, and in relation to antihy- to detect early subtle changes related to
pertensive medications. Similarly, stenotic
blood vessels may deliver a sufficient blood ""The dicrepancy between perfusion imaging
flow when metabolic conditions such as tem- and diffusion weighted imaging may allow the
perature serum sodium and glucose are normal identification of the ischemic not yet infarcted
but this blood flow may fail to meet essential penumbra around an infarct.
26-4 CHAPTER 26
changes in water content (some effacement of

sulci and gyri) at 3-4 hours although the clear
cut appearance of infarction is usually delayed
until 18-24 hours (Warach & Edelman, 1993,
Kalimo et al, 1997).
From the microscopic standpoint indistinct
staining of the neurons (which are more sensi-
tive to anoxia than other elements, e.g., capil-
laries, and glia) may be noted as early as 12
hours. Within 1 to 3 days, swelling or shrink-
age or alteration in the distribution of Nissl
substance ( chromatolysis) may be noted.
Within 2 to 4 days disintegration of cells
occurs. As these neuronal changes are devel-
oping, alterations are also occurring in the
appearance ofaxons (swelling of myelin
sheaths, poor staining, and disintegration) and Figure 26-2. Macrophage stage of reaction in an area
of glial cells (swelling of astrocytes with frag- of necrosis. Approximately 28 days after a hemorrhagic
mentation of processes). infarct of the brain stem. Many macrophages are
While this process of necrosis is underway, jilled with heme pigment. (H & E x 400). (Courtesy
of Dr. John Hills).
various histological responses to the infarction
are also taking place. Within 24 to 36 hours, appearance of mesodermal fibrils in the adja-
the area of infarction is infiltrated by neu- cent tissue. There also occurs in this adjacent
trophilic polymorphic leukocytes (the acute tissue a proliferation of astrocytes (first noted at
response cells). Within 24 hours of infarction, 3 days) with the formation of reaction astro-
phagocytic cells (macrophages) begin to cytes containing large amounts of pink cyto-
appear. These macrophages arise from various plasm in H & E stains. There is a correlated
sources: microglia, blood vessel walls, circulat- proliferation of astroglial fibers. By 4 to 5
ing blood cells. By 48 hours of infarction, weeks a meshwork wall has been formed about
macrophages, filled with fatty debris (from the cavity by these mesodermal and glial fibers.
myelin and cell breakdown), are noted. These Hemorrhagic infarcts occur in 18-48 % of
cells remain the predominant repair cell from autopsy studies. Infarcts due to emboli are
the period 5 days to 30 days (Fig. 26-2). Some more likely to be hemorrhagic (51-71 % com-
of these cells may be found years later at the pared to non embolic infarcts, 2-21%). Venous
edge of the infarct. Ifsome hemorrhagic com- infarcts are often hemorrhagic.
ponent has also been present, products from The syndromes associated with ischemic-
the breakdown of the blood may also be pre- occlusive disease of each of the arteries supply-
sent in these cells. This removal of debris by ing the cerebral hemispheres will now be con-
the macrophages will eventually result in the sidered in greater detail l . The student, howev-
appearance of the cavity that may be seen er, should interpret this material keeping in
grossly.
At the same time that macrophages are 1At present most cerebral vascular disease
removing the debris, the capillaries and astro- involves the arterial circulation. Disease of the
cytes are beginning to engage in repair process- venous circulation is now less common. In the
es. Within several days to weeks after the pre-antibiotic era, infectious processes involving
infarct, new capillaries are noted at the edge of the face , paranasal sinuses the mastoid and
the lesion. There is also a thickening of the middle ear could secondarily involve the venous
capillary walls with increased cellularity and the sinuses and cortical veins.
mind those limitations of correlation that have
been indicated above.
INTERNAL CAROTID ARTERY
The carotid artery may be involved byath-
erosclerosis in its extracranial or intracranial
portions. The most common location for
~ .
stenosis in this system is at the origin of the ves-
sel at the bifurcation of the common carotid
artery into the internal and external carotid .t-.
branches (Fig. 2-27). Another favorite loca-
tion is at the carotid siphon. The branches of
.~ 0
the internal carotid artery are in order as fol-

Figure 26-3. Various types of the 40 infarcts in 52 CRSeS
lows: the ophthalmic, posterior communicat-
of occlusion ofcarotid artery at autopsy. A) Combined
ing, anterior choroidal, anterior cerebral, and MCA and ACA Territories- 37.5%. B) Total MCA-
middle cerebral. With stenosis of the internal 13%. B') Proximal MCA -21%. C) Watmhed 19%.
carotid artery, a variable symptomatology and D) Terminal or deep border zone MCA/ACA- 5%
anatomical pattern of ischemia and infarction (modified from Torvik, A., and Jorgensen, L.: ].
may develop (Fig. 26-3). The pattern and time Neurol. Sci., 3:415, 1966). MCA=middle cerebral
course of the syndrome are dependent on the artery territory, ACA=anterior cerebral artery
territory.
availability of collateral circulation. One may
distinguish transient ischemic attacks (TIAs) may presume that there is ischemia predomi-
which last less than 24 hours with total recov- nantly in the ophthalmic artery distribution
ery2, progressing strokes, incomplete or partial with the more distal carotid branches tem-
strokes and completed total territory strokes. porarily receiving adequate collateral supply
Transient ischemic attacks may be retinal or from the posterior communicating and anteri-
hemispheric and may be related to alteration in or communicating arteries and via lep-
perfusion or to microemboli originating at the tomeningeal anastomosis over the cortical sur-
carotid bifurcation. This discussion will empha- face. With progression of the occlusive process
size the perfusion etiology. even this collateral supply may become inade-
One syndrome involves the occurrence of quate and additional symptoms develop.
repeated episodes of monocular blindness on One of the common patterns of carotid
the side of the involved carotid artery with or artery insufficiency is the carotid border zone
without the later development of hemispheric syndrome (Fig. 26-3, 26-4). With decreased
symptoms e.g. motor and sensory symptoms perfusion by the carotid artery, symptoms will
involving the contralateral extremities. The initially develop in the upper extremity, which
patient may describe a curtain descending over corresponds to the cortical border zone
the field of vision of the involved eye. The between the middle and anterior cerebral arter-
episodes of monocular blindness are referred to ies 3 . As such it receives some overlap supply
as amaurosis fugax. In such cases, when symp- from both the anterior and middle cerebral
toms are limited to monocular blindness we arteries. As perfusion pressure drops in the
2In reality, most TIAs are minutes in duration 3 For additional discussionrefer to Bogousslavsky
and rarelygreater than one hour in duration. This & Regli (1986). Note also that although the
has significance when the use of the thrombolytic carotid (anterior border zone syndrome may be
agent recombinant tissue type plasminogen activa- relatively common as an insufficiency syndrome,
tor (t-PA) is considered requiring a more realistic actual infarction limited to the border zone
definition (see below). This agent must be admin- alone is less frequent (Mounier-Vehier, 1995)
istered within three hours ofstroke onset.
26-6 CHAPTER 26
Figure 26-4. Left carotid stenosis with old infarction

predominantly within the border zone between anterior
and middle cerebral arteries. This 72-year-old male
Figure 26-5. Total MeA. territory infarct aftn' left
had a persistent paralysis of the right upper extremity
carotid clamping and excision 8 months prior to death
with defective position sense at fingers. (Courtesy Drs.
in a 62 year old left handed male during a radical
John Hills, and. Jose Segarra.)
neck dissection. Patient progressed from a weakness of
carotid artery due to severe stenosis, this bor- right handgrip, 8 hours aftn'sur,gery to a complete
der zone will be first affected and the patient right hemiparesis with right central facial weakness
will experience numbness and weakness involv- and a mixed aphasia. Subsequently recovery occurred
ing the arm and hand. in the lower extremity He wrote jargon with his left
hand, could copy but was unable to comprehend.
With increasing stenosis and increasing (Courtesy ofDrs. John Hills and Dr. Jose Segarra.)
ischemia there will be involvement of the face
of cigarettes per day, on June 15, 1985 shortly
with numbness and a supranuclear type weak-
after intranasal "snorting" of cocaine com-
ness. If the ischemia involves the dominant
plained of gradually increasing right sided
hemisphere an expressive aphasia will develop
headache and then fell to the floor with a flac-
due to involvement of Broca's motor speech
cid left hemiplegia with the head and eyes devi-
area. These symptoms indicate the progression
to involvement of the more central cortical
ated to the right.
supply area of the middle cerebral artery. As a
The patient denied any illness and could not
general rule, one may assume that carotid
explain why she was in the hospital. Cranial
ischemia and infarction will occur predomi-
nerves: There was a left homonymous hemi-
nantly over the areas of cerebral cortex within
anopsia, deviation of head and eyes to the left
the peripheral and central supply area of the
and a left central facial weakness. Motor system:
middle cerebral artery (Fig. 26-5).
A flaccid left hemiparesis was present. Reflexes:
Involvement of the area supplied by the anteri-
deep tendon reflexes were initially depressed
or cerebral artery is usually less marked since
on the left side. Plantar responses were exten-
the anterior cerebral artery is more likely to
sor bilaterally. Sensory system: a severe left
receive a collateral supply via the anterior com-
hemisensory deficit, with a neglect of the left
municating artery and via leptomeningeal
side of space and body was present.
anastomosis over the corpus callosum from the
Initial clinical diagnosis: Total right mid-
opposite anterior cerebral artery. At times,
dle cerebral artery territory infarct.
however, both the middle and anterior cerebral
Laboratory data: Initial CT Scan demon-
areas will be involved and infarcted as in case
strated hypodensity (infarction in right frontal
26-1. At times artery to artery embolization
and parietal areas). Right carotid angiogram
will occur involving primarily the middle cere-
demonstrated severe stenosis of the supracli-
bral artery (Fig 26-14).
noid segment of the right internal carotid
Case 26-1: This 23 year old right handed artery with severe stenosis of the M -1 segment
female on birth control pills, smoking one pack of the right middle cerebral artery and multiple
areas of narrowing of the remainder of the became more alert and was transferred to a
right MCA. Left carotid angiogram indicated rehabilitation facility.
only limited cross filling of the distal right mid- The following case histories indicate addi-
dle and anterior cerebral arteries. tional patterns of disease in patients with
On 6-21-85, 6 days after admission the stenotic-occlusive disease of the carotid artery.
previously alert patient suddenly developed a In both cases the disease was in the extracranial
decreased level of consciousness and a fixed, portion of the vessel; thus an opportunity for
dilated right pupil suggesting that tentorial surgical correction of the stenotic lesion was
herniation had been produced by severe edema presented. Of course, similar symptoms could
or hemorrhagic transformation of the infarct. have occurred with disease of the intracranial
CT Scan now demonstrated massive infarction portion of the carotid artery, e.g., with stenosis
and edema-right anterior and middle cerebral at the siphon. However, in evaluating patients
artery territories plus-transtentorial and sub presenting these symptoms, the student should
falx herniation (Fig.26-6). With emergency remain alert to the possibility that surgically
management of the increased intracranial pres- remedial disease is present. The aim should be
sure- (monitor and osmotic agents) the patient recognition of such disease when insufficiency
Figure 26-6. Combined infarction ACA and MCA territories related to seJJere stenosis ofsuprlUlinoid, internal
carotid artery and proximal (Ml) segment of MeA, with infarction territories of right anterior and middle cere-
bral arteries. cr scan. Case 26-1.Refor to text.
26-8 CHAPTER 26
symptoms alone are present, that is, prior to Patients with hemispheric attacks that present
the development of actual infarction. It also with hemiplegia are more likely to proceed to
should be noted that in some cases no pre- completed strokes than those patients with
monitory symptoms will be present but the transient monocular blindness. In the study of
patient will present with a completed stroke Hurwitz et al (1985) cumulative risk for infarct
instead of a transient ischemic attack. A patient after hemispheric carotid TIAs was 27% com-
with carotid TIA's is presented in Case 26-2. pared to 14% for monocular blindness-carotid
Case 26-2: This 54-year-old, right-hand- TIAs. In general, most patients will experience
ed, white male for 7 years had experienced the stroke after one or two transient ischemic
twice per month intermittent 30-60 second attacks. Multiple TIA's over a long period of
episodes of blurring and blacking out of vision time are much less likely to result in completed
in the left eye. Ten days prior to admission, the strokes (Kase et al1987).
patient had a 45-minute episode of minor Not all patients with carotid TIA's are
weakness of the right face, arm, and leg plus found to have significant (>75%) stenosis or
numbness of the right side of the face accom- occlusion of the internal carotid artery. Pessin
panied a transient difficulty in speech (possibly et al (1977) found that only 52% of95 patients
dysarthria, possibly difficulty in word finding). with carotid TIA's had significant stenosis (42%
The patient's mother died of a "stroke" at age if hemispheric, 58% if transient monocular
66 years, and his father, of heart disease at age blindness and 80% ifboth types). The explana-
57. tion for TIA's in patients with less than signifi-
General physical examination: Blood cant stenosis of the carotid artery is not certain.
pressure elevated to 160/100 in both arms. Emboli from ulcerated plaques; emboli from
Bruits (murmurs) were present over each other sources such as the heart (or aortic arch)
carotid artery. The retinal artery pulsation was or micro platelet and fibrin emboli have all
easily obliterated by pressure on the globe of been suggested as possible explanations. (See
the left eye. Peripheral pulses in the lower also Ringelstein et al1983 and Amarenco et al ,
extremities were poor. 1992; Marshall 1971.)
Neurological examination: Intact except The use of the antiplatelet agent aspirin has
for a minor right central facial weakness. been effective in reducing both strokes and
Laboratory data: Cholesterol was elevated myocardial infarctions in patients with TIA's by
to 284 mgUiO. Arteriography (aortic arch study) 22%.
demonstrated a complete occlusion at the ori- A current approach to the management of
gin of the left internal carotid artery. A right carotid TIAs is to promptly image the extracra-
brachial arteriogram demonstrated excellent nial carotid arteries with ultrasound -doppler
collateral circulation with filling of the left ante- (Duplex scan)4. If significant stenosis (>70-
rior and middle cerebral arteries by cross flow 75%) is found at the carotid bifurcation in the
through the anterior communicating artery neck, then magnetic resonance angiography
from the right side. The intracranial portion of (MRA) or classical angiography followed by
the left internal carotid artery filled from the endarterectomy is undertaken. In many cen-
left posterior communicating artery. ters, the initial noninvasive study is the MRA
Subsequent course: A left carotid eliminating the need for both the duplex scan
endarterectomy performed by Dr. Allan and the angiography. The role of carotid
Callow restored blood flow following removal endarterectomy in patients with severe carotid
of the occlusive lesion (atherosclerosis with stenosis of 70-99% and TIA's or non disabling
recent thrombosis) at the carotid bifurcation. strokes was clearly established by the random-
In general, carotid transient ischemic
attacks (TIA) are more likely than vertebral- 4Reftr to Hennerici et al(1992) for a discussion
basilar TIA's to proceed to completed strokes. ofthe technique.
ized North American Symptomatic Carotid artery were unnecessarily subjected to carotid
Endarterectomy Trial (1991), Kistler, et al artery surgery with accompanying morbidity
(1991), Moore et al (1995) and emphasized and mortality of that procedure (see Wmslow
by the long term follow up of these patients et al 1988, Dyken, 1986, Hennerici et al,
(Barnett et al1998). 1986, Levin et al, 1980, Bornstein and Norris,
If significant stenosis is not present, then 1989). The study ofFreischlag et al, 1992 does
the patient is treated with aspirin. If this is not suggest a definite role for the procedure where
effective, then anticoagulation with Warfarin the degree of stenosis is over 75% and where
derivatives may be considered (see Brust 1977, perioperative morbidity and mortality are low
Whisnant et al1978). Such therapy, however, (<3%). The study of Chambers and Norris
is not without risks. The risk of bleeding com- (1986) had previously demonstrated that
plications with anticoagulation is greater than asymptomatic patients with a stenosis of >75%
with the use of antiplatelet agents. had an ipsilateral stroke rate of more than 10%
In Caucasians, most symptomatic lesions of per year. The editorial of Kistler and Furie
the carotid artery occur at the bifurcation of (2000) discusses the effects on both low flow
the carotid artery in the neck. In non- and the formation of thrombus leading to
Caucasians, intracranial lesions increase in fre- embolic phenomena that follows upon steno-
quency5. If attacks persist, angiography may be sis. The results of randomized trials of patients
undertaken to document intracranial lesions with asymptomatic carotid artery stenosis sug-
before embarking on long-term anticoagula- gest that severe stenosis (>90%) may benefit
tion. from surgery but leave unsettled the question
In addition, the absence of a significant of whether lesser degrees of stenosis (50-90%)
extracraniallesion should raise the possibility of may benefit (Barnett, 1993, Barnett & Haines
a source of multiple emboli from cardiac or 1993, The CASANOVA Study Group, 1991,
other sources (see below). Hobson, et al1993, Mayberg & Wmn, 1995).
If total occlusion of the artery is demon- The following case demonstrates a case in
strated, several courses of action have been sug- which the patient began with carotid TIAs pro-
gested: gressed to a carotid border zone syndrome of
a) Emergency removal of an acute throm- infarction and then involved additionally all of
bus; for example, if progression is occurring the middle cerebral artery territory.
(see Walters et al 1987); This may be compli-
Case 26-3 (Patient of Dr. Thomas
cated by intracerebral hemorrhage particularly
Mullins): This 72-year old right-handed white
if infarction has already occurred and blood
male had two episodes of right upper extremi-
flow is restored into infarcted tissue (Piepgras
ty weakness, each of two hours duration,
et al1988).
beginning 2 days prior to admission. Following
b) External carotid to internal carotid artery
the first episode, the patient had transient slur-
bypass. This has been found to be oflittle value
ring of speech, persistent left -right disorienta-
(EC-IC Bypass Study Group, 1985).
tion, dysgraphia, and could not understand
Controversy exists as to the management of
what he had read.
the patient with the asymptomatic carotid
Neurological examination: The onty find-
artery bruit or with asymptomatic carotid
ings related to language function: speech was
artery stenosis. In the past, many of these
fluent with intact repetition, and object nam-
patients with no neurological symptoms or
ing; however, reading comprehension, writing,
with symptoms unrelated to the specific carotid
and left-right orientation were all impaired.
5The effects of race and ethnicity on ischemic Carotids: a bruit was present on the left.
stroke are discussed by Zwejler et at (1995) and Clinical diagnosis: Carotid artery stenosis
Setva &Chimowitz(1995). with TINs reflecting decreased perfusion in
26-10 CHAPTER 26
Figure 26-7. Internal carotid artery occlusion at the bifurcation. TIAs with subsequent infarction of middle
and posterior cerebral artery territories. Case 26-3 (refer to text.) A and B) Left Carotid injection A)occlusion
of left internal carotid just above the bifurcation. B) External carotid anastomotic branches (periorbital etc)
alluw late filling of the left internal carotid artery at the siphon and its branches. C and D) Right carotid injec-
tion C) Lateral view: posterior cerebral artery originates from carotid artery, D) AP view: cross filling of the left
anterior cerebral artery and limited filling of the left middle cerebral artery (arrow).
the border zone followed by thrombosis and Laboratory data: Arteriograms: (a) the
passage of emboli to the inferior division of the left internal carotid artery was completely
middle cerebral artery. occluded just above the bifurcation (Fig. 26-
7A). (b) The left external carotid artery filled 1981).
the left internal carotid artery at the siphon Not all patients with acute carotid infurcts
through anastomosis about the orbit (Fig. 26- continue to progress. In the series oOones and
7B). However, there was a cutoff just below Milliken (1976), 39% of patients remained sta-
the siphon suggesting that the thrombus (clot) ble. Thirty-five percent had gradual improve-
at the bifurcation had extended to this level. ment and 19% had a progressing deficit over
Moreover, the left middle and anterior cerebral 48 hours.
arteries failed to fill in this manner. (c) The left MIDDLE CEREBRAL ARTERY
posterior cerebral artery did originate from this
The middle cerebral artery is the final
segment of the otherwise occluded carotid
branch and, in a sense the direct continuation
~iphon segm~nt but with no retrograde filling
of the internal carotid artery. One of the clas-
mto the basilar artery (Fig. 26-7B). (d) The
sic internal carotid artery syndromes is essen-
ri~t carotid artery filled not only the right
tially a syndrome of the cortical branches of the
ffilddle cerebral and anterior cerebral artery but
middle cerebral artery.
also was the source of the right posterior cere-
Depending on the point of occlusion of the
bral artery (Fig. 26-7C). (e) The right carotid
middle cerebral artery and its branches several
system also supplied the left anterior cerebral
syndromes are possible. Essentially these syn-
artery and to a limited extent the left middle
dromes reflect disease of the lenticulostriate
cerebral artery (Fig. 26-7D).
penetrating branches or the cortical branches.
Subsequent course: On the day following
In some cases, the clinical picture reflects
admission, weakness in the right hand at wrist
involvement of the territory of both penetrat-
and finger extensors recurred. During the arte-
ing and cortical branches due to occlusion at
riogram, the patient was noted to have addi-
the stem or main trunk of the artery.
tional problems with speech. Weakness in the
Syndrome ofthe Lenticulostriate penetrating
right upper extremity increased. Despite sub-
branches: These branches supply the putamen,
sequent anticoagulation, additional progres-
most of the caudate nucleus, the outer seg-
sion occurred with total paralysis of the right
ments of the globus, pallidus, and most of the
upper extremity, aphasia and a right homony-
adjacent internal capsule (particularly the ante-
mous hemianopsia. The CT scan, which had
rior half of the posterior limb). These vessels
been normal on admission now, 72 hours after
ascend with no anastomotic oops between
these events, demonstrated acute infurction
adjacent branches. The classic clinical picture
with severe edema involving the entire cortical
associated with occlusion of these branches is
and deep territory of the middle cerebral artery
that of the pure motor syndrome, relatively
and the cortical territory of the posterior cere-
rapid in onset, involving equally the face, arm,
bral artery but with relative sparing of the ante-
and leg in a spastic hemiplegia (so-called cap-
rior cerebral artery territory and most of the
sular hemiplegia). As discussed by Fisher and
thalamic territory of the posterior cerebral
Curry (1965), there are often no sensory
artery (Fig. 26-8). Coma developed secondary
symptoms and no aphasia. These hemiplegic
to the herniation effects on the brainstem and
symptoms, reflecting capsular damage, tend to
the patient expired 8 days after admission.
predominate initially over any symptoms relat-
Such massive swelling with herniation of
ed to the basal ganglia, although portions of
temporal lobe through tentorium and sec-
the basal ganglia may also be infarcted. If the
ondary brainstem compression is the major
lesion is small «1.5 em.) termed a lacune the
acute cause of death in patients dying after .
patient may demonstrate a rapid improvement,
'
acute carotid artery or massive middle cerebral
so that within weeks or months, there is little if
artery infarctions (31%). Other causes of death
any residual motor disability. However with
are pneumonia (29%), cardiac arrest (17%),
multiple lacunes, deficits may persist (Fig. 26-
pulmonary embolus (13%) (Bounds et al,
26-12 CHAPTER 26
Figure 26-8: Case 26-3 as in figure 26-7. cr Scan

olTtained 72 hours after acute massive progression
demonstrating infaraion and massive edema of the
left MeA territory and the cortical territory of the pos-
terior cerebral artery, with sparing ofACA.
9). As indicated in Fig. 26-10, however, larger
infarcts involving the lenticulostriate territory
may result in a persistent spastic hemiplegia
with considerable motor deficits and symptoms
may include sensory and other features.
The basic pathological process has been
termed segmental fibrinoid arterial degenera-
tion (Fisher 1969). The walls of these small Figure 26-9. Lacunar Infarcts in MeA penetrating
vessels become thickened and converted into a branch territories. A) Multiple small infaraions in a
71 year old hypertensive (210/116) who after multiple
hyalinized material. Usually but not invariably, episodes of right hemiparesis and dysarthria and «dizzy
this occurs on a background of long-standing spells" became wheelchair bound, with apraxia of lips,
hypertension. At times, diabetes mellitus is limbs and gait, pseudo bulbar, bilateral pyramidal
present. The lenticulostriate branches rising as and frontal release signs. B) Detail ofa small lacunae
the initial branches of the middle cerebral from a 48-year-old white male, with severe hyperten-
artery are under relatively high pressure; not sion (250/140). (Courtesy ofDrs. John Hills and Dr.
Jose Segarra.)
only may these vessels become occluded, they
may be the site of small or large intracerebral vessels noted by Fisher (1969). Other disease
hemorrhages also complicating the process of processes may certainly affect the penetrating
hypertension. We shall have cause to discuss vessels and these include: a) small emboli orig-
these vessels again later in this chapter. inating in the heart or arteries, b) the arteritis
However, not all patients with lacunar infarcts ofmeningovascular syphilis (Johns et al1987);
have hypertension or atherosclerosis or dia- c) the arteritis of tuberculous meningitis; d) the
betes mellitus, and at autopsy not all patients vasculitis of autoimmune diseases such as pol-
demonstrate the specific changes in penetrating yarteritis, and lupus erythematosus (see
Millikan and Futrell 1990). Mast et al (1995) tional syndromes have been identified in the
suggest that hypertension and diabetes are subsequent studies of Fisher and other investi-
more related to multiple as opposed to single gators (Fisher 1982, Mohr 1982). These syn-
lacunar infarcts dromes of penetrating branches of various
Other types ofpenetrating branch infarct, so blood vessels are outlined in Table 26-2.
called ((lacunar syndromeS»: A number of addi- Although many of these above lesions can
be demonstrated on CT scans, MRI is the
TABLE 26-2: SYNDROMES OF PENETRATING BRANCHES
OF CEREBRAL VESSELS:
most effective technique for confirming local-
ization (Fig. 26-11) (see Larson et al 1988,
PENETRATING LOCATION OF OCCLUSION Rothcock et al1987).
ARTERY Lacunar State: Over time some patients
SYNDROME have multiple infarcts involving multiple pene-
a) Pure motor Penetrating middle cerebral artery trating branches. The patient then begins to
syndrome of supply to internal capsule, less offen manifest a typical clinical syndrome that has
hemiplegia basilar pontine paramedian arteries
been assigned the diagnosis of "lacunar state",
b) Pure Posterior cerebral penetrating based on the findings at the time of pathologi-
hemisensory branches to ventral posterior lateral cal examination of multiple small cavities (Fig.
nucleus of thalamus or penetrating 26-9,26-11). The patient begins to manifest
middle cerebral arteries to medial
border of the posterior limb of the
internal capsule
c) Dysarthria & Paramedian penetrating branches

Clumsy Hand supplying the pons
Syndrome
d) Ataxic Infarcts of the corona radiata and

Hemiparesis: less offen the posterior limb of the
internal capsule-posterior 11mb (both
middle cerebral artery penetrators)
and to a minor degree, the pons
(basilar-paramedian-penetrating)
e) Hypeslhefle- Inlarenon of Ihe posterior limb

ataxic (posterior medial segment) 01 the
hemiparesis internal capsule and lateral thalamus
(anterior choroidal artery). Less offen
the posterior cerebral artery
penetrating branches are involved.
I) Hemichorea- Inlarcfion of the subthalamus or

hemiballism thalamus penetrating branches
post. cerebral artery, or lateral
putamen of the striatum (penetrating
branches of the middle cerebral artery
(See chapter 19)
g) 'Silent strokes' Found on CT or MRI scan unrelated

Figure 26-10. Lenticulostriaw penetrating branches of
to clinical history.
the middle cerebral amry. This 73 year old hyperwn-
h) caudate infarcts Lesion in caudate with extension to sive had at age 53 susmined a right hemiplegia with
producing slow anterior limb internal capsule - persiswnt and dense motor deficits involving the right
apalheHc (abulic) perforators proximal anterior or central face, arm, and leg. A) Coronal section, B) close
state or hyperactive middle cerebral artery up of the cavity. (Courtesy ofDrs. John Hills and Jose
restless state Segarra).
26-14 CHAPTER 26
ings associated with disease of the basal ganglia

may develop: rigidity and a slowness of move-
ment and at times, a minor degree of tremor.
These symptoms may reflect the damage to the
putamen and globus pallidus or, perhaps, dam-
age to the descending fibers from the premo-
tor areas. This aspect of the syndrome has
sometimes been designated as "arteriosclerotic
Parkinson's disease" and can usually be distin-
guished from the classical Parkinson's disease
(refer to chapters 18, &19). There may be a
variable degree of cognitive dysfunction with
considerable rigidity in problem solving, a loss
of inhibition of emotional responses and
impairment of executive function. Often the
patients appear apathetic and are misdiagnosed
as manifesting dementia or depression.
Subcortical infarcts involving descending
frontal systems are responsible (Wolfe et al
1990).
Syndromes of the Cortical Branches. (Figs.
26-12, 26-13). After providing a series oflentic-
ulostriate branches, the main stem of the mid-
dle cerebral artery divides into two main corti-
cal divisions: a superior division and an inferior
division. At the point of division, the smaller
Figure 26-11. Multiple lacunar infarcts most promi-

nent in penetrating branches left posterior cerebral
artery: thalamus, posterior one third corpus callosum Figure 26-12. Acute hemorrhagic infarction of the
and adjacent white matter of left posterior cerebral central cortical territory of the MeA.: cakific embolus
hemisphere in a 70 year old right handed hypertensive occluded MCA following atheromatous occlusion of the
male with multiple episodes of «collapse", possibly relat- carotid artery at the bifurcation. This 74-year-old,
ed to severe orthostatic changes. A) MRl - T1 weighted right-handed, white male,S days prior to death, had the
sagittal section-12.6 mm left of midline) MRl-hori- sudden onset ofpain in the left supraorbital region
zontal section. and lost consciousness. Upon regaining consciousness,
the patient had a right central facial weakness, a right
an apraxia of gait, and a release of grasp reflex hemiparesis and was mute but was transiently able to
occurs as a result of damage to the descending follow commands. (Courtesy of Drs. John Hills and Jose
fibers from the premotor areas. Clinical find- Segarra.)
carotid disease often due to artery-to-artery
emboli.
Occlusion ofthe main cortical stem produces
a mixed cortical motor -sensory syndrome
involving the contralateral face (supranuclear)
and arm; this is termed a facio brachial paralysis.
If this occurred in the dominant hemisphere a
mixed type of aphasia would also be present
with anterior (nonfluent) and posterior (fluent)
components. Face and language involvement
would be greater than hand involvement. The
degree to which the hand is involved would
Figure 26-13. Cortical branches of the middle cerebral depend on the degree of collateral circulation.
artery. Old infarcts involving much of the total UJrti- Thus only the central cortical territory or the
cal territory of the right middle cerebral artery. This
entire cortical territory of the middle cerebral
72-year-old, right-handed male with severe hyperten-
sion and auricular fibrillation expired after a 3 year artery could be involved.
history of least 4 episodes of left central facial weakness Occlusion ofthe superior division in the dom-
and left hemiplegia involving primarily the arm and inant hemisphere would produce a mixed corti-
a focal seizure involving the left arm. (Courtesy of cal motor- sensory syndrome involving again
Drs. John Hills and Jose Segarra.). predominantly the face and hand plus an
lateral orbital frontal and temporal polar arter- expressive Broca's type aphasia. This syndrome
ies originate. The superior division has pre- has already been illustrated in Chapter 24.
Rolandic branches (to inferior frontal gyrus The less frequently encountered occlusion of
and premotor area including Broca's area in the inferior division branches, producing domi-
dominant hemisphere), Rolandic branches (to nant or non-dominant inferior parietal-post
pre- and post-central gyri), and anterior pari- temporal syndromes including the syndromes
etal branches (to post-central gyrus). The infe- of posterior type aphasias and parietal neglect
rior division includes anterior temporal, poste- already discussed in chapter 24. Refer also to
rior parietal, angular and posterior temporal Caplan et al, 1985, 1986 and Mohr et al,
branches, named after the areas supplied. The 1986.
syndrome that results from occlusion will Combined Syndrome: Total Occlusion of
depend on whether the main cortical stem, the Initial Segment ofMiddle Cerebral Artery (Fig.
superior or inferior division, or the branches 26-5). The resultant syndrome in this case will
thereof have been involved. In general the be the summation of the lenticulostriate and
MCA cortical syndromes are assumed to be cortical branches syndrome. The following
embolic in origin particularly in the Caucasian case history illustrates such an occlusion with
population. The stem, divisions and the corti- massive infarction of the entire territory of the
cal branches of the left middle cerebral artery middle cerebral artery.
are a frequent site for the lodgment of embol-
Case 26-4: This 61-year-old, right-handed
ic material because there is a relatively direct
hypertensive black housewife one week prior to
vertical takeoff of the left common carotid
admission, suddenly fell to the floor while tak-
artery from the arch of the aorta compared to
ing a bath and lost consciousness. She was
the right carotid artery. In addition the middle
found by her son who noted that she was
cerebral artery is the direct continuation of the
unable to move her left arm and leg. Her
internal carotid artery; the cortical branches are
speech had been thick, but no aphasia had
the direct continuation of the main middle
been present. No headache had been noted.
cerebral trunk.
Both parents had died of heart disease and
As noted above, infarcts may occur due to
26-16 CHAPTER 26
hypertension.
Physical examination: Blood pressure was
150/100 and pulse was regular at 84.
The patient was obnmded and slow to respond
but grossly oriented to time, place, and person.
LEFT LATERAL RIGHT LATERAL
Cranial nerves: Papilledema was present bilat-
erally particularly in the right fundus where a
recent hemorrhage was present. The head and
eyes were deviated to the right. The eyes did
not move to the left on command but did
move to the left on vestibular stimulation. The
patient neglected stimuli in the left visual field.
LEFT POSTERIOR RIGHT POSTERIOR
Pain sensation was decreased or neglected on
the left side of the face. A marked left central Figure 26-14. Rigltt middle cerebral artery occlusion
facial weakness was present. Motor system: A Case 26-4. Brain scan. A marked uptake of isotope
complete flaccid paralysis of the left arm and (Hg197) is found throughout the territory of the rigltt
middle cerebral artery (22 days after the event). This is
leg was present. Reflexes: Deep tendon reflexes
demonstrated in the posterior, anterior, and rigltt lat-
were increased on the left compared to the eral scans. (Courtesy ofDr. Bertram Selvemone).
right. The left plantar response was extensor.
Sensory system: All modalities of sensation were edema. In patients with massive middle cere-
decreased on the left side of the body. bral artery territory infarcts due to MCA occlu-
Clinical diagnosis: Acute occlusion of the sion who already had early CT scan evidence of
stem of the middle cerebral artery, possibly brain swelling within 24 hours of the ictus, fifty
embolic, although primary occlusions of five percent of these patients expired, over-
intracranial arteries may occur in the non-
Caucasian population. Hypertensive intracere-
bral hemorrhage was also possible.
Laboratory data: The EEG indicated
severe focal damage with a relative absence of
electrical activity in the right temporal area and
focal 3 to 5 Hz slow waves most prominent in
the right frontal area (Fig.2-23 and CD EEG
adas). Radioactive brain scan demonstrated a
marked right hemisphere uptake of isotope
(Hg197) measuring llx6x6 em., extending
from the right frontal area to the posterior pari-
etal area extending from the surface to the
deep midline (Fig. 26-14). Right brachial arte-
Figure 26-15. Rigltt middle cerebral artery occlusion.
riogram revealed a complete occlusion of the Case 26-4. A) Selective common carotid injection
right middle cerebral artery at its origin reveals rotal rigltt middle cerebral artery occlusion.
(Fig.26-1S). Cerebrospinal fluid contained no (Courtesy ofDr. Samuel Wolpert). B) Reference dia-
significant cells. gram of the major branches of the internal carotid
Hospital course: The patient showed no artery. lCA= internal carotid artery, ACA= anterior
significant improvement during a four-week cerebral artery, .PeA= posterior cerebral artery
(supplied directly from the IC as a continuation
hospital course. of the PCOM posterior communicating artery),
Prognosis for survival during the acute state MCA= middle cerebral artery. (Refer ro Fig. 26-7C
of the first week depends on the degree of and 2-27c for normal reference).
whelmingly of herniation effects. Patients older occur will be most severe in the contralateral
than 45 years had a poorer prognosis than lower extremity with minor involvement of the
younger patients. Infection of the lungs is a contralateral supper extremity and minor or no
serious complication of large infarcts and a involvement of the face. Most patients will
major cause of death during the second week. have involvement of both the cortical and pen-
If the patient survives, prognosis for recovery is etrating branch-subcortical territories. Infarcts
related to the size of infarct. Less than 3 cm. limited to the penetrating branch territories
infarcts may be associated with a good recov- may occur (Caplan et al, 1990). Note that not
ery, greater than 3 cm. with severe disability all vascular syndromes with predominant leg
(Olson, 1991). involvement are due to occlusion of the anteri-
ANTERIOR CEREBRAL ARTERY or cerebral artery. Occlusion of the superior
sagittal sinus or basilar-vertebral disease affect-
In our clinical experience occlusive disease
ing the brain stem may also produce predomi-
of the anterior cerebral artery is much less com-
nant leg weakness (refer to Schneider
mon than that involving the internal carotid or
&Gautier, 1994 for additional discussion).
middle cerebral arteries accounting for approx-
At times both anterior cerebral arteries may
imately 1.8% of all ischemic infarcts -
be essentially branches of the same proximal
Bogousslavsky and Regli 1990). The anatom-
segment. Occlusion of this proximal anterior
ical explanation for this is evident. Each ante-
cerebral artery segment will then result in
rior cerebral receives collateral circulation from
infarction of the medial frontal-parietal areas of
several possible sources: (a) leptomeningeal
anastomotic end-to-end loops from the middle
cerebral artery of the same side, (b) lep-
tomeningeal anastomotic loops from the con-
tralateral anterior cerebral artery over the cor-
pus callosum, and (c) anterior communicating
artery from the contralateral anterior cerebral
artery. Finally, at postmortem examination
atherosclerotic plaques are found less frequent-
ly in the anterior cerebral than in the larger
internal carotid, middle cerebral, basilar, and
vertebral arteries. In the series of
Bogousslavsky and Regli (1990) 63% of the 27
patients had infarcts secondary to an embolus
from the heart or carotid artery.
Penetrating and cortical branches may
be distinguished. The penetrating branches
including a larger vessel, the recurrent artery of
Heubner supply the anterior limb of the inter-
nal capsule and the anterior head of the cau-
Figure 26-16. Anterior cerebral arteries: old bil4teral
date nucleus. The cortical branches: orbital infarcts with due tv severe bil4teral stenosis ACA. (com-
frontal, frontal polar, callosal marginal and per- plete occlusion on right). Left hemisphere inl'oll'ement
icallosal supply much of the corpus callosum was marked (A), with a lesser inl'oll'ement of the right
(genu and body), and the orbital frontal cor- hemisphere (B). This 61-year-old, right-handed female
tex, the medial aspects of the frontal and pari- 16 months prior tv death dePeloped difficulty in speech,
etallobes including the sensory motor areas of right-sided weakness, apraxia of hand mopements and
progressed 2 days I4ter tv an akinetic mute state with
the paracentral lobule and the supplementary
urinary incontinence. (Courtesy of Drs. John Hills,
motor cortex. Symptoms then when they and Jose &garra.
26-18 CHAPTER 26
both hemispheres (Fig .26-16). The resultant clinical results may follow occlusion of this ves-
syndrome will include a more prolonged sel. There is no single characteristic syndrome.
change in personality and affect (due to The initial surgical procedures of Cooper indi-
involvement of the prefrontal and anterior cin- cated that occlusion of this vessel in the patient
gulate areas), an akinetic and mute state with Parkinson's disease as discussed in chapter
(Freeman, 1971) (due to involvement of the 19 resulted in a relief of tremor and rigidity in
prefrontal and premotor areas), urinary incon- the contralateral limbs without the develop-
tinence (due to involvement of the paracen- ment of hemiparesis or other focal deficits. Foix
trallobule, medial premotor, and supplemen- in 1925 first described a triad of hemiplegia,
tary motor areas), and a sensory motor syn- hemianesthesia, and homonymous hemianop-
drome involving both lower extremities (due sia associated with infarction of the territory of
to involvement of paracentral lobule). There the anterior choroidal artery (Bruno et. al.
may also be a significant apraxia of the non- 1989 and Decroix et. al. 1986). With the
dominant hand from damage to the corpus cal- development of CT scan and MRl scan, the
losum depriving the premotor and motor areas syndrome is now more frequently recognized.
in the nondominant motor hemisphere of Essentially this is a variable penetrating or lacu-
information from the dominant hemisphere. A nar syndrome ranging from a pure motor syn-
bilateral release of the grasp reflex is present drome to the full-blown triad.
because of the bilateral involvement of the pre- POSTERIOR CEREBRAL ARTERY
motor and supplementary motor areas. Many
The posterior cerebral arteries usually orig-
of these features may follow unilateral infarc-
inate as the direct continuation of the basilar
tion in lesser degree. Transient mutism and
artery following its bifurcation. At times, then,
transcortical motor aphasia are more promi-
occlusive disease of the vertebral or basilar
nent with dominant hemisphere infarcts,
artery will be manifested by the development
neglect syndromes with nondominant infarcts.
of symptoms within the posterior cerebral ter-
Release of instinctive grasp is usually contralat-
ritory. At times, a mixture of brain stem and
eral to the infarct. An example of infarction in
cerebral hemisphere symptoms will be present.
the distribution of the anterior cerebral arteries
At times, bilateral posterior cerebral artery
complicating aneurysm surgery is provided in
symptoms will be present. Moreover, since the
case 26-9.
cortical and penetrating vessels of the posterior
ANTERIOR COMMUNICATING cerebral artery are the distal branches of the
ARTERY basilar vertebral circulation, they will at times
Penetrating branches from this vessel sup- be subject to embolization from extracerebral
ply the anterior hypothalamus, the optic chi- sources (cardiac) or from occlusive disease in
asm and the suprachiasmatic and paraolfactory the more proximal sections of the basilar or
areas. vertebral arteries. As demonstrated previously
ANTERIOR CHOROIDAL ARTERY in some patients (25%), the cortical divisions of
the posterior cerebral arteries may originate as
This is the only branch of the internal a direct continuation of the posterior commu-
carotid artery that has not yet been discussed. nicating artery.
This vessel supplies the inner portion of the Essentially two categories ofposterior cerebral
globus pallidus, a small adjacent section of the symptomatology may be recognized: (a) syn-
posterior limb of the internal capsule (includ- dromes ofthe penetrating branches, and (b) syn-
ing the area occupied by the ansa and fascicu- dromes of the cortical branches. With main
lus lenticularis) and to a variable degree the trunk occlusions, a mixture of these two syn-
adjacent sector of the ventral posterior lateral dromes may be present.
nucleus of the thalamus and of the lateral Overall, posterior cerebral artery cortical
geniculate or geniculocalcarine tract. Various
TABLE 26-3. COMPARISON OF SYNDROMES FROM
PENETRATING VERSUS CORTICAL BRANCHES OF PCA.
VESSEL SYNDROME
The Penetrating -Occlusion of penetrators to midbrain
Branches. damages the cerebral peduncle, the
-supply the rostral third cranial nerve, and the red nucleus
portion of the (Webers or Benedikt's Syndrome
midbrain and the -Occlusion of penetrators to
thalamus (onen subthalamus & VL nucleus of thalamus
involved in lacunar produces contralateral hemichorea or
infarcts) hemiballismus
Damage to VPMNPL of thalamus Figure 26-17. Posterior cerebral artery: acute hemor-
produces contralateral loss of sensation rhagic infarction predominantly within the distribu-
and possible pain syndrome tion of the riglrt &akarine branch. This 53-year-old
(thalamogeniculate artery- male with a riglrt frontal-anterior temporal glioma
thalamic syndrome). had tentorial herniation with compression of the riglrt
posterior cerebral artery (in addition to brain stem
The Conical -In bilateral posterior cerebral disease structures). (Coumsy ofDrs. John Hills and Jose
Branches impairment of recent memory may Segarra.)
(Fig. 26-17,26-18). occur, accompanied by a significant
-anterior temporal degree of confusion and disorientation approximately 11 :30 AM on the day of admis-
and posterior ±bilateral blindness sion suddenly developed blurring of vision in
temporal branches -If the dominant temporal lobe her left visual field, possibly in her left eye and
to the Inferior and is involved, a confusional
medial surtaces of state may follow unilateral posterior was found to have a left visual field defect.
the temporal lobe, cerebral disease. Shortly thereafter, she developed tingling
posterior cerebral -Ischemia or infarction paresthesias of the left face arm and leg.
artery then divides within the calcarine artery territory Hypertension was under treatment with
into a parleto- produces a contralateral homonymous hydrochlorothiazide and Lasix.
occipHal branch hemianopsia, onen with sparing 01 the
and the calcarine mocular area due to collateral Physical examination: Blood pressure was
ortery to the visual circulation from MCA (see above elevated to 160/70. Weight was elevated to
(calcarine) cortex. if bilateral) (See Chapter 23). 264 pounds. A small ecchymosis was present
under the toenail of the left second digit.
infarcts account for 5% of all infurcts. Usually Neurological examination, (3hours after
the infarcts reflect embolic occlusion (see onset): Cranial nerves: A non-congruous left
Fisher 1986, Pessin et al1987, Koroshetz and homonymous hemianopsia was present greater
Ropper 1987). Among the 54 cases presented in the left temporal field than the right nasal
by Kinkel et.al. (1984), 11% demonstrated field. Reflexes: Deep tendon stretch reflexes
total involvement of the cortical territory. were decreased in the lower extremities (patel-
Most had partial involvement primarily of cal- lar, 1+ and Achilles, 0). Plantar responses were
carine and/or the posterior temporal artery equivocal, with the left probably extensor.
territory. Nine percent had bilateral infarcts. Sensory system: pain and graphesthesia were
The following case history illustrates many decreased over the left foot.
aspects of ischemia within the cortical distribu- Clinical diagnosis: Posterior cerebral
tion of the posterior cerebral artery. This artery ischemia and possible infarct, (possibly
patient demonstrates the general rule that pos- embolic), involving the right calcarine cortex
terior cerebral cortical infarcts are usually and thalamus or a lacunar event involving the
embolic. right thalamus.
Laboratory data: MRI, 4days after onset
Case 26-5: This 55 year old ambidextrous (Fig.26-18) demonstrated a small infarct in the
married white female research coordinator at right occipital visual cortex area in the distribu-
26-20 CHAPTER 26
demonstrated clearing of all neurologic find-

ings. When seen 2 weeks after the event her
only complaint related to some problems in
reading. This patient already been receiving
aspirin at the time of the event and this was dis-
continued. She was begun on lifelong systemic
anticoagulation with coumadin by the consul-
tant cardiologist Dr. Filiberti since she had two
conditions associated with embolization:
paroxysmal atrial fibrillation and patent fora-
men ovale with right to left shunting. The
patient did well over the subsequent 5 years.
Case 26-6 presented on CD ROM pro-
vides an example of a patient with bilateral pos-
terior cerebral artery ischemia, manifested by
acute onset of blindness and confusion.
Figure 26-18. Infarct rigllt occipital area ,calcarine CEREBRAL EMBOLISM
artery braneh territory (Embolus to posterior cerebral
This topic has already been discussed and
artery from heart). MRI. Case 26-5.
illustrated above in cases 26-3, 26-4, 26-5 and
in the chapter on aphasia. The middle cerebral
and posterior cerebral artery cortical branches
are primary targets.
In general, cerebral embolism is a compli-
cation of cardiovascular disease. However, as
we have indicated, artery to artery (the carotid,
vertebral or basilar) embolization of thrombus
or atheromatous material is also frequent.
Rarely emboli may be composed of tumor cells
or, following trauma, of fat or air (Jacobson et
al, 1986; Knoppee et al, 1988). The embolus
in most cases is a fragment of thrombus (clot,
platelets, fibrin, and blood cells) that has
become detached from a larger thrombus
within the heart or proximal artery. The
Figure 26-19. Occlusion of rigllt posterior cerebral causes of such a thrombus within the heart
artery(arrow}. MRA. Case 26-5 as above. are several:
a. A clot will often form in the left auricular
tion of the calcarine artery. MRA (Fig.26-19)
appendage when atrial fibrillation is present.
demonstrated decreased flow in the right pos-
This is often the case when a relative stasis of
terior cerebral artery. There was filling of more
blood in this area occurs as in mitral stenosis
distal branches via anastomatic flow. Holter
(Wolf et al, 1978, 1991, Peterson 1990).
monitoring demonstrated multiple brief
b. A "mural thrombus" may form on the
episodes of paroxysmal atrial fibrillation. The
endocardium in relation to an area of myocar-
transesophageal echocardiogram demonstrated
dial infarction (Foster and Halperin, 1989,
a definite patent foramen ovale with right to
Konnrad, 1984).
left shunting.
c. Thrombus may collect on heart valves
Subsequent course: Re-evaluation of the
(so called valvular vegetations), usually the
patient 22 hours after the onset of symptoms
mitral valve, when these valves are the subject in relation perhaps to transient falls in blood
of infection and inflammation as in bacterial pressure.
endocarditis with embolic material breaking off d. Infarction due to embolic occlusion of a
and entering into the circulation at times of vessel is more likely to be hemorrhagic than a
change in cardiac rhythm. (Hart et al 1990, non-embolic infarction. This is related to
Jones and Siekert, 1989, Salgado et al1989). reperfusion of an area of recent necrosis due to
d. The aorta may be a source of embolic disintegration of the embolus or to the devel-
material (Amarenco et al, 1994,Jones et al opment of collateral (leptomeningeal anasto-
1995, Kistler 1994) motic flow). (Fisher and Adams 1951, Okada,
e. In patients with a patent foramen ovale, 1989, Ogata, et al, 1989.) In such an area, the
within the heart, embolic material mayorigi- walls of blood vessels have also been ischemic
nate in the veins of the legs or pelvis. Such and recently damaged. Such vessels when
patients may have both pulmonary and "para- again perfused under a normal head of pressure
doxical" cerebral emboli. (Lechat et. al. 1988, will then leak blood into the surrounding tis-
Jones et al, 1983). sues. In the study of Honig et al (1993), MRI
Multiple small emboli of cardiac origin may at 3 weeks demonstrated hemorrhagic trans-
occur to many cerebral vessels to produce a formation in 68% of cardioembolic infarcts but
syndrome of multiple small vessel occlusions always without clinical deterioration.
with a resultant clinical picture of dementia, e. Infarctions due to embolic occlusions are
alteration in personality, and so forth. Patients also often subject to rapid improvement
with multiple cerebral emboli also have because with the disintegration of embolic
embolization to extracerebral areas as well, material, blood flow is restored.
such as the femoral artery, the kidney, the Treatment is discussed below.
spleen, and the skin. Emboli to the kidney will MANAGEMENT OF ISCHEMIC
often be detected following the sudden AND OF EMBOLIC DISEASE
appearance of red blood cells in the urine
(hematuria).
As regards management of patients with
Differentiating embolic from non- atherosclerotic ischemic-occlusive disease the
student should consult Biller & Love (2000)
embolic ischemic-occlusive disease. Several
points should be considered: (see also and Brott &Bogousslavsky (2000). For
Ramirez-Lassepas et al, 1987): patients seen within 3 hours of an occlusion
a. Perhaps most important is the fact that usually embolic of the middle cerebral artery,
embolic occlusion of a vessel is sudden. In the use of intravenous t-PA may be considered
general there are no preceding transient if the CT scan does not demonstrate hemor-
ischemic events. At times, the event may be so rhage or more than one third of the middle
sudden that the patient stops speaking in mid cerebral artery territory involved by infarction.
sentence with a complete loss of speech. On For patients seen within 6 hours direct intra-
the other hand, infarction due to ischemic- arterial thrombolysis may be considered. For
occlusive disease is often preceded by one or most patients who have suffered infarcts, there
are no specific curative therapies. Considerable
more transient episodes of ischemia.
b. Since embolic occlusions are sudden, the recovery will occur in a supportive setting for
event may be accompanied by a focal or gener- many patients. Some patients with transient
alized seizure. ischemic episodes or infarcts with minimal
c. Embolic occlusions may occur during residual within the carotid distribution will
any time of the day and often during periods of have treatable extracranial vascular disease,
activity. Ischemic-occlusive infarctions tend to which will benefit from surgical correction of
occur during sleep when blood pressure is rel- the stenosis or occlusion. In addition to direct
atively lower or shortly after arising surgical carotid endarterectomy, the use ofbal-
26-22 CHAPTER 26
loon angioplasty with or without stents is being malformation or to intracranial tumors (such as
developed as for coronary artery disease. Many glioblastomas or metastatic malignancy, Little
patients with transient ischemic attacks or with et al, 1979) or as the complication of the rup-
a prior stroke will have a significant reduction ture of a saccular aneurysm where there is
in stroke risk with antiplatelet therapy (aspirin). extension of blood from the subarachnoid
Anticoagulation has a significant role in the space into the substance of the cerebral hemi-
prevention of cerebral emboli in patients with sphere. In general, however, the term intrac-
atrial fibrillation of both rheumatic and non- erebral hemorrhage is applied to those primary
rheumatic origin but has little value in other massive and medium-sized hemorrhages into
types of occlusive disease. The best treatment the parenchyma of the brain. The major risk
is prevention. The major factors which can be factor is hypertension. However in approxi-
controlled are hypertension, the risk factors for mately 40% of patients, blood pressure is nor-
cardiac disease including the prevention of mal (Brott et al 1986). Other risk factors
rheumatic and coronary artery heart disease, include excessive alcohol intake, and cerebral
cigarette smoking, diabetes mellitus, dietary amyloid angiopathy with deposition of beta
factors and illicit drug use (Refer also to amyloid in cerebral blood vessels. The latter
Bronner et al, 1995 and White et al, 2000, condition is associated with the presence of the
Inzitari et al, 2000). A major risk factor that e-2 and e-4 alleles of the apolipoprotein E
unfortunately cannot be well controlled is the gene. Recurrent hemorrhages may occur at dif-
family predisposition for cerebrovascular or ferent sites. Patients with intracerebral hemor-
coronary artery disease (Graffagnino et al, rhages are seen less commonly on general neu-
1994). For a discussion of ischemic-occlusive
disease involving the basilar-vertebral circula-
tion, the student should refer to the chapters
on the brain stem and cerebellum.
INTRACRANIAL HEMORRHAGE:
There are two types of intracranial hemor-
rhage: intracerebral hemorrhage and subarach-
noid hemorrhage. In the Framingham study
(Sacco et al 1984), intracerebral hemorrhages
constituted 5% of all strokes and subarachnoid
hemorrhage; 9% of all strokes. Both have a
high mortality. The young and middle age
Black population in the United States has an
increased risk of both intracranial and sub-
arachnoid hemorrhage compared to the white
population, (Broderick, et al1992).
INTRACEREBRAL HEMORRHAGE
Intracerebral hemorrhage is primary in 83
%of cases and secondary in the remaining 15%.
Hemorrhage into the brain may occur in
patients receiving anticoagulants, Kase et al
1985, Franke et al1990, or as a complication
Figure 26-20. Multiple cerebral hemorrhages sec-
of various hematological problems which are ondary to acute thrombocytopenia (platelet count of
characterized by bleeding disorders, e.g., 17,000) with acute lymphatic leukemia.cr scan with-
leukemia (Fig. 26-20). Bleeding into the brain out contrast in a 24 year old with headache and acute
may also occur in relation to arteriovenous onset of coma ,clinical brain death and a flat EEG.
TABLE 26-4. INTRACEREBRAL HEMORRHAGE
Location Vessel Freguency*IFigure Clinical Manifestations

Putamen-lateral ganglionic Lenticulostriate penetrators: 33-40% Progressive headache,
mass-internal capsule middle cerebral artery Fig.26-21, 26-22 hemiparesis hemianesthesia,
confusion ,herniation and coma
Temporal lobe stem Superficial small 23% Fig. 2-29 Progressive temporal lobe or
and lobar (Lobar often and medium arteries other cortical mass with focal
secondary to amyloid seizures. Recurrent or mulHple.
angiopathy)
Thalamus Penetrators: posterior 20% Fig. 26-24 Unilateral numbness,

cerebral artery Hemianesthesia, and vertical
gaze impairment
Pons Paramedian penetrators 7% Fig 13-26 Sudden quadriplegia, coma,

of the basilar artery respiratory impairment, death
Small lateral tegmental
lesions may survive.
Cerebellum Branches posterior inferior 8% Fig. 20-13 Sudden headache, vomiHng,

or superiorcerebellar vertigo, ataxia, then extra-ocular
arteries findings and coma
* Based on series of Hier et 01, 1977, Kase et 01, 1982, Kase and Coplan, 1986
rological and neurosurgical services than hypertensive patients. With a fall in blood
patients with occlusive vascular disease and pressure, infarctions would occur. With
those with subarachnoid hemorrhage. Patients restoration of elevated blood pressure, these
with intracerebral hemorrhage are, however, necrotic vessel walls would be unable to take
relatively common when acute general medical the stress of the increased pressure and would
admissions and autopsies are considered. bleed.
There is certainly a predilection for certain d. Another explanation suggests that in
areas of the brain as demonstrated in some cases venous occlusion may have
Table 26-4. occurred. Venous occlusions are usually hem-
The basic pathogenesis involved in intrac- orrhagic.
erebral hemorrhage is not certain. The fact that In both explanations (b) and (c) there is
penetrating arteries such as the lenticulostriate implied a concept of hemorrhagic infarction.
arteries, are also involved in occlusion with In some cases of premonitory ischemia, symp-
lacunar infarction in hypertension has led to toms will be noted.
several hypotheses concerning the etiology of e. It has been suggested that in younger
the hemorrhages: patients when hypertension is not present.
a. The vessel wall may be weakened by this bleeding has occurred from an arteriovenous
process and may dilate and rupture (the miliary malformation, the evidence of which has been
aneurysm of Bouchard and Charcot). destroyed by the massive hemorrhage (Case
b. The vessel may occlude with infarction. 26-7 on CD).
When collateral flow is then introduced into £ The use of sympathomimetic drugs uti-
the acutely necrotic area, hemorrhage occurs. lized in nasal decongestants and cough syrups
c. Related to this hypothesis is the concept in addition to amphetamines and the use of
of fluctuations in blood pressure. Certainly illicit street drugs such as "crack" cocaine have
such wide fluctuations may occur in some also been implicated in younger adults
26-24 CHAPTER 26
sue begin to digest red blood cells at the

periphery of the hemorrhage producing the
yellow-brown iron pigment hemosiderin. At
three weeks, this produces at the periphery, a
rim of orange. The more central area of hem-
orrhage never undergoes phagocytosis but is
converted to a semiliquid mass after several
additional weeks or months.
Figure 26-21. Intracerebral hemorrhage from the pene-
When the brain is examined many months
trating (lenticulostriate) branches of the right middle
cerebral artery. into the putamen with displacement of after a hemorrhage, there will be found a resid-
adjacent structures, and ruptured into the lateral ven- ual cleft or cavity with orange-stained walls.
tricle. This 46-year-old, black female with severe The staining is due to the persistence of hemo-
hypertension (230/130) had the sudden onset of left siderin-containing macrophages. The wall, in
face, arm, leg paralysis,left visual field defect, and then general, is similar to that surrounding the cavi-
72 hours later tentorial herniation with progressive
ty, which results from an ischemic infarct. A
brain stem deterioration. (See Fig. 13-8) (Courtesy of
Tufts Pathology Department.) proliferation of capillaries has occurred with the
formation of connective tissue fibers. In adja-
(Harrington et al1983, Levine et alI990). cent tissue, proliferation of astrocytes has
g. In elderly patients when hypertension occurred with the formation of glial fibers.
mayor may not be present and when the loca- The gross changes over time may be
tion of the hemorrhage is lobar involving the demonstrated with sequential MRI or CT
superficial small and medium sized arteries scans (Fig. 26-22, 26-23).
rather than small deep penetrating branch ves- The clinical manifestations will depend on
sel, a process of "amyloid angiopathy" has been the location and size of the hemorrhage and
identified. Deposits of amyloid occur in the are summarized in Table 26-4. In general with
media and adventitia of these vessels without the most common variety - those into the puta-
the presence of systemic amyloidosis. (See dis- men -there is the sudden onset of progressive
cussion above and Finelli et al, 1984, Molinari, headache, followed by progressive hemiparesis,
1993). and then within minutes to hours by hemi-
The pathological features to be found with anesthesia, confusion, and coma. The progres-
an intracerebral hemorrhage may be briefly sion of symptoms is due to the progressive
summarized. The hematoma may continue to enlargement of the hematoma and to dissec-
expand during the first three hours resulting in tion of the hemorrhage along fiber pathways.
continued deterioration. Within a few hours of Displacement of midline brain stem structures
cessation of the hemorrhage, clotting occurs. and tentorial herniation often occurs. With
In general with hypertensive hemorrhages, these brain stem complications and with exten-
bleeding does not again occur into the same sion of the hemorrhage into the ventricular sys-
area. The blood is not quickly removed from tem, a decerebrate state and a compromise of
the brain parenchyma. If this hemorrhage is respiratory functions develop. Death occurs in
actually a complication of infarction, then in a high percentage of such patients (75 per
the early stages, the changes of ischemic infarc- cent) within hours to days. Overall, 50% of
tion will be noted with infiltration of adjacent patients with large hemorrhages expire. The
ischemic tissue by polymorphonuclear leuko- prognosis for smaller hemorrhages is more
cytes. favorable (21%). Prognosis is directly related to
The actual clot of a hemorrhage will remain a) size of hematoma on CT scan and b) level of
as a red or reddish black mass for a matter of consciousness (Hier et all977,Broderick et al
several weeks. Macrophages that may have 1993). Patients with small hemorrhages may
been already abundant in adjacent necrotic tis- have only a minimal degree of disability since
Figure 26-22. Resolving hematoma right putamen,

hypodensity of a cystic cavity with residual hemosiderin
and dyrtrophic calcification (arrow), on MRI T2, 16
months after the acute hemorrhage. This 61 year old
right handed white male had the acute onset of a left
hemiparesis, had an excellent reCOPery of leg function
but continued to have severe spastic weakness in the left
upper extremity with tonic neck effim, a hemiplegic
gait, decreased pain sensation in left face and arm
and a dressing apraxia left arm.
the hemorrhage displaces structures rather
than destroying structures as in an infarct.
The diagnosis of intracerebral hemorrhage
may be made on the basis of the sudden onset
of symptoms. The onset occurs during a peri-
od of activity as opposed to the pattern for
arteriosclerotic ischemic-occlusive disease
where onset during sleep or shortly after awak-
ening is more characteristic. Occasionally Figure 26-23. A) Acute hemorrhage left thalamus on
warning prodromal symptoms are present; cr Scan of a 72 year old woman with clinical findings
such warning symptoms, however, are more ofsevere hypertension (210/130), dense right sided
characteristic of ischemic-occlusive disease. hemiparesis and sensory deficits plus fluent aphasia.
In general, the cerebrospinal fluid is under B) Old cystic cavity (arrow) on crScan, 2.5 years
later. She had significant sensory symptoms and
increased pressure and usually but not invari-
cortical sensory deficits i.n right arm and leg, ataxia
ably contains red blood celis. The number of ofgait, intention tremor of right hand and leg and
such celis, however, is usually less than that occasional choreiform movements of the right hand.
found in subarachnoid hemorrhage.
At the present time, the major aids in diag- dangerous when increased intracranial pressure
nosis are the CT scan and the MRI scans. is present.
There is then no indication for lumbar punc- As regards treatment, the deep location
ture such a procedure in any case may be within the putamen, thalamus, and pons means
26-26 CHAPTER 26
that surgical evacuation of these massive hem- aneurysm of the posterior communicating
orrhages is not feasible. Moreover, with most artery may compress the third nerve. At times
large pontine hemorrhages, death rapidly an aneurysm of the cavernous portion of the
ensues. With extension of hemorrhages of the carotid artery may invade the pituitary fossa or
putamen or thalamus into the ventricle, death compress the optic chiasm (table 26-5) or rup-
usually occurs within a short time. However, ture into the cavernous sinus. In general, the
expanding masses of more superficial lobar initial symptoms are those related to rupture.
hematoma within temporal or parietal lobe, The usual symptoms are those of sudden severe
offer the possibility of surgical therapy. headache, (the most severe ever experienced by
Cerebellar hematomas when diagnosed prior the patient), vomiting, neck pain, and stiffuess.
to brainstem compromise are often evacuated The latter symptoms are due to meningeal irri-
with a high degree of recovery. Qureshi et al tation. Sudden straining, exercise, or sexual
(2001) have reviewed current approaches to activity often precipitates the headache. In
management. massive rupture, sudden onset of coma may
SUBARACHNOID HEMORRHAGE occur. In a less severe bleed, consciousness is
sometimes well preserved. Often no specific
The diagnosis of primary subarachnoid
focal symptoms are present, and it may then be
hemorrhage is made on the basis of gross
difficult to determine particularly in the
blood present in the cerebrospinal fluid in the
comatose patient, on the basis of the clinical
absence of primary intracerebral hemorrhage
findings alone, the actual site of rupture. At
or trauma. Both of these conditions may have
times, the presence of minor focal signs will
secondary leakage of some blood into the sub-
allow the localization of the aneurysm. Those
arachnoid space. In 85% of cases of primary
cases where consciousness has been preserved
subarachnoid hemorrhage in the adult, the
and where few focal signs are present can of
source of bleeding is a ruptured saccular
course be readily distinguished from cases of
aneurysm. (Refer to table 26-5). The basic
primary intracerebral hemorrhage. In intrac-
pathology in the saccular or berry aneurysm is
erebral hemorrhage, secondary leakage of
a defect in the media and internal elastic mem-
blood into the subarachnoid space may occur,
brane of the vessel wall. Since the media of
but in the early stages although consciousness
cerebral arteries develops in a multicentric
may be preserved or clouded well-developed
manner, adjacent sections meet at arterial bifur-
focal signs are present, e.g., hemiparesis, hemi-
cations where clefts or gaps in the media are
anesthesia, hemianopsia, and quadriparesis.
common. These developmental defects in the
At times in cases of ruptured aneurysm, sig-
media probably occur to some extent in all
nificant focal or bilateral signs of cerebral
individuals. When later in life thinning or loss
involvement will be present. In some cases
of the internal elastic membrane is superim-
coma will be an early sign. In some of these
posed at this point of defect, the thin layer of
cases extension of the hemorrhage into the
intima bulges out and is covered only by the
substance of the cerebral hemisphere has
loose connective tissue of the adventitia. The
ballooned protrusion is referred to as a saccular
6More recent large autopJY studies suggest an
aneurysm.
The unruptured saccular aneurysm is usual- uverallfrequency of intracranial aneurysms of
ly asymptomatic. Unruptured saccular 5% with a population based incidence of sub-
aneurysms occur as an incidental finding in 1- arachnoid hemorrhage secondary to aneurysms
2 percent of routine autopsies6 . Most do not of 10 per 10,000 per year (see Phillips et ai,
rupture and do not cause symptoms. 1980). Patients with autosomal dominant poly-
Occasionally, however, symptoms may be cystic kidney disease or a family history are at
noted prior to rupture. Thus, an enlarging increased risk for aneurysms and require non-
invasive screening (Wiebers and Torres, 1992).
TABLE 26-5: SUMMARY OF THE CAUSES OF SUBARACHNOID HEMORRHAGE (SAH),
ANEURYSM LOCATION AND MANIFESTATIONS.
LOCATION OR TYPE FREQUENCY FREQUENCY AS EARLY MANIFESTATIONS OR SYMPTOMS

ALL ANEURYSMS CAUSE OF SAH OF COMPRESSION PRIOR TO RUPTURE
FIGURE #,
CASE#
I. ANEURYSMS 85% SUDDEN ONSET OF WORST EVER HEADACHE
PLUS STIFF NECK
Junction of post 30% Fig .26-24 Third nerve paralysis since third cranial nerve
Communicating & Cases 12-1, 26-8 runs close to and parallel to the posterior
Intemal carotid (On CD) communicating artery
Bifurcation MCA 20% Fig.26-25 Focal symptoms in MCA terrHory:

Case 26-9(CO) focal weakness or seizure face, speech etc
Junction anterior 30% Fig. 26-26, Compression optic chiasm, or bilateral prefrontal
communicating-anterior 26-27, 26-28 or bilateral lower extremity or coma or mute state
cerebral Case 26-10(CO) or If giant ,dementia. OIIen non localized SAH
Basilar vertebral system 5-10% Variable
MuHiple aneurysms 15% Variable, usually only one is the sHe of SAH
II. OTHER SAH CAUSES 15%
Peri mesencephalic 10% Non localized: worst headache,

stiff neck, drowsiness (Fig. 26-29)
Other: AVM, 5% Variable depending on location (often

mycotic aneurysms distal cortical branches In mycotic).
Seizures are frequent In both.
occurred. At times, rupture from the base of moglobin may also be detected in the spinal
the brain into the third ventricle has occurred. fluid. After 48 hours, increasing amounts of
At times, the vessel beyond the point of rup- bilirubin pigment may be noted with an
ture has been deprived of blood, and infarction increase in the degree of xanthochromia. The
has occurred within its territory. Embolism red blood cells have usually been completely
from clot in the dome of the aneurysm may disrupted by 10 days after the hemorrhage.
occur. At times, spasm of the artery distal to The bilirubin product of this disruption disap-
the point of aneurysm will occur, related per- pears more slowly. The spinal fluid does not
haps to the presence of blood in the subarach- become colorless for 15 to 30 days after the
noid space. Such arterial spasm may produce hemorrhage. In tissues adjacent to the sub-
sufficient vasoconstriction, apparently via arachnoid blood, hemosiderin-filled
adrenergic mechanisms, to result in ischemia macrophages may be seen for several weeks
and infarction. after the acute episode of bleeding. Initially in
Those red blood cells that have entered the the spinal fluid obtained by lumbar puncture,
subarachnoid space undergo a series of the ratio of white blood cells to red blood cells
changes. Within a few hours, disruption of red is the same as in the peripheral blood. With the
blood cells has begun with a yellow discol- passage of time, after the acute hemorrhage, as
oration (so called xanthochromia) of the spinal red blood cells are disrupted and as meningeal
fluid. At this time oxyhemoglobin and methe- reaction occurs, a relative increase in white
26-28 CHAPTER 26
blood cells will be noted.

Evaluation and Management of the
Patient with Subarachnoid Hemorrhage:
Early recognition of subarachnoid hemorrhage
is important since the overall mortality of rup-
tured aneurysms is at least 50% and the sur-
vivors have a significant morbidity. The recent
reviews of Schievink (1997, and van Gijn &
Rinke! (2001) are excellent sources of informa-
tion. Prognostic factors include early recogni-
tion at the time of the initial hemorrhage, age,
level of consciousness and neurological
condition.
Patients presenting at the emergency room
with the sudden onset of the worst headache
Figure 26-24. Saccular aneurysm, (arrow) arising
ever should undergo an immediate CT scan
from junction right internal carotid artery and poste-
rior communicating artery demonstrated by right searching for subarachnoid blood (Fig. 26-29).
carotid arteriogram. This 70-year-old widow, 18 The CT Scan will be negative in 5-10% of
months previously, had the sudden onset ofsevere pain patients, usually those with a minor bleed and
in the right eye and complete third nerve paralysis these patients should undergo a lumbar punc-
which had partially improved in the interim. ture searching for subarachnoid blood. If either
(Courtesy ofDr. Samuel Wolpert.). (Compare to Fig.
of these studies demonstrates subarachnoid
26-7C and 2-27 for non-aneurysm reference).
blood, then immediate angiography should be
performed, followed by immediate surgery
procedure designed to clip the aneurysm.
Surgical therapy has as its primary objective the
Figure 26-26. Saccular aneurysm at junction of ante-

rior communicating and left anterior cerebral artery
situated close to the optic chiasm. This 52-year-old, white
male had the sudden onset one evening of headache,
nausea, and Jlomiting. On examination, the next
morning he was stuporous, inattentiJle, disoriented but
could move all of his extremities, had bilateral
Figure 26-25. Giant aneurysm arising from the Babinski sign and release ofstrong grasp rej1ex£s plus.
bifurcation of the right middle cerebral artery. urinary andfecal incontinence. CSF had > 100,000
(Courtesy of Dr. C. W. Watson.) red blood cells per cu.mm; the supernatant fluid was
xanthochromic. (Courtesy ofDrs. John Hills, Dr. Jose
Segarra)
hemorrhage. Re-bleeding is a major cause of
morbidity and mortality in these patients.
Approximately 33% of patients re bleed in the
first 30 days with a mortality of 42%. Most
episodes of rebleeding occur within the first 14
days particularly between day 5 and day 9.
However, rebleeding continues to occur even
10-20 years after the initial hemorrhage in
patients not subjected to surgical therapy. In
the series ofWmn et al (1977), rebleeding in
such patients was estimated at 3.5% per year
during the first ten years with an associated
Figure 26-27. Saccular anterior communicating mortality of 67%.
aneurysm with rupture into ventricular system. This
Although direct intracranial surgery was at
65-year-old white male, 14 days after a confirmed sub-
arachnoid hemorrhage without definite localizing one time attended by a considerable mortality
findings, had a generalized seizure followed by quadri- and morbidity, major advances including
plegia and coma. (Courtesy ofDrs. John Hills, and microsurgery, neuroanesthesia with more
Jose Segarra) effective control of blood pressure and
prevention of additional subarachnoid hemor-
rhage. Modern advances now under develop-
ment include the use of spiral CT scan angiog-
raphy or high resolution MRA. In some
patients the direct clipping procedures are
being replaced by endoscopic obliteration of
the aneurysm. In patients who survive an initial
bleed, a second bleed is associated with a very
high mortality of 50%. Complications are sum-
marized in Table 26-6.
In considering the matter of therapy, it is
important to examine the mortality of the dis-
ease. In the study of Sacco et al 1984, one
third of the 36 total cases were in coma at the
onset and this group had a 30-day mortality of
83%. Two thirds were conscious at the onset
with a 29% mortality at 30 days. Of this con-
scious group of 24 patients, 15 developed no
deficits and 13 of 15 survived with a 30-day
mortality of 13%. Of the 9 conscious patients Figure 26-28. Aneurysm anterior communicating-
who developed a delayed deficit, the mortality anterior cerebral junction: Sub arachnoid and intrac-
was 56%. The overall 30-day mortality was erebral hemorrhage with rupture into ventricular sys-
tem and hydrocephalus. cr Sean (nonenhanced). This
47%.
51 year old male was found in a confused state and
Many patients (18%) die acutely and may soon lapsed into unconsciousness with mild nuchal
never reach a neurosurgical center. In the rigidity, miotic pupils, decerebrate movements on the
Cooperative Study of Subarachnoid left side, flaccidity on the right side and bilateral
Hemorrhage (Locksley 1969),27% of patients Babinski signs. He improved with osmotic shrinking
who reached a neurosurgical center died with- agents (Mannitol), steroids, ventricular drainage, and
subsequent clipping of the aneurysm, evacuation of clot
in the first week. Of patients dying within 72
and eventually a shunt procedure.
hours, 90% had an associated intracerebral
26-30 CHAPTER 26
TABLE 26-6: COMPLICATIONS OF THE INITIAL Surgeons grading scale is discussed by van Gijn
HEMORRHAGE OR OF A SECOND HEMORRHAGE and Rinkel (2001).
The Unruptured Intracranial Aneurysm:
COMPLICATION PREVENTION These aneurysms may be detected because of
OR TREATMENT
a) compression of cranial nerves, b) angiogram
Recurrence of SAH Prevent by immediate performed in patients with transient ischemic
arteriography and clipping attacks, or ruptured aneurysm at another site c)
of aneurysm after Inlnal SAH the increasing use of CT and MRI scan
Rupture into the ventricle Prognosis poor, coma then (Ojemann, 1981, Wiebers et al 1981, and
with brain stem compression death, possible use of Zacks et alI984). The most extensive study is
Massive SAH with tentortal ventricular drainage and the International Study of Unruptured
and tonsillar hernlanon mannitol Intracranial Aneurysms (Wiebers et al, 1998)
demonstrating a clear-cut relationship of
Dissection into brain Evacuate hematoma and
with hematoma formation clip aneurysm to prevent aneurysm size and risk of hemorrhage.
hemlatlon and rebleedlng Essentially those smaller than 10 mm in diam-
eter on angiographic study at the time of diag-
Vasospasm secondary Calcium channel blockers nosis are unlikely to subsequently rupture,
to aminerglc substances (Nimodipine) and increase
In blood blood pressure after clipping cumulative rate of rupture was less than 0.05 %
aneurysm to Increase per year. If the patient already had a repaired
perfusion aneurysm at another site after subarachnoid
hemorrhage the rate of rupture was 0.5% per
Acute or chronic For acute shunt after
hydrocephalus due to ventrtcular drainage year. For aneurysms of 10 mm or more in
blockage of cisterns, For chroniC shunt diameter, the rate of rupture approached 1.0 %
ventrtcles and subarachnoid per year for both types of patient the previous-
space ly untreated and the previously treated at
another site (about 20X-ll X the rate for the
Seizures Treat with annconvulsants:
phenytoin or phenobarbital smaller aneurysms). The rate of rupture for
giant aneurysms (> than 25mm in diameter)
Compressive effeCls of Clip and decompress was 6% in the first year. Currently, MRI
large and giant aneurysms aneurysm
angiography can reliably detect unruptured
Cardiac arrhythmias Treat with pacemaker or aneurysms greater than 2-3 mm in diameter,
appropriate ann-arrhythmia although many earlier studies have utilized
agents 5mm in diameter as the sensitivity cut off (see
Wiebers and Torres). When two or more
intracranial pressure plus the use of CT scan- members of the same family have aneurysms,
ning have resulted in a marked improvement in MRA of asymptomatic members should be
results (see Adams et al1987, 1983, Biller et al considered.
1988, Ohman and Heiskanen, 1989, Ropper NEUROLOGICCOMPLICATIONS
and Zervas, 1984). The use of calcium chan- OF BACfERIAL ENDOCARDmS
nel blockers has decreased vasospasm-induced (see CD ROM for, case 26-11 and
infarction. Figures 26-30, 26-31)
Patient selection is of considerable impor-
tance and this is dependent on grading of the Osler in 1885 first recognized the neuro-
patient as regards level of consciousness and logical complications of endocarditis (associa-
the presence or absence of focal neurological tion of fever, heart murmur and hemiplegia).
deficit. The Classification of Hunt and Hess, The neurological effects of infections of the
1968, (Table 26-7) utilizes a 5-grade scale. heart valves remain a major problem. Patients
The World Federation of Neurological with rheumatic heart disease were once the
TABLE 26-7 HUNT AND HESS ClASSIFICATION-WITH COR- Included within this diagnostic category of
RELATIONS vascular malformations are a variety of patho-
logical entities, (based on frequency) such as 1)
GRADE DESCRIPTION PROGNOSIS arteriovenous anomalies, 2) cavernous
AsymptomaHc or minimal Excellent if angiomas, 3) venous malformation, 4) telang-
headache and slight ea~y surgery iectasis 5) arteriovenous fistulas and 6) dual
nuchal rigidHy
vascular malformations. All are congenital.
2 Moderate to severe Excellent if (However, arteriovenous fistulas may occur
headache and nuchal early surgery with trauma e.g. carotid cavernous). In gener-
~gidity but no neurologic al these represent developmental (at times on a
deficit hereditary basis) tangles of abnormal vessels
3 DrOWSiness, confuSion, Excellent if within the substance of the brain (less often
or mild focal deficit early surgery involving meningeal vessels). These abnormal
vessels provide arteriovenous shunting of
4 Stupor, moderate to Poor unless on
blood. Since the vessels are abnormal with
severe hemiparesis, CT, treatable
early decerebrate rigidHy hydrocephalus defects in their walls, bleeding into the sub-
and vegetative disturbance or hematoma stance of the brain (producing an intracerebral
hematoma) or into the subarachnoid space
5 Deep coma; decerebrate Very poor
rigidity and moribund unless as above TABLE 26-8: NEUROLOGIC COMPLICATIONS
appearance. OF BACTERIAL ENDOCARDmS
major patients at risk. At present, other major COMPLICATION FREQUENCY MANIFESTATIONS

etiologic factors have emerged including intra- Cerebral embolism 17% (6-31 %), Usually MCA cortical
venous drug addiction, prosthetic valves, and 3% of all termory or stem
the use of various intravenous and intracardiac cerebral emboli (see above)
lines. Multiple 11% Confusional state or
The streptococcus (particularly viridans) micro-emboli personality change
remains the predominant organism, although or seizures
increasingly Staphylococcus aureus and fungi
Mycotic 2-10% Subarachnoid
must also be considered. The overall incidence aneurysm (2.5-6 % of hemorrhage often
of neurological complication in large series all aneurysms) more distal branches
from the Mass. General Hospital] amounts to of the MCA
39% (Pruitt et al, 1978). In 16% of endocardi-
Intra cerebral 7-8% Usually
tis patients, the neurological complication was
hemorrhage lenHculostrlate
the initial complaint. The development of neu-
rological complications had a significant effect MeninglHs 16% In 50% of purulent
on prognosis. If neurological complications usually staphylococ
were present, mortality was 58%, if not present, cus was idenHfled
20%. The major neurological complications are Brain abscess Single large Usually munlple and
summarized in table 26-8. is not common microscopic- possible
Durack (1995) discusses the prevention of confusional state
infective endocarditis. or seizure
ARTERIOVENOUS Intectlon ot Nota common Spinal cord or root

MALFORMATIONS (Refer to vertebrae or disc syndrome, compression
space wnh anhough
CD ROM for Fig. 26-32, 26-33, 26-34
compression osteomyellHs
and case 26-12 in which a long standing syndromes may occur
seizure disorder was secondary to an
AVM)
26-32 CHAPTER 26
sinus is primarily a disease of the infant less than

one month of age and reflects dehydration and
other systemic and perinatal factors. Refer to
the recent report ofDeVeber et al (2001) for a
more complete review.
Figure 26-29. Perimesencephalic,unlocalized sub-

arachnoid hemorrhage. Non enhanced cr scan
demonstrating blood in the interpeduncular,
prepontine, suprasellar and ambient cisterns. This 46
year old woman experienced the acute onset of ('the
worst headache in her life" lethargy and nuchal
rigidity but had an otherwise normal neurological
examination. Two series ofangiograms and all
hematologic studies were normal. She has done well
O11er the subsequent 7 years.
may occur. Moreover, these abnormal vessels
are also prone to occlusion with the develop-
ment of local infarction of cerebral tissue .In
general; these malformations produce symp-
toms earlier in life than do saccular aneurysms.
They are moreover less often fatal. Thus sev-
eral episodes of subarachnoid hemorrhage may
occur without loss of life. The initial manifesta-
tions are as follows: seizures, often focal in 50%,
intracerebral hemorrhage in 20 %, and sub-
arachnoid hemorrhage in 20%. Although
involving primarily the cerebral hemisphere,
the brain stem, spinal cord or cerebellum may
be involved.
DISORDERS OF VEINS
AND SINUSES.
Cavernous sinus thrombosis or cortical vein
thrombosis may occur in adults due to infec-
tion and has already been discussed. Occlusion
of the superior sagittal and lateral and straight
CHAPTER 27
Cerebral Hemispheres:
Neuropathology and Clinical Correlation II.
Non-Vascular Syndromes
PART I: TRAUMA ter systems at a subcortical and brain stem level.
In the era of the automobile, bicycle, and Contusions and Lacerations (Fig 27-1):
motorcycle, trauma to the head constitutes one More serious injuries of the cerebral hemi-
of the most frequent neurologi-cal problems sphere involve contusions, lacerations, intra-
presented to emergency room physicians. Not cerebral hemorrhages and edema.
all head injuries involve the brain. Significant Contusions (local areas of swelling and cap-
scalp lacerations and simple skull fractures may illary hemorrhage resembling bruises) are
be present without the development of signifi- found particularly at the anterior temporal
cant neurological deficits. On the other hand, poles and the under surfaces of the frontal and
closed head injuries may be present with signif- temporal lobes. These contusions of the cere-
icant neurological signs but without major bral cortex occur as a result of the sudden
external signs of head trauma (i.e., scalp and impact of the cortex against the bony wall of
skull appear intact). the skull. The anterior portions of the anterior
Concussion: Perhaps the most common and middle fossa provide relatively constricting
neurological syndrome occurring in relation to compartments favoring the development of
head trauma is the cerebral concussion, a syn- such contusions. Contusions may directly
drome characterized by a transient alteration of underlie the site of the blow to the skull (so-
consciousness and of higher cerebral functions called coup injuries) or may be across from the
lasting a matter of minutes to hours, following site of injury (so-called contra coup injuries).
a blow to the head. Consciousness mayor may When examined at autopsy years later, the
not be transiently lost at the onset. The patient brain may show small orange-yellow colored
complains of "being in a dazed state" with areas of depression on the orbital-frontal and
blurring of vision and a sense of unsteadi-ness. anterior-temporal areas (plaques jaunes).
Memory is often impaired for events during Intracerebral hemorrhages may also be pre-
this period following the injury: post-traumat- sent. These are usually multiple and small.
ic amnesia. The transient inability to record
and recall events that occur after the traumatic
event is called anterograde amnesia. In addi-
tion, memory for events which occurred min-
utes, hours, or even several days prior to that
injury may be impaired: retrograde amnesia. As
recovery occurs, this period of retrograde
amnesia may shrink.
No definite pathology has been associat-
ed with cerebral concussion; the pathophysiol-
ogy remains unclear. There is some indication
Figure 27-1. Old contusion and laceration of the right
that differential acceleration or deceleration of orbital frontal area (arrow). This 59-year-old white
the brain and skull may force the cerebral cor- male had a long history of heavy alcohol intake In
tex against the hard surface of the skull pro- addition to the traumatic lesion shown above, the
ducing a transient neuronal dysfunction. patient had clinical and pathological evidence of
Rotational forces may also set up stresses that an old Wernicke's encephalopathy involving the
result in the stretching (shearing) of white mat- mammillary bodies and of akoholic cerebellar corNeal
degeneration. (Courtesy ofDr. Jose Segarra)
27-2 CHAPTER 27
Occasionally, a single large hematoma may be sinus, the tissue over the mastoid may show
present requiring surgical therapy if mass delayed hematoma with discoloration of the
effects are present. skin and subcutaneous tissue - ("Battle sign").
Lacerations of the brain involve actual tears
in the cortical surface. Both lacerations and EXTRADURAL HEMATOMAS AND
contusions may result in the appearance of SUBDURAL HEMATOMAS
some red blood cells in the subarachnoid space. Of great importance from the neuro-
In general, patients with contusion and lacera- logical standpoint are these two traumatic con-
tion have a loss of consciousness in relation to ditions in which progressive compres-sion of
the injury. Residual alterations in mental func- the cerebral hemispheres occurs. These are
tion, memory and personality are often noted. conditions where early recognition and treat-
Such alterations are uncommon with a simple ment will produce excellent results. The failure
concussion. Focal neurological findings may be of recognition will result in progressive deteri-
present during the acute stage, at times remain- oration of neurological status with death as the
ing as residual deficits. Severe focal deficits such eventual outcome. Note that large traumatic
as hemiparesis or aphasia are, however, usually intracerebral hematomas will also produce a
absent. progressive course and these lesions may also
Complications of Skull Fractures: benefit from surgical therapy (see also Zervas
Certain types of skull injuries provide serious and Hedley-White 1972). The use ofCT scan
problems as regards the brain and require sur- has revolutionized the diagnostic approach to
gical attention. Thus, depressed skull fracture these problems: (see Cordobes et al 1981,
may compress the cerebral cortex, with bony Markwalder 1981, Masters et al1987).
splinters lacerating the dura and cortex. Extradural Hematoma: Extradural
Penetrating head injuries (the object caus- hematoma is a complication of skull fractures
ing trauma has penetrated the skin, bone and that extend across a groove containing a
meninges) may introduce contaminated ·mate- meningeal artery usually the middle meningeal
rial into the brain, producing abscess formation artery. Less often the skull fracture has torn a
and meningitis. Fractures involving the cribri- large venous sinus. Since the bleeding is usual-
form plate with laceration of the overlying dura ly arterial and brisk and the extradural space is
and arachnoid may result in the loss of olfacto- narrow (normally the dura is closely applied to
ry sensation (anosmia) and cerebrospinal rhin- the skull), compression of the cerebral hemi-
orrhea: the drainage of spinal fluid through the sphere soon results with the rapid development
nose. The presence of such a pathway, of and progression of neurologic symptoms. The
course, allows for the ready entry of bacteria classic description is usually that of a short peri-
from the nasopharynx: into the cerebrospinal od of unconsciousness related to the acute
fluid spaces, producing recurrent episodes of trauma, then a short lucid interval, which is fol-
meningitis. Air may also enter the intracranial lowed by progressive confusion and coma. A
cavity through this passageway. Both air and rapidly progressive hemiparesis is often noted
infection may also enter when skull fractures with the development of a fixed dilated pupil
extend into any of the paranasal sinuses or the on the side of the hematoma indicating uncal
middle ear. In the latter instance, a cere- herniation by the mass that may be placed lat-
brospinal fluid otorrhea may occur: drainage of erally over the temporal lobe. At other times, as
spinal fluid from the external ear canal. Such in the following case history, these lateralized
basilar skull fractures may extend across the findings may be overshadowed by the rapid
petrous pyramid or tear the tympanic mem- progression to a stage of functional midbrain
brane. Blood may be present in the external ear transection.
canal or behind the tympanic membrane. If the Case 27-1: This twenty-two-year-old,
basilar skull fracture extends into the sigmoid white airman, during a winter storm, was
NEUROPATHOLOGY: NON-VASCULAR SYNDROMES 27-3
involved in an auto accident at 11 :30 p.m., in bleeding middle meningeal artery branch.
which he struck his head against the wind- There was a rapid improvement in the patient's
shield. The patient apparently was dazed, per- status. The patient returned to active duty but
haps unconscious, for a matter of seconds to was experiencing some problems related to
minutes. He was taken by ambulance to the changes in recent memory, motivation and
emergency room of the nearby army hospital personality.
where a brief evaluation indicated that the Subdural Hematomas: Subdural
patient was alert, without definite neurological hematomas (Fig. 27-2, 27-3) represent the
findings, but skull X-rays did indicate a linear accumulation of blood within the subdural
fracture over the right temporal area space overlying the cerebral convexities. Such
The patient was apparently alert upon his hematomas may be acute, subacute or chronic.
arrival on the ward. However, by 5 a.m., the The acute and subacute types are clearly associ-
patient was reported by the nurses to be agitat- ated with trauma. The acute type is usually
ed and confused. associated with other significant injuries of the
Neurological examination: (8 a.m.) brain such as cerebral contusion, laceration and
Mental Status: The patient was agitated and intracerebral hematomas. With tears in the
unable to cooperate. He was moving all limbs arachnoid, blood from the lacerations passes
sitting up in bed, holding his head, which was into the subdural space. Moreover, small bridg-
tender to palpation moaning and hyperventi- ing veins from the pia arachnoid to the superi-
lating to a marked degree. He answered only or sagittal sinus are also likely to be torn. The
occasion-al questions and then with a yes or clinical picture of the acute subdural hematoma
no. Cranial Nerpes: Pupillary responses were is often then modified by the clinical manifes-
sluggish. The right pupil was perhaps slightly tations of these associated injuries. At times,
larger and slightly more sluggish than the left. however, the typical picture of a rapidly pro-
Reflexes: Deep tendon reflexes were increased gressive supratentorial space-occupying lesion
bilaterally. Plantar responses were bilaterally with progressive obtundation of consciousness
equivocal. and the signs of tentorial herniation will devel-
Neurological diagnosis: Possible evolving op in acute (24 to 48 hours) relationship to the
acute bilateral epidural or subdural hematoma head injury. The chronic variety may appear
Subsequent course: Progression occurred. after closed-head trauma, often apparently triv-
By 4 pm, the patient was now deeply comatose ial. At times, there may be no definite history
with little response to stimulation. The pupils of trauma.
were now bilaterally fixed and dilated. The four The subacute and chronic subdural
limbs were extended in a decerebrate posture hematomas develop after a variable latent peri-
with significant spasticity on passive motion. od of days, weeks, or months following the
The degree of spasticity in the upper limbs injury. The bleeding is venous from small
could be modified by tonic neck maneuvers. bridging veins passing from the pia arachnoid
The plantar responses were bilaterally extensor. to the superior sagittal sinus. The resultant
Spontaneous respirations were now irregular accumulation of blood then is relatively slow.
and infrequent, and the patient required the Associated injuries to the brain are usually not
assistance of a mechanical respirator. present. The blood in the subdural space is not
Revised Neurological diagnosis: Acute readily removed and remains adherent to the
tentorial herniation with brain stem compres- dura. Fibroblasts and blood vessels grow from
sion secondary to epidural hematoma. the dura at the edges of the clot, producing a
Subsequent course: A general surgeon thin membrane that separates the clot from the
immediately placed burr holes and evacuated arachnoid. At the same time, a thicker layer of
an epidural hematoma over the right temporal- connective tissue and blood vessels is forming a
parietal area. He coagulated and ligated a membrane where the clot is adherent to the
27-4 CHAPTER 27
Figure 27-2. Subdural hematoma. This 69-year-old

patient with Parkinson's disease had many dizzy spells
and had fallen frequently. (Courtesy ofDrs. John Hills
and Dr. Jose Segarra)
inner layer of the dura. The hematoma often

continues to increase in size apparently for sev-
eral reasons: continued venous oozing may
occur; moreover, bleeding may occur from the
blood vessels that are growing into the
hematoma from the dural surface. Finally, it
has been suggested that as some breakdown
occurs within the clot, a fluid with high protein
content is produced. The resultant fluid of
high osmotic pressure then attracts more fluid
into the hematoma.
The clinical manifestations are those of a
progressive supratentorial mass lesion. At
times, progressive focal symptoms and signs are
present; for example, hemiparesis, aphasia and
focal seizures. Eventually, alterations in con-
sciousness occur, often of a fluctuating nature.
With eventual tentorial herniation, a fixed
dilated pupil and the signs of a progressive
functional midbrain transection are noted.
Often, however, a syndrome is present in Figure 27-3. Chronic subdural hematoma, bilateral
CI'Scans. Case History 27-2. A) Non-contrast
which focal symptoms and signs are not promi- enhanced. B) Contrast Enhanced: note enhancement
nent, perhaps reflecting the fact that bilateral at membrane margins. This 83-year-old female - 3
subdural hematomas are present in a high per- months after a motor vehicle accident in which she
centage of cases. The resultant picture then is struck her head, developed fluctuating confusion and
that of a progressive state of confusion with lethargy. (See text for details).
fluctuating alterations in consciousness. A syndrome, progressive headache may be pre-
bilateral grasp reflex is often present. sent although this complaint as well as the past
Eventually, if untreated, coma and the signs of history of head trauma may be difficult to elic-
tentorial herniation develop. In both types of it when the patient is admitted to a hospital in
a confused state. Parkinson's disease are also at increased risk
Case 27-2. (Patient of Dr. Alex perhaps because such population groups are
Danylevich). This 83-year-old white female more prone to unsteadiness and falls (See dis-
struck her head in a motor vehicle accident 2 cussion of chapter 18). In the patient with cor-
months prior to admission. She had sustained tical atrophy as in Alzheimer's disease, the
fractures of her ribs and left clavicle. She had a bridging veins may be stretched and thus more
scalp hematoma in the right frontal area. She prone to tear. Because of the atrophy, a large
was admitted to her local hospital at that time amount of blood may accumulate in the sub-
for several days. She was described as having dural space without producing early symptoms
post-traumatic antero-grade and retrograde of headache and other symptoms.
amnesia and obtundation, which cleared over The problem also exists in the infant during
her several day hospital stay. She returned to the first year of life. The picture presented,
her usual activities but then was readmitted however, differs significantly from that seen in
with a three-day history of increasing confu- the adult because in the infant, separation of
sion, lethargy followed by a mute state. the sutures may occur, allowing the intracranial
Neurological examination: Mental status: cavity to expand. The onset is then often non-
The patient was lethargic, mute and did not specific and nonfocal: an enlargement of the
follow commands even when relatively alert. head, a failure to thrive, a failure to gain
Cranial net7Jes: Pupils were 2 mm. and reac- weight, and a failure to reach developmental
tive. There were sudden paroxysmal nystag- landmarks. At times, generalized seizures,
moid deviations of the eyes to the right. Motor vomiting, and papilledema may be noted.
system: Tone was increased in the right leg. The etiology often relates to presumed birth
Reflexes: Plantar responses were extensor bilat- trauma.
erally. A related problem is the occurrence of sub-
Clinical diagnosis: Chronic subdural dural effusions in infants following H.influenza
hematomas, probably bilateral. meningitis.
Laboratory data: The CTscan (Fig. 27-3)
demonstrated significant bilateral chronic sub- MANAGEMENT OF SEVERE
dural collections much denser on the left where HEAD TRAUMA
the lateral ventricle was obscured and shifted to Severe head injuries represent major prob-
the right. Serum sodium was low at 117 lems requiring intensive care. Such patients
mEq/liter generally are brought to the emergency room
Hospital course: Serum sodium was cor- in coma or an obtunded state. As opposed to
rected. Then, bilateral subdural hematomas the patient with a simple concussion (where
were removed via burr holes on the right and a any loss of consciousness is brief - minutes),
bone flap on the left where substantial chronic these patients continue with an altered level of
membrane and fluid were found. Neurological consciousness for hours, days, weeks or
examination eight hours after conclusion of the months. From a pathological standpoint, these
procedure, indicated an alert patient who had patients are found to have contusions, lacera-
no apparent language disorder and no weak- tion, and multiple hemorrhages within the
ness. She did develop transient right face and substance of brain and associated edema and
hand focal motor seizures that were treated infarction. These findings may be diffuse or
with anti-convulsants. concentrated in the diencephalic and midbrain
There are patients who are at increased risk areas involved in maintaining consciousness. At
for subdural hematomas: patients receiving times, the direct effects of trauma have been
anticoagulant medications, or with bleeding complicated by cardiopulmonary arrest due to
disorders, (e.g., as in leukemia. The elderly, chest injuries or on a central basis producing
chronic alcoholics, and patients with anoxic encephalopathy. Most do not have
27-6 CHAPTER 27
epidural or subdural hematomas (epidural in dence of such post-traumatic seizures. Most

15%, subdural in 15%). The details of manage- head injuries in civilian life, however, are not
ment are considered in Jennett and Teasdale penetrating missile wounds but rather blunt
1981, Bullock and Teasdale 1990, Jaffe and and non-penetrating injuries (closed head trau-
Wesson 1991, White and Likavec 1992, and ma), and under these circumstances, seizures
Ropper, et al1988. Essentially, the emergency are much less common. Thus, in the series of
critical care management of the traumatic Jennett, the overall incidence of seizures in
comatose patient involves the following major 1000 consecutive blunt head injuries was
steps. approximately 5 percent over a four-year peri-
1. ABC -Stabilization of vital functions od. In sununary, the post-traumatic seizures
including Airway, Breathing and Circulation are more likely to occur in those head injuries
(control of bleeding and blood pressure). where actual structural damage of the cerebral
2. Rapid neurological evaluation with rapid cortex has occurred.
rating of the level of consciousness (see chapter 2) Post-Concussion Syndrome: Another rela-
29). tively common late complication of head trau-
3. Emergency CT scan should be obtained ma is the post-traumatic or postconcussion
.A simple cervical spine series at the same time syndrome consisting of recurrent episodes of
should serve to rule out cervical fractures and headache and dizziness (vertigo or light-head-
dislocations. edness). The episodes often appear to be pre-
4. Epidural hematomas, significant subdur- cipitated by exercise or change in posture from
al hematomas and large focal intracerebral the recumbent to the upright. The severity and
hematomas require emergency neurosurgi-cal duration of the syndrome bears no relationship
intervention. to the severity of the trauma; the episodes may
5. Monitoring and management of continue for years after a trivial injury. In a few
increased intracranial pressure are necessary cases, the vertigo may be related to a traumat-
where contusions, edema, small intracerebral ic disturbance of the labyrinth. Patients may
hematomas, and small ventricles are present on develop benign positional vertigo. In many
CT scan). cases, the dizziness is actually a light-headed-
6. Temperature, electrolytes and fluid bal- ness related to anxiety and hyperventilation. In
ance and nutrition must be maintained to general, no actual pathology is found. As a
avoid the metabolic causes of coma. general rule, stable, well-motivated individuals
7. Seizures must be treated. who are anxious to return to their previous
8. Prevention of deep vein thrombosis in occupation or studies do not experience this
the lower extremities, and of the subsequent syndrome in severe degree. On the other hand,
complication of pulmonary embolus (Geerts et individuals with disorders of personality or psy-
al,1994). choneurosis or with problems in adjusting to
Late Effects Of Head Trauma 1) Post- studies or employment, appear to be severely
Traumatic Epilepsy: The seizures may be focal affected (Evans 1992).
or generalized. Penetrating injuries of the In recent years, there has been recognition
head, as in wartime wounds from bullets or of possible long duration changes in memory
shrapnel, are likely to be associated with post- and cognitive function following concussion or
traumatic seizures. In the World War II series other mild head trauma primarily on the basis
of Watson, 41.6 percent of such patients devel- of neuropsychological testing (see Capruso and
oped seizures within 3 years of the injury, the Levin 1992, Packard 1994 for additional dis-
majority within 6 to 12 months. There is some cussion of cognitive effects of head trauma).
evidence that factors such as the location of the
wound within the cerebral hemisphere and the PREVENTION
complication of abscess may influence the inci- Trauma is the most frequent cause of death
and disability in children and young adults. that particular tumors occur at particular ages.
Neurological trauma to brain and spinal cord, In childhood most intracranial tumors are
constitutes the major reason for prolonged infratentorial; in adult life, the larger propor-
costly hospitalizations in young adults since tion are supratentorial. Meningiomas, glioblas-
such patients require prolonged intensive criti- tomas, metastatic carcinomas, pituitary adeno-
cal unit and low term rehabitative care. The mas, vestibular Schwannomas (or neurinomas),
long-term effects of interruption of what were are tumors of the adult. On the other hand,
once hopeful productive careers cannot be cal- medulloblastomas and ependymomas are pri-
culated simply in terms of the billions of dollars marily tumors of childhood, while brain stem
involved but must also take into account the and spinal cord gliomas are found primarily in
personal and family miseries, which are older children, adolescents and adults
incurred. Many of the problems are pre- It is also evident that knowledge of the cell
ventable. Table 27-1 summarizes the measures type of a tumor taken in isolation does not nec-
available for prevention of head injuries. essarily enable the observer to predict the
Other traumatic problems include a.) anos- future biological and clinical behavior of the
mia as in case 30-3 on CDROM (shearing of tumor. Identity of the cell type and knowledge
the olfactory filaments passing through cribri- of the location of the tumor does allow for a
form plate), b.) carotid/cavernous fistula and higher order of prediction.
c. ) dissections of the carotid and vertebral Thus, glial tumors may arise in the cerebral
arteries. hemisphere, the brain stem, and the cerebel-
lum. The biological behavior of the tumor in
each location is quite different. Thus, most
PART II: NEOPLASMS
glial tumors of the cerebral hemispheres in the
Based on the previous chapters, it is evident adult are highly malignant. They are rapidly
TABLE 27-1: PREVENTION OF HEAD INJURIES
PREVENTATIVE MEASURES RESULTS OF PREVENTATIVE MEASURE

1.Trl-comer seat belts Mondatory use has been demonstrated to slgnlficanUy
reduce head, face, chest and spinal cord injuries.
2. StrIct enforcement of driving regulations regarding The majority of severe accidents involve the disregard of
alcohol and drugs these regulations. Often the use of these agents is
combined wHh excessive speed.
3. Mandatory use of safety helmets by bicycle Reduces the frequency of:

and motorcycle riders a. Head and neck injury deaths,
b. Severe head trauma morbidity
c. Minor head and neck Injuries,
d. Post-traumatic epilepsy - one of the few
preventable causes of one of the major diseases
of the nervous system.
4. Strict regulation of boxing - professional and amateur Reduce the incidence of multiple small contuSions and
wHh mandatory use of helmets. Compulsory suspensions lacerations of the orbitol trantal and temporal areas etc,
or revocattons after knockouts should be required Based which resuH in a chronic frontal lobe syndrome,
on long-term neurological, EEG and CT scan studies of 'the pinch drunk" state and possible post traumatic
professional boxers (Ross at al 1983). Many medical Parkinsonian state.
organizations Including the AMA and the American
Academy of Neurology have gone so far as to call
for the elimination of all professional boxing
5. Effective regulation of sales of arms. Weapons constitute a major cause of Injuries

and deaths In adolescents and young adults.
27-8 CHAPTER 27
growing invasive necrotic tumors with variable migraine headaches, or disease of the nose,
cell morphology and frequent nuclear mitotic nasal sinuses, orbits or acute or chronic disease
figures. The brain stem and spinal cord astro- of the cervical spine. Headaches that awaken
cytoma, usually seen in children and young the patient from sleep, or are produced by
adults, on the other hand, is usually slower positional changes or by coughing or similar
growing and has a more constant cellular and maneuvers should raise questions about a pos-
nuclear pattern. The cerebellar astrocytoma is a sible non-benign pathology. Even under these
limited cystic and encapsulated tumor of low circumstances, the majority of patients will fall
histological grade, which can be removed in its into a benign pathology group. Acute onset of
entirety with essential cure of the patient. headache, "the worst ever" may indicate a sub-
The clinical manifestations of a particular arachnoid hemorrhage or meningitis.
tumor are determined in part by the cell type 1. Migraine Headaches. In general migraine
of the tumor (astrocytoma, meningioma) and (vascular headaches) occur intermittently, are
its biological activity (benign meningioma, throbbing, accompanied by nausea and vomit-
low-grade astrocytoma, or highly malignant ing and may be unilateral or bilateral. They are
astrocytoma). Much more important in the classified as migraine with aura if focal symp-
determination of clinical signs and symptoms is toms such as visual phenomena lateralized tin-
the location of the tumor. This applies to both gling or other cortical phenomena precede the
the local symptoms and signs (focal cortical headache. They are classified as migraine with-
symptoms and signs or posterior fossa symp- out aura if the headache occurs without these
toms and signs) and to the general symptoms phenomena.
and signs such as headache, vomiting, drowsi- 2. Periodic cluster headache. This variety of
ness and papilledema that reflect the increased unilateral vascular headache often awakens the
intracranial pressure resulting from the tumor patient from sleep each night over a period of
mass, cerebral edema, and blockage of the ven- 1 to 2 weeks. They are throbbing but also
tricular system. Focal seizures are more likely to involve acute sharp pain localized to the eye.
occur with low-grade gliomas and menin- Usually, the headache is accompanied by uni-
giomas and less likely to occur with highly lateral tearing of the involved eye and unilater-
malignant gliomas. al nasal congestion. They are usually relieved
Headaches: Headache in patients with by inhalations of oxygen. Such headaches must
brain tumors may reflect not only increased be differentiated from the unilateral pain of
intracranial pressure but also the direct or indi- glaucoma. Acute maxillary sinusitis may also
rect compression of pain sensitive intracranial produce unilateral pain in the maxillary and
structures such as blood vessels, dural sinuses, ophthalmic distribution accompanied by nasal
meninges or cranial nerves at the base of the congestion, local tenderness, swelling and ery-
brain. At the present time, less than 50% of thema.
patients with brain tumors complain of 3. Muscle tension headaches tend to occur
headaches. Headache as an early symptom is on a daily basis, and tend to occur as the prob-
more frequent in patients with highly malig- lems of the day build up. They are described as
nant gliomas, and less frequent in low-grade a pressure or aching type pain located in the
gliomas and meningiomas. Supratentorial frontal areas but often spreading to the tempo-
tumors tend to produce frontal, temporal, ral and occipital areas. Often increased tension
orbital or parietal located headaches. may be palpated in the temporalis, frontalis or
Infratentorial tumors tend to produce occipital cervical muscles. Degenerative disease of the
or upper cervical located headaches. cervical spine is frequent and such patients may
In general, patients with headaches alone have chronic muscle tension and aching pain in
have another (non tumor) explanation for the the cervical and occipital areas.
headaches. This includes tension headaches, 4. Another common cause of headache is
occipital neuralgia. This occurs in patients with of two neurosurgeons with extensive experi-
prior whiplash injuries who have unilateral ence in the surgery of brain tumors. The
sharp pains in the distribution of the occipital autopsy data of an earlier period when the
nerves or the cervical 2-nerve root. These postmortem examination was more frequently
patients will have significant local tenderness performed is also presented.
on palpation of the occipital nerve at the occip- Metastatic tumors are under-represented in
ital notch. The pain is relieved by cervical trac- the operative series since patients with multiple
tion or local injection of the occipital nerve. metastatic tumors are not considered surgical
Brain Twnor Epidemiology: The overall candidates. Pituitary adenomas were of partic-
relative frequency of the various types of ular interest to Cushing and, thus, are over-
tumors affecting the central nervous system represented in the operative series. The true
varies from series to series depending on clinical frequencies are somewhere between the
whether a surgical or autopsy series is being operative and autopsy incidences. It is impor-
reported. In addition, the particular interests of tant to realize that silent meningiomas may be
the neurosurgeon have often resulted in a spe- found on CT scans or MRI scans or at autop-
cialized tumor type being referred to a particu- sy in older patients. Small pituitary adenomas
1ar neurosurgeon. Table 27-2 presents the data are found frequently at autopsy.
TABLE 27-2 RELATIVE FREQUENCY OF VERIFIED It is also important to place in perspective,
INTRACRANIAL TUMORS (AFTER MERRITT, 1967) the overall frequency of brain tumors.
1. Primary intracranial tumors diagnosed
TYPE OF COMBINED AUTOPSY prior to death occur in 11.8 patients per
TUMOR NEUROSURGICAL SERIES OF 100,000 per year (Radhakrishman et al, 1995).
SERIES OF 4349 3010 CASES 2. Asymptomatic tumors. In the same series
CASES (Grant (Courville) 7.3 patients per 100,000 per year are found to
and Cushing} have asymptomatic tumors.
Type of Tumor Percent of Total Percent of Total
3. Pediatric age group: Brain tumors are
Gliomas 43.0 41.5 the most frequent form of all solid neoplasm
(medulloblastomas, brain stem and cerebellar
Meningiomas 15.0 11.6 astrocytomas, ependymomas). Among all
Metastatic Tumors 6.5 23.7 malignancies in the pediatric age group, brain
tumors are out ranked only by leukemia. In the
Pituitary Adenomas 13.0 3.4 age group 15-34 years, malignant gliomas are
the third leading cause of death from cancer.
Acoustic Neuromas 6.5 2.5
4. Overall malignant gliomas alone account
Congenital Tumors 4.0 3.5 for 2.5% of deaths due to cancer. Among
adults, more die of primary brain tumors than
Blood Vessel Tumors* 3.0 7.8
of Hodgkin's disease or of multiple sclerosis.
Miscellaneous: 9.0 5.7 5. Moreover, 13% of the overall 385,000
papillomas, cancer deaths per year have some clinical evi-
Granulomas** dence of central nervous system involve-ment.
and sarcomas
Autopsy studies suggest that 25% of patients
* There are very few true tumors of blood vessels dying of cancer have intracranial metastases.
(hemangioblastomas and anglablastic meningiomas). With cancer of the lung, the percentage is even
Today many of the "tumors" of this group would be higher.
considered maifonnations.
** Today Infectious granulomas would nof be considered in Etiology Of Primary Brain Twnors
this series. In some paris of the world tuberculomas and
For the majority of cases, no specific factors
parasitic granulomas still conslilule a significont percentage
of mass lesions coming to surgery or autopsy.
can be identified.
27-10 CHAPTER 27
1. Radiation of the head early in life for PRIMARY INTRINSIC TUMORS OF

unrelated reasons, certainly does significantly NEUROEPITHELIAL ORIGIN
increase the risks, for all types oftwnors involv- The most frequent twnors affecting the
ing the nervous system including, gliomas cerebral hemispheres are those arising from
(2.6X), meningiomas (9.5X), and nerve sheath glia. Those of the astrocytic series are by far the
twnors (18.8X), compared to a matched con- most frequent whether operative or autopsy
trol group. Overall risk for 1.5Gy neural tissue series are considered (Table 27-3). Within this
dose was 6.9X control and 20X control for group the glioblastoma is the most frequently
2.5Gy tissue dosage. (Ron et alI988). encountered, based on autopsy statistics. In the
2. A possible increased risk for the develop- era of Cushing, glioblastomas were often not
ment of gliomas following occupational expo- subjected to surgery. (See below for more
sures in the petrochemical, chemical and rub- recent data and approaches).
ber industries has been discussed by a number Oligodendrogliomas are relatively infrequent
of authors (Selikoffand Hammond 1982). and ependymomas involving the cerebral
3. Head injury of a significant nature, e.g., hemispheres are rare.
depressed skull fractures, may be associated Astrocytic tumors. In general these
with meningiomas. twnors infiltrate the cerebral hemisphere. The
4. In a small number of patients, certain astrocytomas have been subdivided into vari-
familial syndromes may be present as predis- ous types. According to the classification of
posing factors, e.g., neurofibromatosis associat- Kernohan and his associates (1952), these
ed with acoustic neuromas, meningiomas and twnors were subdivided into four grades based
gliomas (of various types - including optic on their histological degree of malignancy. This
nerve), and tuberous sclerosis associated with classification to a variable degree, replaced the
astrocytomas. older nomenclature of Bailey and Cushing
5. Black (1991) and Shapiro and Shapiro (1926), which classified the glial twnors on an
1992 have reviewed concepts of oncogenesis, embryological basis (The twnor was classified
as applied to primary brain twnors, Oncogenes after the actual or hypothetical embryological
that potentiate or initiate cell mitosis may cell of closet resemblance). More recent classi-
behave inappropriately or excessively in neo- fications have utilized features, which correlate
plastic cells. Alternatively, or in addition, neo- with prognosis (see Burger et al 1985, 1987;
plastic cells may have lost twnor suppressor Daumais-Duport et al 1988). Features of
sequences. Chromosomal analysis has identi- importance in grading are degree of (1) hyper-
fied deletion loci on chromosome 22 in menin- cellularity; (2) pleomorphism, including
giomas, chromosome 17 and 22 in acoustic nuclear atypia and mitosis; (3) vascular prolifer-
neuromas and chromosomes 10 and 17 in ation; (4) necrosis.
astrocytomas. Chromosome 7 has been impli- In the discussion, which follows, we will
cated with increased frequency in the cells of utilize the several classifications as well as the
malignant gliomas. most recent classification of the World Health
5. Other Factors. The role of various other Organization as modified by DeAngelis (2001)
growth factors and of immune mechanisms From a prognostic standpoint, the follow-
remains to be clarified. Hormonal factors are ing grades of astrocytoma are recognized.
undoubtedly of importance in meningiomas. A. The low grade Astrocytoma Tumor
These tumors are more common in women (grade I or n astrocytoma). This is a mildly
than men (2:1 ratio), may undergo growth hypercellular twnor with a variable degree of
during pregnancy and are more common in pleomorphism but with no vascular prolifera-
women with carcinoma of the breast. Estrogen tion and no necrosis There are increased num-
and progesterone receptors have been demon- ber of mature astrocytes of relatively normal
strated in meningiomas (Lesch et alI987). appearance with no evidence of mitosis. Those
arising in the cortex are composed predomi- asm and diencephalon. Ther term polar spon-
nantly of protoplasmic astrocytes and were gioblast was at one time applied to this type of
referred to as "gemistocytic"; the cell resem- tumor.
bles reactive astrocytes. Those arising in the Grade II - The major example in this
white matter are composed predominantly of group is the low grade fibrillary astrocytoma
fibrillary astrocytes and sometimes referred to demonstrating a greater hypercellularity with
as "piloid or pilocytic". Grossly, the lesion is greater pleomorphism (mitosis present) but
non-encapsulated, firm, and granular and gray. with no vascular proliferation or necrosis. Most
Cysts may be present. At times, the only hint of (65-95%) present with seizures either focal or
the lesion may be a lack of distinction between secondarily generalized and initially the neuro-
gray and white matter. On CT the cyst may be logical examination may be without focal fea-
evident. The lesion, however, is usually best tures. Most eventually progress to high-grade
seen on MRI scan, which initially does not malignant gliomas. The appearance of progres-
demonstrate tumor enhancement. sive neurological findings and of tumor
enhancement in the MRI or CT scan may sig-
Grade I - Mild, hypercellularity with little nifY such a progression. The median survival
pleomorphism or mitosis. The major example despite therapy is 5 years but some survive for
is the pilocytic astrocytoma that is predomi- 10-15 years. Case 27-3 presented on CD
nantly a tumor of children and adolescents. ROM provides an example of the course of
The predominant cell type is usually the fibril- such a tumor with onset of generalized
lary astrocyte, a relatively uniform elongated seizures at age 30 and followed for over 11
mature astrocyte infiltrating along white matter years prior to surgery and radiotherapy.
tracts and often found in the pons, optic chi- B. Malignant Astrocytoma: These tumors
TABLE 27-3 THE OVERALL INCIDENCE OF VARIOUS TYPES OF ALL VERIFIED NEUROEPITHEUAL TUMORS·
TYPE OF GLIOMA NEUROSURGICAL SERIES AUTOPSY SERIES AVERAGE SURVIVAL:

(CUSHING) (COURVILLE) MONTHS AFTER
Total Number= Total Number= ONSET OF SYMPTOMS··
862 PERCENT 1259 PERCENT
Astrocytoma grade I 30.0 23.0 76
Astrocytoma grade II 4.0 1.0 28
Glioblastoma (Astrocy- 24.0 52.0 12
toma grades III &IV)
Polar Spongioblastoma 4.0 2.0 46

Ganglioglloma 0.3 2.0
Oligodendroglioma 3.0 1.0 66

Ependymoma 3.0 6.5 32
Medulloblastoma 10.0 6.0 17
Pinealoma 2.0 1.0
UnclassHied 20.0 4.0
* The series are not reslrlcled to !he cerebral hemisphere but include all gliomas.
** Aller Menilll967
27-12 CHAPTER 27
correspond to histologic grades III and IV and standpoint a marked hypercellularity is present
unfortunately are the most common glial with marked variability of cellular and nuclear
tumors with an annual incidence of 3 to 4 per appearance (Fig. 27-5) Multinucleated cells
100,000 populations. Two tumors are includ- and mitotic figures are frequent (4-5 per high
ed: the anaplastic astrocytoma and the very power field). Hyperplasia of blood vessels is
malignant glioblastoma. Both types of tumor very evident (endothelial proliferation). The
have a significant contrast enhancement on CT additional feature of necrosis serves to distin-
and MRI scans which is often an irregular ring guish this tumor from the anaplastic astrocy-
like area at the apparent margin. In actuality toma. The vascular proliferation often results in
the tumor extends beyond this border into the hemorrhage into the tumor. The vascular
adjacent tissue. hyperplasia of adventitia and endothelium may
Grade IlL' The anaplastic astrocytoma be so prominent as to suggest actual sarcoma-
tends to begin between the ages of 30 to 50 tous alteration. Both the hyperplasia of the
years. Characteristics include a significant blood vessel wall and the rapid growth of the
degree of hypercellularity, a significant degree tumor often result in a tumor that out grows
of pleomorphism and a moderate degree of the blood supply with resultant necrosis within
vascular proliferation (Fig 27-4). Median sur- the tumor. Grossly, the presence of hemor-
vival with aggressive treatment is approximate- rhage and necrosis is evident (Fig. 27-6). These
ly three years. Treatment is similar to that dis- features are also evident on CT scans (Fig. 27-
cussed for glioblastoma below. 7), which will demonstrate area of hemor-
Grade IV,' The glioblastoma multiforme
accounts for 80% of all malignant gliomas, with
the highest frequency of onset of symptoms
between the ages of 50 to 70 years. However
there are two categories within this group: pri-
mary glioblastomas that tend to begin in older
individuals (mean age 55years) and secondary
glioblastomas, occurring in somewhat younger
individuals (mean age 45 years). These latter
tumors have begun as a lower grade of tumor
and then have secondarily evolved so that
younger patients often appear to have a longer
duration of disease From the histological
Figure 27-5. Glioblastoma surgical histological fea-

tures. Case27-4. Refer to text and Figure 27-7
Figure 27-4. Gemistocytic astrocytoma, demonstrating A} lDw powered field demonstrating marked cellular-
a relatively high grade of malignancy: swollen astro- ity and marked vascular proliferation with areas of
cyte; with nuclei often bizarre and multinucleated micro-hemorrhage (approximately 100x in original).
displaced to the periphery. (H & E x 400). (Courtesy of B} High powered field demonstrating marked pleo-
Dr. David Cowen, Columbia-Presbyterian, Neuro- morphism; giant cells and mitotic figures (approxi-
pathology) mately 400x in original).
rhage, necrosis, and edema and with contrast, hemisphere, often along white matter systems
a considerable degree of ring enhancement. to involve other areas of the brain (e.g., via the
Prognosis and Treatment: For malignant corpus callosum to involve the opposite hemi-
astrocytomas, surgery may be employed for sphere). At times, a multi-centric origin may be
purposes of decompression and for debulking suspected. Necrosis and hemorrhage are fre-
the tumor mass so that fewer malignant cells quent; and progression of neurological deficit
remain to be destroyed by radiotherapy. For is often rapid. At times, the episodes of
the glioblastoma, median survival with surgery necrosis and hemorrhage may suggest vascular
only is 6 months, with surgery and radiothera- accidents.
py, 12 months. The role of chemotherapy is The variable clinical course of a glioblas-
uncertain, the percentage of long-term sur- toma in younger (40 year old) patients has
vivors maybe moderately increased. (Refer to already been presented in chapters 21 and 24.
DeAngelis, 2001 for additional discussion). In Those cases should be reviewed at this time.
the study of Shapiro et al (1989), 29-37% of The clinical course in an older patient with a 4-
patients with glioblastoma receiving radiother- 5 day course prior to diagnosis, which initially
apy survived for 18months Chemotherapy suggested a possible cerebrovascular event, is
produced minor additional survival (approxi- presented as case 27-4 and in Figures 27-5 &7.
mately 2-3 months). In retrospect, it was evident on the CT scan
In general younger patients with polar and at surgery that the acute onset reflected the
lesions who are able to tolerate extensive resec- hemorrhage and necrosis, which had occurred
tion, radiotherapy and perhaps chemotherapy
have the longer survivals (Scott et al, 1999).
Why do these patients do poorly? Although at
times these tumors may arise superficially in the
cerebral cortex, more often they seem to orig-
inate in the subcortical white matter. They then
appear to infiltrate widely through the cerebral
Figure 27-6. Glioblastoma multiforme of the left tem-

porallobe compressing brain stem and ventricular sys-
tem. This 43-year-old white male had the onset ofshort
((dreamy" states preceded by a distinctive UJste and a
sensation offamiliarity. Despite a craniotomy and
radiation therapy, the patient had a 14-month course Figure 27-7. Glioblastoma: case 27-4.Refer to text.
characterized by a progressive right hemiparesis, a cr scans A) Non-enhanced cr scan demonstrated a
nominal aphasia, a severe receptive aphasia, increas- low-density mass in the left frontal parietal parasagit-
ing disorientation, lethar,qy, headache, vomiting and tal region, with areas of hemorrhage. B). cr scan
papilledema. (Courtesy of Drs. John Hills and Jose (with contrast) demonstrated an irregular rim of
&garra) enhancement.
27-14 CHAPTER 27
within the tumor.

Case 27-4 (patient of Dr. Tom Mullins):
This 68 year old right handed white male was
admitted to St Vincent Hospital with an appar-
ent 4 to 5 day history of difficulty in doing cal-
culations and in speaking, "he could think of
the word, but had difficulty getting it out".
Speech was limited to short phrases with loss of
connectors and sentence structure. Writing was Figure 27-8. Oligodendroglioma. A relatively uni-
form mosaic pattern of cells with a small nucleus sur-
impaired but repetition, comprehension, nam-
rounded by a clear halo of cytoplasm is evident. A
ing and reading were intact. Motor system: Fine small area ofcalcification is present in this field;
motor movements of the right hand were much larger areas of calcification were evident in
impaired. Tone was increased on the right. other fields. (H & E x 400) (Courtesy of Dr. David
Reflexes: The right patellar reflex was increased. Cowen).
Bilateral Babinski signs were present.
Initial Clinical Diagnosis: Diagnosis was
uncertain. The abrupt onset suggested possible
vascular event such as embolus to the middle
cerebral artery but overall pattern including
bilateral Babinski sign without significant
hemiparesis was unusual.
Laboratory data: EEG: Focal left hemi-
sphere delta and theta slow wave activity. CT
scan (Fig.27-7): A) the non-enhanced study
demonstrated a low-density mass in the left Figure 27-9. Ependymoma of the fourth ventricle.
frontal-parietal parasagittal region with areas of Clusters of ependymal cells are arranged as rosettes or
as perivascular pseudorosettes. (H & E x 125)
hemorrhage. B) The contrast-enhanced study
(Courtesy ofDr. John Hills).
demonstrated an irregular rim of enhance-
ment. Angiograms indicated an avascular mass acute onset reflected the hemorrhage and
in the left frontal-parietal area necrosis that had occurred within the tumor.
Subsequent course: Dr. Alex Danylevich This was a rapidly growing, extremely malig-
performed a subtotal resection of this tumor nant tumor, which apparently had outstripped
that was found to contain blood clot and cystic its blood supply despite the neovascularity.
fluid. The histology of the tumor was glioblas- Other types of glial tumors: oligoden-
toma multiforme (Fig. 27-5). The patient sub- drogliomas: this variety of glioma is found in
sequently received 4000cGy whole brain radi- the cerebral hemisphere of young and middle
ation and an additional 2000cGy to the tumor aged adults constituting 5 -20 % of all glial
site. Three months following surgery, the tumors. The majority is low grade with a long
patient developed increasing obtundation. CT course of5-15 years; refer to case 18-2. A small
scan revealed a large left frontal necrotic mass. percentage are anaplastic or mixed tumors con-
Fever, hypocalcemia and hypernatremia devel- taining anaplastic astrocytoma elements. (Fig
oped and he expired one month later. 27-8 demonstrates the histology)
Comment: This patient presented with Other tumors of neuroepithelial origin:
what appeared to be an abrupt onset of lan- This group contains two very common tumors
guage problems raising the question of a cere- of the pediatric patient: (1) Primitive neuroec-
brovascular accident. In retrospect, it was evi- todermal tumor: medulloblastomas (Fig.27-9
dent on the CT scan and at surgery that the and case 20-1), and (2) ependymomas (Fig.27-
immune competent population.
(2) Tumors of blood vessel origin: Probably
the only true vascular neoplasm intrinsic to the
central nervous system is the hemangioblas-
toma of the cerebellum composed of embry-
onic vascular elements. Giant aneurysms
angiomas or arteriovenous malformations of
the brain and meninges are composed of adult
vascular elements and are not neoplasms but
Figure 27-10. MedulloblRstoma. Clusters ofsmall cells may have mass effect. Hemangioblastomas are
with densely staining nuclei are present. (H & E x
discussed in chapter 20
400) Refer Chapter 20for illustration of a gross speci-
men. (Courtesy of Dr. Dallid Cowen).
EXTRINSIC TUMORS
10). These brain tumors of the posterior fossa Meningiomas: The most common extrinsic
constitute the most common solid malignant tumor above the tentorium is the meningioma.
tumors found in the pediatric population. Meningiomas constitute 20% of all types of
These tumors have been discussed and illus- brain tumors. Based on the epidemiological
trate in chapters 13 and 20. data from Rochester Minnesota
The other 2 tumors in this group are rare (Radhakrishnan et al, 1995) meningiomas
(1) Ganglioglioma or neuroastrocytoma: now have a total annual incidence of 7.8 per
considered to represent the dilfuse infiltration
100,000 populations but the true incidence of
by a low-grade astrocytoma among neurons of
symptomatic meningiomas is 2 per 100,000.
the cerebral cortex - basal ganglia or dien- Most meningiomas (74%) are asymptomatic
cephalic nuclei. At times, this type of histolog- and are discovered at autopsy or on imaging
ical picture has been noted in the lesion of studies performed for unrelated problems (Fig.
tuberous sclerosis. (2) Pinealomas: These rela- 27-11). Meningiomas are tumors of the adult
tively rare tumors of the pineal have been con- population 30 to 70 years of age. They are
sidered already in relation to the brain stem
more frequent in females due to the fact that
(Chapter 13). The most common tumor of the
many meningiomas contain estrogen recep-
pineal region is the germinoma. tors. There is an additional increased incidence
in patients with breast cancer, at times provid-
OTHER PRIMARY
ing a diagnostic dilemma. Meningiomas arise
INTRINSIC TUMORS OF NON
from arachnoidal cells embedded in the dura.
NEUROEPITHELIAL ORIGIN
Normally, arachnoidal villi invaginate into the
(1) Primary central nervous system lym- venous sinuses as arachnoidal or pacchionian
phomas: Prior to 1980, primary intrinsic granulations but arach-noidal cells may be
tumors of the nervous system of non-neuroep- embedded in the dura. In addition, fibrous and
ithelial origin were considered rare. Primary vascular elements are, to a variable degree, also
lymphomas of the central nervous system have included in these tumors. The variable compo-
now assumed increasing importance and are sition has resulted in a histologic classification
no longer rare. In general these malignant according to the following main types:
tumors have B cell surface markers and are of 1. A syncytial or meningothelial variety
the diffuse large cell subtype. They were for- composed of clusters of cells similar to the
merly designated reticulum cell sarcoma or outer layer of arachnoid arranged in nests or
microgliomas. As with glioblastomas, the peak whorls and surrounded by layers of elongated
incidence occurs in the 50 to 70 year age or flattened cells.
range. The increased incidence has occurred in 2. A fibrous variety in which interlacing
both the immune suppressed (AIDS) and the bundles of fibro-blastic elements predominate.
27-16 CHAPTER 27
Figure 27-11. Meningiomas: incidental discuvery multiple asymptomatic in a 71-year-old ambidextrous female
with a normal neurological examination had a history of a transient left posterior thalamic ltuunar infarct which
WIlS confirmed on subsequent MRI studies. Those studies also disclosed right prefrontal and right parietal asympto-
matic meningiomas A) non-enhanced - Tl - right parllSagittal section, B) enhanced - T1 -frontal coronal section,
C) enhanced Tl parietal coronal section. No changes occurred O1Ier the next 5 years.
3. A psammomatous variety (probably the out a dural attachment within the ventricle or
most common type) consisting of the same within the Sylvian fissure. Although not invad-
type of arachnoidal cells, arranged in a whorl. ing the brain the otherwise benign menin-
In the center of the whorl is an area of hyalin- gioma may invade the overlying bone of the
ization arranged in concentric lamellae and cal- skull. Others excite an osteoblastic reaction in
cified (psammomatous granules). The calcifica- the overlying bone with a marked local thick-
tion is often visible on plain X-rays of the skull. ening of the bone (hyperostosis). What is
4. A less common angioblastic variety, that important about meningiomas is not their his-
appears spongy both on gross and microscopic tological cell type (sarcomatous degeneration is
examination, because it contains multiple small rare) but their location; in general they are
vascular channels. (At times, the term heman- readily amenable to neurosurgical removal. In
giopericytoma has been applied to this type of asymptomatic cases, the risks of surgery may
meningioma. ) outweigh any conceivable benefit to the
5. A mixed or transitional variety. patient.
Considerable overlap is apparent as demon- Meningiomas tend to occur in certain spe-
strated in Figure 27-12. cific locations outlined in Table 27-4.
It is unclear that these different histologic
types have prognostic significance. However a
small percentage (7%) from a histologic stand-
point have atypical or frankly malignant fea-
tures of a sarcoma. Regardless of the histolog-
ic type, all meningiomas on molecular analysis
have a loss of chromosome 22q. A similar
defect occurs in patients with neurofibromato-
sis type 2. These latter patients often have mul-
tiple meningiomas in addition to bilateral
Schwannomas of the vestibular nerve
These tumors are in general benign and Figure 27-12. Meningioma. Histological appearance
ofa mixed or transitional type meningioma.
slow growing. Almost all occur external to the
Interlacing fibrous bundles and whorls of meningothe-
brain with a dural attachment - compressing, lial cells are present in addition to a calcified psam-
displacing, and at times invaginating into the momabody (arrow). (H & E x 100) (Courtesy of Dr.
brain. Rarely, the tumors may be found with- David Cowen).
TABLE 27-4 MENINGIOMAS
LOCATION FREQUENCY* MANIFESTATIONS

Parasaglttal 21-23% (or 33-50%)
a) Rolandic Focal motor or sensory seizures or leg weakness (cases 1-1,18-1),
b) Prefrontal Fig. 27-20 on CD Personality change and dementia (Cases 22- 3)
Lateral convexity 17% Focal motor seizures hand or face
Sphenoid wing 9-17%

a) Inner third Unilateral exophthalmos and optic nerve atrophy + contralateral papilledema··
b) Middle third Bilateral papilledema then inner or outer third ftndlngs
c) Outer third Temporal lobe seizures (Fig 27-13).
Anterior fossa 8-18%

a) Olfactory groove Unilateral anosmia, prefrontal syndrome, dementia (see case 22-4)
b) Tuberculum sellae May mimic pltuHary tumor, with compression of optic chiasm,
prefrontal syndrome
Posterior fossa 7% See chapter 13,CP angle, foramen magnum and tentorial syndromes
Other sHes
a) Intraventricular Not common Hydracephalus
b) Spinal cord Spinal cord compression see chapter 9
* Series of Cushing & Eisenhardt (1938), of Courville (1967) and of Taveras and Wood (1964)
** Foster -Kennedy syndrome (See case 23-1)
The course of several meningiomas has length of survival after the diagnosis of cancer,
been presented already in several of the case metastatic spread to both brain and lep-
histories ofChapterl, 18,22 and 23. tomeninges has increased in frequency.
1. The most frequent site of primary tumor
TUMORS OF PITUTARY GLAND -
is the lung accounting for almost a third of the
see chapter 16 and below.
cases. It has been estimated that almost half of
Other Extrinsic Tumors Involving the all patients with small cell and non-squamous,
Brain Refer to Table 27-5 non-small cell carcinoma of the lung, at autop-
sy will have cerebral metastasis (Cox et al
SECONDARY TUMORS - 1979).
Metastatic Tumors: 2. The second most frequent site of prima-
The greatest number of secondary tumors ry lesion is the breast. Several examples have
of the central nervous system is spread from a been presented in Chapter 21.
distant site via the blood stream. The majority 3. Certain tumors, which have a lower
spread to the cerebral hemisphere or to the overall frequency of occurrence than carcino-
cerebellar hemisphere. Metastatic lesions may ma of the lung and breast, have a particularly
be solitary or multiple. (Fig. 27-18,27-19,27- high frequency of metastatic spread to the
20). In the series ofDelattre et al, 1988,47% brain:(a) malignant melanoma (usually multi-
of patients with metastatic lesions to the brain ple), b) hypernephromas (often solitary), and
on CT scan had single lesions. These secondary (c) choriocarcinoma. (In the surgical series of
metastatic tumors represent a significant per- Delattre et al, (1988), lung malignancies
centage of patients seen with intracranial accounted for 40%; melanoma for 11% and
tumors in a general hospital population. As kidney cancer for 11%.)
already noted, 25% of cancer patients have Treatment Solitary metastatic lesions may
cerebral metastases at autopsy. With increasing be subjected to surgical removal, since median
27-18 CHAPTER 27
survival is significantly improved in series where

surgery plus radiation is compared to radiation
alone: 40 weeks versus 15 weeks (Patchell et al
1990). At other times, when multiple metasta-
sis occur; radiation therapy or hormonal thera-
py may be employed, with a significant reduc-
tion in symptoms (for additional discussion see,
Posnerl990, 1992).
Carcinomatous meningitis: Malignant cells
are present in the CSF implanting on nerve
roots, cranial nerves, hemispheres and
meninges (Fig. 27-20,27-21). Breast cancer,
lymphoma, lung cancer and melanoma are the
most frequent primary lesions. Hydro-cephalus
is frequent. Additional discussion and illustra-
tive case histories will be found in Hedges et al
1988. Wmkler and DeLaMonte 1987, Gruber
and Sobel 1992, Little eta al1974, Olson et al
1974.
Local Invasive Tumors: Direct extension of
tumors to involve the brain is less common
than metastatic disease. Common primary sites Figure27-13. Outer third Sphenoid wing menin-
are carcinomas originating in the nasopharynx gioma. The dura overlying the sphenoid has been
and nasal sinuses. These tumors may erode the reflected revealing a large meningioma (arrow) com-
base of the skull or spread through the foram- pressing the inferior surface of the anterior temporal
lobe and adjacent orbital frontal area. This 73-year-
ina at the base of the skull to involve cranial
old black male had a 14-year history ofcomplex partial
nerves such as nerves V and VI. Treatment and generalized tonic clonic convulsions. (Courtesy
involves local radiation; results are dependent Drs. John Hills and Jose Segarra).
on the capacity for response of the primary
lesion. The central nervous system may be
involved by all of the general types of organ-
ill. INFECTIONS: isms that infect other systems of the body: bac-
TABLE 27-5-oTHER EXTRINSIC TUMORS INVOLVING THE BRAIN
TYPE LOCATION STRUCTURES INVOLVED OR MANIFESTATION

Craniopharyngioma Suprasellar Pituitary, hypothalamus, optic chiasm (Fig. 27-14)
Epidermoid, Bone of skull, dura or cisterns C-P angle or suprasellar
DermoidslTeratomas Usually midline Pineal, pituitary, 4th ventricle
Chordomas Clivus Compression of ventral brain stem, basilar artery
Colloid cysts* F. Monro of Third ventricle, Acute hydrocephalus with acute headache and coma, onen
intermillent due to ball valve mechanism (Flg.27-15, 27-16)
Schwannomas** Posterior fossa: C-P angle, vestibular nerve most common (see Chap.12)
• The colloid cyst of the third venllicle although uncommon must be recognized in the emergency room, since death may resuK.
•• Except for Schwannomas at CP angle (Fig.27-17), which may also arise from cranial nerves (jugular foramen) and from the sensory
nerve roots, all of these tumors are relatively rare. Refer to chapter 13.
Figure 27-15. Colloid cyst of the third ventricle. This

20-year-old male had sudden attacks of headache; with
the last such attack he presented to the emergency room
with rapid onset ofcoma and death.
degree other systems of the body in a general

14A or focal manner. The student should bear in
mind that the clinical and pathological mani-
festations of an infectious disease reflect not
only the direct effects of the invading organism
but also effects that indicate the body's defen-
sive responses to invasion. Moreover, when
immune mechanisms have been suppressed, as
in AIDS (acquired immune deficiency disease),
organisms that do not usually invade the brain
or other organs of the adult patient, may
14B assume major invasive roles. Examples include
toxoplasmosis, fungi, cytomegalovirus, etc.
Figure 27-14 Craniopharyngioma. A 23-year-old Infections involving the nervous system
.female with a 6-year history of headaches and amenor- may be considered under two broad categories:
rhea followed by diplopia and papilledema. Contrast 1. Those infections which involve the cen-
enhanced scan demonstrates suprasellar calcification
tral nervous system or subdivisions of the cen-
with large cyst which projects upward into the third
ventricle A) thin sections through suprasellar region; tral nervous system in a general or diffuse man-
B) sagittal and coronal reconstructions. ner, and
2. Those infections which involve the cen-
teria, viruses, rickettsiae, fungi, protozoa, and tral nervous system in a focal (or multi-focal)
helminths. Certain organisms do have a manner
predilection for the central nervous system and
FOCAL INFECTIONS OF
often for particular segments or certain systems
THE NERVOUS SYSTEM
of the neuraxis. Thus, we have already seen that
the virus of poliomyelitis involves predomi- The problem of focal infections of the ner-
nantly the motor neurons of the anterior horn vous system has an importance far out of pro-
and brain stem. Bacteria such as meningococ- portion to the actual frequency of occurrence
cus and haemophilus influenzae involve pre- of such cases. These focal infections represent,
dominantly the meninges. In most instances, in general, rapidly progressive and compressive
when infectious agents involve the central ner- space-occupying lesions and they often require
vous system, they also involve to a variable emergency neurosurgical intervention.
We have already seen that at the level of
27-20 CHAPTER 27
spinal cord, focal infections are essentially

extradural in location. The favorite site of acute
focal infection is the fatty tissue of the epidural
space. The resultant clinical picture is that of a
Figure 27-17 Vestibular (acoustic) neuroma or

Schwannoma. Microscopic examination of these tumors
usually indicates two tissue types: interwoven bundles
ofspindle-shaped cells with alignment of nuclei in the
form ofpalisades; and looser, somewhat cystic areas. (H
& E x 100) (Courtesy of Dr. David Cowen,
Columbia-Presbyterian, Neuropathology).
Figure 27-16 Colloid cyst of third ventricle. This 23-

year-old right-handed male had a 4-6 week history of
generalized throbbing hetukuhe and episodic visual Figure 27-18. Multiple metastatic tumors to cerebral
obscuration with bilateral papilledema and enlarge- hemisphere from malignant melanoma, with sec-
ment of the blind spots. cr scan demonstrated a third ondary hemorrhage into several of the pigmented
ventricular colloid cyst at the level of the foramen of lesions in a 40-year-old white female with excision of
Monro with secondary dilation of the lateral ventri- primary melanoma of the left knee with dissection of
cles. A) Contrast enhanced cr at horizontal level just the left groin 5 years prior to death. She had multiple
above foramen of Monro. B) Coronal reconstruction. cutaneous metastatic nodules despite chemotherapy and
All symptoms disappeared after Dr. Alex Danylevich then, right temporal hetukuhe, nausea and vomiting
drained and removed this cyst and shunted the ven- sudden coma with papilledema and sluggish pupils
tricular system. (Courtesy of Dr. John Hills
bophlebitis of the venous sinuses and of the
feeding cortical veins is a not unusual compli-
cation. The pus is present in a space that offers
Figure 27-19. Multiple metastatic tumors to brain.

cr scans demonstrate multiple high-density lesions
with low-density centers, and surrounding areas of
edema. Minor enhancement occurred in some of the
lesions with contrast. This 43-year-old white male with
a 30-pack -year smoking history and a poorly differen-
tiated adenocarcinoma with invasion ofperibronchial
lymph nodes and ofparietal pleura initially presented
with hemoptysis. Four months later he presented with a
one-day history of confusion, lethargy and frontal
release signs and died one month later.
rapidly progressive extradural compressive
lesion of the spinal cord. The symptoms and
signs are due both to the direct damage from
compression and the indirect destruction of tis-
sue produced by vascular compression and
occlusion. At the level of the spinal cord also,
spinal cord compression, may result from the
involvement of and collapse of vertebral bodies
by chronic tuberculosis.
Figure 27-20. Multiple metastatic tumors to brain
ACUTE FOCAL INFECTIONS adjacent to ventricular system and subarachnoid space
INVOLVING THE BRAIN with carcinomatous meningitis. Which process was the
primary one-periventricular solid metastatic lesions
Three syndromes should be considered: or the carcinomatous meninsitis remains uncertain.
1. Subdural empyema, 2.Purulent brain This 51 year old white male teamster had progressive
abscess, and 3. Focal viral cerebritis - h. headaches for 6-7 weeks and a 2 week history of a pro-
simplex. gressive third nerve paralysis. cr scans and MRI scans
demonstrated at least 5 distinct areas of contrast
1. Subdural empyema: In general, subdural
enhancing metastatic tumors. CSF contained 90 cells
empyema occurs as a result of the direct exten- consistent with non small cell carcinoma. Chest x-ray
sion of purulent infection from an adjacent demonstrated a lesion in the upper lobe of the right
focus of infection in the nasal sinuses or middle lung. He received radiotherapy and dexamethasone
ear or following compound skull fractures. The with improvement in headache. Three weeks later he
nasal sinuses are now implicated as the major developed weakness, tingling and depression of reflexes
in both lower extremities, plus urinary and fecal
source of infection. Osteomyelitis of the inter-
incontinence.
vening bone is a frequent finding; throm- A) T1 horizontal section. B) T1 coronal section.
27-22 CHAPTER 27
tary brain abscesses tend to be located in the

frontal or temporal lobe of the cerebral hemi-
sphere or in the cerebellar hemisphere. Direct
introduction of infected material may occur in
relation to trauma, e.g., compound skull frac-
tures, or in relation to neurosurgical proce-
dures. Finally, hematogenous spread may occur
in patients with a primary source in the lung, in
patients with bacterial endocarditis and in
patients with cyanotic congenital heart disease
where the blood may bypass the screening sys-
Figure 27-21. "Meningeal Carcinomatosis". Five
years after a complete remission from diffuse histiocytic
tem of the lungs. Patients with pulmonary
IYJn.phoma (Stage III-B non-Hodgkin's lymphoma), arteriovenous fistula are also at special risk.
which had presented with symptoms offever, night Such hematogenous spread is more likely to
sweats, abdominal pain and lymphadenopathy, this 77- result in multiple abscesses rather than a soli-
year-old female had a biopsy proven recurrence of dis- tary abscess.
ease (lymph nodes and bone marrow). She had drowsi- Since the introduction of antibiotics, there
ness; poor recal~ right eyelid ptosis and diffuse weakness has been a significant decrease in the number
of the left lower extremity with tenderness over left
fomoral and sciatic nerves. Over 2 days she progressed of patients presenting with brain abscess partic-
to a complete pupil sparing right third nerve paralysis, ularly in the number of cases where the abscess
incomplete left CN III paralysis (down gaze was pre- is secondary to sinusitis and mastoiditis.
served), left CN VI paralysis, bilateral peripheral Moreover, among the remaining patients there
facial paralysis, decreased hearing on left, and bilater- has been a decrease in the percentage of cases
al toe extensor weakness. CSF cytology (approximately
with an identifiable primary focus of infection
1000x) demonstrated large pleomorphic neoplastic cells.
The patient received intrathecal chemotherapy and an increase in cases without an identifiable
(Methotrexate). (Courtesy pathology department St. primary focus. These latter cases may reflect
Vincent Hospital) instances where partial antibiotic therapy has
very little resistance to the expansion of this eradicated the primary focus but not the brain
purulent mass. The mass is apparently never abscess.
well encapsulated although in older cases after As might be expected, the most common
the removal of the pus, a fibrinous exudate will organism is Staphylococcus aureus.
be found on the inner surface of the dura and Streptococci and pneumococci are also
the inner surface of the arachnoid. The respon- encountered as responsible organisms. Rarely,
sible organism is most commonly the under special circumstances, a fungus infection
Staphylococcus aureus. A sterile secondary may be implicated, e.g., mucormycosis in
inflammation is usually present in the sub- severely debilitated diabetics and aspergillosis
arachnoid space. This results in spinal fluid in patients receiving immunosup-pressive ther-
findings on lumbar puncture of moderate apy after renal transplantation or in patients
increases in cells and protein but a normal with AIDS.
sugar and negative culture. When the cerebral hemisphere is involved
Case history 27-5 on the CD presents an the clinical symptoms will correspond to the
example of subdural empyema. specific area impacted with focal seizures and
2. Purulent brain abscess: A brain abscess rapidly evolving focal neurological deficits as
(Fig. 27-22) reflects the spread of purulent the prominent features.
infection to the brain by several pathways. The electro-encephalogram is likely to
Direct extension may occur from a nearby show continuous focal 0.5 to 2 cps slow wave
focus of infection in the nasal sinuses or mas- activity indicating severe focal damage (refer to
toid or middle ear. For this reason many soli- Fig. 2-22). The CT scan (Fig.27-23) will usu-
of the world these infections are a common
cause of mass lesions, seizures or hydro-
cephalus. (See also discussion of AIDS)
GENERAL OR DIFFUSE INFEC-
TIONS: We will consider this section in
detail on the CD ROM
This category of diseases is usually present-
ed in detail in microbiology courses and in the
infectious disease sections of internal medicine.
a. Those involving primarily the lep-
tomeninges (pia and arachnoid) producing lep-
Figure 27-22. SublUute brain abscess (arrow) with tomeningitis. Generalized infection of the dura
associated ventriculitis. This 41-year-old white male, as
(pachymeningitis) is uncommon. (Fig.27-24,
a child, had a fibroma of the right maxillary sinus
that had been treated with surgery and radon
27-25)
implants. Four months before death he deve/Qped the b. Those involving primarily the parenchyma
first of 4 episodes of meningitis with headtUhe, nuchal of the brain, producing encephalitis. (Fig.23-
rigidity, fover, and chills; cerebrospinal fluid con- 26,27-27)
tained 495 white blood cells (75% polymorphonuclear) There are some infections, often viral, that
and a CSF-mgar of 40 mg./lOO mi. He had chronic involve both structures producing, a menin-
sinusitis of right maxillary and ethmoid sinuses on x-
goencephalitis.
rays and de.foct in the bone and dura in relation to the
right ethmoid sinus. (Courtesy ofDrs. John Hills and
Jose Segarra). MENINGmS (Leptomeningitis)
This is the most common form of infection
ally demonstrate a contrast ring-enhancing
of the nervous system. The manifestations of
lesion.
meningitis depend on the organism involved,
In general the outcome in the untreated
~e age of the patient, and the underlying phys-
brain abscess is fatal. Treatment consists of sur-
lCal status of the patient. Acute, subacute and
gical drainage and total excision of the abscess
chronic forms may be considered.
cavity. In addition appropriate antibiotic thera-
Acute Purulent (Bacterial or Septic)
py must be administered. In the series of
Meningitis): This is the most common form
Loeser and Scheinberg (1957), surgical thera-
of infection of the central nervous system
py in the period 1940-1944 was associated
among patients requiring hospitalization . In
with a 47 percent mortality. By the period
each case, a specific bacterial organism may be
1949-1956, an era of specific antibiotics, this
isolated from the cerebrospinal fluid (CSF) in
mortality had dropped to 19 percent.
the sub-arachnoid space. In addition, the spinal
A brain abscess involving the right parietal-
fluid shows evidence of an acute inflammatory
occipital area has already been presented in
reaction. The fluid is cloudy and under
Chapter 23. In reviewing that case, the student
increased pressure with large numbers of white
should keep in mind that events in a temporal
blood cells, predominantly polymorphonuclear
lobe abscess may proceed at a much more rapid
leukocytes, e.g., 90 to 98 percent of 500 to
pace as regards tentorial herniation with third
40,000 white blood cells per cubic mm. The
nerve and brain stem compression.
CSF sugar content is markedly reduced, rela-
CHRONIC FOCAL OR MULTIFO-
tive to the blood sugar. Normal spinal fluid
CAL INFECTIONS: GRANULOMAS:
sugar is >50% of the blood sugar. Gram stain of
The followings infections may produce granu-
the spinal fluid, latex agglutination tests of CSF
lomas: tuberculosis, cryptococcus, larva of the
and cultures will allow identification of the spe-
pork tape worm (cerebral cysticercosis), toxo-
cific organism. The specific organism and the
plasmosis and schisto-somiasis. In some parts
recommended treatment are indicated in Table
27-24 CHAPTER 27
Figure 27-24. Acute meningitis (pneumococcal). This

57-year- old white male had been living in a nursing
home with a diagnosis ofchronic undifferentiated
schizophrenia. Two weeks previously he had become less
responsive than usua~ then developed a temperature
of 104degreesfor which he received penicillin. On the
day of admission, the patient fell out of bed and became
comatose. Cerebrospinal fluid was cloudy with 11,861
with blood cells (80% polymorphonuclears) and a sugar
of 36-mg./100 mi. Culture of the cerebrospinal fluid
subsequently revealed S. pneumoniae. A left and then
bilateral fixed dilated pupils developed followed by
Cheyne-Stokes periodic respirations, decerebrate pos-
ture, and death. At autopsy, the brain was swollen with
a yellow-green purulent exudate present in the sub-
arachnoid space. (Courtesy of (Drs. John Hills and Jose
Figure 27-23. Brain Abscess. cr Scan: A) Non- Segarra)
enhanced demonstrates an edematous mass in white
matter of right posterior temporal parietal-occipital
areas with compression of the right lateral ventricle.
B) With contrast a 3-4 cm ring-like enhancement
occurs. This 53-year-old left handed white male with
borderline diabetes mellitus had been treated for an
abscess in the muscle of the abdominal wall due to
anaerobic Bacteroides with incision drainage and
antibiotics. Seven days later he developed severe "blind-
ing" right sided headaches, confusion, difficulty in
reading, word finding, following commands, repeti-
tion ofshort phrases plus flat affect, a neglect of the left Figure 27-25. Acute meningitis (pneumococcal). The
visual field and a mild left hemiparesis. All neurolog- subarachnoid space is filled with inflammatory cells,
ical findings resolved over the next 2 days after treat- predominantly polymorphonuclear leukocytes. There
ment with antibiotics, dexamethasone and mannitol has been artifactual detachment of the pia from the
(to reduce cerebral edema) and immediate evacuation cortical surface. (H & E x 400). (Courtesy of
of the abscess. (Courtesy ofDrs. Ralph Sama and Pathology Department, Tufts University School of
Bernard Stone) Medicine).
27-6. fontanelle of an infant will be under increased
Clinical Presentation: The clinical picture pressure and bulging. An older infant or a child
of acute purulent meningitis depends on the is likely to have nuchal rigidity (resistance to
age of the patient. An infant under 6 months of passive flexion of the neck) in addition to fever,
age may be febrile, listless and drowsy and may convulsions, and coma. A posture of
vomit and fail to take feedings. The anterior
opisthotonos may be present (extreme exten- has been markedly reduced so that the actual
sion of head, neck, trunk. and limbs). mortality in meningococcal meningitis is now
The older child and adult with meningo- 3%, although the mortality in patients with
coccal meningitis will usually have a prodro- overwhelming meningococcemia may still
mal period characterized by symptoms of an approach 40%. For S. pneumoniae the case
upper respiratory infection, low-grade fever, fatality rate remains high at 21 %due to the age
and various body aches. With septicemia and, of the patients. The case fatality rate for
then, the subsequent involvement of the H.intluenzae is 6 % and for group B strepto-
meninges, the symptoms of chills, vomiting, coccus 7% percent. Eleven to 19% of survivors
severe headache, and nuchal rigidity occur, of meningococcal disease have sequelae usually
often followed by an alteration in conscious- minor if treated early (peripheral facial weak-
ness. The signs of central nervous system ness, hearing loss), at times major: focal neuro-
involvement often appear relatively abruptly. A logical deficit or focal seizures or loss of a limb.
skin rash is common in the stage of bacteremia. There are several possible complications of
Small or large areas of skin hemorrhage meningitis. While these are more likely to
(petechiae and purpura) due to involvement occur in delayed or untreated cases, some may
and occlusion of the skin capillaries occur dur- occur in those patients receiving adequate
ing the process of septicemia and are caused treatment. With a marked increase in intracra-
either directly by the organism or indirectly as nial pressure (at times, lumbar subarachnoid
a result of disseminated aggregation of platelets cerebrospinal fluid pressure at lumbar puncture
into small thrombi. may be 600 mm. of CSF compared to a nor-
The early recognition of acute purulent mal pressure oflSO mm.) herniation ofmedi-
meningitis is of importance. If it is untreated, al temporal areas through the tentorium may
serious intracranial complic-ations develop and occur with compression of the third cranial
death is the usual outcome. Prior to the era of nerve and midbrain. A vasculitis may involve
specific antimicrobial therapy, the mortality was blood vessel walls, resulting in occlusion of cor-
close to 90%. With specific therapy, this figure tical arteries and veins. The occlusion of corti-
TABLE 27-6:ACUTE BACTERIAL MENINGITIS: COMMON ORGANISMS AT SPECIFIC AGES AND RECOMMENDED TREATMENT
AGE OF PATIENT BACTERIAL ORGANISMS RECOMMENDED TREATMENT (All are intravenous)

(on cuHure)
0-1 Month B. Streptococcus* Penicillin G(piUS in neonates Initially gentamicin
for 72 hours)
1-23 months s. Pneumoniae-45%, Vancomycin plus a broad-spectrum cephalosporin

N.menlngHidls-31 % for S. Pneumonia (see below for N. meningilldls)
2-18 years N. Menlngitidls Penicillin G**
19-59 years S. Pneumoniae-60%; See above

N.menlngltidls-20%
>60 years S. Pneumonlae See above
* Prior to introduction in 1990 01 H.lnfluenzae conjugate vaccine Immunlzalion; most cases were due to this organism.
Recommended treotment for H.lnfluenzae is ceIh1axone
** For epidemics 01 N. menlngHidls in developing counlrles, 0 single intramuscular InJecllon 01 a suspension 01
chloramphenicol in 011 has proven to be eIIecIIve.
*** Less common agen1S: L. monocytogenes ampicillin + gentamicin,
*** Enterobacteriaceae-broad speclrUm cephalosporin +omlnoglycoside.
27-26 CHAPTER 27
cal veins and superior sagittal sinus may lead to TABLE 27-7 TREATMENT RECOMMENDATIONS BASED ON
hemorrhagic infarction of the parasagittal CSF STAINS PRIOR TO CULTURE RESULTS
frontal parietal areas with a resultant weakness
of the lower extremities and focal seizures. In
Identification of Treatment Recommendations
Agent in CSF (Intravenous)
addition, a further increase in intracranial pres- (Gram stain)
sure may occur. before Culture
As we have already indicated, a thick exu- COCCI
date at the base of the brain (somewhat more Gram positive COCCi: Vancomycin plus a broad
likely to occur in pneumococcal meningitis) spectrum antibiotic
Gram negative cocci Penicillin G
may damage cranial nerves and also obliterate
the subarachnoid cisterns. The end result may BACILLUS
be a significant degree of hydrocephalus since Gram positive bacilli Ampicillin (or penicillin G)
cerebrospinal fluid will be unable to pass up plus aminoglycoside
Gram negative bacillus Braad spectrum cephalosporin
over the hemispheres to the areas of absorp- plus aminoglycoside
tion. In the child, a progressive enlargement of
the head occurs. EMPIRICAL APPROACH
Overall, in the recent series of Pomeroy et Children <1month Ampicillin + broad spectrum
cephalosporin and vancomycin
al (1990), 14% of children had neurological
Children >1 month Vancomycin +cefotaxime
deficits that persisted beyond a year after bacte- or cellriaxone
rial meningitis. Of these 10% had only sensory-
neural hearing deficits and 4% had multiple
as opalescent). A relatively small number of
neurologic deficits. Seven percent had late,
white blood cells is present (5 to 2000 per
non-febrile seizures. (See also Taylor et al1990
cubic mm. and usually less than 500 per cubic
and Smith 1990).
mm.) in comparison to acute purulent menin-
Treatment: The present recommendations gitis. Moreover, the white blood cells are pre-
Table 27-7. (Quagliarello &Scheld, 1997, dominantly mononuclear (lymphocytes and
Rosenstein et al, 2001) as to choice of intra- monocytes). The sugar content of the spinal
venous antibiotics which are to be started fluid is normal. Moreover, smears, agglutina-
based on the Gram's stain of the CSF when the tion studies and bacteriological cultures of the
patient is first seen but before csf or blood cul- spinal fluid fail to reveal a responsible organism.
tures are available are presented in Table 27-7. In general, the causative organism is a virus:
ECHO, Coxsackie, non-paralytic
Once the organism has been identified on
poliomyelitis, mumps and lymphocytic chori-
cultures or agglutination studies of CSF or
omeningitis.
blood the recommendation of Table 27-6
The student should note, however, that a
should be followed.
similar cerebrospinal fluid reaction may also
Acute Aseptic Meningitis: In these cases, characterize certain diseases where a secondary
the clinical signs and symptoms of meningitis meningeal reaction occurs: subdural empyema,
are present in the sense that the patient com- brain abscess, and venous sinus thrombosis. At
plains of headache and stiffness of the neck. times, a similar spinal fluid formula may be
Vomiting and nuchal rigidity are present. noted in a viral encephalitis. The aforemen-
However these findings are usually less fulmi- tioned viral agents may, of course, at times pre-
nating than those in acute purulent meningitis, sent a combined syndrome of meningoen-
e.g., sudden coma and purpura in the adult is cephalitis.
unlikely; consciousness is usually well-pre- Moreover, at times several more significant
served. The spinal fluid, moreover, is often subacute infections in their early stages may
clear or only minimally cloudy (often described present a predominately mononuclear reaction
in the spinal fluid: tuberculous and cryptococ- encephalitis. Even in epidemics of encephalitis
cal (fungal) meningitis. Bacterial organisms will or poliomyelitis, there may be many subclinical
be absent on routine smears and cultures of the cases. For example, for Japanese encephalitis,
cerebrospinal fluid. However, both of these the ratio of subclinical to overt clinical cases has
infections are characterized by a low spinal fluid been estimated at 200 or 300:1 (Monath
sugar, and appropriate stains and cultures (and 1988).
in the case of cryptococcal infection specific In general, most cases falling into this cate-
antigen studies) will eventually disclose the gory reflect viral infection. Evidence of viral
organism. These infections, although not com- particles will be found as inclusions within the
mon at the present time, in the non-immuno- cytoplasm or nuclei of neurons. With the
suppressed population, are of importance exception of the spirochete, bacteria do not
because a) specific therapy is required, b) with produce a diffuse encephalitis, although bacte-
the increase in cases of acquired immune defi- ria may produce multiple areas of abscess for-
ciency syndrome; the incidence of these dis- mation. Other infectious agents may produce
eases has increased. encephalitic involvement of the nervous sys-
Differentiation of the various types of viral tem. The rickettsiae which are intermediate in
meningitis may be made by specialized size between bacteria and viruses, usually pro-
immunological techniques for the measure- duce signs of a meningoencephalitis in addition
ment of neutralizing antibodies. Viral meningi- to a characteristic skin rash. Examples are
tis is a self-limited disease. No specific treat- typhus, and Rocky Mountain spotted fever).
ment is available (see below, however, under Moreover, certain protozoal parasites may
H.simplex). Recovery is in general complete - invade the central nervous system producing a
unless, the meningitis is an epiphenomenon in subacute encephalitis Examples include toxo-
the midst of an encephalitis. plasmosis and trypanosomiasis (African
Other types such as aseptic, tuberculous, Sleeping Sickness).
fungal, meningovascular neurosyphilis and Encephalitis may be acute or chronic. Most
other spirochetal infections are considered cases fall into the acute category; most viral and
on the CD ROM rickettsial diseases are acute. On the other
hand, the spirochetal infection and protozoal
ENCEPHALmS: This topic is consid- infections of the central nervous system are, in
ered in detail on the CD Rom and in gener- general, chronic or subacute processes.
al medical texts. See also figures 27-26 and Recently, however, several viruses and prions
27-27. A brief introduction is provided have been implicated in chronic diffuse pro-
here. gressive processes (previously considered to be
The term encephalitis refers to a diffuse of an unknown etiology) involving the nervous
invasion of the parenchyma of the brain by an system.
infectious agent.
At the present time, clinical presentation of ACUTE ENCEPHALmS: ACUTE
encephalitis is probably less common than VIRAL INFECTIONS
those diseases considered under the category of
The pathology of viral infections of the
meningitis. During particular epidemics certain
neural parenchyma involves a viral invasion of
infectious agents involving the central nervous
neurons with the production of intranuclear or
system have produced a large number of cases
intracytoplasmic inclusions (Fig 27-27) and the
with encephalitis. However, subclinical or
acute degeneration and destruction of nerve
minor diffuse involvement of the central ner-
cells. There is a cellular infiltration of neural tis-
vous system probably occurs in the course of a
sue and an accumulation of inflammatory cells
number of common viral diseases, primarily as
about the degenerating nerve cells, in a perivas-
a mild aseptic meningitis or meningo-
cular location (Fig. 27-26). The cells are usual-
27-28 CHAPTER 27
Figure 27-27. Encephalitis. Rabies. Negri bodies are

present as cytoplasmic inclusions in neurons of the
Figure 27-26. Encephalitis (herpes simplex). A signifi- hippocampus. Intracellular inclusions are characteris-
cant collection of mononuclear cells is present in the tic of viral diseases. (H&E 100x) (Courtesy of Dr.
perivascular space with infiltration of adjacent cere- Thomas Smith)
hral cortex. This 32-year-old patient had the acute ized centers, tissue culture techniques may be
onset offover, headache, and generalized convulsions. employed.
Over a 30-day period, he developed increasing stupor,
bilateral extensor plantar responses, and dilated pupils.
c. Application of acute and chronic sero-
(H & E x 320). (Courtesy ofDr. John Hills). logical tests to measure antibody levels (com-
plement fixation or antibody neutralization
ly mononuclear although in some processes, tests).
e.g., acute poliomyelitis or in a severe case of It had been traditional to divide these viral
encephalitis, there are often noted a significant infections into neurotropic group (primary
number of polymorphonuclear leukocytes at involvement of the central nervous system) and
times involved in neuronophagia. A microglia a non-neurotropic group (involvement of the
proliferation is often noted in the involved central nervous system in humans is usually
neural parenchyma. To a variable degree adja- secondary to or less prominent than involve-
cent meninges may be infiltrated by inflamma- ment of other organ systems). As we will dis-
tory cells. Depending on the degree of cuss with the herpes group of virus infection,
meningeal infiltration and on the severity to the distinction is to some degree artificial. The
which the underlying parenchyma is involved, infections with the neurotropic may be epi-
a variable increase in cells (predominantly lym- demic (the arthropod bourne viruses such as
phocytes) will be noted in the spinal fluid. equine encephalitis or West Nile) or non epi-
Occasionally a normal cell count may be pre- demic such as rabies.
sent, more often 100 to 500 cells per cubic A more modern classification divides virus-
mm. are present. The protein content is usual- es into those containing RNA and those con-
ly increased; the sugar and chloride content are tainingDNA.
normal. Examples of RNA containing viruses
The differentiation of the particular virus include: the enteroviruses (polio, Coxsackie,
involved depends on: ECHO), the arboviruses (Eastern and Western
a. The specific clinical pattern of the dis- Equine, Japanese, etc.) rubella, mumps and
ease: some viruses involve particular areas of measles, rabies and HIV.
the central nervous system; some have associat- Examples of DNA containing viruses
ed involvement of other organ systems. include Herpesvirus, papovavirus and pox-rus-
b. Virus isolation studies: inoculation of virus. An overview of viral encephalitis is pro-
blood, nasal washings, excretions, cere- vided in the review of Whitley (1990).
brospinal fluid, or fresh post-mortem brain tis- Neurotropic Group: Epidemic group:
sue into susceptible animals. In some special- Within the epidemic group several infections
may be grouped together because they share dren predominantly, has approached 75 per-
common characteristics: a) Equine cent, with significant residuals in those recover-
encephalomyelitis with Eastern U.S.A., ing. Encephalitis lethat;gica (WIn Economo's
Western U.S.A., and Venezuelan subtypes( encephalitis) occurred as an epidemic in the
Deresiawicz et al,1997). b) Japanese B period 1916-1926. More recent case have
encephalitis (probably the most common been described by Howard and Lees(1987). A
form. World wide in recent years). c) Russian viral etiology was suspected but never con-
tick encephalitis. d) St. Louis encephalitis. firmed: the means of transmission remained
e)West Nile encephalitis a recent problem in uncertain. This infection differed from the pre-
the eastern United States (Nash et al 2001, viously described varieties of encephalitis in the
Tyler, 2001) f) LaCrosse virus encephalitis sense that although diffuse, the pathology
,probably the most frequent variety in the U.S. tended to be concentrated in a periventricular
in recent years (McJunkin et al, 2001). location with severe involvement of structures
In each of these infections a relatively dif- bordering the aqueduct and third and fourth
fuse involvement of the cerebral cortex, dien- ventricles. The periaqueductal region and
cephalon, brain stem and cerebellum occurs. In other structures of the midbrain were particu-
each, an arthropod, usually a mosquito, has larly affected. Reflecting the significant involve-
been implicated as a vector of transmission. A ment of the midbrain and of the associated
species of bird or mammal has often served as structures of the extrapyramidal system, disor-
a reservoir of infection. For these reasons, cases ders of eye movement and movement disor-
have occurred predominantly in a seasonal ders of various types were prominent; in addi-
manner. (In northeastern United States, for tion to the more general symptoms oflethargy,
example, most cases of Eastern equine and headache and fever. Since the involvement of
West Nile encephalitis have occurred in the late the cortex was less severe, seizures and focal
summer or early fall months, a time when mos- cortical deficits were less frequent. The mortal-
quitoes are frequent). Vaccines are available for ity approached 25%. Among those who sur-
prevention of some of the more common vari- vived, post encephalitic residuals were com-
eties (Hoke et al, 1988 ). mon. In contrast to other forms of encephali-
tis, Parkinson I s disease and other disorders of
The clinical syndrome in most cases is extrapyramidal function were frequently noted;
characterized by the sudden onset of headache, the Parkinson I s disease usually appeared to
vomiting, drowsiness, confusion, convulsions, emerge or evolve as a symptom after the clear-
coma, fever, plus or minus, stiffuess of the ing of the acute symptoms (see chapter 19).
neck. Evidence is often present on examination Acute anterior poliomyelitis, the other
of the patient of diffuse and, at times, multifo- member of this epidemic group of neurotropic
cal involvement at multiple levels of the neural viruses, has already been discussed in relation
axis: coma, confusion, myoclonic jerks, status to the spinal cord. The portal of entry is the
epilepticus, decorticate or decerebrate rigidity gastrointestinal tract. The central nervous sys-
and cerebellar findings. In some cases, cranial tem is involved either by spread along the axis
nerve findings, aphasia and hemiplegia, will be cylinders or via a generalized viremia. The virus
present. The duration of the disease is a matter involves predominantly the large motor neu-
of days to several weeks. The state presented by rons of the anterior horn and of the brain stem
the patient may be described as an encephalopa- with lesser involvement of other neurons in the
thy. The major differential diagnosis is that of spinal cord.
toxic metabolic encephalopathy. A variable Non epidemic neurotropic virus infections
mortality occurs in part related to the age of The two most familiar members of this
the affected patients. The mortality of Eastern group - Herpes zoster (discussed previously)
equine encephalitis, which has affected chil- and rabies - do not have their major effects at
27-30 CHAPTER 27
the level of cerebral cortex. sive immunization with antiserum containing

Rabies: The virus of rabies is present in the antibodies to rabies has been demonstrated to
saliva of rabid animals and invades the central be much more effective. The current vaccine is
nervous system several weeks to months after a the human diploid cell vaccine, the current
bite from an infected animal (dog, cat, wolf, antisera - human rabies immune globulin.
fox, raccoon ,squirrel, or bat). The virus travels Previous treatment protocols involving ner-
to the central nervous system along peripheral vous system derived vaccines resulted in post
nerves. The symptoms relate to the character- vaccinal demyelinating reactions. Once symp-
istic involvement of nuclei of the brain stem, toms have developed, no effective treatment is
Purkinje cells of the cerebellum, and pyramidal available. In under developed areas of the
cells of the hippocampus (Ammon's horn). In world a high mortality occurs. (see Baer &
addition, there is a significant inflammation Fishbein 1987 and Fishbein &Robins,1993 for
and necrosis of the spinal cord or brain stem at a review of epidemiology and current concepts
the segmental site corresponding to the radic- of treatment.).
ular dermatome involved by the bite. The cere-
bral cortex is relatively intact and consciousness Non-Neurotropic Vaal Infections:
is preserved. These viruses were traditionally considered
The initial symptoms consist of numbness as not producing significant symptoms of cen-
and tingling in the distribution of the involved tral nervous system involvement. Indirect evi-
peripheral nerve, followed by headache, vomit- dence suggests that some of these viruses
ing and a stage of agitation. This latter stage is (mumps, measles, enterovirus) do invade the
characterized by restlessness, generalized con- central nervous system in a much greater per-
vulsions, and at times, visual and auditory hal- centage of otherwise asymptomatic cases. In
lucinations. Marked alteration in emotions some of these diseases, e.g., herpes simplex,
occurs: unreasonable fear, rage and depression. there is evidence of direct invasion of the cen-
In this stage laryngeal and pharyngeal spasm tral nervous system when the syndrome of
(with fear of water, "hydrophobia") is promi- acute encephalitis occurs. In other viral infec-
nent. In a later stage of flaccid paralysis, impair- tions, e.g., mumps and measles, it is often
ment of vocal cords and of respiratory centers unclear when central nervous system symp-
develops. In approximately 20 percent of cases, toms develop, whether one is dealing with an
an ascending flaccid paralysis dominates the actual viral invasion of the central nervous sys-
acute stage (Plotkin and Koprowski, 1978). tem producing an acute encephalitis (direct
Death occurs within 2 to 5 days of onset of invasion of neurons), or whether one is observ-
central nervous system symptoms. At autopsy, ing an immunological reaction to infection
the diagnosis may be established in man or elsewhere pro-ducing an acute allergic post-
other infected animals by the findings of char- infectious encephalomyelitis, (white matter
acteristic acidophilic (eosinophilic) inclusions predominantly involved with perivenous
(Negri bodies) within the cytoplasm of hip- demyelina-tion ).
pocampal pyramidal cells (Fig.27-27).
Because of the long incubation between 'JYpes Of Non-Neurotropic Vaal
exposure to the virus and the development of Infections:
neurological symptoms, prophylactic treat- 1. The herpes virus family. included
ment is possible. Thus, the administration of a herpes simplex, herpes zoster/varicella,
vaccine containing the attenuated virus(first cytomegalovirus and Epstein Barr.
introduced by Pasteur), induces the produc- The Herpes simplex virus (HSV) has two
tion of anti-bodies, and may prevent the devel- types - Type 1 associated with the common cold
op-ment of neurological symptoms. The com- sore of the lip or oral cavity, often activated by
bination of this active immunization with pas- fever and Type 2 genital herpes with labial vagi-
nal and penile infection. In both instances, the present and to the level of consciousness.
virus remains in a latent form in neural ganglia. Therefore, if the diagnosis is strongly suspect-
(Baringer and Swoveland, 1973), particularly ed on clinical grounds - treatment is begun as
the trigeminal ganglion in the case of Type I soon as possible, even though the ancillary lab-
HSV and the sacral ganglia in the case of Type oratory studies are not yet confirmatory. In
2HSV. most instances, a brain biopsy is not obtained
Type 1 HSV is the most common cause of unless the patient fails to respond to therapy.
non-epidemic; sporadic acute encephalitis in Even with acyclovir therapy, 53% of patients
the United States. The early signs of headache will die or will be severely impaired. (See dis-
and fever are followed by the development of cussions of Hanley, 1990; Whitley, 1992).
signs that suggest involvement of limbic struc- Type 2 HSV in adults is associated with an
tures one or both temporal lobes, and at times aseptic meningitis or with severe radicular
orbital frontal (Fig.30-i). The virus apparent- symptoms involving the sacral segments. The
ly gains access to the central nervous system by latter may include urinary retention (Caplan et
infecting structures that are related to the olfac- al,1977).
tory system, perhaps by axonal transport along Type 2 HSV infection in the infant or fetus
the olfactory bulb and its anatomical connec- results in severe disseminated disease with
tions. In some cases spread may be hematoge- multi-system involvement of brain and viscera.
nous (see review of Picard et al ,1993). 2. Paramyxovirus group includes mumps
Personality and behavioral changes may be pre- and measles. In the child and adult mumps
sent for days or a week; followed by seizures, encephalitis is rare. In the fetus and neonate,
hemiparesis and aphasia. Rapid or subacute mumps virus infection has been implicated as a
progression to a stage of increasing coma then possible cause of aqueductal stenosis produc-
occurs. In a small number of cases, the patient ing hydrocephalus (see Johnson and Johnson
may present with an overwhelming rapidly fatal 1969).
state characterized by repeated generalized Measles virus infection may be associated
convulsions; myoclonic jerks of the extremities, with a variety of central nervous system syn-
decerebrate rigidity, coma and periodic com- dromes including:
plexes in the EEG. In contrast in a small num- a. an acute or subacute encephalitis
ber of cases, the clinical picture is that of a pro- b. a post infectious encephalomyelitis
gressive subacute dementia and confusional c. subacute sclerosing pan-encephalitis:
state. The CSF demonstrates increased pres- (SSPE) a form of progressive chronic
sure, and a variable number of mononuclear encephalitis manifested by dementia, ataxia,
cells plus or minus a variable small number of seizures and myoclonus. The disease usually
red blood cells. The electroencephalogram develops - in a delayed manner after an early
may provide evidence of focal or bilateral tem- childhood measles infection. There is a reacti-
pOrallobe abnormalities, including slow waves. vation of the measles virus within the CNS.
At variable points in the disease course, the 3. Retrovirus - Human Immunodeficiency
radioactive brain scan, contrast enhanced CT Virus (HIV-l): This virus infects cells of the
scan or MRI will demonstrate focal or bilateral immune system (e.g., T helper lympho-cytes) -
temporal ( and frontal) abnormalities: enhanc- producing an acquired-immune deficiency
ing necrotic lesions with considerable edema. state (AIDS). Carriers who may be in an early
Sequential serological studies of blood and or asymptomatic stage of the disease outnum-
CSF may be useful in the diagnosis. The treat- ber actual cases of AIDS or AIDS-related com-
ment of choice is intravenous acyclovir which plex (ARC). In the United States during the
can be administered without serious side 1980s specific groups were at high risk: (a)
effects. The response to treatment is directly homosexual or bisexual men (66%); (b) intra-
related to how long the symptoms have been venous drug users (17%); (c) heterosexual -
27-32 CHAPTER 27
sexual partners ofpatients with AIDS (4%); (d) lum and memory systems. Refer to CD ROM
recipients of blood and blood products (3%); for an approach to classification.
and (e) combined risk - homosexual or bisexu- B. Nutritional disorders: Refer to the CD
al male - also drug user (8%)1. By the year ROM Table 27-8 and to general medical texts
2001,Sekowitz quoted figures of 36 million C. Toxic Disorders: These are considered
people world wide infected with HIV, with an in detail on the CD ROM and in general med-
additional 21.8 dead of AIDS. Approximately ical texts. Heavy metals effects are summarized
70% of cases occur in sub-Saharan Africa where in Table 27-9 Various central nervous systems
there are two types of epidemics : 1) a hori- pharmacologic agents taken in excess may all
zontal transmission in adults spread primarily produce effects on CNS function. Some such
by heterosexual contact and to a lesser degree as sedatives, anticonvulsants, benzodiazepines
by shared needles and 2) a vertical transmission or narcotics may produce depression of cogni-
,infected mothers give birth to infants who tive function and or ataxia and eventually in
have been infected in utero. Significant num- severe overdose coma. Neuroleptics may pro-
bers of cases are also occurring in the duce extrapyramidal effects. Hallucinogens and
Caribbean, southeast Asia, and South America. amphetamines may produce a psychosis. Use
The nervous system is involved in at least 60% of the latter may be associated with hemor-
of patients with clinical disease:The infections rhagic strokes Cocaine may produce arrhyth-
may be generalized or focal due to the immun- mias and stroke. Carbon monoxide may pro-
odeficiency state. Thus, there is an increased duce headaches or coma.
incidence of cryptococcal fungal meningi- C. Complications of Endocrine disor-
tis(lO%) and of toxoplasmosis granuloma (5%). ders: see CD ROM regarding diabetes, thy-
A high percentage of patients (>30%) have a roid disease, pituitary hormones etc.
direct invasion of the CNS by the virus pro- D. Remote effects of malignancy: see
ducing a subacute encephalitis referred to as CD ROM and chapter 21
AIDS dementia or HIV, meningitis. In patients V. DISORDERS OF MYELIN: Refer to
with acute HIV-l infection 24% have an asep- CD ROM. See also Chapters 9 and 13.
tic meningitis. Figures 27-28 and 27-29 demonstrate cases
with clinical involvement of the cerebral
Other infections of the nervous system hemispheres.
(spirochetes, fungi, protozoa, and tubercu-
losis ) will be considered on the CD ROM.
IV. SYSTEM DISORDERS: The fol-

lowing section is included in detail on the CD
ROM and in general medical texts. The fol-
lowing subsections are included:
A. Degenerations: These disorders are
considered in the chapters on muscle, periph-
eral nerve, spinal cord, basal ganglia, cerebel-
1 These percentages vary markedly in different

geographic areas and in different population
groups. Heterosexual cases are increasing
significantly among drug users or their contacts
and in Africa, South America and Southeast
Asia. New cases among homosexual males are
decreasing.
TABLE 27-8:NUTRITIONAL AND RELATED DISORDERS OF
THE NERVOUS SYSTEM*
STRUCTURES VITAMIN (S) MANIFESTATIONS

INVOLVED DEFICENT
Cerebral -Niacin -Pellagra: dementia,
Cortex dermatitis, diarrhea
-Pyridoxine -Seizures (possibly of
hippocampal origin)
-B12 -Dementia
Corpus Specific unknown, Marchiafava -Blgnami

callosum possibly toxic, disease: dementia and
described in~lally apraxia. May be seen
w~h excess of In pafients who also
Italian red wine. have Wemicke-
Possible role of Korsakoff syndrome.
thiamine.
Diencephalon -Thiamine Wemicke-Korsakoff

and bralnstem syndrome (Ch. 30)
and
cerebellum-
Periventrlcular
Pons Specific unclear Central pontine

but does follow too myelinolysis. Patient
rapid correction Is mute, spastic and
of hypo-nafremia akinetic (Chapter 13) Figure 27-28. Multiple sclerosis: cerebral involvement.
A) Severe involvement of the cerebral white matter hRS
Cerebellum Thiamine or Alcoholic cerebellar occurred, with multifocal gray sclerotic lesions RS well
multiple B degenerafion (Ch. 20) RSlarge confluent lesions in a periventricular loca-
tion. The large confluent lesions and the relative spar-
Spinal cord B12 Combined system ing of the arcuate fibers is reminiscent of Schilder's
disease (Ch.9) diffuse sclerosis. Destruction ofaxons, RS well RS of
myelin, hRS occurred in the larger lesions. This patient
Peripheral Thiamine, or Nutritional mixed
had the onset of multiple sclerosis at age 26 and had a
nerves pyridoxine or sensory neuropathy
B12 or or with thiamine progressive course so that by age 30, the patient WRS
multiple B beri-beri. essentially bedridden with paralysis of all four extrem-
ities, marked impairment of vision, and marked
OptiC nerves Thiamine, B12, Optic neuropathy internuelear ophthalmoplegia, and by age 33 had a
riboflavin (retrobulbar neuropathy severe dementia. B) A more typical area of demyelina-
usually bilaferal) tion in the periventricular subcortical white matter is
demonstrated in this coronal section from another case
• Muscle may also be Involved In an alcoholic myopathy-specific of multiple sclerosis. (Courtesy ofDr. John Hills).
unknown but multiple B suspected.
• In Infants and children denciencies of proteins and fat may
retard development of nervous system.
27-34 CHAPTER 27
TABLE 27-9: EFFECTS OF HEAVY METALS ON THE NERVOUS SYSTEM
METAL ACUTE AND HIGH LEVEL CHRONIC LOW LEVEL

Lead Encephalopathy: ocute In adults: motor peripheral neuropathy
cerebral edema In children long term retardation of
cogniflve function/Intelligence quotient
Inorganic mercury Acute gastrointestinal, renal and Cerebellar degeneraflon and the 'mad hailer
hemafologic effects syndrome': demenfla and psychosis
Organic mercury Blindness, cerebral, cerebellar, pyramidal,

and anterior hom cell degenerafion primarily
affecting fetus infants and children
(Minimafa Bay in Japan etc)
Arsenic Acute hemorrhagic encephalopathy Peripheral neuropathy: sensory/motor
Copper Hepafolenticular degenerafion: Wilson's

Disease -genetiC defect- (Chap. 19)
Manganese Parkinson's disease
Figure 27-29. Multiple sclerosis. MRI scans. This 38 year old white female bank employee had a 15 year history of
relapsing-remitting secondarily progressive multiple sclerosis initially affecting spinal cord lJJermitte's sign), then
optic nerves ,then cerebellum and cognitive function. CSF indicated an IgG index of2.42 (normal 0.45 + 0.1) with
3 oligoclonal bands (normal < 1). In the 5 years following this MRI, she developed dementia and a bedridden state.
A) T1 sagitf41 section. B) 12 horizontal section.
CHAPTER 28
Problem Solving: Part IV
Diseases of the Cerebral Hemispheres
LESION DIAGRAMS: For each of the fol-

lowing diagrams indicate the structures
involved by the cross hatched lesion. For each
structure involved, indicate the expected clini-
cal symptoms or signs with appropriate lateral-
ization. Where appropriate, indicate the vascu-
lar territory involved or the designation of the
most likely type of pathology. (Diagrams to be
inserted).
Figure 28-3.
Figure 28-1.
Figure 28-4.
Figure 28-2.
Figure 28-5.
28-2 CHAPTER 28
Figure 28-6.
Figure 28-9A
Figure 28-7.
Figure 28-9B
L R
Figure 28-8 Figure 28-9C

CASE HISTORY PROBLEM SOLVING PART IV: CEREBRAL HEMISPHERE 28-3
CASE mSTORY PROBLEM SOLVING 3. Motor system:
PART IV: CEREBRAL HEMISPHERES There was minor weakness of the left arm and
These cases represent the gamut of disease left leg with an increase in tone in the left arm
affecting the cerebral hemispheres. The and left leg (minor spasticity).
pathology represented may be tumor, infarc- 4. Reflexes:
tion or hemorrhage. Some of the lesions are a. Deep tendon reflexes were everywhere
intrinsic; others are extrinsic. The nature of the increased on the left side.
pathology may be uncertain; the location of b. Plantar responses were extensor bilateral-
the pathology, however, should be evident to ly but much more prominently so on the left.
you. 5. Sensory system: No definite abnormalities
Diagram each lesion. If the etiology appears were present.
to be vascular, attempt to identify the vessel 6. Head & Neck:
involved.
a. There was resistance to flexion at neck.
Case 28-1: This 53-year-old, right-handed,
b. No bruits were present over neck, orbits
white housewife had experienced intermittent
and head.
right-sided headaches and retro-orbital pain
QUESTION:
for approximately 2 months. Five days prior to
admission to the neurological center, the What is the most likely clinical diagnosis at this
patient awoke from a sound sleep at 7:00 a.m. point?
complaining of the most severe headache she LABORATORY DATA:
had ever experience. "It felt like something
bursting inside my head". This was accompa- 1. Skull and chest X -rays were normal.
nied by nausea and vomiting. Patient was 2. Lumbar puncture:
admitted to her local community hospital. a. Opening pressure was 300 mm of CSF;
Two days prior to transfer to the neurological closing pressure was 150 mm ofCSF.
center the patient reported ptosis and diplop- b. The fluid was grossly bloody. First tube
ia. Severe headaches persisted, requiring the demonstrated 55,000 red blood cells per cubic
administration of meperidine hydrochloride millimeter and 60 white blood cells per cubic
(Demerol hydrochloride). millimeter. Third tube demonstrated 72,000
red blood cells per cubic millimeter.
NEUROLOGIC EXAMINATION
c. The CSF protein was 84 mg/IOO mI.
The patient was a well-developed white female The spinal fluid sugar was 60-mg/100 mI with
with blood pressure of 160/90. Cardiac a simultaneous blood sugar of90-mg/100 mI.
status was normal.
1. Mental status: The patient was lethargic but HOSPITAL COURSE:
easily aroused. When aroused, she then The patient remained relatively stable and alert
responded with alert, appropriate until definitive procedures were performed.
responses. QUESTIONS:
2. Cranial nerves: 1. Based on the symptoms and signs in this
a. The right pupil was dilated and sluggish case what is your diagnosis?
in response to direct or consensual stimulation 2. How do you interpret the results of the
with light. The left pupil was of normal size. lumbar puncture?
Ptosis of the right lid was present. There was 3. If you had seen this patient in the emer-
partial weakness of right medial rectus, inferior gency room directly at the onset of symp-
rectus, and inferior oblique and superior toms, which study would you have
rectus. obtained? Would the lumbar puncture have
b. All other cranial nerves were intact. been your initial study?
28-4 CHAPTER 28
4. Where is the basic pathologic lesion locat- days later, the patient experienced another
ed? Be specific. transient episode of weakness and numbness
5. Indicate the single most definitive diagnos- involving the left arm. Approximately four
tic procedure that should be performed in weeks later definitive diagnostic studies were
this case prior to definitive therapy. When performed.
should this be performed? QUESTIONS:
6. Define definitive therapy in this case. When 1. What is the most likely diagnosis?
should this therapeutic procedure be per- 2. Outline your approach to effective manage-
formed? ment.
7. Discuss the complications of this disorder. 3. Which non-invasive studies would you
8. Discuss prognosis of this clinical problem. obtain and when would you obtain those
studies?
Case 28-2: This 56-year-old right-handed 4. You have obtained these studies and the
white male truck driver, on the day prior to results confirm your clinical diagnosis.
admission, had the sudden onset of a transient Which physician would you now consult?
monocular blindness involving the right eye. 5. Which surgical procedure would now be
On the morning of admission the patient appropriate?
developed a weak, numb and useless left arm. 6. Indicate the classical definition of a transient
These symptoms had shown considerable ischemic attack (TIA). Now indicate the
improvement by the time of his initial admis- more modern operational definition that
sion that afternoon. takes account of new developments in the
PAST mSTORY: acute treatment of ischemic stroke. What is
the definition of the term reversible
1. The patient smoked two packs of ciga- ischemic neurological deficit (RIND)?
rettes/day. What is the definition of the term complet-
2. Occasional symptoms of intermittent clau- ed stroke? What is the meaning of the term
dication had been present. stroke in evolution?
PHYSICAL EXAMINATION: Case 28-3: This 32-year-old white male was
1. Blood pressure was 150/80; pulse was 100 admitted to the hospital because of severe
and regular. headache, confusion and aphasia. The patient
2. Bruits were present over the right carotid, had been in good health except for frequent
left subclavian, and both femoral arteries. headaches for the 10 years prior to admission.
3. Posterior tibial pulses were absent. Six days prior to admission at approximately
4. There were no cardiac murmurs. 2:00 p.m., the patient returned from a hunt-
ing trip, and went into the bathroom. His wife
NEUROWGIC EXAMINATION: heard a noise, a thud, as though the patient
1. Mental status: Intact. had fallen to the floor. She found the patient
2. Cranial nerves: Intact. lying on the floor, moaning and groaning, as if
in pain. The patient showed evidence of sig-
3. Motor system: There was minor weakness
nificant confusion; he was, however, moving
and incoordination of the left hand.
all his extremities and she surmised that he had
4. Reflexes: Intact.
no actual paralysis. The patient was admitted
5. Sensory system: Intact. to his local hospital, where a lumbar puncture
SUBSEQUENT COURSE: demonstrated the presence of blood in the
spinal fluid. Over the next few days, the
Six days later, the patient had a focal motor patient complained more and more of
seizure involving his left arm. Twenty-three
headaches, became more and more agitated, movement at the shoulder and elbow. The
and increasingly restless. He was subsequent- patient continued drowsy and intermittently
ly transferred to a neurosurgical center. agitated. Some observers felt that the patient
now had a slightly larger pupil on the left side
GENERAL PHYSICAL than on the right. Specific diagnostic and
EXAMINATION: therapeutic procedures were performed.
There were no remarkable features. Blood QUESTIONS:
pressure was 125/70. 1. Indicate the original pathology and location
of pathology.
2. Indicate the complications of this pathology
1. Mental status: that occurred prior to surgery and within 2
a. Patient was oriented for time and place weeks of the initial episode.
b. The patient was sleepy but agitated when 3. Indicate the specific diagnostic procedures
roused from sleep that were performed to localize the lesion
c. The patient had difficulty with word prior to surgery.
selection and would not cooperate in repeat- 4. What primary indications for surgery were
ing simple words or identifying simple objects present in this case?
d. The patient often spoke words that were When should surgery be undertaken? Which
unrelated to questions he had been asked or to surgical procedure should be performed?
the conversation.
2. Cranial nerves: SUBSEQUENT COURSE:
a. A minor right visual field defect was sug- The patient then underwent a surgical proce-
gested dure 12 days after the initial episode.
b. A right central facial weakness was pre- Postoperatively the patient had a marked right
sent hemiplegia, with increase in the degree of
3. Motor system: A minor weakness of the right aphasia. This was a mixed type of aphasia;
upper extremity was present. When when the patient did speak, he used jargon and
outstretched, the right hand rapidly fell down- he also appeared unable to understand lan-
ward. guage.
4. Reflexes: Eleven days postoperatively, the patient devel-
a. Deep tendon reflexes were symmetric. oped fever ofl04° and a recurrence of nuchal
rigidity. Spinal fluid examination now indicat-
b. Plantar response was extensor on the
ed 1200 white blood cells (92% polymor-
right, flexor on the left
phonuclear); spinal fluid sugar was 50-
5. Sensory system: All modalities were intact.
mg/100 mI with blood sugar ofl30-mg/100
6. Neck: Marked nuchal rigidity was present. mI. Specific treatment was administered.
The patient complained of severe pain on neck
QUESTIONS:
motion.
5. Indicate the diagnosis that explains this
HOSPITAL COURSE: complication of fever and nuchal rigidity.
Be as specific as possible in terms of the
Over the next four hospital days, the patient
agent producing fever.
developed increasing expressive aphasia,
increasing right central facial weakness and 6. How would you treat this complication?
increasing weakness of right upper extremity.
SUBSEQUENT COURSE
The degree of right upper extremity weakness
was now marked, with total paresis of move- At the time of discharge, the patient was alert
ments of right hand and partial paresis of and oriented, but had a significant expressive
aphasia and a moderate hemiparesis (arm
28-6 CHAPTER 28
greater than leg) in addition to a right central and Dr. Huntington Porter): This 73 year old
facial weakness. Four months after the initial right handed white businessman from Maine
episode, the patient had a generalized convul- was involved in an auto accident approximate-
sive seizure. Two to three weeks later, he had ly 10 days prior to admission, in which his auto
a focal seizure characterized by clonic move- was struck by a heavy logging truck. The
ments of right upper extremity. One year after patient walked away from his car but was
the initial episode, patient had focal seizures dazed and amnestic for the events of the next
consisting of clonic contraction of the right 15 minutes. This condition however then
face accompanied by arrest of speech. These cleared. At the emergency room of his local
seizures were preceded by a sensation of tight- hospital skull x-rays were normal and the
ness in the face. Twenty-one months later, the patient was found to have no significant
patient was reported as having frequent focal injuries except for ecchymosis about the right
seizures characterized by numbness of the eye and knee. The patient subsequently how-
right hand and face, followed by transient ever did note a steady bilateral frontal tempo-
paralysis of the right lower extremity. Follow- ral headache, which would on occasion awak-
up 33 months after that indicated several en him from sleep and which gradually,
minor seizures every day involving numbness became worse. Five days prior to admission,
of the right hand and perioral area of face. some fogginess in thinking was noted and the
Neurologic examination almost 6 years after patient's family reported some personality
the initial episode, indicated the following sig- change. The patient reported some weakness
nificant residual deficits: of both legs in getting out of a bathtub per-
1. Hesitancy in speech with mild expressive haps somewhat greater on the right side. Two
aphasia and a more significant nom ina I days prior to admission, the patient was noted
aphasia. In addition, left right confusion to be sleeping longer. On the day of admis-
was present. sion, the patient and his physician noted a
more persistent left sided weakness. The
2. Right upper quadrantanopia.
patient was admitted to the neurology service.
3. Mild right central facial weakness.
4. Minimal weakness, right upper extremity in PAST mSTORY:
a right-handed man. Hyperthyroidism had been under treatment
5. Deep tendon reflexes were increased on the for three years. Three years prior to admission,
right side with a right extensor plantar the patient had been evaluated for a minor
response. episode of dizziness, which had occurred in
The patient was treated with specific medica- relation to bradycardia and a transient fall in
tions resulting in a reduction of the frequency blood pressure. The neurological consultant at
of his focal seizures. that time had noted a totally normal examina-
QUESTIONS: tion .The right carotid pulse however was
7. In the years following surgery, the patient noted to be decreased compared to the left.
had focal sensory and motor seizures
NEUROLOGIC EXAMINATION
involving hand and face. Indicate the med-
(day of admission):
ications to be used in the treatment of these
episodes. 1. Mental status: The patient was alert, well
8. The patient also had secondarily generalized oriented in all three spheres with an excel-
seizures in the post-operative years. lent knowledge of current events. He could
Indicate the recommended medical treat- remember 4/5 objects in 5 minutes. His
ment. digit span was 8 forward and 5 in reverse.
2. Cranial nerves: All were intact except for a
Case 28-4 (patient of Dr. George Robertson questionable left central facial weakness.
3. Motor system: hip. The patient became increasingly more
a. There was a significant decrease in lethargic. Thirty hours after admission, the
strength predominantly distal in the left leg. right pupil was found to be sluggish in
To a lesser degree, a mild weakness of the left response to light. The pupils which had been
upper extremity was present. previously symmetrical were now asymmetri-
b. The patient dragged the left leg in cal, the right measured 3.5 mm, the left 2.5
walking. mm. An emergency carotid arteriogram was
4. Reflexes: Deep tendon stretch reflexes were performed. Based on that study, a surgical pro-
increased bilaterally in a symmetrical man- cedure was immediately undertaken by the
ner. Plantar responses were flexor. neurosurgeon, Dr. Bertram Selverstone.
5. Sensory system: All modalities were intact The patient made a rapid recovery.
Examination, 10 hours after surgery, demon-
6. Carotids: The right carotid pulse was
strated an alert and well-oriented patient who
decreased as previously but no bruits were
was able to lift his leg off the bed and had only
present.
a minimal weakness in the left upper extremi-
QUESTIONS: ty. Pupils were now equal. The deep tendon
reflexes were now symmetrical and the plantar
1. It is an often quoted axiom in neurology
responses were now flexor. At the time of hos-
that 75% of neurological diagnosis is based
pital discharge, 13 days following surgery, the
on the history. This patient was seen before
neurological examination was now normal.
the era of the CT scan and yet the most like-
ly diagnosis was clear. What is your diagno- QUESTIONS:
sis as regards location of the lesion and the 6. What change if any would you now make in
nature of the pathology? Be specific. your diagnosis?
2. Is the apparent decrease on palpation of the 7. Which complication of the original disorder
right carotid pulse of any significancd has now occurred?
3. How would you evaluate this patient at this 8. How would you manage that complication?
point in time utilizing current technology? 9. What did the carotid arteriogram demon-
4. An EEG was performed demonstrating strate?
focal 3-5 Hz slow wave activity. Predict the 10. Which diagnostic procedure would you
location of that abnormality. perform today? Describe the expected
5. The patient had some transient symptoms results of that study?
after the initial trauma; he was dazed and 11. Which surgical procedure was performed?
amnestic for a short period of time. What Describe the most likely surgical findings.
term is applied to those symptoms?
Case 28-5: This 62-year-old white right-
HOSPITAL COURSE:
handed male research associate, 18 months
A progressive change in neurological status prior to admission, had the onset of focal
was soon evident. Twenty-four hours after motor seizures, which would begin in the left
admission, the patient was found to be inter- side of the tongue, and then spread to the face,
mittently lethargic, if roused, he was able to shoulder, arm, and hand.
answer questions but it was evident that he was At the same time, he would note spread of tin-
disoriented for time. In addition deep tendon gling paraesthesias over the same parts of the
reflexes were now increased on the left side, left side of the tongue, face, and hand.
and a left Babinski sign was now present. Later Neurologic examination at that time was not
that day, increasing weakness of the left arm remarkable.
and leg developed. The patient was unable to
Anti-convulsant medication produced a signif-
raise the arm at the shoulder or the leg at the
28-8 CHAPTER 28
icant reduction in focal seizures. However, 1 sion and angina pectoris had the acute onset of
month prior to admission, the patient had a a right-sided weakness while at work. She had
focal seizure that was followed by transient no change in consciousness, no sensory symp-
residual weakness of left face and hand. toms, no impairment oflanguage function and
Three weeks prior to admission, a minor no headache. She had experienced no vertigo,
degree of weakness of the left hand developed. no diplopia, no vomiting and no visual symp-
This progressed in degree and also began to toms. She had no complaints of chest pain or
involve the left leg and left side of face, as well. of shortness of breath.
Two weeks prior to admission, right-sided
PHYSICAL EXAMINATION:
headache developed.
Blood pressure was elevated to 180/120
NEUROLOGIC EXAM:
1. Mental Status: Intact
2. Cranial Nerves: Intact except for a severe 1. Mental status: This was entirely intact, with
left central facial weakness. no evidence of aphasia.
3. Motor System: 2. Cranial nerves: A marked right central facial
weakness was present with minimal devia-
a. Weakness of the left hand was present,
tion of the tongue to the right.
with thumb opposition most severely
involved. Minor weakness was present in the 3. Motor system: A dense right hemiparesis was
left lower extremity. present.
b. In walking, the patient dragged the left 4. Reflexes:
lower extremity to a minor degree. a. Deep tendon reflexes were increased on
4. Reflexes: the right.
a. Deep tendon reflexes were increased on b. The plantar response was extensor on the
the left. right (sign of Babinski).
b. Instinctive grasp reflex was present on the 5. Sensory system: All modalities were intact.
left.
LABORATORY DATA:
5. Sensory System:
Assume the EKG was not relevant and the
a. Graphesthesia was decreased over left face
cerebrospinal fluid studies were normal.
and hand.
b. Tactile localization and two-point discrimi- HOSPITAL COURSE:
nation were decreased over the left hand. The patient was stable and alert during the
QUESTIONS: next 2 days and at her request, was transferred
1. Where is the lesion? Be specific. to her local hospital.
2. In terms of the pathological diagnosis, list QUESTIONS:
the three most likely possibilities. 1. What is the most likely diagnosis? How
3. Indicate the most definitive laboratory test would you confirm the diagnosis?
for establishing the diagnosis and the 2. Contrast Case #1: Assume that this patient
expected findings. presented with a I-month history of 5 tran-
4. Indicate the other studies that would be sient episodes of numbness and weakness of
useful and the expected findings. the right hand. In addition, the patient had
5. Indicate a plan of management for each of experienced two or three episodes of sud-
the possible diagnoses. den transient blindness of the left eye. Then
on the morning of admission, she awoke
Case 28-6: This 58-year-old white right- with numbness and weakness of the right
handed female with a past history of hyperten- hand and arm, with increased deep stretch
reflexes at the right biceps, triceps, patellar recommended. An alternate course of
and Achilles tendons and a right sign of action is followed. No significant change
Babinski on plantar stimulation. You also occurred over the next 10 days except for
find errors in position sense and in graphes- transient lethargy and the minimal return of
thesia involving the right fingers and hand. deep tendon reflexes. Discuss these issues.
The patient has moderate but incomplete 6. Why were the deep tendon reflexes acutely
recovery over the next week. At no time depressed on the side of the hemiparesis?
does the patient complain of headache.
What is your conclusion as to the most like- Case 28-7: This 14-year-old right-handed
ly diagnosis? How do you establish the white female was admitted with a chief com-
diagnosis and manage the case? plaint of "draining left ear" and left frontal
3. Contrast Case #2: Assume that this patient headache. Approximately 4 weeks prior to
has a history of rheumatic heart disease with admission, the patient had the onset of pro-
mitral stenosis and atrial fibrillation. The gressive pain in the left ear accompanied by
patient suddenly, while at work at 11:00 fever up to 104 degrees F. Four days later a
a.m., stopped speaking in mid-sentence fall discharge from the left ear developed. Three
to the floor with a focal seizure involving days later a total left sided facial paralysis devel-
the right side, with subsequent generaliza- oped. The patient was evaluated at the
tion. On recovery from the post-ictal con- Massachusetts Eye and Ear infirmary where
fusion, the patient is found to manifest: drainage of the left middle ear was performed
1. Mental status: Patient appears alert but has yielding purulent material. Culture of this
a dense global aphasia. drainage revealed Staphylococcus aureus .the
2. Cranial nerves: patient was treated with antibiotics with a
a. A dense right homonymous hemianopsia. complete resolution of symptoms. However
one week prior to admission, the patient devel-
b. Deviation of head and eyes to the left.
oped a constant severe left frontal headache
c. A dense right central facial weakness.
with swelling about the left eye. There was
3. Motor system: A dense flaccid right hemi- now a recurrence of discharge of a thick green
paresis purulent material from the left ear. Two days
4. Reflexes: prior to admission, the patient developed con-
a. A depression of the deep tendon reflexes fusion and delirium. She was also noted to
at the right arm and right leg. have marked difficulties in language function
b. A right Babinski sign. and in calculations.
5. Sensory system: Absence of all sensory
GENERAL PHYSICAL
modalities on the right side.
EXAMINATION:
Assume that the initial CT scan at one hour
after onset of symptoms is interpreted as nor- Temperature was normal at 98.6 degrees F.
mal and that the cerebrospinal fluid is clear The patient appeared chronically ill. Gauze
with no cells. soaked with purulent drainage was present in
the left external auditory canal.
QUESTIONS:
4. After seeing this patient at 12 noon in the
emergency room, what conclusions do you 1. Mental status:
reach as to diagnosis and what course of a. The patient was oriented for the day and
action do you recommend? year but not for the month. There was consid-
5. Unfortunately, the patient is found to have erable confusion as to past and recent events.
contraindications to the therapy, which you b. She had a marked deficit in naming
objects. Even when the name of the object was
28-10 CHAPTER 28
supplied in a multiple-choice scenario, she was hemispheric 2 -3 Hz slow wave activity.

unable to recognize the correct name. QUESTIONS:
Paraphrasing was evident. She was able to 5. Do you wish to alter your diagnosis or
carry out spoken commands. Simple writing diagnostic approach?
and spelling were intact but reading of isolat- 6. Outline your approach to therapy. Which
ed words was defective. She had no left-right categories of physicians would you consult?
confusion. She was able to identifY and to
point out the various parts of her body with SUBSEQUENT COURSE:
the exception of the thumb. Dr. Daniel Miller of the ENf service per-
c. At times, the patient acted in a "silly" formed a left mastoidectomy and epidural
manner and would giggle inappropriately in exploration. Pus was present in the softened
response to questions mastoid cells. Purulent granulation tissue
2. Cranial nerves: extended into the adjacent epidural space.
a. Fundoscopy demonstrated papilledema Cultures were obtained and antibiotics were re
with elevation of the disk on the right. A instituted. Over the next 4 day improvement
recent hemorrhage was present just below the occurred in the clinical and EEG findings but
disk of the right eye. then findings worsened. Dr. Sam Brendler of
b. A minor peripheral left facial weakness the neurosurgical service then performed
was present, most prominent in frontalis mus- more definitive procedures. Following surgery,
cle. the patient had a nominal aphasia and a non-
c. Hearing was decreased on the left. congruous right visual field deficit with some
3. Motor system: Strength, gait and cerebellar sparing of the inferior quadrant. The patient
functions were intact. had a single generalized convulsive seizure, 6
years after surgery and anti convulsants were
4. Reflexes: Deep tendon reflexes were intact.
instituted. At that point in time, the nominal
The right plantar response was equivocal;
aphasia had shown marked improvement; she
the left was flexor.
hesitated and stumbled over words. The right
5. Sensory system: All modalities were intact.
visual field defect was unchanged.
QUESTIONS: QUESTIONS:
1. What is your diagnosis as regards localiza- 7. Which procedures were performed by the
tion and pathology? neurosurgeon?
2. What laboratory studies would you request? 8. Explain the visual field deficits.
3. Would you perform a lumbar puncture on
this patient? JustifY your answer. Case 28- 8: This 29 year old right-handed sin-
4. What is your explanation for the left periph- gle white female schoolteacher was about to
eral facial weakness? testifY in court in the late afternoon on the day
of admission, when she suddenly dropped to
LABORATORY DATA: the floor. She began to babble but did not lose
1. White blood count and differential were consciousness. She was taken to the emer-
normal. gency room of the local hospital at 4:15 p.m.,
2. Skull and mastoid X-rays indicated an acute where she was initially described as "confused,
mastoiditis on the left with an increased disoriented, unresponsive to questions, and
density throughout the left mastoid extend- not verbalizing". At 7:50 p.m., she was subse-
ing throughout the medial aspect of the quently described as agitated with garbled
petrous ridge. speech. Later that evening, she was transferred
3. EEG was abnormal because of focal and to this hospital.
PAST ruSTORY: HOSPITAL COURSE:
Patient was receiving birth control pills. By 48 hours after onset, speech had shown
some improvement. The patient was using
GENERAL PHYSICAL more recognizable words. Occasional appro-
EXAMINATION: priate two-word phrases were employed. The
1. Blood pressure 120/70. dense right hemiparesis had persisted but the
Pulse 90 and regular right homonymous field cut and the sensory
2. No heart murmurs were present. pain deficit were no longer present. By 72
3. No bruits were present over the carotid hours after onset, slight movement was pre-
arteries and carotid pulses were strong. sent in right lower extremity. However at 5
4. Neck was supple with no nuchal rigidity. days after onset, the patient had the sudden
development of a cold, pulseless left arm.
NEUROLOGICAL EXAMINATION: QUESTIONS
1. Mental Status: The patient was anxious and 1. Localize the lesion.
alert with intermittent agitation. She appeared 2. Characterize the speech deficit at various
to understand but only intermittently followed stages. Did this patient have a dysarthria or
verbal commands. She used only a few words. aphasia? If aphasia was present was this pri-
She attempted to name objects but produced marily a fluent or non fluent.
only paraphasia and jargon speech. 3. Discuss the use of the term "confusion".
2. Cranial Nerves: Discuss the use of the term "babbling".
a. A right homonymous hemianopsia was 4. Discuss the pathology and likely etiology
present and pathophysiology. If vascular indicate
b. There was decreased pain and touch over the vascular territory.
the right side of the face. 5. What other information would you wish to
c. A right central facial weakness was have?
present. 6. This patient was seen before the era of the
3. Motor System: A dense right hemiplegia was CT scan. Assume that this patient had
present. arrived in the emergency room today 30
4. Reflexes: minutes after the acute events, and you are
a. Deep tendon stretch reflexes were the emergency room physician or the con-
increased in the right upper and lower extrem- sulting neurologist how would you manage
ities with clonus at the right patellar and this problem.
Achilles tendon reflexes.
b. The plantar response was extensor on
right and flexor on left.
5. Sensory System: An apparent right hemisen-
sory deficit was present to all modalities.
LABORATORY DATA:
1. CSF pressure was normal at 160, with clear
fluid (cells = 0, protein =llmg'lAl, sugar =
75mg% with blood sugar ofl04).
2. Skull X-rays were normal.
3. EKG - normal.
CHAPTER 29
Alterations in Consciousness:
Seizures, Coma and Sleep
BASIC DEFINITIONS decrease in cerebral perfusion. This decrease in

Consciousness: The waking state in which perfusion may be due to a general peripheral
the individual has awareness, with " the ability vasodilation (vasovagal reaction) or hypoten-
to perceive, interact and communicate with the sion or a decrease in cardiac output. The loss of
environment and others in the integrated man- consciousness almost always occurs when the
ner which wakefulness normally implies" patient is in an upright position. The actual loss
(Zeman, 2001). of consciousness is preceded by prodromal
Sleep: A normal periodic alteration in con- symptoms that last from seconds to minutes:
sciousness with various stages. Sleep is an active light-headedness, weakness, "dizziness",
physiologic process dependent on a complex sweating and blurring and dimming of vision.
interaction of cerebral cortex, hypothalamic The patient is observed to slump limply to the
and brain stem areas. Metabolic activities such around (as opposed to the patient with epilep-
as oxygen use remain normal. The level of con- sy who usually stiffens and then falls violently
sciousness may be fully restored by an appro- to the around). Tonic or clonic movements are
priate stimulus rare but may occur. The period of uncon-
Sleep disorders: This term includes such sciousness is brief, usually a matter of seconds,
major disorders as insomnia, hyposomnia, nar- occasionally a minute. During this time, the
colepsy and sleep apnea as well as sleep walking patient is noted to be pale and sweaty. The
(somnambulism) and abnormal movements pulse is usually weak and the blood pressure
during sleep. often reduced. The return to consciousness is
Abnonnalities of consciousness: occur in rapid occurring usually when the patient
a brief paroxysmal manner in seizures and syn- assumes a recumbent position. There is no sig-
cope and in a more prolonged manner in nificant period of mental confusion following
coma. the episode
Seizure: A sudden (paroxysmal) alteration Coma: an abnormal state in which various
in behavior due to an excessive discharge of degrees of prolonged alteration of conscious-
cerebral cortical neurons .The alteration in ness occur. In contrast to sleep, coma is a pas-
behavior may be limited or may result in a gen- sive process in which a loss of function has
eralized convulsive seizure. The state of con- occurred. Metabolic activities are depressed.
sciousness may be unaffected, may be altered Stimulation will not restore a full and persistent
or may be lost. Seizures represent an alteration state of consciousness. Various gradations of
in the usual balance between excitation and coma exist. In describing the degree of coma,
inhibition. Seizures and epilepsy are most fre- it is best to use operational terms describing
quent in the infant and in the elderly. brain stem reflexes, response to stimuli etc. The
Epilepsy: A chronic condition in which Glasgow coma scale provides such an
seizures recur at variable frequency over time. approach. Various terms continue in use , in
The period of seizure activity is termed the deep coma the responses to stimuli are com-
ictus or ictal event. The time between seizures pletely lost. In moderately deep coma, rudi-
is termed the interictal period mentary responses of a reflex nature only are
Syncope: a condition in which conscious- present (e.g.. corneal reflex. withdrawal of a
ness and usually posture are briefly impaired in limb to painful stimulus), but psychologically
a relatively sudden, manner due to a general Wlderstandable responses to external stimuli
29-2 CHAPTER 29
and inner need are absent. Various terms have distinguish several other conditions: acute mas-
been employed to describe lesser degrees of sive infarct of the dominant hemisphere may be
impairment of consciousness: semicoma, mute and hemiparetic. (3) in late Parkinson's
stupor, obtundation or lethargy disease marked rigidity, akinesia and mutism
Confusion: an abnormal state character- my be present but the patient is alert. (4) a sim-
ized by an impaired capacity to think clearly ilar state may follow bilateral destruction of the
and with customary speed to perceived stimuli putamen or globus pallidus (apallic state).
and to remember current stimuli. Confusion Refer to Segarra (1970).
includes disorientation and memory impair- Locked in syndrome (pseudo akinetic
ment. In addition to confusion associated with mutism or pseudocoma): a state in which the
an altered state of consciousness, confusion patient is aware and conscious but because of
may also occur with an alert state in patients paramedian pontine infarction usually related
with dementia (chapter 30) to thrombosis of the basilar artery, is unable to
Delirium: an abnormal state in which agi- provide verbal responses. When the midbrain is
tation (of motor activity) is present in addition intact, the patient may provide responses by
to confusion. opening or closing the eyes or by vertical eye
Akinetic mutism: a state in which the movements.
patient lies in bed with eyes open but fails to Brain death: Up until the late 1960s,
move or to speak. There are two types. (1) In patients were declared dead when cardiac (and
the mesencephalic/diencephalic variety, usual- respiratory) activity ceased. With the cessation
ly due to occlusion of a penetrating branch of of cardiac respiratory activity, neurological
the posterior cerebral artery or of the proximal function ceased within 3-4 minutes. With the
/mesencephalic artery segment of the parame- development of cardiopulmonary resuscitation
dian branch at the top of the basilar artery and of life support equipment, an era dawned
bifurcation, there is a state of apathetic or som- in which cardiorespiratory function might be
nolent akinetic mutism in which the patient continued or restored but function of the brain
remains in a lethargic state most of the time. could not be restored. Thus, the advance of
The patient may open his eyes in response to technology required an expansion of the prior
strong stimulation but soon closes them and definition of death to include brain death. In
returns to a lethargic state. Paralysis of vertical most jurisdictions, either by legislative law or
gaze and of other extraocular movements is by court decision case law, brain death is rec-
usually found. Infarction at the diencephalic- ognized as legal death.
mesencephalic junction is bilateral and includes Brain death is defined by the following cri-
rostral midbrain tegmentum, the adjacent pre- teria:
tectal area, subthalamus, periventricular gray 1. An absence of consciousness.
matter at the posterior end of the third ventri- 2. No cerebral responsivity is present.
cle: midline thalamic nuclei: reticular nucleus 3. No brain stem reflexes are present.
of the thalamus and intralaminar nuclei of the 4. No spontaneous respirations are present.
thalamus (centrum medianum). (2) In the S. If obtained, the EEG will show no
bilateral frontal type of hyperalert akinetic evidence of cortical electrical activity.
mutism (vigilant coma) the patient will follow 6. Spinal cord reflexes may be present.
with intact eye movements and will cycle (alter- 7. The state is irreversible: reversible meta-
nation periods of agitation). The medial, bolic and toxic conditions have been eliminat-
orbital and anterior surfaces of the frontal lobes ed, a sufficient period of time has elapsed and
plus adjacent cingulate gyri or the septal area appropriate studies have been performed to
are involved. Although the patient lies immo- establish a diagnosis.
bile in bed, he provides some suggestions of It is important to note that in those patients
alertness in the sense of appearance. We should who meet the criteria of brain death but where
ALTERATIONS IN CONSCIOUSNESS: SEIZURES, COMA AND SLEEP 29-3
respiratory and blood pressure support is con- (2) for a given age and level of alertness: awake
tinued, cardiac arrest usually occurs within vs. drowsy vs. asleep, the frequency and rhythm
days, rarely in weeks. will fall within certain parameters.
Persistent vegetative state or neocortical All abnormalities of the electroencephalo-
death: this term refers to a state in which neo- gram then will represent deviations from these
cortical death or disconnection has occurred two general rules.
but brain stem reflexes and spontaneous respi-
ration are preserved. Although this condition Type 1 abnormality: termed focal.
had long been recognized within the larger The following sub types may be listed:
group of chronic coma, following cardiac res- a. Focal slow waves correlated with a focal
piratory arrest and trauma, Jennett and Plum cortical dysfunction with the quality of damage
popularized the specific term in 1972. Such (Fig. 2-22 and CD ROM Atlas )
patients have periods of ''wakeful'' eve opening b. Focal spikes and sharp waves correlate
and movement. The EEG is usually isoelectric with a focal dysfunction having the quality of
(or occasionally demonstrates a burst suppres- excessive neuronal discharge that is partial
sion pattern). The major cause of the syn- epilepsy (Fig.29-1). Spikes have a duration of
drome is cardiac pulmonary arrest with subse- less than 75 milliseconds; sharp waves have a
quent resuscitation. There is diffuse damage to duration of the greater than 75 milliseconds.
neocortex and hippocampus. At times, laminar Both are named from their sharply contour-
necrosis is present. The patient may live for rapidly rising slope These abnormalities are not
weeks, months or years. Such patients never to be confused with the spike of the short dura-
regain consciousness. The management of this tion action potential of the axon (a matter of 1-
state and the ethical dilemmas involved in the 2 msec) for they represent summated post
continued care of this patient has been a major synaptic potentials. Single focal spikes may
area of medical and legal controversy. occur in interictal (interseizure) periods with-
out the occurrence of the actual focal seizure.
THE BASIS OF THE In general, the clinical focal seizure is likely to
ELECTROENCEPHALOGRAM: occur when frequent repetitive focal spikes
Review chapter 17 (Cerebral cortex) occur or when the focal spike is followed by an
for a discussion of this subject. after discharge. Any focal seizure may secon-
darily generalize (Fig.29-2) Additional exam-
ABNO~SOFTHEEEG ples of focal spike discharges with specific cor-
AND CORRELATION WITH relation have already been presented. Focal
SEIZURE DISORDERS: Refer to (partial) epilepsy is the predominant seizure
chapter 2 for examples of normal and disorder in those patients with onset of seizures
non-seizure abnormalities. after the age of 15 years and occurs in 45% of
Kershman and Jasper (1941) delineated the patients with seizure onset prior to
two major categories of EEG abnormalities to age 15.
be found in seizure disorders: (1) those find- c. Focal voltage suppression correlates
ings which were focal and (2) those findings with a reduced electrical activity in the tissue
which were bilateral and relatively symmetrical underlying the electrodes for example the pres-
and synchronous. The international classifica- ence of a subdural or intracerebral hematoma,
tion of seizures and of the epilepsies has or massive cerebral infarction (Fig. 2-23).
continued to follow this long established The 2nd type of abnormality is termed
distinction. generalized and the following subtypes are
There are two general rules for the normal recognized:
electroencephalogram (1) the left and right a. Continuous generalized slow wave
hemisphere are relatively similar in appearance activity or dominant activity slower than the
29-4 CHAPTER 29
lA \ r f .\" ,
LA't r- ANt t
NftT-IIW1T
w,o. 1. - POSTT
PM-oee.
~
,... """"'-.........~~~~~~~-:!:.
UltE~"'Ntt L
Figure 29- ]A. Focal spike discharges in the left tem-

porallobe with phase revmal at the left anterior
temporal electrode. Case 22-1-Refor ro text. Left tem-
poralglioma, with frequent clinical seizures origi-
nating in temporal lobe LAT.E =lAteral fronta~
ANT.T. =Anterior tempora~ MID.T. =Mid tempo-
PAIl - ace. ra~ POSI'.T. =Posterior tempora~ PAR. =parieta~
, I
OCc. =occipital. lB. Focal spike discharge in the
~ K P. UI. NIl 332~H
right parasagittal Rolandic area (Cz-C4) in a 28
I •• e.
year old woman with focal seizures beginning with
clonic movements of the left thigh and numbness of
alpha rhythm correlated with a generalized the left leg. Transverse bipolar montage. Case 18-
dysfunction having the quality of damage (Fig. l.Refer ro text. 1C. Focal spike discharges with
2-24,2-25) phase reversal at left mid temporal electrode in a 46
year old man with subarachnoid hemorrhage sec-
b. Generalized rhythmic paroxysmal ondary ro a middle cerebral artery aneurysm, The
electrical discharges correlated with general- patient had focal sensory seizures beginning in the
ized epilepsy: Spike-slow wave complexes, right face rongue or thumb. Case 26-9 on CD ROM
polyspike -slow wave complexes and polyspike
(repetitive fast spike discharges). Depending on cortex and the acute or chronic effects of cor-
the clinical findings, and frequency of dis- tical isolation or deafferentation are being seen.
charge, (e.g. slow I-2hz vs, 2.5-4 Hz vs >4hz Seizures do not arise from an area of total
spike-wave or polyspike-wave complexes), necrosis since dead neurons do not discharge.
these EEG findings may be associated with Surviving neurons must be present (for exam-
idiopathic (primary) generalized or secondary ple at the margin of an infarct or hemorrhage).
generalized epilepsy. As explained below, this The pathological causes of focal (partial)
latter term is to be distinguished from partial seizures are variable, dependent in part on the
epilepsy with secondary generalization. age of the patient and those pathological
c. the generalized burst suppression processes affecting cerebral cortex that are
pattern discussed in chapter 17. common at that particular age (Table 29-1).
d. Generalized suppression of all electri- The incidence of seizures following specific
cal activity correlated with neocortical death pathological processes: Essentially seizures will
or with the deepest stage of anesthesia. occur in approximately 50% of meningiomas
UNDERLYING BASIS OF THE Jow grade gliomas, oligodendrogliomas and
FOCAL SEIZURE AND FOCAL SPIKE brain abscesses involving the cerebral cortex.
DISCHARGE: High-grade gliomas have a lower frequency of
Focal seizures indicate a focal cortical approximately 35%. Seizures will occur in 25%
dysfunction and imply an underlying focal of all cerebral infarcts with a higher %in embol-
cortical pathology. In some cases the actual ic MCA infarcts of 45%. Cortical migration dis-
pathology is in the white matter just below the orders have a significant association with focal
threshold (motor cortex or mesial temporal
areas) rather than an area of high relative
threshold (prefrontal or occipital areas). (Refer
to chapter 17.)
The Epileptic Focus And The Epileptic
Neuron: At times, focal seizures may occur in
acute or subacute relationship to penetrating
head injuries or to the cortical ischemia that
follows a cerebral embolus and such patients
are more likely to have recurrent seizures. In
10 SlC.INfU"IAL
"" II.C.''''''''=-----.J many cases however the spike discharge and
the focal seizure begin as a late effect. It is cus-
Figure 29-2. Generalizati6n from an experimental tomary to distinguish in all cases between the
focal spike discharge in the left suprasylvian area (SS) interictal spike and the ictal discharge. The ictal
of the cat. Aftn'discharge of repetitive spikes occurred discharge accompanies the clinical seizure. The
at the focus with subsequent spread to other recording spike discharge recorded at the surface repre-
areas of the same and contralateral cerebral hemi- sents summated excitatory postsynaptic poten-
spheres. P.S= posterior sigmoid gyrus (sensory cortex);
V. =visual projection area of marginalgyrus. tials. Spike discharges at the cortical surface,
(Calibrations: 1 second and 100 u volts) From Marcus, then, are recorded as predominantly surface
E.M., Watson, C. w., and Goldman, P.L: Arch. Neurol. negative waves. The more recent studies of
15:525, 1966 (AMA). Conners (1998) utilizing isolated columns of
seizure disorders (exact % unclear) possibly horizontal layers of rat neocortex in vitro have
because of aberrant circuits (Duchowney, indicated that the discharges are primarily initi-
2000) Refer to Table 29-2 on CD ROM ated in the large pyramidal neurons of layer
Regional Cortical Variations in the 5.Discharges may then propagate both verti-
Capacity For Seizure Discharge: A given cally and horizontally. Schmidt and Wilder
pathological process is more likely to cause (1968) define the focus as a group of abnormal
seizure discharge if it involves an area of low cells ("epileptic neurons") with certain unique
properties. Engel (1989) has summarized
TABLE 29-1. CAUSE OF PARTIAL SEIZURES: many of the studies utilizing the best-studied
acute model of partial epilepsy: topical applica-
Age Cause tion of penicillin. Similar changes are observed
Within the first Acute birth trauma in chronic models.
48 hours of life - (poor prognosis), (1) In the acute and the chronic focus there
Within the first Birth trauma and congenital malform- are bursting units discharging in a
2 years- ations (e.g .. Porencephalic Cyst) paroxysmal manner at high rates of discharge
up to 1000 Hz with high amplitude paroxys-
From 2 to 10 Yrs. Birth injury and head trauma mal depolarization shifts (PDS) as the intracel-
From 10 to Head trauma and late effects of lular correlate of the bursting unit discharge.
20 years- pathology in Infancy and childhood The PDS corresponds to activation of gluta-
(complex partial seizures), mate-mediated synapses.
(2) In addition abnormally hypersynchro-
From 20 to Head trauma and neoplasms and
50 years- late effects of pathology acquired in nous activity oflarge numbers of adjacent neu-
infancy and childhood (complex rons occurs; the PDSs of most of the neurons
partial seizures), within the focus summate to produce the inter-
ictal spikes recorded at the surface by the EEG.
Over 50 years Tumor and vascular infarcts and
degenerations, (Alzheimer's disease). The PDs are followed by prolonged after
hyperpolarizations (AHPs). The AHP reflects
29-6 CHAPTER 29
activation of calcium and voltage dependent trlx), gliosis, mechanical deformation of neu-
potassium channels in addition to GABA/A ronal processes a progressive loss of dendritic
and GABAjB synapses. These AHPs summate spines, the development of recurrent collateral
to produce the EEG surface recorded slow excitatory synapses and partial loss of afferent
wave that follows the EEG spike discharge, as input (possibly inhibitory) to the neuron.
a spike slow wave complex. Within the hippocampus, neuronal loss and
(3) Neurons in the cerebral cortex sur- gliosis are accompanied by sprouting of mossy
rounding the focus develop large membrane fibers. It is uncertain whether the changes at
hyperpolarization. This "inhibitory surround" the chronic focus in the human focus relates to
limits the spread along the surface from the a decrease in the inhibitory transmitter
focus but also may interfere with normal activ- (GABA) or an increase in the excitatory trans-
ities of those surrounding neurons (Prince and mitter (glutamate). See Ribak 1986,
Wilder (1967). The inhibitory surround is in a McDonald et al, 1991, Selzer &Dichter, 1992
sense built into the columnar organization of Secondary epileptogenesis: Two experi-
the neocortex. mental models involving the chronic focus sug-
As long as discharge is restricted to the pool gest that persistent spread of discharge from a
of neurons within the seizure focus, in general focus may produce persistent alterations in
there are no clinical manifestations. excitability in those cortical and subcortical
When however surround inhibition is sur- areas that are the targets of the propagated dis-
mounted and after-hyperpolarization decreas- charge. These projection areas then eventually
es, propagation to other regions (cortical and take on the capacity for independent genera-
subcortical) occurs and clinical seizure phe- tion of focal or multifocal discharge.
nomena results. The first model was described by Morrell
Propagation from the focus: (1960,1991) - the mirror focus. The second
Propagation of discharge from the focus, model was described shortly afterwards by
occurs via several pathways: (1) short intracor- Goddard (1969) the kindling model. (Refer
tical pathways involving synapses and neurons also to Mayersdorf&Schmidt, 1982 and to
within the adjacent neuropil, (2) long fiber sys- chapter 30).
tems to other cortical areas within the same
cerebral hemisphere, (3) callosal and other MULTIFOCAL ABNORMALITIES
commissural pathways to the contralateral Many traumatic injuries and other patho-
cerebral hemisphere, and (4) descending path- logic processes do not produce limited focal
ways to basal ganglia, thalamus, reticular for- damage. Thus, a blow to the occipital area of
mation of the brain stem, and to the spinal the skull may not only produce injury to the
cord. Obviously, the specific pattern of spread occipital cortex at the site of the blow, but may
will depend on the location of the focus and on also produce contusions of the cortex at a dis-
the anatomical connections or projections tance from the site of injury: the anterior tem-
from the particular cortical area. Refer to chap- poral poles and frontal poles and orbital frontal
ter 18 for additional discussion. It is important surfaces. The end result may be multifocal slow
to realize that any focal spike discharge may waves, implying multifocal damage or multifo-
become secondarily generalized (Fig.29-2). cal spikes, which in turn implies the evolution
From a clinical standpoint, any focal seizure of multifocal areas of excessive neuronal dis-
may become a secondarilygeneralized seizure. charge. Another possible explanation for mul-
Histological changes at the focus: tifocal spikes when a unilateral pathology may
(Babb&Pretorius, 1997) There are multiple be present is discussed above under secondary
changes at the chronic focus: damage to capil- epileptogenesis. Note also that multiple foci
laries, fibroblastic and capillary ingrowth from may interact to produce bilateral discharges as
meningeal adhesions (meningocerebral cica- discussed below.
GENERALIZED EPILEPSY OR GEN- associates (1960) indicated a concordance rate
ERALIZED SEIZURES: for monozygotic twins of 70-100% and for
In the International Classification of the dizygotic twins of 5-15%. Seminal studies by
Epilepsies, this category is defined as those Metrakos and Metrakos (1961) demonstrated
seizures that are generalized from their that the 2.5-3.5 discharge associated with idio-
onset. Other terms that have employed in the pathic epilepsy was inherited as an autosomal
past are essential, nonsymptomatic and crypto- dominant. Other studies have suggested a gen-
genic or idiopathic-but all of these are now eral predisposition gene with other modifYing
used in a somewhat different context. The term genes determining whether and what type of
idiopathic is now used again for this clinical seizures will occur. The specific altered
category. genetic process is unknown, but studies by
In this category of epilepsy and seizures no Janqua and Andermann (1989) suggested sig-
focal origin is evident for the electrical dis- nificant abnormalities of amino acids in the
charge and the clinical, seizure is characterized serum of both patients and first-degree rela-
from its onset by the loss of consciousness and tives-particularly increased levels of the excita-
or by motor manifestations that are bilateral tory amino acid glutamic acid.
and symmetrical. In general, these seizures 5. The seizures are usually very responsive
begin in childhood or adolescence. to medication
This type of electrical abnormality and the 6.The overall course is benign
correlated clinical seizure disorder should be Included within this division are the fol-
contrasted to the focal spike and the focal (or lowing that shortly will be discussed in greater
partial according to the International detail:
Classification) seizure disorder where a focal 1. childhood absence epilepsy (CA)
origin is clearly evident and where total loss of 2. juvenile absence epilepsy (JA)
consciousness is usually not the initial sign of 3. juvenile myoclonic epilepsy OME)
the seizure. Such a distinction becomes a little 4. generalized tonic clonic seizures on
blurry when complex partial seizure, particu- awakening
larly those arising in the frontal lobes are con- 5. isolated generalized tonic clonic seizure
sidered. (GTCS)
Within the overall category of general- 5. benign myoclonic epilepsy of childhood
ized epilepsy or generalized seizures, the B. Secondary or symptomatic
classification has two divisions (A). The generalized epilepsy has the following
major category of: primary generalized or features.
idiopathic epilepsy. (B) secondary or symp- 1. A diffuse or multifocal pathology is
tomatic generalized epilepsy. usually present
A. Primary generalized or idiopathic 2. The neurological examination is
epilepsy has the following features: abnormal
1. No specific underlying gross neu- 3. Mental retardation is present or psycho-
ropathology is present. However as we will dis- logical deterioration develops
cuss below there is now evidence that an 4. The background EEG is abnormal
underlying cortical micro dysgenesis may be 5. There is in some cases a progressive
present. course; deterioration may occur
2. Neurological and psychological - intel- 6. Response to medication is usually poor
lectual status are usually normal 7. A familial genetic background mayor
3. The background EEG activity is relative- may not be present
ly normal for the age Included in this category are the follow-
4. A familial genetic background is often ing syndromes:
present. Early twin studies by Lennox and his 1. The various progressive myoclonic
29-8 CHAPTER 29
epilepsies beginning in infancy, childhood, ties are interrupted. For example, if in the
adolescence and adult life - many due to spe- midst of eating, the patient may stop with his
cific metabolic disorders; lipidosis, lysosomal spoon in mid air. The interruption is relatively
storage diseases and mitochondrial disorders abrupt in onset and relatively abrupt in cessa-
2. Infantile spasms: with the associated tion. The patient's awareness and motor activ-
EEG pattern of hypsarrhythmia (high ampli- ities return promptly at the end of the episode.
tude irregular asynchronous spikes and slow Memory is defective only for the period of the
waves) and often as well a decremental pattern seizure. It is as though the patient, although
resembling burst suppression during sleep physically present, has been absent as regards
(Fig29-3). his higher cortical functions for the brief inter-
3. Lennox Gastaut Syndrome: childhood val of the seizure. In actuality, the impairment
encephalopathy with associated EEG pattern of awareness, the impairment of response
of "slow"(1-2Hz.) spike-slow wave complex- capacity and the impairment of motor activity
es. This syndrome may be a residual of infantile is a relative phenomenon, occurring in variable
spasms. The term "petit mal variant" has been degree. Thus, some patients may be unaware
employed in the past. In addition to atypical of phrases or numbers that are provided as
absence seizures, atonic drop attack seizures, auditory or visual stimuli during the episode.
tonic seizures and generalized tonic/clonic Other patients are aware of these same stimuli
seizures may occur. Multiple foci are often pre- and are able to repeat them during questioning
sent and section of the corpus callosum may at the end of the episode. Some patients are
decrease the interaction of these foci (see able to continue a familiar recitation during the
below). absence seizure. Whether a response to a stim-
ulus occurs during these brief seizures may, in
A. PRlMARYjIDIOPATIllC part, depend on the intensity of the stimulus
GENERALIZED EPILEPSY: and the motivation and past experience of the
MAJOR SYNDROMES: patient. It is the degree of interruption that is
1. Childhood absence epilepsy (CA) that variable. There are minor motor phenomena
usually begins between 5-10 years of age has that may often accompany the seizure: eye
the correlated EEG pattern of generalized rel- opening, eyelid and myoclonus of facial
atively symmetrical and synchronous bursts of extraocular muscles. Automatisms of mouth,
3 Hz (2-1/2- 4 Hz) spike slow wave complex- jaw and hands may also occur. Some minor loss
es (Fig.29-4). The spike components of the of postural tone in the neck muscles may occur,
bursts are most prominent in the frontal- causing the head to fall onto the chest. Usually
Rolandic parasagittal recording areas. In some many attacks occur per day interfering with
cases, the bursts may contain considerable school work. In most patients the attacks may
polyspike-slow wave components, particularly be triggered by hyperventilation.
during drowsiness and sleep. Short bursts of In many families there is strong evidence of
spike slow wave complexes (1-2 seconds) in a genetic (autosomal dominant) predisposition
general, will have only limited or no definite to primary generalized epilepsy-based on EEG
clinical accompaniment. Bursts of 3-30 sec- studies. In such families the genetic predisposi-
onds duration are in general accompanied by tion, is apparently for idiopathic epilepsy and
some interruption of consciousness. The not absence seizures per se. There is a predom-
absence seizure consists of a short (3-30 sec- inance of females affected. For most families a
onds) interruption of consciousness in which polygenic pattern rather than a monogenic pat-
general postural tone is relatively well pre- tern of inheritance is suspected. The high con-
served. During this brief period, the patient is cordance rate in identical twins was noted by
observed to stare, oblivious to stimuli intro- Lennox cited above. In a minority of cases
duced into the environment. Ongoing activi- there is little evidence of a genetic background
' F- MONO
, - c
c- MONO
c-o L!n~t~JI~~'~W~l h\. I ~~~~.~
R
T- MONO L
'-T l
o-MOHO
L
T-O
R
R
PR . AGE 6 _'" , EEG NO. 'VlgS

.r-~/~ .
AGE"
Figure 29-3. Hypsarrhythmia in an infant with Figure29-4. Generalized 3 Hz spike wave discharge.
myoclonic spasms &.fer to Text: &.ferential This 19 year old male had a long history offrequent
(Monopolar) recordings from frontal (F), rolandic absence seizures characterized by a blank stare flicker-
(C), temporal (T), and occipital (0) areas. ing of the eyelids and a failure to respond to instruc-
and the seizures apparently reflect perinatal or tions. This accompanying BEG discharge in this
episode was of 8 seconds duration. Other episodes were
other multifocal and diffuse pathological of 20--40 seconds duration.
processes beginning in early childhood.
The seizures and the EEG pattern are par- may be strong enough to throw the patient to
ticularly responsive to medications such as the floor or isolated and weak enough to result
ethosuximide, trimethadione and valproic acid. in the twitch of a finger. In 40% of patients, the
Since approximately 50% of theses patients will discharges and often the myoclonus are trig-
also have generalized convulsive tonic clonic gered by intermittent photic stimulation with a
seizures, valproic acid may be the preferred stroboscope (Fig.29-6). In some series, associ-
medication since it has significant therapeutic ated with absence seizures the 3 -4Hz spike
actions against both types of seizures. Note wave or polyspike slow wave EEG are more
that the terms pyknolepsy and petit mal common. This syndrome of juvenile myoclonic
absence seizure have been employed in the epilepsy is now recognized as the most com-
past. mon variety of primary generalized epilepsy
2. Juvenile absence epilepsy (JA) has a
similar EEG pattern. The attacks are less fre-
quent and there is a higher incidence of gener-
alized tonic clonic seizures. There is no ' ANt T - MONO L ~,___"""","""'-..r1
male/female difference. R ~f\;J'Ij"'-

3. Juvenile myoclonic epilepsy (JME)
was identified in 1957, by Janz and Christian,
as a syndrome which incorporated features of ' PAIl - MONO
juvenile onset tonic-clonic and myoclonic

seizures with a bilateral symmetrical and syn-
chronous 4-5 Hz polyspike-slow wave pattern
(Fig.29-5). Myoclonus may be defined as a Figure 29-5. Generalized bursts ofpoly spikes and slow
sudden rapid jerk or twitch resulting from the waves. Juvenile myoclonic epilepsy in a 13 year old who
had the onset ofsudden single generalized myoclonic
sudden contraction of one or more muscle
jerks, which initially were sufficiently violent to throw
groups. The jerks may be bilateral and sym- the patient to the floor but did not impair conscious-
metrical or multifocal. Facial muscles, extraoc- ness. Neurological examination has remained normal
ular muscles, and head or limbs or body may and the patient has never (now age 22 years) experi-
be involved. The intensity of the contraction enced generalized convulsive seizures or petit mal
absences.
29-10 CHAPTER 29
I tt. after two seizure-free years.

Anatomical differential diagnosis of
r • c
myoclonus: The anatomical substrate for
C • 0
myoclonus is variable. In the monkey,
myoclonus may occur as a result of bilateral
F • T
epileptogenic foci in the motor cortex or the
adjacent premotor cortex. A similar cortical
T • 0
onset of discharge has been noted in the light
sensitive baboon (papio, papio). Myoclonus
1WI1SS E.S. MiE HI." IEEG NO. sellJo
~ttN~
10-19-87
may also occur in various extrapyramidal dis-
eases involving the basal ganglia or ventro-Iat-
Figure 29-6. Generalized bursts ofpoly spikes and slow eral nuclei of the thalamus. In patients with
waves triggered by photic stimulation. Juvenile Parkinson's disease, myoclonic jerks may com-
myoclonic epilepsy with phorosensitivity. This young
plicate the use of L-dopa (in addition to the
woman at age 13 had the onset ofgeneralized convul-
sive seizures and offrequent myoclonic seizures involv- more common choreiform dyskinesia).
ing eyelids and arms. The myoclonic seizures involving Segmental myoclonus has been described in
eyelids, facial muscles and limbs were clearly triggered viral diseases involving the spinal cord.
by bright flickering light. In the non-cortical varieties of myoclonus,
beginning in the adolescent or young adult it is possible to have the behavioral phenome-
years (12-18), accounting for 7-12% of all non without the occurrence of accompanying
seizure patients depending on the series (see spike or polyspike-slow wave discharges in the
Dreifuss, 1989; Delgado-Escueta, 1989). electroencephalogram. In the cortical variety of
Almost all patients have both generalized myoclonus, conduction of discharges to the
tonic-clonic and myoclonic seizures, the latter brain stem and spinal cord occurs along both
often precipitated by sudden awakening, sleep pyramidal and non-pyramidal pathways.
deprivation, alcohol consumption or stress. Stimulus sensitive myoclonus refers to the
This syndrome has considerable significance precipitation of myoclonic jerks by sound, light
In the early genetic studies of EEG photo- flash, proprioceptive or tactile stimuli. Usually,
sensitivity- this particular trait appeared to be the underlying disease is a diffusely distributed
inherited as an autosomal dominant (Fig 29-7), process. In some cases, it is primarily cortical;
although the majority of affected relatives did in others it is primarily non-cortical. The dis-
not have clinical seizures (Watson &Marcus, ease process involves neurons primarily rather
1962). In more recent studies, of JME than white matter.
(Delgado-Escueta et al, 1989), 50% of Etiological and prognostic classification
probands had a 1st or 2nd degree relative with of myoclonus:
epileptic seizures. Among 1st degree relatives 1. Benign-nonprogressive myoclonus -sud-
of the proband, 80% of symptomatic siblings den jerks on falling asleep or on awakening as a
and 6% of asymptomatic siblings had diffuse 4- common normal phenomenon. . A familial
6hz poly spike slow wave discharges. Linkage variety of essential myoclonus-may also occur.
analysis suggested a relationship to chromo- 2. Non-progressive myoclonus as a mani-
some 6,although subsequent studies have sug- festation of idiopathic epilepsy: the JME syn-
gested linkage to 15q in other families drome.
(Delgado-Escueta etal, 1999) Therapy is very 3. Symptomatic Generalized epilepsy,
specific: Valproic acid will totally control usually with mental retardation
seizures in 80% of patients but must be contin- a. Infantile spasms
ued on a relatively lifelong basis. In the series b Lennox-Gastaut syndrome.
ofJanz (1985), 91% of patients had recurrent 4 . Progressive myoclonic disorders
seizures when anticonvulsant was discontinued (Berkovic et al,1991,Serratosa et al,1999).
.'50 J.'ERCENT 7A
PLICl<ER
SENSITIve
• • SISUJ\S
. 1II\0'l'lIERS
() I
40 I'IUlQUllHCY OP . FLlCXl!ll I!VO;(l!O BEG ADNCWIALITII!S
AS A l'UtC1'I0/I OF AGB A/fD SI!X
NON SlUWR5 SUIlGIlOUP

MALBS "=693 F&lALl!S N =559
COIPARJlBU! VALUES Pat RIlATIVES OP SlX1Y
30
PUCICl!R SllNSITIVE P ~OPOSJT I AI\!! SHOWN .
20
o PATHERS
10
MAIJ! ... ~ _ _ ..
,It ____ ..,.-' ..
o ,"
0- 5
6-10
.
: le...20
Jl- H, 21- 30 31-'0 41 - 50
AGe IN YllARS
61 - 70 70+
Figure 29-7A. The BEG trait:phorosensitivity as a function of age and sex in 1256 consecutive non seizure
patients. The role ofgenetics is also demonstrated in the relatives of 60 phorosensitive propositi matchedfor
age.Almost all of the propositi had idiopathic epilepsy. Almost all of the phorosensitive relatives did not have epilepsy.
BRC!NT 7B
YGllT Sl!N'SITIVB
f!R£(JJIMC\" OP LIG!fr EVC«.En lEG ABNORMAtt'rY

AS It PUNCTYOi ~ AGE
SIJZUR! ~0Ui> VERSUS Nal SnZURE Q<O!JP
.4
-5 6-10 Ll-15 16-20 21 .. 30
AGE SPAN '_YUkS )
Figure 29-7B.Phorosensitivity as a function ofage and seizure hisrory.Consecutive seizure and nonseizure patients.
The frequency of this trait in those patients with focal (partial) epilepsy did not differ from the nonseizure patients.
The excess ofphorosensitivity in the 10-20 age seizure group reflected the occurrence of idiopathic epilepsy in this age
group. The excess in the 50-70 age seizure group may have reflected the occurrence of diffuse disorders in this age
group.
29-12 CHAPTER 29
a. mitochondrial disorders, responses are usually extensor during the attack

b.lipidosis-lysosomal storage diseases and will remain extensor during the early part
c. myoclonus epilepsy of Unverricht and of the postictal period. The following EEG fea-
Lundborg tures are correlated with the clinical sequence:
d. Lafora's disease fast spike discharge at 8-20 Hz with the tonic
5. Infectious-viral related phase (Fig.29-8A), repetitive spike wave or
a. acute encephalitis e.g. acute herpes polyspike wave generalized discharge of gradu-
simplex. ally decreasing frequency with the clonic phase
b. subacute inclusion body encephalitis- (Fig.29-8B, C, D), a short period of relative
reactivation of the measles virus electrical silence in the electroencephalogram
c. Spongiform encephalopathy- (Fig.29-8E) with the initial post ictal stage.
Creutzfeldt-Jakob disease-prion disorders Slow wave activity of 1-3 Hz is then apparent
6. Metabolic disorders and is correlated with the period of depression
a.uremia of consciousness. With clearing of confusion,
b. hypocalcemia the electroencephalogram gradually returns to
c. C02 narcosis a normal frequency range. During interictal
d. anoxic encephalopathy: acute or chronic periods, the electroencephalogram in patients
effect who are subject to generalized convulsive
e. pyridoxine deficiency state of infancy seizures may present a variable appearance. The
£ L-Dopa toxicity record often is normal. Generalized bursts of
4. Generalized tonic clonic seizures polyspike and slow waves may occur. In some
(GTCS): The stereotype of the generalized cases, focal or multifocal abnormalities may be
convulsion, the grand mal seizure, consists of present even though a clinical focus of seizure
two phases: the tonic and clonic. Occasionally onset was not apparent. The causes of GTCS at
myoclonic jerks of increasing frequency may various ages is indicated in Table 29-3. The
precede the actual loss of consciousness and the preferred treatment of idiopathic epilepsy char-
tonic phase. Unless the tonic clonic convulsion acterized by generalized tonic clonic seizures is
represents a secondarily generalization of a par- valproic acid. For some patients phenytoin may
tial seizure, the onset is abrupt, with loss of be utilized.
consciousness the initial sign. The patient stiff- Other conditions must be distinguished
ens and, if standing erect, is thrown to the from generalized tonic clonic seizures: several
floor. Respiration is arrested and the pupils conditions in which a loss of consciousness and
dilate. After a short but variable period of 10 postural tone occur must be differentiated
to 30 seconds, the tonic stage then, passes into from generalized tonic clonic seizures.
the clonic stage. The symmetrical jerks of (1) Syncope
clonus then slow in frequency and cease. The (2) Akinetic (atonic) seizures are seizures
total duration of the actual uncomplicated in which the patient falls suddenly to the floor
tonic/clonic phase is usually a matter of 1 but then stands up again almost immediately.
minute. This state is followed by a short but The loss of consciousness is brief In some
variable period of coma, followed by, stupor, cases, there may be no definite evidence of an
confusion and drowsiness. The total duration actual loss of consciousness. In some cases, the
of confusion and drowsiness is usually less than fall represents a sudden loss of postural tone; in
30 to 60 minutes. The patient will be amnesic other cases, the fall represents a massive
about the onset of the attack, about subse- myoclonic jerk that throws the patient violent-
quent events of the seizure and about the pos- ly to the floor. Atonic or akinetic seizures are
tictal period of confusion. If the bladder has frequently seen in the Lennox Gastaut syn-
been full, incontinence of urine will have drome in which other seizure types: atypical
occurred during the seizure. The plantar absence seizures (termed previously petit mal
variant) generalized convulsive seizures and in
A
many cases, tonic seizures are also present.
(3) Drop attacks in the adult may occur
in relation to ischemia in the paramedian
branches of the basilar artery with transient B
dysfunction in descending motor pathways and
of the motor centers of the pontine or
medullary reticular formation. In such cases,
consciousness is usually preserved but patients c
often have other symptoms suggesting that
basilar vertebral insufficiency may be present
(see Chapter 13). o
OVERVIEW OF PRIMARY/
IDIOPATIllC GENERALIZED
EPILEPSY E
(1) The Overlap Of Syndromes: As L
demonstrated in Table 29-4 from Genton

(1995) although clinical syndromes and
their EEG patterns have been delineated, it
1200pV
is important to emphasize the considerable I see.
overlap among the various subcategories.
Many ofthe models to be discussed below illus- Figure 29-8. Experimental generalized tonic clonic
trate an overlap ofsyndromes. In addition, both seizure with out focal onset in a monkey. The animal
in the human cases and in the experimental was tonic during the fast 8 Hz spike discharge ofseg-
ment A. The animal had repetitive clonic jerks, dur-
models, there is not a 1 to 1 correlation of EEG ing the poly spike -5low wave discharges ofsegments
and behavior. B, C and D, gradually decreasing in frequency. The
(2) The Genetic Molecular Biology Of period of relative electrical silence shown at the end of
Idiopathic Epilepsy: For most cases this has segment E and the subsequent period of 1-2 cps slow
not yet been established. However a number of wave activity (not shown) corresponded to the post-
specific genetic mutations involving channels ictal depression of consciousness. Bipolar recordings
from left and right premotor - precentral areas.
and receptors have been identified. Recent
papers by McNamara (1999), Prasad et al same region. A missense mutation occurs with
(1999) and Steinlein, (1999) have reviewed the addition of serine to the 2nd transmem-
this topic. Specific defects have now been iden- brane amino acid sequence. This mutation is
tified in several varieties of presumably mono- present in all affected individuals and in the
genic seizure disorders. "carriers" (there is a penetrance of 70 - 80 %).
(a) Partial idiopathic epilepsy: In a Norwegian family with the same syn-
Autosomal dominant nocturnal frontal lobe drome, an extra leucine was inserted in to the
epilepsy (ADNFLE). This type of nocturnal terminal end of the 2nd trans membrane
motor seizure disorder (at times with sec- domain on the same receptor subunit.
ondary generalization) was originally misdiag- The overall result of this mutation is a sig-
nosed as a sleep disorder. In a large pedigree nificant reduction of calcium permeability and
reported from Australia, linkage to the 20-q a hypoactive receptor. The additional step nec-
13.3 chromosome site has been established. essary to produce seizures is unclear. However
The a4 subunit of the neuronal acetylcholine it is possible that since some acetylcholine
nicotinic receptor (CHRNA4) maps to the receptors are in a presynaptic location a
29-14 CHAPTER 29
TABLE 29-3:CAUSES OF NON FOCAL GENERALIZED TONIC Iy a 2nd locus on chromosome 15 q 24 has
CLONIC CONVULSIONS been identified; this site also contains multiple
subunits of nicotinic cholinergic receptors.
AGE ETIOLOGY (b) Generalized idiopathic epilepsy:
NEW BORN Metabolic: Na/K, alkalosis, hypoglcemia, Benign, familial neonatal convulsions
hypocalcemia, pyridoxinedeficency, (BFNC). This is also a rare autosomal domi-
dependency, aminoacidurias
nant disorder in which partial or generalized
(phenylketonuria), respiratory lanoxia,
perinatal pathology clonic convulsions start around the 3rd postna-
tal day and persist until week 6. Approximately
INFANT Metabolic disturbance, febrile 12% of patients have seizures again later in life.
convulsions·, meningitis lencephalitis, In most families linkage to chromosome site
Residuals of perinatal pathology
20 q 13.3 occurs with a missense mutation in
CHILD Febrile «5 years), idiopathic epilepsy, the gene for the voltage gated potassium chan-
meningitis/encephalitis nel-KCNQ2. There is a loss of amino acids in
the sequence at the pore of the channel. The
ADOLESCENT Idiopathic epilepsy···, drug use
and withdrawal: mutation abolishes the potassium currents that
are activated by depolarization. As a result
YOUNG ADULT Alcohol/drug withdrawal··, excitability is increased. In a few families, the
cocaine use, idiopathic epilepsy mutation occurs at the KCNQ3 site on chro-
OLDER ADULT Alzheimer's disease and other mosome 8 with a similar effect on excitability.
degenerative disorders, anoxic Both KCNQ2 and 3 are predominantly
encephalopathy expressed in the brain. Neurological develop-
ment is otherwise normal.
"" Abrupt withdrawal or reduclion of intake aner chronic intake of
alcohol may trigger seizures within 7-48 hours of the withdrawal. A similar mutation in another potassium
During this period the EEG may demonstrate precipHation of channel, KCNQl, produces the cardiac
myoclonus and of electrical discharges by phoHc sHmulation. arrhythmia of the long QT syndrome.
There are in these cases of alcohol withdrawal, correlations with (c) Generalized idiopathic epilepsy:
low serum magnesium, increased pH and low pC02 levels (see Generalized epilepsy with febrile seizures
Victor, 1990). More recent cellular studies of sedative drug with-
plus (GEFS+). In this autosomal dominant
drawal are discussed in Ca~en et al. 1990. In these cases the
post-ictal state may then merge into a more prolonged agitated
syndrome, febrile seizures occur before 3
and confusionol state of delirium tremens. This same clinical state months or after 3 years of age. In addition
may also follow withdrawal from short-acling barbiturates, however and this is of particular interest, mul-
meprobamate, diazepam (Valium) and other benzodiazepines. 1 tiple forms of classical idiopathic seizures occur
"Febrile canvulsions are frequent in the age group under 5 years without fever including absence, myoclonic,
and occur predominanfly between 6 months and 3 years of age. atonic, and generalized tonic-clonic. Different
I! has been esHmated that 4 to 7 percent of all children under the members of the same family may have different
age of 5 years will hove at least one generalized convulsive types of these seizures despite the presence of
seizure (the majority febrile). Children with febrile seizures have a
the same genetic mutation. The mutant gene
high familial incidence of seizure disorder suggesHng a factor of
geneHc predispasHion. A significant propartion (but not the majori-
ty) of these children will be found later to also have non-febrile 1It is important to realize that in patients with
convulsions. underlying predisposition to either partial
""" Note that 86% of JME patients also hove generalized conVUl- seizures (as in post-traumatic epilepsy) or to pri-
sive tonic clonic seizures. A related syndrome is that of epilepsy mary generalized epilepsy withdrawal effects
with generalized toniC cloniC seizures on owakening which differs from acute use ofrelatively moderate amounts of
from JME - only in the absence of myoclonic seizures (see
alcohol may precipitate seizures. These patients
Dreifuss, 1989).
then are more sensitive to withdrawal from alco-
decrease in calcium flux might reduce the hol and other sedative agents (see Mattson.
release of GABA at this location. More recent- 1990).
maps to chromosome locus 19 q 13.1. A increased neuron density in the molecular
mutation in the beta subunit of a voltage gated layer, (a prominent feature in idiopathic epilep-
sodium channel, (SCNIB) occurs as a result of sy), this was most severe in the frontal lobes,
amino acid substitution of tryptophane but also present in other cortical areas. Recent
for cysteine. quantitative MRI studies have also raised the
This is a rapidly evolving area; additional question of cerebral grey matter structural
discoveries are to be expected. Note however, changes in all types of patients with idiopathic
that in most seizure disorders in the human epilepsy most prominent in juvenile absence
patient, penetrance is often incomplete and epilepsy (Woermann et al, 1998) In addition
transmission may be polygenic. among patients with JME, more specific MRI
Later, in our discussion of the idiopathic and PET scan changes have been noted in
epilepsies, we will discuss other genetic defects superior frontal and mesial frontal gyri
in rodent models (Woermann et al, 1999) These patients may
(3) The Underlying Neuropathology Of also have a correlated deficit in visual working
ldiopathic/primary Generalized Epilepsy: memory.
Although a longstanding general criteria cited (4) Underlying Pathophysiology: A
for this disorder was that no structural neu- number of models of idiopathic epilepsy are
ropathology be present, it is now evident that available, which reproduce the behavioral and
cortical micro dysgenesis is present in those electrical (EEG), and pharmacologic features
cases that come to autopsy. In most cases, of these disorders. If the genetic and biochem-
neuons are found in the molecular layer which ical pathophysiology is known in man, this
is normally relatively devoid of neurons. In the should be reproduced. Unfortunately, except
series ofMeencke (1996),100% ofl2 patients for a small number of the clinical syndromes
with childhood absence epilepsy and 100% of 3 that we have earlier reviewed, in relation to
patients with JME had significant micro dysge- genetic disorders of channels, these latter fea-
nesis; but none had severe migration disorders tures are often unclear. In general ,because of
in the deeper cortical layers. In contrast 50% of phylogenetic differences in cortical and callos-
24 patients with infantile spasms had micro al development, observations in the monkey
dysgenesis and 13% had severe migration dis- may be more difficult but have greater validity
orders. Among 30 patients with the Lennox- in terms of generalization to man. In the mod-
Gastaut syndrome, 50% had micro dysgenesis els of absence seizures there is the question of
and 16% had severe migration disorders. whether the process recorded in the EEG
Among 27 patients with temporal lobe epilep- reflects the activity of cerebral cortex alone or
sy, only 7% had micro dysgenesis but 11% had of the effects of an interaction of thalamus
severe migration disorders. In terms of with cerebral cortex. Studies in the rat are con-
TABLE 29-4:SEIZURE TYPES IN IDIOPATHIC EPILEPSY SYNDROMES IN 253 CONSECUTIVE CASES.
MODIFIED FROM GENTON
MAJOR SYNDROME # OF CASES SEIZURE TYPE(S)

Absences GTCS Myoclonic Other
Childhood absence 73 100% 44% 3% 7%
Juvenile absence 28 100% 75% 11% 11%
Juvenile myoclonic 59 22% 86% 95%
GTCS on awakening 30 7% 100% 13%
Isolated GTCS 39 100% 11%

29-16 CHAPTER 29
sistent with the thalamo cortical frontal rolandic cortex. As regards GTCS the
interaction. Studies in the monkey suggest a EEG discharge can be reproduced in a prepa-
cortical basis As regards the JME syndrome, ration composed of cerebral cortex and corpus
the baboon with light induced myoclonus pro- callosum. Table 29-5 below provides a sum-
vides a model in which the discharges begin in mary of pathphysiology.
TABLE 29-5: OUniNE OF MODELS OF IDIOPATHIC EPILEPSY PATHOPHYSIOLOGY:
REFER TO CD ROM FOR ADDITIONAL DISCUSSION.
TYPE OF SEIZURE SUBSTRATE OF MECHANISM FOR BEHAVIOR

TYPE OF MODEL EEG SEIZURE BILATERAL SYNCHRONY
ABSENCE
1. midllne/intralamlnar Recruiting response Unclear probably Arrest 01
thalamic stimulation thalamo-cortical corpus callosum movement
Fig.29-9 Stimulus related 3Hz SW interacfion.
Reier to Chapter 17.
2. Bilateral symmetrical Cerebral cortex. Bilateral Corpus callosum Absence: eyeopening, staring,
premotor loci (monkey) 2.5-3.5 Hz SW persists in arrest 01 movement il anterior
Fig.29-1 0, 11, 12 bilateral cortical callosal premotor. Greater myoclonus
isolate preparation. il posterior premotor.
3. Feline general penicillin Onset in the cerebral cortex, Corpus callosum Impairment 01 responsivity
epilepsy (cat) Fig. 29-13 later In the specilic thalamic during bursts plus.
nuclei later in nonspecific myoclonus 01 lace/
thalamic nuclei. Thalamic extremities
nuclei are recruited into a
cortical/thalamic-cortical
oscillation. 3.5-6 Hz SW
4. GAERS(rat) Discharges are predominant Corpus callosum Animals are immobilized with
(Generalized absence in frontoparietal cortex and myoclonus lace/extremities
epilepsy 01 the rat- d posterolateral thalamus, and impairment 01
Slrasbuurg) Thalamo-cortical interaction responsivity during
is required . 7-11 Hz SW the bursts.
MYOCLONUS
1. Subthreshold penty Motor cortex: bilateral Corpus callosum Bilateral myoclonic jerks
- lenetetrazol (monkey) 3HzSW 01 extremities
2. Bilateral motor cortex loci Motor cortex: initially Corpus callosum Myoclonus 01 extremities
bilateral spike discharges then GTCS**
3. Photosensitive baboon Origin in lrontal/rolandic Corpus callosum bilateral myoclonus 01 eyelids,

Cortex (areas 4,6). lace and limbs. At times,
Bilateral 4Hz Polyspike progression to GTCS
slow wave. Blocked by
DOPA agonists
GTCS Generalized Tonic Clonic Seizure
Threshold dose 01 Cerebral cortex: onset at Corpus callosum GTCS ollen preceded by
Pentylenetetrazol low threshold areas bilateral myoclonic jerks
(monkey/cat). e.g. motor cortex. Pattern
Reier to chapter 17 is similar in bilateral
lor illustrations cortical callosal isolate
Genetic Models in the Mouse-(Table
29-6 on the CD ROM):At present 6 inbred
mouse strains have been reported with spike
wave discharges and absence seizures. In each
of these strains the bilateral bursts of spike
wave discharge are accompanied by behavioral
,. ;. "
-- LO
Figure 29-10. Experimenml3 Hz spike wape discharge

following bilateral symmetrical epileptogenic foci in
anterior premotor cortex of the monkey. Effects of
hyperventilation as in patients with absence seizures
.A= just prior to hyperventilation; B, C, D., Two to
three minutes after beginning of hyperventilation.
Figure 29-9. ExjJerimenml3 Hz spike wape discharges SF= superior fronml gyrus, Pre C =precentral gyrus
following midline or intralaminar thalamic stimula- Pre 0 = preoccipiml area. From Marcus, E.M., and
tion. A stimulus-related bilaterally synchro1WUS spike Watson, C. w.: Arch.Neurol.19: 103,1968 (AMA).
and wape discharge is produced in cat cerebral cortex Refer also to chapter 17for an additional example of a
by repetitipe 3 cps stimulation of the Massa interme- 3-4 Hz spike wape discharges in this preparation.
dia. (From Jasper, H, and Droogleever-Fortuyn, J.:
Res.Publ.Ass.Nerv.Ment.Dis. 26:272-298,1947).
12A
9
1·1 I, A
c
Figure 29-11. Bilateral symmetrical foci: anterior
premotor cortex. Correlation of behapior (absence
seizure) with bilateral 3 Hz spike-slow wape discharge.
Continuous bipolar recordings: premotor to precentral.
Segments A and Bare continuous. 1) Head mopes to
midline and eyes are wide open. 2) Smrt of testing
with pencil moped back andforth across pisual fields.
The animal failed to follow. 3) Light mp on nose pro- 12B •
duced only partial blink but 1W other response of hands
or head. 4) Hands were mpped; without response Figure 29-12. Prolonged bilateral synchro1WUS 2-3.S
although during non-seizure periods, animal had pig- Hz spike-slow wape and poly spike slow wape discharges
orously grasped the pencil.S) Animal now blinked in the cortical callosal preparation following the pro-
fully to approaching object complete eye closure then duction of bilateral epileptogenic foci. A) The isolated
opening; no mctile stimulus to 1Wse was required. 6) bilateral cortical callosal preparation in the cat
Animal now followed pencil with head and eye, turn- (From Marcus, E.M., and Watson, C. w.: Ach.Neurol.
ing as pencil moped towards the animal's left peripher- 14:632, 1966). B. The pattern of discharge. Similar
al field. Licking also occurred (had 1Wt occurred results may be obmined in the monkey. From Marcus,
during seizure). Reproduced with permission from E.M., Watson, C. w., and Simon, S.A.: Epilepsia, 9:243,
Marcus, E.M., et al Epilepsia, 9:2371968b (Blackwell). 1968 (Blackwell).
29-18 CHAPTER 29
for the spike-slow wave discharge. The minimal

substrate is built into the design of cerebral
cortex and of the cortical -callosal circuits.
There is little doubt that discharges having
begun in cerebral cortex do subsequently
spread to the thalamus, basal ganglia, the brain
stem and spinal cord and these structures do
reverberate back to cerebral cortex. However
to what extent, the cortico-thalamo-cortical
Figure 29-13. Generalized penicillin epilepsy in the oscillation is necessary to produce and sustain
cat: 1M administration. Generalized bursts ofpolyspike the spike -wave complex in the human is
and 3-5 Hz spike --wal'e discharges occur. From Gloor,
P.Epilepsia 20:571-588,1979 (Blackwell). uncertain. The idiopathic epilepsies and the
spike wave discharge may represent a biological
arrest and the discharges are blocked by drugs spectrum, rather than a unitary disease as noted
that are effective against absence seizures by Berkovic et al (1988)
(Noebels et al 1997).However almost all of 4.Behavior is a more complex matter.
these strains have other neurological deficits There is a representation and re representation
usually related to cerebellar degeneration and of patterns of behavior at various levels of the
the discharge consists of a 6-7 HZ spike and neuraxis.
wave. The importance of these strains relates
to the monogenic inheritance of actual or pre- WHY ARE AWARENESS AND
sumed ion channel mutations (Ca++ or RESPONSIVITY ALTERED DURING
Na+/H+). Table 19-6 on CD-ROM modified THE ABSENCE SEIZURE? SEVERAL
from Barclay and Rees(1999) summarizes the EXPLANATIONS ARE POSSIBLE.
major findings. Other genetic seizure disorders
1) There is widespread involvement of
in rats are discussed by Noebels et al (1997)
cerebral cortex in seizure discharge; particular-
and Sarkisian et al (1999)
ly of the multimodality sensory projection areas
CONCLUSIONS REGARDING and of other frontal and temporal association
THE BILATERAL SYNCHRONOUS areas involved in working memory etc., so that
DISCHARGES OF IDIOPATHIC these areas can not participate in their normal
EPILEPSY: activities
2) There is impairment in the capacity of
1. All of the models leaving aside the mouse the thalamus to transmit information.
models suggest that the basic pathology 3) Both of these explanations are opera-
involves an increased hyperexcitability of neu- tional in the intact individual since discharge of
rons at the cortical level. This is consistent with cerebral cortex secondarily spreading to thala-
the now available neuropathological data and mus via the cortico -thalamic system will also
MRI data in man. alter the capacity of the thalamus to transmit
2. The bilateral synchrony in the various information.
models in the monkey, baboon, cat and rat is
dependent on the corpus callosum and the WHAT ARE THE MECHANISMS FOR
related major commissures. There is no direct ENDING SEIZURE DISCHARGE?
anatomical substrate in the thalamus of the
The total explanation for the cessation of
human providing the basis for the bilateral syn-
the seizures is not entirely clear but presumably
chrony found in idiopathic epilepsy.
could include various inhibitory processes
3. There may be multiple possible mecha-
involving the cortex, subcortical nuclei, thala-
nisms providing the substrate for the oscilla-
mus and brain stem. In this regard, we should
tions of excitation and inhibition responsible
note that the activity of isolated cerebral cortex
is characterized by bursts of activity with inter- 12ug/mI.above that level the half-life increases
vening periods of relative electrical silence. with blood level. The time to achieve steady
There are then intrinsic mechanisms within state is approximately 4-SX the halflife. Dosing
cerebral cortex for cessation of discharge. This schedule relates to half-life. Note that primi-
is then the most likely overriding considera- done is in part converted to phenobarbital,
tion. Additional discussion of the role of struc- both metabolites have anticonvulsant action.
tures such as the red nucleus, basal forebrain, The molecular basis of anticonvulant
pontine and medullary reticular formation and drug action: Refer to table 29-9.
the pars reticularis of the S. Nigra will be found In general anticonvulsants that are effective
in the cited references (Gale, 1990,Moshe against partial and secondarily generalized
&Sperber, 1990). seizures are effective in the experimental maxi-
mal electroshock test,( a model of seizure
GUIDELINES FOR MANAGEMENT spread) and produce Na+ channel blockade. In
OF SEIZURE DISORDERS: general those drugs that are effective against
Evaluation: Over 7S% of diagnosis in neu- spike wave epilepsies, particularly absences are
rology is dependent on the history, this is even effective against experimental pentylenetetra-
more important with regard to seizure disor- zol induced seizures, elevate threshold and
ders. However in this case, information must produce T type Ca++ channel blockade.
be obtained from witnesses regarding events However benzodiazepines and barbiturates are
for which the patient may have little recollec- also effective against this type of experimental
tion. Information from the patient and wit- seizure.
nesses regarding focal manifestations, aura etc Teratogenic and side effects of anticon-
is vital. The neurological examination is critical vulsant medications
in terms of the presence or absence of signs 1. teratogenic effects in the offspring of
suggesting focal cortical pathology. Laboratory the pregnant seizure female. In general, the
studies should include a complete blood count, non-seizure population has a 2.S% risk of mal-
blood sugar, calcium, electrolytes and creati- formation, seizure patients not on anticonvul-
ninejbun. The electroencephalogram per- sants - a 3.5% risk. Seizure patients on anticon-
formed during awake and sleep states may pro- vulsants - S.S% risk. Teratogenic effects occur
vide information regarding focal or generalized primarily in the first trimester and consist of
electrical seizure discharges or slow wave activ- cleft lip, neural tube closure defects and con-
ity. The yield of the EEG may be increased by genital heart disease. The risk of malformation
activation procedures such as sleep deprivation is increased if any of the following factors is
(SD), hyperventilation (HV) and photic stim- present: (1) poor seizure control (2) polyphar-
ulation (PS). All patients should have an imag- macy (3) high blood levels (4) use oftrimetha-
ing study. Based on the information considered dione. Risk of neural tube defects can be sig-
above, whenever possible this should be an nificantly reduced by administration of folic
MRI. When this is not possible, then a CT scan acid.
with and without contrast should be obtained. 2. Other side effects of anticonvulsants
Specific aspects of seizure management are fall into general groups:
considered in Table 29-7. The use and proper- a. Allergic - dermatological, hepatic,
ties of anticonvulsants are considered in Tables immune for which the drug must be discon-
29-8,29-9,29-10 tinued
The upper limit of therapeutic range for all b. Dose related (ataxia, drowsiness, dizzi-
of these agents is variable related to protein ness, diplopia )- for which the dose must be
binding etc. For valproic acid, the upper limit lowered
of therapeutic range is 100-IS0 ug/mI. The c. Chronic - hematological, lymphatic
half-life of phenytoin is constant only up to (lymphoma, lupus, etc.
29-20 CHAPTER 29
TABLE 29-7: MANAGEMENT OF SEIZURE DISORDERS
PROBLEM MANAGEMENT EXPECTED RESULTS

SINGLE GTCS No specific anti convulsant treatment if Annegers et al (1986)
(1) History indicates, no focal features, no prior minor seizures, Found recurrence rate of
normal growth and development, no mental retardation, 16% @1 year,
and no family history of seizure disorder 22%@3 years,
(2) Neurological examination is normal 26%@5 years.
(3) EEG with sleep deprivation, HV and PS is normal
(4) Imaging studies are normal
(5) Conditions such as fever, sleep deprivation, alcohol and drug
withdrawal or use of drugs such as cocaine, isoniazid or other
agents or metabolic conditions lowertng threshold are present.
RECURRENT (1) Rule out metabOlic abnormality and mass lesion, In generalized /idiopathic
SEIZURES Prevent additional seizures with anticonwlsants epilepsy complete control In 63%
(EPILEPSY) (See Tables 7, 8, 9, 10). (2) Start with monotherapy push dose and significant reduction In an
to seizure control or toxicity. (3) If still no control use second additional 25%. In complex
or third major agent then newer add on agents. partial, complete control In
(4) Treat for 3-5 years seizure free, If at that point, 20-35%. If seizure free 5 years
EEG Indicates no seizure discharges, consider gradual and discontinue medication
withdrawal from medications 30% relapse over 10 years
RELAPSES If on anllconvulsanlS: (1) Recurrences are more likely

(1) Compliance issues, omission of medication. Check levels. If focal rather than idiopathic, or
(2)lnsufficlent daily dosage.Check levels and adjust dose. if long nme before inlnal seizure
With phenytOin check the free unbound fraction (usual therapeutic control or If seizure discharges are
range is 1- 2 ug/ml). Altematively push dosage until therapeutic still present in EEG. (2) Intensive
effect is anal ned or dose related toxicity occurs. re-evaluation at an epilepsy center
(3) Wrong medication for the type of seizure-reevaluate In with video EEG monitoring will
terms of history and EEG. Do long term video-EEG monitortng. resuit in a significant number of
Whether on or off medications consider following factors: patlenlS reclassified with treatment
(1) Sleep deprivation (2) Alcohol or drug withdrawal modlHed. (3) Combination of
(3) Fever or metabolic abnormalities or use of antihistamines. epilepsy +alcoholism or drug
(4) Falls with frontal or temporal injuries =addinonal foci. addiction difficult to treat because
(5) Epileptic status producing hippocampal sclerosis so that off compliance issues and with-
additional foci of seizures resuitlng in complex partial seizures. drawal effects triggering seizures.
Re-evaluate in terms of history, EEG &monitor.
(6) Secondary eplleptogenesls. (I) Underlying progressive
disorder is present. (8) Possible pseudo seizures + actual
seizure disorder.
REFRACTORY (1) Consider all factors listed above. (2) If focus Is well defined, In patients with complex partial
PATIENT and psychiatric issues are not present consider surgery after epilepsy due to mesial temporal
DESPITE USE intensive non-Invasive :t Invasive monitoring, and determination scleroSiS, 78% had complete
OF 3 of dominance. Because of high incidence of complex parnal seizure control at one year after
TRADITIONAL seizures usual procedure Is anterior/mesial temporal resection. anterior medial temporal
MEDICATIONS Less offen, resections In frontal lobe. (3) If poorty controlled resection (DoyJ8&Spencer(1998)
secondary generalized epilepsy (e.g.Lennox Gastaut) (see also Wiebe et al,2001).
or multiple foci consider vagal stimulator or corpus callosotomy. With frontal lobe resections,68%
became seizure free. Vagal
stimulator will reduce seizure
frequency. Callosotomy will
decrease GTCS and drop anacks
but facal seizures may increase.
EPILEPTIC Discussed below

STATUS
TABLE 29-8: PHARMACOLOGIC PROPERTIES OF THE MAJOR ANTICONVULSANT DRUGS
AGENT USUAL DAILY USUAL DAILY DOSING HALF-LIFE BLOOD LEVEL BLOOD LEVEL
DOSE DOSE ADULTS (ug/ml) TOXIC
CHILDREN (mg) (TOTAL) ~~~~VE
(MG/KG)
Phenobarbital 3-5 90-180 lX/day 96+/- 12 >15 (4-13) >40
Phenytoin 4-7 300 SplH 2X/day 24± 12 >10 >20
Prlmldone 10-25 750 SpUt 3X/day >6 >12
Ethosuximide 20-30 1000 Split 2X/day 30± 6 >40 >100
Corbamazepine 8-20 600-1400 SplH 3X/day 12±3 >8 (4-13) >13
Valproic Acid 15(lnitial) 1000 Split3-4X/day 8 >50 >125

15-30 2600
(maintain)
TABLE 29-9: MOLECULAR BASIS OF ANTICONVULSANT DRUG ACTION

MODIRED FROM RHO' SHANKAR (1999) ON CD ROM
TYPE OF ACTION DRUGS* TRADITIONAL DRUGS* NEWER AGENTS

(l) InhibH voltage gated sodium channel PHT, CBl, VPA FBM, LTG, TPM, ZNA
(2) Enhance GABAIA receptor CI-channel: PB, BZD FBM, TPM
(3) Increase brain GABA VPA VGB, GBP, TPM, TGB
(4) Inhibits Na+currents through non NMDA receptor TPM
(5) Inhibits Ca++ currents through NMDA receptor FBM
6) Inhibit slow threshold Ttype voH gated Ca++ channel ESM (?VPA) ZNA
7) InhlbHs brain carbonic anhydrase AZM
orugs* PHT, phenytoin; CBZ. carbamazeplne; VPA. valprolcacid: henobarbllal; BZD,benzodiazepines;

ESM, alhosuximide; AZM,acetazolamlde; FBM,falbamalll; GBP, gabapenlin; LTG,lamatrigine;
TPM, Iopiramalll; TGB, lIagablne; VGB, v1gobalrln; ZNA. zonlsamlde
STATUS EPILEPTICUS - This is a fre- lasting > 30 minutes or intermittent seizures

quent major neurological emergency. Overall lasting >30 minutes without regaining con-
incidence is at least 41-61 cases per 100,000 sciousness. Since the usual tonic clonic seizure
population. Less than I year of age the inci- is usually <1-2 minutes in duration, most
dence is 156 per 100,000, in the over 65 year experts would now shorten the time before
group ,the incidence is 86 per 100,000 popu- treating as epileptic status to 5-10 minutes.
lation. Overall 30% of cases are generalized The earlier the treatment, the lower the mor-
from the onset and 32-43% are secondarily bidity and mortality. The epidemiologic data of
generalized after focal onset. This acute condi- DeLorenzo et al (1995) as presented in table
tion must be recognized and treated as rapidly 29-11 indicates a current overall mortality of
as possible. The strict terminology of the 22% in cases meeting the 30 minutes criteria.
International Classification of Epileptic The greatest risk of mortality occurs in those
Seizures defines epileptic status as any seizure cases that are generalized from the onset or are
29-22 CHAPTER 29
secondarily generalized after focal onset and in diac arrest as possible complications. Due to
the over 65 age group where mortality is 38%. damage to hippocampal areas prolonged grand
The causes of morbidity and mortality are cere- mal status may be followed by prolonged con-
bral anoxia, cerebral edema, aspiration pneu- fusion and a residual impairment of recent
monitis, hyperthermia, hypotension and car- memory as well as temporal lobe seizures.
TABLE 29-10 SEIZURE TYPES AND DRUG CHOICE*:
Seizure Type Drug Choice -Traditional Drug Choice - Newer* **

Partial and secondarily generalized PHT, CBZ, VPA LTG, TPM, ZNA, GBP, TGB**
Absence ESM, VPA
Myoclonic VPA, BZD
Primary generalized tonic/clonic VPA, PHT, CBZ
Infantile spasms ACTH, BZD
Status epilepticus: generalized, partial) BZD (intravenous)
* Drugs= PHT, phenytoin; CBZ, carbamazepine; VPA, valproicacid: henobarbital; BZD, benzodiazepines;
ESM, ethosuximide; AZM, acetazolamide; FBM, felbamate; GBP, gabapenHn; LTG,lamotrigine;
TPM, topiramate; TGB, Hagabine; VGB, vigabatrln; ZNA, zonisamide ACTH = adrenocorticotrophic hormone
** With the exception of LTG all of these newer agents are adjunctive add on agents
*** Additional new agent for partial seizures - levetiraetam
**** LTG may also be utilized In the Lennox-Gastaut syndrome
TABLE 29-11: EPIDEMIOLOGY OF STATUS EPILEPTICUS (SE) BASED ON DATA OF DELORENZO ET AL (1995)
Age Range Incidence* Mortality Major Past History Type Seizure Type Seizure Type Of
Per % Etiology Of Epilepsy In SE: In SE: Seizure In
100,000 % Partial % Partial To SE: GTCS %
GTCS
<1 year 156
1month-15 year 38 2.5 Non CNS 38 28 32 32

(pediatric) infection
(52%)
Low levels
(21%)
16-59 years 27 14 CVA: acute 54 24 43 27

(Adult, non elderly) or Remote
(>41%)
Low Level
(34%)
>65 -80+ 86 38 CVA: acute 30 Included Included Included

or Remote in Adult in Adult In adult
(61%)
Total 41-61 22 42
* These are minimum figures. Extrapolating from 1118 data for Richmond Virginia 10 1I1e total
U.S. papulation resul1s In an eslimate of 152,000 cases and 42,000 deaths per year.
The etiology of status epilepticus can be als of intravenous therapy with benzodi-
divided into three major groups: azepines.
I. Status in patients with prior seizures due This is a skeleton outline of management of
to (a) acute withdrawal or omission of medica- status for greater details see Delgado-Escueta,
tion (b) new metabolic factors and fever. 1982 and Pellock & Delorenzo, 1997.
(Group I constitutes 42% of all cases). SLEEP STAGES: ANATOMICAL
II. Status as an acute or remote effect of a BACKGROUND
focal process most frequently a cerebrovascular Sleep is characterized by a sequence of clin-
accident (CVA). However, frontal lobe tumor ical and EEG stages (figure 29-14): Stage W:
or abscess may also be the underlying focal Awake -alpha rhythm of 8-13 Hz with sup-
process. pression of alpha rhythm and emergence oflow
III. Status as the acute manifestation of sys- voltage fast activity on eye opening or intense
temic disease such as non-CNS infection in arousal. Stage 1- drowsiness ~ecease in alpha
infants or children (52% of all cases in this age amplitude and emergence of intermittent 4-7
group), and alcohol withdrawal or metabolic Hz theta activity. Stage 2- early sleep -high
factors or hypoxia in the adult. amplitude diphasic or triphasic sharp waves are
Treatment has 4 essential components: present over the vertex areas-termed K com-
(1) Assure stability of vital functions: plexes, or vertex sharp waves intermixed with
(a) Airway (b) Breathing (c) Circulation: main- 14-15 Hz spindles. Stage 3 & 4 are character-
tain blood pressure in normal range (d) main- ized by increasing amounts of 0.5-3 Hz delta
tain temperature in normal range (generalized slow wave activity (3 =delta 20-50% of the
seizures will produce hyperthermia due to cen- time, 4=delta >50% of the time). Stages 2,3,4
tral mechanisms). Draw blood levels are referred to as slow wave or NREM (non
and chemistries. Administer intravenous 50% REM) sleep. Stage Rem After 90 minutes in
glucose. the normal human, there then emerges a dif-
(2) Stop the seizures: intravenous benzodi- ferent stage of sleep characterized by low
azepines: lorazepam, (0.1mgjkg at rate ofl-2 amplitude alpha rhythm and fast activity, rapid
mg/min to maximum dose of 8 mg) or eye movement and a loss of muscle tone. This
diazepam (5-20 mg at rate ofl-2 mg/min), or stage is also called paradoxical sleep since the
midawlam. individual is deeply asleep but the EEG corre-
(3) Prevent additional seizures: load with sponds to a stage of relative wakefulness. This
intravenous fosphenytoin (18-20 mg/Kg at stage is associated with dreaming.
rate of 50 mg/min). BRAIN STEM, DIENCEPHALIC
(4) Determine the cause: this will require AND CORTICAL STRUCTURES
EEG and CT scan or and lor MRI, blood lev- INVOLVED IN CONSCIOUSNESS
els, etc as well as neurological examination and AND SLEEP.
observation of the seizures. Must still make REM sleep: recent studies have indicated
distinction - focal versus generalized. an interaction of several areas in the brain stem.
(5) If status does not end rapidly at the Cholinergic neurons in two nuclei located in the
emergency room level continued intensive care pontomesencephalic tegmental area of the
unit monitoring, including continuous EEG reticular formation: the pedunculopontine
will be required. General anesthesia including tegmental (PPT) and the lateral dorsal tegmen-
intravenous pentobarbital may be required. tal (LDT), discharge during REM sleep. These
(6) Non-convulsive status: For acute onset neurons send fibers to the thalamic relay and
of confusional states, consider the diagnosis of reticular nuclei. In contrast, during REM stage
complex partial and absence status: The diag- of sleep there is an inhibition of activity in the
nosis will depend on immediate neurological serotoninergic neurons in the midline raphe
examination and immediate EEG as well as tri- nuclei of the pons and medulla, in the nora-
29-24 CHAPTER 29
TABLE 29-12: ROLE OF FOREBRAIN, DIENCEPHALIC AND BRAIN STEM STRUCTURES IN SLEEP AND COMA
STRUCTURE BEHAVIORAL CHANGE EEG CHANGE

Basal forebrain, preoptic, orbital Induction of sleep, Slow wave stage of sleep
frontal: stimulation
Rostral (anterior) hypothalamus:

preoptic, suprachiasmatic
-Lesion* -Insomnia -Desynchronized. Aroused
-Stimulation (low frequency) -Decreased spontaneous activity
and of muscle tone
Caudal hypothalamus +upper midbrain

-Lesion* -Hypersomnolent -Slow wave pattern
-Stimulation (lOW frequency) -Behavioral activation.
Lateral hypothalamus-Iesion* Periodic narcolepsy/cataplexy
Thalamus
-Anterlor/dorsomedlal
---Lesion ---Insomnia
---Stimulation ---Sleep induced ---Slow wave
-Intralaminar system
---Lesion ---Lethargy
---StimUlation (high frequency) ---Wakefulness ---Desynchronized aroused
Mesencephalic reticular formation

-Lesion -Coma -Slow waves with no arousal
-Stimulation (high frequency) -Shifts animal from sleep to wake -Shifts from slow to low volt fast
Midline raphe nuclei pons and medulla Amarked increase in the total duration Persistent awake pattern
serotonergic neurons: lesion of wakefulness. Sleep decreased
by 80 -90 0/0
* Hypothalamic lesions based on neuropathologic correlafion s1udles 01 Von Economo In encephalitis lelharglco.
otherwise s1udles 01 Hess (1949)
drene1lJic neurons of the locus ceruleus in the growth hormone and of cortisol. Most non-
pontine tegmentum and in the histamine1lJic primate mammals sleep during the day and are
nuclei in the hypothalamus. Thus it is possible awake at night. Primates, in general, sleep at
to speak of "REM on", as opposed to "REM night and are awake during the day. It is also
off neuron~". (See reviews of Steriade, 1992 evident that, these cyclic rhythms are also
and Chokoverty, 2000 and table 12). Both the altered by the light dark cycle. Experimental
cholinergic and the monoamine areas appear to studies reviewed by Moore (1990), indicate
be controlled by the ventrolateral preoptic that in the presence of constant light (referred
nuclear complex (Lu et al, 2000). Table 29-13 to as free running), the cycle still occurs and
summarizes the relationship between these TABLE29-13: RELATIONSHIP OF BRAIN STEM NEURONS
centers in relation to sleep stages. AND SLEEP STAGES (ARER SAPER ET AL 2001)
Circadian Timing System And
Anatomical Basis Of Sleep Wake Cycles: Transmitters! Awake Slow REM Stage
Sleep-wake behavior, occurs on an alternating neurons Stage Wave
cyclic basis, referred to as circadian. Other Stages
endocrine and hypothalamic functions also are Cholinergic 2+ 0 2+
subject to rhythmic variations over the period
of approximately 24 hours. e.g. secretion of Monoamines 2+ 1+ 0
that the pacemaker for this rhythmic cycling is Figure 29-14. Polysomnogram.An all night 7-hour
located in the suprachiasmatic nucleus of the sleep study demonstrating the periodicity of sleep with
hypothalamus. The major projections of the the rapid eye mwement (REM) stage (arrow on inter-
suprachiasmatic nucleus are to other nuclei of rupted block line) occurring at 60-90 minute inte1'1'als.
the hypothalamus - primarily to the anterior ~ote that in addition to sleep stages, snoring, respira-
hypothalamus. The hypothalamus has recipro- non, EKG, mwements, arousals and oxygen satura-
tion are all recorded. (Courtesy of Sleep Disorders
cal connections to the brain stem reticular for-
Institute of Central New England /DR. Jay Phadke)
mation and projects to the nucleus basalis and Refer also to Fig. 29-16.
to the cerebral cortex.
Additional studies have demonstrated a • Both conditions may occur rarely on a
neurological basis following lesions of the ros-
retinal hypothalamic pathway and a lateral
tral hypothalamus and preoptic area or anteri-
geniculate hypothalamic pathway to this nucle-
or or dorsomedial thalamus (Lugaresi -1992).
us allowing for the entrainment of this nucleus
by visual, light dark influences. An additional • An infrequent cause of fragmented sleep
with frequent awakenings is central sleep apnea
input is also present from the serotonin secret-
which may be due to the following conditions:
ing neurons of the midbrain raphe nucleus.
a. autonomic system lesions, b. high spinal
The secretion of melatonin by the pineal gland
cord lesions, e.g., bilateral cordotomy for con-
is regulated by the suprachiasmatic nucleus.
trol of pain, c. medullary lesions, d. abnormal-
This hormone, in turn, can significantly modi-
ities at the craniocervical junction, e. muscular
fY the cyclic activity of neurons within the
disorders, £ congestive heart failure. The
suprachiasmatic nucleus.
DISORDERS OF SLEEP:I. Insomnia, changes in blood gases may result in significant
effects on cardiac rhythm, sudden death may
II. Excessive Daytime Sleepiness.
occur.
I. Insomnia is defined as an inability to
enter a state of sleep. Hyposomnia is defined • The most common medical condition asso-
as a reduction in sleeping time.
ciated with insomnia relates to anatomical prob-
29-26 CHAPTER 29
• The most frequent causes of disorders

affecting the initiation and maintenance of
sleep (the insomnias) relate to non-neurological
factors (1) poor sleep hygiene including excessive
daytime sleep in elderly patients, (2) Underlying
psychiatric disorder, (3) pharmacologic factors,
(4) Alterations in sleep wake cycle, jet lag, etc
n. Excessive daytime sleepiness: As with
insomnia - the major causes of excessive som-
nolence, particularly daytime somnolence, are
not associated with specific neuropathological
causes.
-In most patients excessive daytime sleepiness
is a reflection of poor nighttime sleep. This
includes sleep apnea such cases may be studied
with all night sleep studies utilizing polysomnog-
Figure 29-15. Extessive daytime sleepiness. cr scans raphy.
which had been normal 7 years previously now. -Specific neuropathological lesions producing
Demonstrated bilateral thalamic paramedian infarcts somnolence are not common, Tumors or
confirmed on MRI. Angiograms, echocardiogram and encephalitis or infarcts (Figure 29-15) involving
CSF were normal and EKG nonspecific. This 64-year- the areas cited in table 29-12 may produce som-
old riglrt handed usually extroverted male had the
nolence (Culebras, 1992).
acute onset of excessive nocturnal snoring and the fol-
lowing day foil asleep on multiple occasions even while -Narcolepsy: Narcolepsy is a disorder char-
driving. He also had a change in personality,failure acterized by paroxysmal attacks of sleep and of
to complete his thougJrts, and problems in recognition of a desire to sleep. Following a period of sleep
familiar photographs. Examination, 6 days later, that varies from minutes to hours, the patient
demonstrated only hypertension (l80/100), a subdued awakens refreshed. As in normal sleep, the
appearance a decrease in spontaneous speech and finger patient can often be aroused from sleep by
agnosia. He returned to baseline within 3 weeks and
had no additional episodes over the next 4 years. strong stimulation. Most cases have no known
structural pathology and the neurological
lems of the airway. For example, patients with
examination is normal. At times, a family histo-
sleep apnea syndrome, particularly obstructive
ry of a similar disorder is present. The specific
sleep apnea syndrome (who as discussed below,
genetic aspects are not clear, whether multifac-
also manifest excessive daytime sleepiness), will
torial or autosomal dominant remains uncer-
have frequent nocturnal awakenings. These
tain. There is a relationship to the HLA (HLA
patients who may be obese or have abnormali-
= Human leukocyte antigen - histo compatibil-
ties of the pharynx, or short crowded necks
ity complex) located on chromosome 6, linked
may have collapse of the pharynx and cessation
gene - DW-2 (see Honda and Matsuki, 1990).
of airflow, while diaphragmatic efforts contin-
There is no relation to epilepsy.
ue, often resulting in snoring. More important
from a physiological standpoint, hypoxemia
2The effects of hypoxemia, of C02 retention and
often occurs (arterial p02 actually falls as mea-
of the apneas - are much more complex. The
sured by pulse oximetry) and C02 retention
responses ofthe respiratory centers to hypoxia and
also occurs. With or without the fall in p02,
hypercapnia may be altered (see Grunstein and
the decrease in airway results in increased
Sullivan, 1990). Changes in heart rate and
diaphragmatic effort and frequent arousals
rhythms may occur with fatal arrhythmias -
with fragmentation of sleep. As a result, the
resulting in sudden death during sleep (see
patient has excessive daytime sleepiness. 2
Krieger, 1990).
As regards the underlying basis for nar- MUlTlF't.E SLEEP LATENCY TEST
TImo"'OIofo
colepsy, recent studies summarized by Silber , 2
,_,0
~ • 5
010' 02 ,000'.30 14:00-'. 15.-01 '2
and Rye (2001) indicate a marked decrease in I~~
_.ta..cy
_2ta..cy
,0
:LO
2.5
SO
:1-0
'0
15
<0
)0
so
the content of a peptide, hypocretin-I (Hert- =t!...~ .~ ,u
I) synthesized by the cells of the ventral and
lateral hypothalamus in the brains and CSF of
patients with narcolepsy. These neurons inner-
vate all of the cholinergic and monoaminergic
arousal centers discussed above. Many of the
patients with narcolepsy manifest other periodic
disorders that occur frequently enough to be
grouped within the tetrad of the narcolepsy syn-
drome: cataplexy, sleep paralysis and hypnogenic Figure 29-16. Narcolepsy. Multiple sleep latency tests
hallucinations. demonstrating mean sleep latency for 5 naps of2 min-
Cataplexy refers to a sudden loss of muscle utes with REM onsets in the first 2 naps at 4.5 and
tone and of postural reflexes, usually occurring 12.5 minutes. In contrast the all night sleep study
in relation to laughter or sudden emotional demonstrated sleep onset at 6.7 minutes and REM
onset at 60-90 minutes. This 32-year-old woman had a
stimulation. Sleep paralysis refers to episodes of 7-year history offalling asleep during the day, ifsit-
inability to move and occurs in relation to the ting at the table or in a car. She also had episodes of
process of falling asleep or awakening. sleep paralysis. Her mother had narcolepsy. (Courtesy
Hypnogenic hallucinations are vivid sensory, of Sleep Disorders Institute of Central New England
dream- like experiences that occur upon awak- /DR. Jay Phadke) Stages =stages of sleep, R =REM.
ening. Many aspects of the narcolepsy syn- episodes do not occur for 90 minutes). In the
drome have been related to the desynchro- multiple sleep latency tests, five daytime, 20-
nized, rapid eve movement (REM) stage of minute naps are offered at 2-hour intervals.
sleep. Thus, the multiple sleep latency tests will Mean sleep latency and mean REM sleep laten-
demonstrate the early occurrence of periods of cy after onset of sleep are calculated. Patients
desynchronized sleep and rapid eye move- with narcolepsy have daytime sleep latencies of
ments in these patients shortly after onset of approximately 2-3 minutes, control subjects 7-
sleep (as contrasted to normal where such 12 minutes. Within the 20-minute nap peri-
TABLE 29-14: ETIOLOGY OF COMA OF ACUTE ONSET. ADAPTED FROM PLUM &POSNER (1966)
M.=AJ..:::.O
= R..:....:C
::.:.:
A:.:.::
TE:.::.G=OR..:.:.y_.....:..F.:.::
RE=-=Q:=
UEc..:.:
Nc.=..Cy'----_.....:..:..:
M= EC:..:...:
H:..:cAN=IS:..:..:.M,-- _ _ ---=E:.c.:
VA.=LUATION
Toxic/metabolic/diffuse 68% Diffuse biochemical disorder, Early depression of consciousness
e.g. alcohol intoxication without focal findings
hypoglycemia, overdoses,
ketoacidosis, anoxia, encephalitis,
Supratentorial 18% Herniation due to mass lesions Lateralized hemisphere findings before
with compression of brain stem brain stem findings then herniafion
e.g. tumor or abscess of temporal lateral (ipsilateral fixed dilated pupil
lobe, intracerebral hemorrhage, then bilateral findings) or central
massive MCA infarct (Cheyne Stokes respiration then bilateral
midbrain with bilateral fixed pupils)
with progressive rostral-caudal
deterioration of brain stem function
Infratentorial 10% Direct damage to brain stem: Onset with brain stem findings usually
basilar artery thrombosis, bilateral e.g .. Bilateral pyramidal tract
pontine hemorrhage and pontine findings
- -- --- - -- - - --- - - - -- -- --
29-28 CHAPTER 29
ods, all patients with narcolepsy will have two consciousness does not exist. Thus patients with
or more REM periods. (REM within 15 min- cerebral anoxia resulting in wide spread lami-
utes of sleep onset is referred to as REM onset nar necrosis of the cerebral cortex are in a state
sleep as demonstrated in Fig.29-16). In the of irreversible coma.
human, the most effective agents in preventing Care Of The Comatose Patient: Several
the narcolepsy are those drugs that enhance general rules must be followed if life is to be
the presynaptic release of norepinephrine. preserved in the comatose patient until such
Agents include methylphenidate and pemo- time as recovery has occurred. The ABC (air-
line. The tricyclic antidepressants, such as Pro- way, breathing, circulation) approach has
triptyline are effective in preventing the cata- already been presented in relation to the man-
plexy, through blockage of norepinephrine and agement of status epilepticus. The patient must
serotonin re-uptake. be placed on the side and turned every two
hours to avoid aspiration and passive conges-
COMA IN MAN tion of the lungs. This will also serve to avoid
In discussing depression of consciousness in decubitus ulcers. Joints must be manipulated
man, we will consider separately two aspects: passively through their full range of motion
(1) the patient who presents at the emergency several times per day to avoid contractions. The
room or on the general wards of the hospital legs should be protected from the weight of
with acute of subacute onset of coma; (2) the bedclothes by cradle. Sand bags should main-
patient with prolonged depression of contain physiological ankle extension. Pressure
sciousness. areas should be protected by foam rubber to
Emergency Onset Of Coma: In the emer- avoid decubitus ulcers.
gency room evaluation of the patient in coma Suctioning is required at period intervals to
of relatively acute onset, the physician is con- avoid aspiration of nasal and oral secretions.
cerned with the differentiation of three gener- While the intravenous route may provide fluids
al etiologic categories as presented in table 29- and glucose temporarily, this will not allow
14: administration of adequate protein, lipids and
Prolonged Disturbances Of carbohydrates. Careful nasogastric feeding will
Consciousness: There are two major causes be required to maintain nutritional status, in
(1) intrinsic diencephalic and mesencephalic dis- the short term. After 7-10 days, if swallowing
orders as in infarcts or infiltrating gliomas (As reflexes have not returned, the placement of a
discussed above von Economo's encephalitis percutaneous gastrostomy or jejunostomy
was once included in this category) (2) disor- should be considered. Nutritional intake and
ders producing a diffuse loss of neurons in cere- urinary output must be recorded. A condom
bral cortex as in cardiac arrest with anoxic catheter or indwelling catheter will be required
encephalopathy and laminar necrosis. with periodic replacement. Urinary tract and
An apathetic-drowSy state may occur in respiratory infections must be treated with
relation to bilateral infraction of the frontal antibiotics but prophylactic antibiotics should
lobe and basal forebrain territory within the not be administered. Constipation and fecal
distribution of the anterior cerebral arteries, as impaction should be avoided by the periodic
in anterior communicating-anterior cerebral use of mild cathartics. Enemas may be
aneurysms. required. Low dosage cutaneous heparin may
It is evident then that from an anatomical be administered to prevent thrombophlebitis.
standpoint, the conscious state reflects a com- For more complete discussion see Ropper and
plex interaction between brain stem structures, Kennedy 1988, and Weiner 1992.
diencephalic structures, and the basal forebrain Prognosis In Coma: Management of the
areas on the one hand, and the cerebral cortex neurological patient includes not only diagno-
on the other. Without functional neocortex, sis of the underlying location of lesion and of
the underlying neuropathology but also assess- Failure to regain brain stem reflexes by 24
ment of the prognostic implications of the hours, is an extremely poor prognostic sign,
diagnosis. From the standpoint of advice to the essentially no patient recovers. At one day, the
family of the comatose patient, and from the absence of motor withdrawal and of sponta-
standpoint of allocation of limited, costly neous eye movements was associated with 95%
intensive care resources, early assessment must in recovery or vegetative state and severe dis-
be made as to the likelihood of survival and ability in 4%. If brain stem reflexes have recov-
recovery. This is best done in a uniform, repro- ered by 24 hours, failure to regain conscious-
ducible and if possible, quantitative manner. ness by day three, has a poor prognosis, failure
Considering coma in general, prognosis also to regain signs of consciousness by day 7, an
relates in general to age of patient and etiology. even bleaker prognosis. At 7 days, absence of
The prognosis for patients with coma sec- motor response to commands and absence of
ondary to head injuries or intracranial hemor- spontaneous eve movements - was associated
rhage, often is better than for patients with with no recovery or vegetative state outcome
coma secondary to cardiac arrest. For such in 100% of cases. (See Maiese and Caronna,
patients, the standard method utilized is the 1988).
Glasgow Coma Scale. Values are assigned for The use of the EEG and of evoked may also
(a) degrees of eye opening (E) Spontaneous = be of help in assessing prognosis. (Marcus and
4; nil = 1: (b) best motor response (M) obeys Stone, 1984).
= 6; nil = 1: (c) verbal response (V) oriented =
5. Nil = 1. The total coma scale is then com-
puted E + M + V and may range from 3-15.
There is a clear-cut correlation: patients with a
low scale are unlikely to recover; those with a
high score are very likely to survive with a good
quality of survival.
Essentially, most patients with cardiac arrest
outside of the cardiac intensive care unit have a
very poor prognosis. For assessing recovery
after hypoxic ischemic coma or other forms of
non-traumatic coma, Levy et al (1985) have
utilized evaluation of brain stem reflexes:
(including eye movements, corneal and pupil-
lary responses), motor responses and verbal
responses. Patients who, at first assessment,
within the first 24 hours (usually at 6 or 12
hours after onset), had no corneal, pupillary or
oculovestibular (caloric) responses, did not
recover or remained in a chronic vegetative
state, in 97% of cases. Only 1% had a good
recover or moderate disability. By 24 hours, if
three of the following (corneal, pupillary or
oculovestibular, or motor responses) were not
reactive, 98% remained in vegetative state or
had no recovery.
Absence of pupillary responses at initial
examination was associated with no recovery or
vegetative state in 94%, severe disability in 6%.
CHAPTER 30
Learning, Memory, Amnesia, Dementia, Instinctive
Behavior and the Effects of early Experience
DEFINITIONS of the nervous system. The process may be sta-

( 1 ) Learning: a relatively permanent tic or progressive. Included in the definition in
addition to the focal disorders involving hip-
change in behavior that results from practice
or experience. Learning is the process of pocampus and diencephalon are more gener-
acquiring knowledge about the world alized disorders such as dementia, amentia and
(Kupperman, 1991). This definition implies mental retardation.
(6) Dementia: A progressive impairment of
plasticity in central nervous system function
and it also implies plasticity in the formation of previously intact mental faculties without loss
stimulus response connections. The definition of consciousness. In general, in the most com-
excludes changes in behavior result-ing from mon type, Alzheimer's disease, the loss
involves initially and most severely recent
maturation, sensory adaptation and fatigue.
(2) Memory: the processes or neural
memory and the ability to learn and retain new
mechanisms involved in the encoding and memories. To some extent, particularly as
storage or repre-sentation of an experience time passes, other areas of mental capability are
and the retrieval of that information. At times also affected: remote memory, abstract reason-
the definition is restricted to the "read in" ing, insight, arithmetic abilities, language func-
consolidation and storage stages and the terms tion, personality mood and social behavior. In
remembering and retrieval are defined as the other types personality is initially affected, fol-
"read out phase" of learning. lowed later by memory.
(3) Instinctive behavior: complex behav-
(7) Amentia: The term amentia implies a
ior occurs on the first presentation of the trig- non-progressive congenital absence or relative
gering stimulus. Such behavior occurs in all deficiency of mental faculties. At times, in the
species even those raised in isolation. In birds, absence of an adequate history, the distinction
complex behavior may be triggered by hypo- may be difficult to make. The term mental
thalamic or midbrain stimulation. retardation is somewhat less specific, referring
(4) Imprinting: Not all behavioral pat- to retardation in the development of mental
terns are learned or instinctive. Certain behav- abilities or retardation in the development of
ioral patterns require exposure to a specific stim- intelligence.
ulus at a critical period in development. The LEARNING IN MAN AND RELEVANT
concepts of imprinting evolved from the study ANATOMICAL SUBSTRATE
of "following" behavior in newly hatched Classification of learning and the
chicks. Thus, chicks will usually follow their anatomical substrate: (Squire & Zola-
natural mother since during the specific critical Morgan, 1991, Desimone, 1992, Rolls,
period after hatching they are usually exposed 2000). Essentially two broad categories are
to the mother. However, if chicks do not considered:
encounter the mother but rather encounter a I. Declarative (Explicit) learning - This
man, they will tend to follow the man. Critical refers to the conscious recollection of facts or
periods in human postnatal development have events. This system is rapid; one trial may be
also been demonstrated. sufficient.
(5) Disorders of memory: This problem II. Non-Declarative (Implicit or
may reflect focal or more generalized disease "Reflexive") - This refers to a non-conscious
30-2 CHAPTER 30
alteration of behavior by experience. This type TABLE 30-1 TYPES OF LEARNING AND NEURAL SUB-
of learning is slow and requires multiple trials. STRATE
Table 30-1 presents the neural substrate for
these types of learning TYPE ANATOMICAL
SUBSTRATE
STAGES OF HUMAN MEMORY: I Declaranve: conscious, facts or events
DECLARATIVE LEARNING
-Stage 1: short terml Prefrontal
The terminology employed has changed working/immediate memory
with time particularly as regard the terms short
term and long-term memory. As presented in -Stage2: long term memory: Limbic system:
labile stage (TranscriptiOn! hippocampus-thalamus
table 30-1, there are essentially three major
transduction and
stages. consolidation)
Immediate or short term working
memory- This stage has been discussed in -Stage 3: long term memory: Diffuse cerebral cortex
chapter 18.This is a matter of seconds (esti- stage of remote memory
mated as dO seconds. Total capacity has been 11 Non Declarative: non conscious, reOexlve
estimated as less than 12 items. It is best exem-
plified in simple digit repetition as in digit span - Motor habH and -Cerebellum, striatum
testing or the immediate repetition of three or skill learning and motor cortex.
5 objects or the delayed response test utilized -ClaSSical and operant -Amygdala for emotional
in monkeys and children. Monkeys with pre- conditioning responses,
frontal lesions and infants less then 8 months -Cerebellum for
(presumably with immaturity of the frontal motor responses
function) are unable to consistently perform -Non associative learning: Reflex mechanisms of
the task. The neural substrate undoubtedly Sensitization·1 habituation)·· spinal cord and brain stem
involves the reception in the appropriate pri-
mary sensory projection area with relay to the -Priming: recall of words! Neocortex
objects improved by prior
adjacent sensory association cortex; for exam- exposure to these stimuli
ple, areas 18,22, 5/7 then transfer to the mul-
timodal posterior parietal cortex, then relay to *SensHization=increased response 10 non noxious stimuli
prefrontal area for very short term storage and aIIer presentation of noxious stimulus
then relay to motor association cortex and **Habiluation=decreased response 10 a benign stimulus
then to motor cortex if the information is to when this is presented repeatedly
be recited to the examiner (as in the digit span are involved in this stage. It should be noted
or immediate recall tests). that RNA turnover does increase in tissues
Long-term memory. Labile stage - This undergoing learning-like experiences. RNA
stage may be considered a transcription and turnover also increases in areas of neural tissue
transduction stage. The duration of this inter- subjected to repetitive stimulation. It is clear
mediate process has been variously estimated that interference with RNA synthesis or with
in infrahuman species as a matter of20 to 180 protein synthesis (by the use of the antibiotic
minutes. The time required is probably short- puromycin) interferes with this stage of mem-
er as one descends the phylogenetic scale. ory. Presumably, as we will discuss below, an
Theoretically, this stage involves the transcrip- accompanying change in synaptic connection
tion from a relatively localized reverberating is beginning to occur.
neuronal circuit, indicated in the immediate The neural structures involved are the
memory stage, into a more permanent macro- entorhinal cortex, parahippocampal gyri, the
mole-cular form of recording. It has been hippocampus, the fornix, and the anterior and
hypothesized that RNA and protein synthesis dorsal medial nuclei of the thalamus. (see
LEARNING AND MEMORY, AMNESIA AND DEMENTIA 30-3
Zola-Morgan and Squires, 1990, and below). influences and in general present in the infant.
These structures are inter-related as the "lim- There are learned, secondary drives or motiva-
bic system" previously discussed. From a clini- tional forces such as achievement, anxiety, and
cal standpoint, we evaluate this stage of mem- dependency. These are learned drives in the
ory with delayed recall test (list of 5 objects to sense that motivations, such as desire for
be remembered for 5 minutes)l and by asking acquiring money and fame, or particular fears
the patient to recite a paragraph ("cowboy"or or guilt are not present in the infant and are
"gilded boy story") that he has just read or not present in all members of a species. During
heard. This ability to learn and to retain new the process of development, previously neutral
experiences and new material is often referred cues may become attached to primary drives
to as retentive memory. Disturbance of this and take on the capacity to motivate perfor-
stage in memory will be considered later under mance. Some drives such as severe anxiety may
the topic of the amnestic-confabulatory syn- trigger responses that are not goal-directed,
drome. thereby interfering with learning. In contrast,
Long-term Memory: stage of Remote lesser degrees of anxiety may motivate perfor-
Memory - This phrase is not discretely local- mance.
ized. Rather, it represents a diffuse storage 2. Motivation also affects the central
throughout the cerebral cortex and possibly process of interpretation of stimuli (percep-
other areas of the central nervous system. tion). In a sense, what we see depends upon
Long-term memory would appear to relate what we wish to see and upon our frame of ref-
more to the actual volume of cortex remaining erence particularly where the stimulus is
intact than to any specific localized process ambiguous.
(consistent with the concept of Lashley). 3. Whether stimuli are perceived will also
Although not discretely localized, it must be depend on the general state of attention or
recalled that the read out mechanism for such alertness of the individual mediated by the
remote memories may be triggered by stimu- reticular formation. In addition prefrontal and
lation of the lateral aspect of temporal lobe in parietal cortex influence attention.
the particular abnormal situation of patients 4. At times retention may be intact but the
who are subject to complex partial seizures of search and read out mechanism may be tem-
temporal lobe origin (refer to Chapter 22). In porarily defective. This may account for the
such patients, ablation of the area that on stim- phenomena of shrinking retrograde amnesia
ulation produces the remote memory does not following head trauma.
abolish this remote memory. From a clinical
NEUROBIOLOGICAL MECHANISMS
standpoint, we evaluate this stage of memory
IN MEMORY AND LEARNING -
asking the patient to indicate his date of birth,
date of marriage, dates of World War I and II, The psychologist, Hebb, in 1949 had pro-
and so forth. posed that when in associative learning the
axon of neuron A - fires synapses on neuron B
FACTORS INFLUENCING in a persistent manner, a growth process or
LEARNING AND MEMORY metabolic change occurs in one or both neu-
In the consideration of the learning rons such that the probability or efficacy of
process, it is important to realize the influence neuron A firing neuron B is significantly
of several additional factors. increased. Subsequent studies (reviews of
(1) Motivational drives alter the rate of Kandel & Hawkins, 1992, Kandel & O'Dell,
learning. There are primary or instinctive dri- 1992) have confirmed these observations and
ves such as hunger thirst, sex present in all demonstrated that the synaptic connection
members of a species, irrespective of cultural between neuron A and B could be strength-
ened by a third (modulatory neuron) - acting
1 Other tests utilize 3 objects for 3 minutes.
30-4 CHAPTER 30
to enhance - release of transmitter from the cortical area so that eventually spontaneous
terminals of the presynaptic neuron. If neuron seizures occur. Both the mirror focus and kin-
A and the modulatory neuron -discharged dling have been proposed as possible demon-
simultaneously, then the connection between stration models oflong-term synaptic changes
neuron A and B would also be strengthened in that may be involved in learning. That is, the
an associative manner in a variety of classical alteration of neuronal function as a result of
conditioning and in the hippocampus in rela- experience.
tionship to spatial learning. Subsequent studies (3) Modification of cortical motor and sen-
indicated that eventually the number of presy- sory maps. (See chapter 17). These maps are
naptic terminals was increased providing an not fixed but instead have a plasticity, which
anatomical basis for this type of learning. can be modified by experience.
Long-term potentiation: Bliss and Lomo (4) The corpus callosum also has a role
(1973) demonstrated that brief, high frequen- in learning. Thus, a monkey or human
cy trains of action potentials within each of the trained to carry out a task with one hand, e.g.,
three major pathways of the hippocampus how to follow a maze or somatosensory dis-
would produce a long lasting increase in crimination, for roughness, etc., does not have
synaptic strength in that pathway lasting for to relearn that task when the other hand is uti-
hours in the anesthetized animal but for days lized - a rapid transfer of the learned skill or
and weeks in the alert, freely moving animal. discrimination has occurred.
The CA3 to CAl Shaffer collateral pathway (5) Early Experience And Postnatal
and the perforant-afferent pathway to the den- Brain Devdopment (Refer to Spitz, 1945,
tate gyrus have associative learning properties Harlow, Lewis et al1990, Siegel et al, 1993,
and the model of Hebb is followed. The pre Martine al 1991, Sirevaag& Greenough,
and postsynaptic neurons must fire simultane- 1985, 1987, Hubel &Wiesel, 1963). A num-
ously. The transmitter involved is glutamate. ber of studies have demonstrated a significant
Both NMDA and non-NMDA receptors are effect of early environment of the Urlant animal
involved. Similar long-term potentiation has or human at critical periods on later brain
been subsequently demonstrated in other development and function. These observa-
areas of cerebral cortex. The basic point to be tions may be related to the phenomena of
made is that long-term potentiation provides a imprinting. Beyond a certain critical age of 15
possible mechanism for the labile period of months in the human Urlant, and 6-12 months
memory - the transition period which main- in the Urlant monkey these changes related to
tains memories for hours, days and weeks, environmental deprivation are irreversible.
while more permanent transduction is occur- Cultural deprivation at a somewhat later stage
ring in terms of protein, RNA, etc. of childhood may also produce long-term
effects on psychological development. These
PLASTICITY IN THE
studies also demonstrate correlated changes in
NERVOUS SYSTEM
the microscopic structure and biochemistry of
(1) Mirror focus: Repeated experimental the cortex, or basal ganglia or hippocampus.
focal seizure discharge with repeated transcal- These considerations provide a biological
losal response will produce changes in the foundation for the use of "head start" pro-
excitability of the contralateral hemisphere so grams in preschool and primary grade students
that eventually an independent focal disharges from culturally deprived backgrounds. (Refer
develops. to Hellmuth, 1968.)
(2) Kindling: Repeated subthreshold
stimulation of the amygdala or hippocampus, DISORDERS OF RECENT MEMORY:
or of the frontal cortex in many species will THE AMNESTIC-CONFABULATORY
over time alter the excitability of widespread SYNDROME: WERNICKE-
KORSAKOFF ENCEPHALOPATHY:
Wernicke, in 1881, described a syndrome to learn by the examiner. A significant disori-
that is of relatively acute onset, occurring in entation for time is usually present. The
alcoholics or nutritionally deficient patients memory disturbance involves both retrograde
and consisting of a triad: mental disturbance amnesia (events prior to the illness) and antero-
(confusion and drowsiness), paralysis of eye grade amnesia (events since the onset of the
movements, and an ataxia of gait. The basic illness). The deficit in memory for recent
cause of the syndrome is a dietary deficiency of events may be transient, clearing with contin-
thiamine. As a deficiency of thiamine and of ued treatment, or may be more persistent. The
the other B-complex vitamins also results in a persistence of these disorders of recent memo-
peripheral neuropathy, symptoms relevant to ry and of the state of confusion as a chronic
this degeneration of peripheral nerves often phenomenon is referred to as KorsakofPs psy-
will be present as an associated finding. The chosis. In the studies of Victor et al, patholog-
basic pathological process consists of a necro- ical examination of the brain in these latter
sis of neural parenchyma and a prominence of cases revealed persistent lesions in the dorsal
blood vessels due to a proliferation of adventi- medial and anterior nuclei of the thalamus in
tial and endothelial cells. Petechial hemor- contrast to cases ofWernicke's encephalopathy
rhages also occur about these vessels. The without the persistent memory deficits. The
pathological findings involve the gray matter following case history illustrates the problem
surrounding the third ventricle, aqueduct and of Wernicke's encephalopathy.
the fourth ventricle. Lesions in general are Case 30-1. Patient of Doctor John
usually most prominent in the mammillary Sullivan and Doctor John Hills): This 62-year-
bodies and the medial thalamic areas. Table old, white, right-handed stonecutter had been
30-2 correlates the symptoms/signs with a known heavy alcoholic 6-8 week spree
lesion location drinker for many years. Two years previously,
The Memory Disturbance: As drowsiness the patient had been admitted to the Boston
clears it will often be noted that a severe deficit City Hospital because of delirium tremens
in recent memory is present, particularly if the (tremor and visual hallucinations). Two
patient has delayed seeking medical diagnosis months prior to admission shortly following
and treatment. The patient will be unable to the death of a brother-in-law, the patient
learn new material. He will have little memory began his most recent drinking spree.
of events surrounding his illness but will have Apparently, he had drifted aimlessly for 5
little difficulty recalling events in the distant weeks with no definite food intake for a
past. The patient may demonstrate confabula- month. He unaccountably found himself in
tion supplying imaginary answers for questions Florida, not knowing where he was and why
concerning the recent past and for questions he was there. The patient was brought back by
involving new material he has been requested his £unily and hospitalized at his local commu-
TABLE 30-2: WERNICKE'ENCEPHALOPATHY
SYMPTOMISIGN LESION LOCATION EFFECT OF THIAMINE

Ophthalmoplegia (bilateral) Predomlnanlly CN VI, less of 1111 Rapid, reversal hours to days
Nystagmus Vestibular nuclei Clears over days
Drowsiness Perlaqueductal greyl Clears over days

Perivenlricular diencephalon
AtaXia: galt &heelto shin Anterior superior vermis cerebellum Hsevere may persist as
alcoholic cerebellar degeneration
ConfuSion/memo!}, defiCit Dorsal medial/anterior thalamic nuclei If persists: Korsakoff psychosis

30-6 CHAPTER 30
nity hospital with diplopia, ataxia, marked Clinical diagnosis:

impairment of memory and complaints of 1) Wernicke' encephalopathy
numbness of his fingertips and unsteadiness of 2) nutritional poly neuropathy
gait. After beginning treatment, he was trans- Hospital course: The patient was treated
ferred to a neurological center with thiamine. There was a significant
General physical examination: enlarged improvement in extraocular functions. The
liver with the edge palpated approximately 2- patient had no diplopia after the day of admis-
1/2 finger breadths below the costal margin. sion. There was no significant change in his
Neurological examination: Mental sta- mental condition or peripheral neuropathy.
tus: The patient was markedly disoriented for Evaluation 3 months later indicated persistent
time and place Confabulation was also evident disorientation for time and place and severe
when it was suggested that he had recently selective deficits in memory (delayed recall was
seen various fictitious persons or was in partic- still grossly defective) suggesting a residual
ular locations. The patient was unable to state Korsakoff psychosis.
his age but could provide his birth date. He In many cases, the state of confusion in
was confused with little insight as to his disori- Wernicke's encephalopathy is preceded by or
entation, or his condition. At times, the accompanied by a period of delirium tremens
patient often indicated to visitors that his indicating alcohol withdrawal. The use of
mother and father were still alive, though both intravenous glucose feedings without supple-
parents had been dead for over 20 years. The mental intravenous thiamine during such a
patient's digit span was normal at 7 forward withdrawal state may actually increase the
and 6 in reverse. The patient could name vari- requirements for thiamine, thus exacerbating
ous objects correctly when these were present- the thiamine deficiency state. For this reason,
ed to him and yet he was unable to retain any all patients under treatment for alcohol with-
memory of which objects had been presented drawal (or admitted to the hospital with a
to him five minutes previously. He was unable recent past history of alcoholism) should be
to retain any information concerning a story treated with high dosage B vitamin therapy as
that he had been requested to learn. well, on the presumption that they are candi-
Calculations reading and writing were intact. dates for nutritional deficiency.
Cranial Nerves: There was horizontal diplop- In general, as we have indicated, the major-
ia on right lateral gaze. A minor weakness of ity of patients with Wernicke's encephalopathy
the right lateral rectus was suspected3 . progress to a more persistent memory distur-
Honwntal nystagmus was present on lateral bance. Victor and Adams reported that 75
gaze, bilaterally and vertical nystagmus on ver- percent of their 86 cases progressed to a per-
tical gaze. Motor System: a minor degree of manent amnestic confabulatory syndrome.
weakness was present in the distal portions of The Korsakoff syndrome with its particular
the lower extremities. There was no longer an deficits in memory may also occur in other dis-
ataxia of gait but a positive Romberg test was ease states involving the diencephalon:
present. Reflexes: Deep tendon reflexes were ( 1) Tumors involving the posterior but not
absent at patellar and Achilles even with rein- the anterior hypothalamus affect recent mem-
forcement. Sensory System: Pain and touch ory.
were decreased in the lower extremities below (2) Infarcts of the medial or anterior but
the mid calf Vibratory sensation was absent at not the posterior thalamic areas may also pro-
the toes and decreased over the tibia to a duce defects in recent memory. Refer to case
marked degree and to a lesser degree over the 30-7 and Fig. 30-10 below. In the study of
knees and at fingertips and wrists. Position von Cramon et al (1985) a combined lesion of
sense was decreased at fingers and toes. both the mamillothalamic tract and the ventral
portion of the lamina medullaris interna were
most effective in producing amnesia. (See also (1958). These observations stimulated consid-
Graff-Radford, et al, 1990 and Tatemichi, et erable clinical and experimental investigation.
al,1992) Extensive studies in the monkey by Squire and
(3) Lesions of the fornix may also be asso- Zola-Morgan (1991) have now clarified the
ciated with significant problems in memory relative roles of these structures.
recording. Such damage is likely to occur with Essentially, monkeys with selective bilateral
colloid cysts or with the surgical procedure lesions of the hippocampus are impaired in
necessary to remove this potentially life-threat- memory tasks that involve the ability to
ening nonmalignant tumor (see-Fig 27-11). acquire new information (declarative memory)
The effects are most prominent if bilateral but but are not impaired in their capacity for skill
may also occur with unilateral left-sided dam- and habit learning (that is, non-declarative
age. Recall that the fornix is the major outflow memory). The type of task employed by
pathway from the hippocampus. Defects in Squire and Zola-Morgan is the delayed non-
recent memory have also been reported in matching to sample: A single object is present-
tumors involving the posterior or anterior por- ed; after a delay, two objects are presented -
tion of the corpus callosum. the original object and a novel object. The ani-
(4) Lesions of the basal forebrain as in mal is rewarded for choosing the novel object
anterior communicating artery rupture. (Irle and rapidly learns to select the novel object.
et al, 1992 Morris et al 1992) may produce Monkeys with selective bilateral lesions of hip-
persistent anterograde and retrograde pocampus, parahippocampal and entorhinal
amnesia. cortex were even more impaired than mon-
BILATERAL LESIONS OF keys with a selective hippocampal lesion. The
HIPPOCAMPUS (BILATERAL entorhinal/parahippocampal areas receive
MESIAL TEMPORAL LOBE input from all of the higher sensory association
neocortical areas and then project via the per-
LESIONS):
forant and alvear pathways to the hippocampal
The anatomy of the hippocampus and its formation. There are however other inputs to
connections has been considered in detail in the hippocampus. Monkeys with bilateral
chapter 22, and should be reviewed at this lesions of the perirhinal cortex and parahip-
time. pocampal cortex sparing the hippocampus also
Bilateral Ablation: Scoville and Milner demonstrated severe impairment on these
(1957) were the first to observe the effects of same memory tasks. Combined bilateral
bilateral mesial temporal lesions following lesions of hippocampus, parahippocampal
bilateral ablation of the anterior two-thirds of gyrus and perirhinal cortex produce greater
the hippocampus and the parahippocampal impairment of memory than the selective
gyrus with removal of the uncus and amygdala lesions of hippocampus and parahippocampal
(Corkin et al, 1997). This surgical procedure gyrus. Monkeys with selective bilateral lesions
had been performed for treatment of temporal of entorhinal cortex demonstrated impairment
lobe epilepsy in a patient who had bilateral but recovered when retested at 9-14 months
temporal lobe epileptic spike foci. Following (Leonard et al, 1995). All of these monkeys
surgery, a gross loss of the ability to retain cur- had no impairment of remote memory.
rent experiences and to learn new material was Monkeys with lesions of the amygdala demon-
noted, in addition to a significant retrograde strated a marked alteration in emotional
amnesia. Remote events were well recalled. It behavior but had no impairment on memory
should be noted that a similar defect might fol- tests (see chapter 22 and Zola-Morgan et al,
low unilateral ablation of the temporal lobe 1991).
structures if disease were present in the con- While most patients with bilateral medial
tralateral temporal lobe (Penfield and Milner temporal lesions have both retrograde and
30-8 CHAPTER 30
anterior grade amnesia, several recent studies ment of the occipital cortex. In these cases,
have allowed a differentiation of these two transient episodes may occur and may be diffi-
aspects of amnesia. Zola-Morgan et al, 1986, cult to distinguish from the syndrome oftran-
reported that a patient with selective bilateral sient global amnesia.
lesions of the entire rostral caudal extent of We should note at this point, that the pos-
field CAl of the hippocampus (due to global terior cerebral arteries via their penetrating
ischemia) had enduring anterograde amnesia branches also supply the medial diencephalic
but minimal retrograde amnesia. Rempel- areas. Such ischemia in the posterior cerebral
Clower et al, 1996, confirmed this in an addi- circulation, then, might well produce ischemia
tional group of three patients. On the other of the dorsal median nucleus, the anterior thal-
hand, Kapur et al (1992) described a patient amic nuclei, and the mammillary bodies. Thus,
with a closed head injury who had severe post- in the case of persistent memory deficit fol-
traumatic retrograde amnesia (extending back lowing posterior cerebral artery lesions report-
to childhood) but only mild patchy antero- ed by Victor et al (1961), the areas ofinfarc-
grade amnesia. On MRI scan, there was bilat- tion involved not only the hippocampal for-
eral damage to anterior temporal cortex and to mation and fornix but also the mammillary
a lesser degree prefrontal areas. There was no bodies. An example of bilateral medial thalam-
damage to hippocampus, thalamus or other ic lesions producing alterations in recent mem-
limbic structures of the diencephalon. ory has been provided in Chapter 29.
Disease involving the medial temporal Unilateral Infarcts: The study of Ott and
areas may occur under a variety of circum- Savez (1992) demonstrated the occurrence of
stances and may result in an inability to retain the amnestic syndrome following infarcts
current experiences and to learn new material. within the territory of the posterior cerebral
Material learned and already stored in long artery involving the hippocampus or the thal-
term remote memory will be intact. In the amus. In 85% of unilateral infarcts, the lesion
clinical discussion that will follow, we will often was left sided.
be considering the medial temporal areas in a Transient Global Amnesia Syndrome:
more general sense. As already noted early This syndrome involves the sudden onset of a
cases of destruction of medial temporal areas defect in memory. The memory deficit is sim-
were nonselective. Damage to hippocampus ilar to that which occurs in the amnestic con-
also included damage to amygdala and the fabulatory syndrome seen in Wernicke's
adjacent cortex. encephalopathy. There is a significant retro-
Bilateral Infarction - Bilateral infarction grade amnesia for the events of the preceding
of the hippocampal areas may occur with dis- days, weeks, and months. This retrograde
ease of the posterior cerebral artery (Victor et amnesia slowly clears over a period of hours.
al, 1961 and De Jong et al1969). Occlusions The patient has a persistent amnesia for the
of the posterior cerebral arteries usually reflect period between the onset of the attack and the
embolic events with the embolus originating point of complete recovery. During the period
in the heart or at a lower level in the vertebral of the episode, the patient is unable to learn
basilar circulation. The ischemia or infarction new material, that is, the patient is unable to
of the mesial temporal areas may be accompa- register new memories. Apart from this defect,
nied by ischemia or infarction of the territories the patient usually shows no other abnormali-
of the calcarine arteries. In other cases steno- ty of behavior during the episodes. For some-
sis of the basilar artery may produce decreased time, a possible vascular etiology involving the
blood flow in both posterior cerebral arteries. posterior cerebral arteries (or basilar vertebral
In still other instances, the ischemia apparent- system) has been postulated. Whether the
ly may be limited to the medial temporal area, selective transient ischemia involves the hip-
that is, hippocampal areas, with little involve- pocampal formation, rather than the dien-
cephalic areas remains unclear. As discussed, Store of information was quite intact.
the hippocampus is more likely to manifest a The patient had marked difficulty with
selective vulnerability to anoxia and would be delayed recall. He could recall none of the 4
expected to show functional impairment prior objects after 5 minutes. He could not remem-
to the medial thalamic areas. Mathew and ber any of the three test phrases given to him
Meyer (1974) demonstrated that elderly when asked about these 5 minutes later. He
patients with transient global amnesia had one did recall in a vague manner that a memory
or more risk factors for vascular disease and 4- test had been given him. was unable to
vessel angiography demonstrated significant remember his visit to his family physician ear-
lesions in the vertebral basilar and posterior lier in the day. Digit retention, however, was
cerebral systems. Patients with single episodes relatively well -preserved; 6 forward and 5
had no permanent impairment of memory. backward. The patient had no defects in calcu-
Those with recurrent episodes had some lation. There was no evidence of a construc-
degree of permanent memory impairment, as tional apraxia. Language function was entirely
well as mild visual spatial or visual motor dys- intact.
praxia. Several recent studies confirm the pre- Clinical diagnosis: Probable transient
viously postulated ischemic etiology but leave global amnesia
undecided the location of the ischia: thalamus Laboratory data: EEG and CSF were all
versus hippocampus (Goldenberg et al, 1991 within normal limits.
Stillhard, et al, 1990 Lin et al, 1993). The The brain scan demonstrated a small area
majority of patients makes an apparent total of increased uptake of radioisotope (Hg197)
recovery and do not have significant infarcts in the left temporal region.
(see Melo, 1992). The following case history Hospital course: Over the several hours
illustrates this syndrome. A transient disease following admission, the patient gradually
process involving the temporal areas is sug- regained his ability to retain new information
gested but not proven. and to recall the events of the preceding 3
Case 30-2: This 55-year-old, right-hand- weeks, the more remote events being recalled
ed, white male, college professor, awoke at first. The memory for the events of the day
3:00 a.m. on the morning of admission in an prior to admission was regained last. This pat-
uneasy and restless state. He was confused as tern is referred to as a shrinking retrograde
to time, kept repeating himself and asking the amnesia. The specific events that occurred on
same questions. His wife arranged for him to the morning of admission were never recalled.
be seen early in the morning by his family The following morning delayed recall was
physician who lived a short distance away. At four-out-of-four objects after 8 minutes. The
approximately 8:00 he became lost driving a patient's mental status and neurological exam-
familiar route to his doctor's office and when ination were otherwise within normal limits.
he arrived with the assistance of his wife, he All brain scan findings had resolved at 5
was unable to explain why he had come. He months. No additional episodes occurred dur-
could remember no significant events from the ing the one-year after the acute episode.
3-week period prior to the onset of his illness.
Stimulation Of The Temporal Lobe:
The patient's more remote recall and other
intellectual capacities remained intact. Bilateral stimulation of the temporal lobe
Neurological examination: When exam- or unilateral stimulation with secondary spread
ined in the early afternoon, findings were to the contralateral hemisphere may occur
essentially limited to the mental status exami- during limited electric stimulation of the medi-
nation: the patient was beginning to regain al temporal structures during epilepsy surgery
some of his ability to retain new information or unilateral electroshock therapy, during gen-
he was still disoriented for the day and month. eral stimulation of the brain (electrical shock
30-10 CHAPTER 30
therapy or a spontaneous generalized convul- amnestic syndrome. In 1987, an outbreak

sive seizure), or during a temporal lobe characterized by gastrointestinal symptoms
seizure. Thus, it may be demonstrated that and neurologic symptoms occurred in Canada
electrical stimulation of the depths of the tem- in 107 persons who had eaten cultivated mus-
porallobe in patients susceptible to temporal sels from Prince Edward Island. The acute
lobe seizures can produce a defect in memory phase symptoms consisted of headaches,
for recent events without disturbing the seizures and hemiparesis. Twenty-five percent
patient's ability to recall remote memories. In of patients had persistent severe anterograde
general, the longer the stimulation, the longer amnesia. PET scanning demonstrated
the duration of retrograde amnesia and the decreased glucose metabolism in the medial
longer the recovery time before the new temporal areas. In the four patients who died,
memories can be recorded. Table 30-3 sum- necrosis and loss of neurons occurred pre-
marizes the example cited by Doty, (1967) dominantly in the hippocampus and amyg-
A primary or secondarily generalized con- dala, (Teitelbaum, et aI, 1990). Two patients
vulsive seizure is followed by a period of also had involvement of the dorsal medial thal-
confusion during which the patient is con- amic nucleus. Not all patients with the persis-
fused, unable to record new information and TABLE 30-3: STIMULATION OF "DEEP" TEMPORAL
uncertain of memories prior to the seizure. In STRUCTURES (AFTER DATA OF DOTY, 1967)
general, on recovery from this period of
confusion, the patient is amnestic for the entire
Duration of Length of Length of
period from the beginning of the seizure until
Stimulation Retrograde Anterograde
the clearing of the postictal confusion. The
Amnesia Amnesia
patient usually, however, has no impairment of
2 seconds Just prior to 1·2 minutes
retrograde memories up to the point of the stimulation
seizure. Thus any "aura" may be recalled. The
effects produced by electrical stimulation of the 5 seconds Current day 5·10 minutes
hippocampus may also occur as relatively selec- 10 seconds Previous 3 weeks 1-3 hours
tive ictal and postictal phenomena in a complex
partial seizure originating in mesial temporal
lobe structures as illustrated in the case history tent memory deficits had uncontrolled status
30-3 presented on the CD ROM. Focal epilepticus - which may also produce hip-
temporal lobe seizure phenomena were fol- pocampal damage. The mussels were found to
lowed by a period of impaired recent memory be contaminated by domoic acid produced by
with an inability to record new memories. a form of marine vegetation; Nitzchia pun-
Selective Vulnerability of the gens. Domoic acid has structural similarities to
Hippocampus to Anoxia Or Hypoglycemia the natural excitatory transmitter glutamic acid
or Status epilepticus: As discussed in chapter and to kainic acid. Both kainic acid and
22, transient or permanent defects in memo- domoic acid bind strongly to the glutamate
ry may occur. The effects of repeated seizures receptor. Domoic acid is 30 - 100 X more
on the hippocampus may involve more than potent than glutamate and 2 - 3 X more
simply the effects of hypoxia. Excessive dis- potent than kainic acid. Experimental adminis-
charge of neurons may also damage the neu- tration of domoic acid or of kainic acid to rats
rons due to excitotoxic effects of the glutamate produces limbic seizures, memory disorders
transmitter. and degeneration of the hippocampus.
Toxic effects on the hippocampus: A Herpes Simplex Encephalitis: As dis-
recent accidental intoxication of nature pro- cussed in chapter 27, the virus; herpes simplex
vides additional information about selective type 1, the agent responsible for the common
damage to the hippocampus resulting in an cold sore, may on occasion invade the central
nervous system (Fig 30-1) and produce sever- indicate that not only is there no memory of
al syndromes In addition to the more com- the actual period of unconscious-ness and the
mon acute generalized or focal encephalitis a following confusional state but also that there
third rare syndrome results from a more local- is defective memory for a period of time pre-
ized involvement of the medial temporal struc- ceding the period of injury. The patient has
tures and is characterized by a subacute but then both an anterograde and retro-grade
progressive dementing process and temporal amnesia. In general, the longer the period of
lobe seizures. retrograde amnesia the more severe the head
The disturbance of mental status is charac- injury and in general, the longer the period of
terized by confusion and disorientation with a time before memory will be regained. As
defect in memory for recent events and often recovery occurs, the period of retrograde
for remote events as well. There is a marked amnesia is gradually reduced. The underlying
inability to form new associations. The selec- pathophysiology has been discussed previously
tivity of the memory disturbance is less evident in the section on trauma.
in these cases than in those cases of hippocam-
PROGRESSIVE DEMENTING
pal disease previously discussed in detail.
PROCESSES
TRAUMATIC AMNESIA:
Introduction
Perhaps the most common transient
impairment of memory occurs in relation to As already defined dementia refers to a
progressive impairment of previously intact
mental faculties. In general, in the most com-
mon type, Alzheimer's disease, the loss
involves initially and most severely recent
memory and the ability to learn and retain new
memories. To some extent, particularly as
time passes, other areas of mental capability are
also affected: remote memory, abstract reason-
ing, insight, and arithmetic abilities, language
function, personality mood and social behav-
ior. In other types, such as the "frontal tem-
Figure 30-1. Herpes simplex encephalitis. poral dementias", personality and behavior are
Predominant involvement of medial and inferior
involved earlier than memory .In still other
temporal structures (and of insula) by an ",ute
necrotic process is evident, although a generalized types, Lewy body dementia, motor function is
encephalitis was also present. Same case as Figure early involved followed by memory. In gener-
27-26. (Courtesy of Dr. John Hills) al, these processes involve the older adult pop-
ulation. However, certain rare disorders pro-
head injury. When blunt trauma to the head ducing a progressive dementia affect infants,
occurs, consciousness is lost. As the individual children and adolescents and the young or
recovers consciousness, there is a period of middle-aged adult. Some of these pediatric
confusion before a return to normal behavior. disorders reflect known or suspected inborn
The loss of consciousness and the subsequent and genetic errors of metabolism:
period of confusion in such patients are often aminoaciduria, lipidosis, galactosemia,
referred to as concussion. Following this peri- Hurler's disease (accumulation of
od of confusion, there is often a period during mucopolysaccharides), and leukodystrophies.
which behavior is otherwise normal but the Other disorders are placed in the degenerative
ability to form new memories is defective. category because in general the etiology
Examination of the patient at that time will remains unknown; e.g., spongy degeneration.
A detailed consideration of these various early
30-12 CHAPTER 30
onset problems is beyond the scope of this frontal and temporal areas but sparing the
text. Dementia is a major medical problem motor cortex, sensory and visual areas. In
because ofits high frequency in the elderly and some cases, (more often presenile) involve-
because of the significant aging of the popula- ment of the parietal association areas is evident
tion. life span has been significantly extended as well. There is a thinning of gyri and widen-
but the capacity to prevent the dementing dis- ing of sulci. There is usually a secondary dilata-
orders is limited. The prevalence of dementia tion of the lateral ventricles. These findings in
and of Alzheimer's disease in the general pop- patients with senile dementia overlap with the
ulation is presented in Table 30-4. patients in the same age group without
The frequency of various types of demen- dementia. In presenile patients, there is less
tia is indicated in Table 30-5. overlap with non-demented patients and the
At one point the dementias were classified atrophy and the microscopic changes dis-
as cortical (Alzheimer's was cited as the most cussed below are also more widespread. There
common example), or subcortical is no one to one relationship of the degree of
(Parkinson's, Huntington's, PSP, were cited as neocortical atrophy with the severity of the
subcortical examples). However, degeneration dementia. These overall findings are reflected
of the subcortical basal forebrain nucleus of in the neuroimaging studies. Thus, patients
Meynert is prominent in Alzheimer's disease with a significant degree of dementia may
and cortical pathology or indirect cortical manifest only a minimal degree of neocortical
effects can be demonstrated in most of the so- atrophy as noted on the CT or MRI scan. On
called subcortical models. Although rare thal- the other hand, it is not unusual to find elder-
amic dementia may occur. An example is pro- ly patients with a significant degree of neocor-
vided in case history 30-7 below. tical atrophy on such radiological studies that
demonstrate relatively little actual cognitive
ALZHEIMER'S DISEASE:
impairment. There is, however a significant
The most common cause of a progres- correlation in Alzheimer's disease between the
sive impairment of mental faculties in the older degree of atrophy of the hippocampus and the
adult population is the degenerative disease presence of dementia. This hippocampal atro-
known as presenile or senile dementia phy is evident on the CT scan but is best seen
(Alzheimer's disease). Whether the process is in MRI studies that utilize measurements of
called presenile or senile is arbitrary, based on hippocampal volume (Fig. 30-3). It is evident
the age of the patient. When the process then that the earliest changes occur in the
begins before the age of 65 years, the designa- hippocampus and entorhinal cortex.
tion presenile is used; when the process begins The microscopic changes probably have a
after the age of 65 years, the designation senile higher correlation with Alzheimer's disease
is employed. The basic pathological process than the gross changes in neocortex. These
(Perl, 2000) is, however, the same. Grossly microscopic changes may be outlined as
(Fig. 30-2), there is an atrophy of cerebral cor- follows:
tex, involving primarily in a diffuse manner the
TABLE 30-4: PREVALENCE OF DEMENTIA AND AlZHEIMER'S DISEASE
AGE RANGE YEARS 60-64 65-69 70-74 75-79 80-84 85-93 ****
Overall all TypeS/100** 0.4 0.9 1.8 3.6 10.5 23.8
Alzheimer's DlseaseJl 00*** 0.3* 3.2* 10.8*
* For Alzheimer's disease, age ranges are 60-69,70-79,80-89

** Derived from Bachman et 01, 1992 (Framingham). *** DeI1ved from Rocca et 01 (1991)
**** Skoog et 01, 1993, In 494palien1s at age 85 (Sweden) overall prevalence 29.8%: Severe 11 %, moderate, 10%, mild 8%.
TABLE 30-5: CAUSES OF DEMENTIA gic), the locus ceruleus (nonadrenergic), and
the amygdala.
NEUROPATHOLOGICAL & PERCENTAGE 3. Loss of dendritic spines and branches
CLINICAL SYNDROME* OF TOTAL affects the pyramidal neurons of the temporal
Alzheimer's disease 55% and frontal cortex and the limbic cortex.
Dementia with lewy bodies 15-20% Normal aging individuals actually have an
increase in dendritic trees until the 80s and 90s
MuHi-infarct and other 15% are attained.
vascular dementla"" 4. Neurofibrillary tangles, develop with-
Combined multi-infarcVvascular 12% in the cytoplasm of the surviving large pyrami-
plus Alzheimer's disease dal neurons of these neocortical areas and the
hippocampus (Fig. 30-4, 30-5). These tangles
Other degenerative causes""" <3-5% are composed of the spiral (helical) winding of
• Derived from Tomlinson et 01, 1970, McKeith & Bum, 2000 paired protein filaments probably derived from
and other sources the protein skeleton of the cytoplasm. They
*. Vascular demenHa includes a variety of syndromes: 1.A single contain tau proteins, a normal constituent of
infarct in areas criHcal for memory. 2) Infarcts (slngle or multi- microtubules. Normally these tau proteins are
ple) In Which total volume ot cortex desfroyed is >1OOml. 3) highly soluble .In Alzheimer's disease, the tau
Small vessel disease producing multiple lacunar infarcts) protein found in the paired helical filaments is
senile leukoencephalopathy: involving periventrlcular whHe hyper phosphorylated and highly insoluble.
matter in associaHon wHh hypertension (Roman et 01, 1993)
These insoluble tau aggregates in the tangles
*** Frontal-temporol demenHa including Pick's disease, are usually complexed with another protein
HunHngton's disease, Progressive Supranuclear Palsy (PSP) ubiquitin. The anterior frontal, temporal neo-
1. Loss of neurons in the cerebral cor- cortex, and particularly the medial temporal
tex: The large pyramidal cells of the frontal, area (hippocampus and entorhinal cortex) are
temporal and parietal association areas neocor- primarily affected. The amygdala, basal fore-
tex and particularly the hippocampal and relat- brain, cholinergic nuclei, thalamus, substantia
ed medial temporal areas. Some loss of neu- nigra and locus ceruleus are also affected. Betz
rons occurs in all normal aging individuals but cells of the motor cortex and the Purkinje cells
the degree in Alzheimer's is markedly greater. of the cerebellum are resistant to the degener-
2. Loss of neurons in certain subcortical ation. Neurofibrillary tangles also occur in a
nuclei that project to cerebral cortex: The number of other eNS diseases that have been
basal forebrain nucleus of Meynert (choliner- grouped together as tauopathies. It is likely
that the change in tau protein represents a
response of neurons to a variety of pathologi-
cal insults of a genetic and non-genetic nature.
These include such entities as Down's syn-
drome, post encephalitic Parkinson's disease,
amyotrophic lateral sclerosis/Parkinson-
dementia complex observed primarily on
Guam, progressive supranuclear palsy, corti-
cobasal degeneration, and hereditary frontal
temporal dementia (linked to chromosome
17), as well as dementia associated with repeat-
ed head trauma in boxers.
Figure30-2. Cortical atrophy as found in presenile Some neurofibrillary tangles will be found
and senile dementia ofAlzheimer type. There is in the brain of intellectually normal individuals
widening of sulci and narrowing of the gyri, particu- primarily in the anterior medial temporal areas,
larly in frontal areas.
30-14 CHAPTER 30
already discussed in relation to Parkinson's dis-

ease. These cases are labeled as the Lewy body
variant of Alzheimer's disease.
What distinguishes the patient with
Alzheimer's disease from the normal elderly
patient and from the other tauopathies is the
presence of the senile neuritic plaque to be dis-
cussed below.
5. Dystrophic neurites - These are altered
neuronal processes axons, dendrites and/or
synaptic terminals - found free in the neuropil
as well as surrounding senile plaques (Fig. 30-
4) The study of McKee et al, 1991, noted a
significant increase in these dystrophic neurites
in Alzheimer's disease and a high correlation
of the number of both dystrophic neurites and
neurofibrillary tangles with the severity of
dementia.
6. Extracellular Plaques (senile or neu-
ritic plaques) containing insoluble fibrils of
amyloid -beta proteins (Fig.30-4, 30-6, 30-
7). In Alzheimer's disease fragments of abnor-
Figure 30-3. AtrfiJ!hy ofthe hippocampus in

Alzheimer's disease. MRl: area of hippocampus cir-
cled for quantitative analysis. A) Normal hippocam-
pus in a 92-year-old patient with Parkinson's disease
but normal cognitive function. B) Severe atrophy of
hippocampus in a 72-year-old patient with well devel-
oped Alzheimer's disease. Neocortical atrophy is also
present. (Courtesy of Dr. Daniel Sax).
but in comparatively small numbers. In the
studies of Tomlinson, 5% of normal patients of
40 years had some minor involvement. By the
seventh decade, 50% of patients had some
involvement and all 90-year-old patients were
affected to some degree. In Alzheimer's dis-
Figure 30-4. Alzheimer's Disease: Microscopic
ease not only is the anteromedial temporal Features: This 87-year-old female had a 7 year history
lobe affected to a much greater degree but also of a progressive dementia. This 100 x magnification
there is widespread involvement of the remain- section of the hippocampus CA-I sector, stained with
der of the hippocampus and marked involve- the Bielschowsky silver stain demonstrates the follow-
ment of the neocortex. ing features: (1) Loss of neurons, (2) argyrophilic
In some patients with clinical Alzheimer's neurofibrillary tangles in sUYJIiving pyramidal cells,
(3) senile plaques containing fragments ofsilver
disease, an alternate form of neuronal inclu-
staining neuronal and glial processes, (4) dystrophic
sion is found in the cortical pyramidal cells; the neurites, silver staining processes surrounding the
Lewy body composed of a-synuclein protein plaques (Courtesy Dr. Tom Smith).
mal appearing neuronal processes (axons and the plaque is the internal fragment of the amy-
dendrites) surround the amyloid core of these loid precursor protein. Selkoe (2001) provides
plaques. There is also evidence of surrounding additional discussion of the mechanisms of
altered astrocytes and microglia. The plaques cleavage.
have a predilection for the frontal temporal A secondary area of controversy involves
and parietal association neocortex and particu- the relationship between the B.amyloid (and
larly accumulate in the medial temporal areas. the senile plaque) and the neurofibrillary
A "diffuse" deposit of amyloid in the neuropil, degenerative changes in the neurons and the
in a non-fibrillar form and without the altered loss of neurons. One hypothesis suggests that
glia and without the surrounding dystrophic the local microglial activation, reactive astrocy-
neurites may occur in otherwise normal indi- tosis and cytokine release surrounding the
viduals. Similar amyloid may also accumulate plaque may produce a cascade of effects that
in the walls of cerebral blood vessels. damage the neuron. An alternative hypothesis
The primary constituent of the amyloid is based on the demonstration by Yankner and
core of the plaque is the B (beta) amyloid pep- Mesulam, (1991) of a direct toxic effect when
tide of28-43 amino acids. This peptide is gen- B.amyloid is added to tissue cultures of mature
erated by proteolytic cleavage of a larger trans- neurons. In contrast, a neurotrophic effect is
membrane glycoprotein containing 695, 751 evident when B.amyloid is added to a tissue
or 770 amino-acid residues: the amyloid pre- culture of immature neurons. (For a review of
cursor protein (APP). This cleavage is mediat- the controversy surrounding these studies and
ed by a series of proteolytic enzymes alpha, the studies of the effects of direct injection of
beta and gamma secretase. The B. amyloid in B.amyloid into the brain, see Marx, 1992).
That there is some relationship of the senile
plaques to the total process is evident, from
several standpoints.
a. The plaques tend to be concentrated in
those areas with severe neuronal loss and with
a high density of neurofibrillary changes.
b. The relationship of Alzheimer's disease to
Down's syndrome. Patients with Down's
syndrome have trisomy 21. The gene for the
amyloid precursor protein localizes to chro-
mosome 21. Patients with Down's syndrome
who have in a sense a triple dose of this
chromosome develop a severe dementia once
they reach age 40-50 (almost 100% after age
50). The dementia from a clinical and neu-
ropathologic standpoint is identical to
Alzheimer's disease. Moreover, patients with
Down's syndrome dying in their teens, 20s or
30s before clinical dementia has developed will
demonstrate a significant accumulation of
plaques and changes surrounding the plaque
prior to the development of neurofibrillary
changes. Thus, the plaques may be the earli-
Figure 30-5. Neurfibrillary tangles in pyramidal est change.
neurons of the hippocampus. Bielschowsky sillier stain.
100X magnification. (Courtesy of Dr. Thomas Smith) c. In some families with hereditary
30-16 CHAPTER 30
with late onset disease, the frequency of the E4

allele is increased to 0.40. Inheritance of one
or two alleles of the E4 variant increases the
density of senile plaques, increases the risk and
lowers the age of onset of the late onset dis-
ease. Patients with two E4 alleles had an aver-
age age of onset 68 years; with one E 4 allele;
79 years and with no E4 allele, 84 years. By
age 80, over 90% of patients with two E 4 alle-
les developed Alzheimer's disease, whereas
only 50% of patients with no E 4 allele devel-
oped the disease by this age. ApoE 4 is a risk
factor but not an invariant cause of late onset
Alzheimer's disease. The E-2 variant may pro-
vide some protection from the disease. As
Figure 30-6. Senile plaque. Silver stain 100x regards the mechanism, this is not entirely
magnification. Courtesy of Dr. Thomas Smith}. clear. High concentrations of Apo E are found
in liver and brain. with production in brain by
Alzheimer's disease of relatively early onset - a
glial cells. In the Alzheimer brain, ApoE has
linkage to chromosome 21 could be demon-
been localized to the senile plaque and to neu-
strated. In many of these families, missense
rons containing neurofibrillary tangles. The
mutations in the amyloid protein precursor
Beta amyloid peptide binds more rapidly to
have been demonstrated. These tend to cluster
at the beta secretase cleavage site, others occur
just after the gamma secretase cleavage site. All
of these various mutations would result in
enhanced production of increased amounts of
beta amyloid. However, other familial cases
have localized to chromosomes 14 or 1. In
both of these latter sites, there has been local-
ization to mutations in presenilin 1 or 2. These
are membrane proteins that apparently regu-
late gamma secretase activity. Other late onset
familial cases localize to chromosome 19.
Other familial cases "The Volga Germans"
localize to none of these chromosomes. The
monograph of Pollen (1993) provides a
review of the search for the genetic basis of the
disease.
Late onset cases: All of these various
mutations do not explain the majority of late
onset non-familial Alzheimer's disease cases.
Chromosome 19 however does provide a
locus for the apolipoprotein E (ApoE) gene.
Three variants (alleles) are found in the gener-
al population: E2, E3 and E 4.The E3 allele is
the most common with a frequency of 0.73 Figure 30-7. Senile plaque. Immunologic stain for
.E4 has a frequency of 0.14. In families with beta amyloid. 100 x magnification. (Courtesy of Dr.
late onset Alzheimer's disease, and individuals Thomas Smith).
the E 4 form than to the E 3 form .In contrast (McKhann, et al, 1984). See also Markesbery
the E 3 form binds to tau protein forming a (1992), Katzman (1993).
stable molecular structure, whereas the E 4 The following case history presents an
form does not bind to the tau protein. example of presenile dementia.
Additional discussion of this topic will be Case 30-4: This 64 year old right handed
found in Strittmatter et al (1993), Sanders et white male formerly an administrative assistant
al (1993) and Corder et al (1993). Additional for the veteran's administration and newspaper
discussion of the molecular biology will be distributor was evaluated for progressive
found in Selkoe (2001). impairment of recent memory of 10 year's
Clinical findings and course: The clinical duration. At age 60, delayed recall was limited
symptomatology in Alzheimer's disease relates to 0/4 and there was minor time disorienta-
to a progressive impairment of mental facul- tion. During last year there were now person-
ties, usually beginning with recent (retentive) ality changes and word finding difficulties.
memory. Initially, the social graces, remote Family history was negative.
memory and rational reasoning capacities are Neurological examination: Mental sta-
well preserved. As the disease progresses, these tus: The mini mental status exam indicated a
aspects of mental function are also affected. In total score of 19 out of 30. He had particular
general, during the early stages, focal motor problems in time orientation. He was able to
findings do not develop, deep tendon reflexes do the immediate recitation of three objects
remain symmetrical and plantar responses are and of a test phrase but could remember none
flexor. It is not unusual to have a significant of these on a delayed recall test. He also had
degree of nominal aphasia present as the mem- difficulty copying a test figure. The patient was
ory impairment becomes more severe. (The often tangential in his answers and demon-
patient is unable to recall the names of strated inappropriate joking. Motor system: pre-
objects.) Apraxias are also not unusual in these motor / frontal lobe functions were abnormal
cases. As the disease progresses a release of a with a release of the instinctive grasp reflex,
grasp reflex is also often noted. In late stages, and impairment of motor sequences.
frontal lobe gait apraxia becomes prominent Clinical diagnosis: Alzheimer's disease
and eventually, bilateral Babinski signs emerge. Laboratory data: All studies were normal
Eventually, the patient becomes bed ridden except a CT scan demonstrated significant
and unable to care for daily needs. A terminal dilatation of the temporal horns suggesting
state of paraplegia in flexion or a fetal position hippocampal atrophy, in addition to a general
may be the final posture. Not all cases have the increase in lateral ventricular size with blunting
same initial appearance and not all have the of the angles of the frontal horns. ASPECT
same rate of progression (see Mayeau, 1985). scan demonstrated slight decrease in perfusion
In some cases, focal aphasia with apparent in the left parietal region.
focal atrophy may be noted as an early presen- Subsequent course: After 10 weeks of
tation (Mesulam, 1982) but these cases are treatment with 5mg per day of donepezil
more likely to fall into the diagnostic category (Aricept) a centrally acting acetylcholinesterase
of frontal temporal dementia. In a consider- inhibitor and high dosage of vitamin E (a pos-
able percentage of patients late in the disease sible antioxidant), the test score had increased
course, myoclonus or generalized seizures or to 25 out of 30 with particular improvement
partial seizures may develop and account along in the delayed recall section of the exam. There
with post infarct seizures for a significant was however no change in personality.
increase in the frequency of seizure disorders Administration of the acetylcholinesterase
in the elderly. Criteria for the clinical diagnosis inhibitor temporarily improved memory func-
of Alzheimer's disease have been outlined in tion for approximately 18 months. However
the report of an N.I.H. work group by age 67, behavioral disturbance (agitation,
30-18 CHAPTER 30
ed to postpone nursing home placement by

approximately 15 months. The rational for the
use of acetylcholinesterase inhibitors is based
on the demonstration by Drachman and
Leavitt (1974) that administration of scopo-
lamine, an anticholinergic drug that crosses
the blood brain barrier, would produce a tran-
sient syndrome similar in many respects to the
memory and cognitive changes of Alzheimer's
disease. Subsequent studies demonstrated a
marked loss of neurons in the basal forebrain
nucleus of Meynert, a major source of cholin-
ergic fibers to the cerebral cortex.
(Whitehouse et al 1981 Rogers et al, 1985
editorial of Growden 1992). However, a sim-
plistic cholinergic hypothesis is insufficient to
explain all of the features of Alzheimer's dis-
ease. Administration of acetylcholine esterase
inhibitors in mild cases (mini mental status
score of 10-25) has only a limited value as in
case 30-4. Other neuronal systems are
involved (noradrenergic synapses are also
involved. The hippocampal system is severely
involved).
The Evaluation of the Patient with
Alzheimer's disease: The primary purpose of
a complete evaluation in these cases is to rule
out the treatable causes of dementia. In addi-
Figure 30-8 Creutzfeldt-Jakob Disease: Histological tion, several less frequent causes of dementia
features: (A) low power H&B - approx. 40", (B) high
power H&B - approx.150x. Diffuse micro vacuoliza- must be differentiated from Alzheimer's dis-
tion of the neuropil and neuronal cell bodies is present ease. The treatable causes of dementia are out-
in this biopsy offrontal lobe. This 45-year--old female lined in table 30-6. The usual screening tests
presented in November 1992 with a 3-4 week history are the following: TSH, B12, and folate, RPR
ofprogressive ataxia and mental deterioration. BEG or VDRL and CT scan. Other causes of pro-
evolved into the characteristic periodic pattern. gressive dementia are outlined in table 30-7.
Patient expired after a total course of approximately 5
weeks. (Courtesy ofDr. Tom Mullins and Dr. Tom Case 30-7: (Patient of Dr. Thomas
Smith) Mullins). This 74-year-old right-handed
aggression nocturnal wandering and sexual widow presented to the emergency room at St
disinhibition) and urinary incontinence were Vmcent hospital on 2-19-02 with an 8-10
becoming major problems. He could no week history of worsening memory problems.
longer be managed in his home and day care In December 2001, accompanied by her
setting despite the use of haloperidol and he boyfriend she made her affiual trip to Florida.
was placed in a nursing home At age 69, he Although she had been in her usual state of
was now described as relatively nonfluent, and independent living prior to her departure, she
very confused and restricted to a wheel chair. was found to have serious problems with
He was "stiff and afraid" when requested to memory on arrival. She was unaware as to
walk. where she was. In a telephone conversation
The use of the donepezil has been estimat- with her daughter, "she was talking non-
TABLE 30-6: TREATABLE AND RELATED CAUSES OF DEMENTIA
CATEGORY SPECIFIC ETIOLOGY TEST

Infeelions -Teniary syphilis (general paresis)· -RPR, or specific FTA or CSF VDRL
-AIDS dementia -If Indicated HIV
Nutrifional B12, thiamin, niacin B12 and folate levels

Intoxicafions Various (Refer to chapte r27) Toxicology screen +if suspected Pb,
Endocrine Hypothyroid TSH, then if +, T4, T3
Tumors Frontal meningiomas, and gliomas·· CT or MRI scan
Post traumatic Chronic subdural hematomas CT scan
Hydrocephalus NPH, etc, (ataxia>dementia) CT scan, Improve after CSF removal (30cc)
Vascular Various types of vascular demenfia MuHlple strokes+ mullifocal signs, CTIMRI
Pseudodemenfia Depresslon>dementia + variability Trial of anfidepressanfs
Other meningeal CarCinomatosis of meninges MRI, CSF cytology
* An example of general paresis case 30-5 is presented on Ihe CD ROM **See case 30-7 and Rg 30-10 below.
OIher progressive disorders producing dementia are summarized in Table30-7.
sense". During the next 2 months, memory copy a figure. She was unable to draw a clock
and word finding continued to deteriorate. with the hands set at 11:10. Motor system:
She was taken to the emergency room of the Although strength and tone were normal, her
local hospital in Florida where a CT scan with- gait was broad-based and shufBing. Reflexes:
out contrast on 02/07/02 demonstrated mild Patellar and Achilles reflexes were absent but
cortical atrophy but no acute process. Her son plantar responses were flexor.
drove to Florida and found that her memory Clinical diagnosis: 1) Subacute dementia
was poor and her conversation did not make etiology uncertain possibly of Alzheimer's or
sense. "My husband is in the service: my Lewy body type. Various entities such as
mother died last year." However she could chronic subdurals, tumor etc to be ruled out
play cards with her grand daughter. Her gait 2) Peripheral neuropathy, most likely etiology
was slow and stooped. She had urinary incon- at this age diabetes mellitus.
tinence on her way to the bathroom. Laboratory data: Basic GBG and
She had no history of alcoholism and took chemistries: Normal except for an elevated fast-
various vitamins and herbs. ing glucose. GTscan (Fiq' 30-10): An enhanc-
Family history: her brother had died of a ing 2.75 cm tumor with a necrotic center was
brain tumor of unknown type. present in the thalamus at the level of the
Neurologic examination: The positive upper third ventricle. There was bilateral
findings were the following: Mental status: involvement of the anterior and medial thala-
The patient was awake and alert. Overall mus but with no involvement of the posterior
Mini-Mental Status Sore was 19/30.The thalamus or hypothalamus. The study suggest-
major problems were in orientation and in ed a lymphoma or glioblastoma
delayed recall. She was able to indicate that she Subsequent course: Stereotaxic biopsy of
was in a hospital in Massachusetts and the date the right thalamus: Frozen section raised the
was February. She registered 3 objects but question of a lymphoma or glioblastoma but
could not recall any in 3 minutes. She was special immunological stains were consistent
however able to read, name objects, follow with a glioblastoma. Necrosis and endothelial
instructions, spell "world" backwards and hyperplasia were present. The patient was
30-20 CHAPTER 30
TABLE 30-7: OTHER PROGRESSIVE CAUSES OF DEMENTIA
DISORDER DISTINGUISHING CLINICAL PATHOLOGY

Diffuse lewy* Parkinsonism and psychotic features Diffuse lewy body involvement of cortical &
Body Disease with relative sparing of memory at onset subcortical neurons + senile plaques
Huntington'sDisease Chorea and personality changes at onset Atrophy caudate/putamen + cortex, seen
Autosomal dominant, high penetrance CAG trinucleotide repeats
Frontalflemporal 1) Personality changes early, memory 1) Bilateral prefrontal atrophy early,
Dementia (several changes late. 2) progressive nonfluent hippocampus late 2) lobar lefltemporal-frontal
types) aphasia at onset. 3) semantic dementia frontal atrophy, 3) Bilateral temporal atrophy
In 40% autosomal dominanttauopathies with gliosis and/or spongy changes.
are found linked to chromosome 17. In some Pick's bodies.
Creutzfeldl- Jakob Rapidly progressive dementia, myoclonus, Transmissible spongiform encephalopathy -
seizures, pyramidal, basal ganglia signs Prion disorder (Fig 30-8).
(+cerebellar in 50%). Familial **and Periodic EEG complexes in sporadic (Fig. 3D-g).
new variant (bovine) cases have a In new variant, diffuse amyloid plaques
younger onset, a slower course and +spongiform changes.
greater cerebellar involvement.
• CD ROM Case 30-6. **10-15% of Creutzfeldt Jakob cases have an autosomal dominant mutation on chromosome 20 (prion protein)
treated with dexamethasone and radiotherapy

with improvement in gait.
Figure 30-9 Creut:ifeldt-Jakob disease: Biopsy pr01Jen

spongiform encephalopathy EEG Features: Frequent Figure 30-10: Thalamic dementia secondary ro
periodic discharges ofgeneralized triphasic blunt spikes a gliobiasroma. Case 30-7: cr scan with con-
are present at a late stage of the disease. This 58-year- trast. An enhancing tumor with a necrotic cen-
old male was admitted on 01/18/93 with a brief suba- ter in1Jol1Jes the anterior and medial thalamus
cute onset of ataxia and mild cogniti1Je deficits and a without in1Jol1Jement of the posterior thalamus.
mildly abnormal EEG. He e1Jo/1Jed rapidly O1Jer a 4-
week period, (from onset ro death) both from the clinical
and EEG standpoint. (Courtesy ofDr. Tom Mullins
and Dr. Sandra Horowitz.)
CHAPTER 31
Case History Problem Solving: Part V
General
Case 31-1: This 59-year-old, white male, mar- c. There was a resting tremor of the right
ried plumbing contractor, approximately 7 upper extremity at the shoulder, wrist, and fin-
years prior to admission, had the onset of a gers. The tremor was rhythmical at 3 to 4/sec.
tremor of the right hand occurring mainly at and pill rolling in type.
rest. One year prior to admission, the patient d. There was a plastic resistance to passive
had noted progression. The tremor was now motion with an intermittent cogwheel compo-
present at the wrist and shoulder in addition to nent in the right upper extremity at the
the fingers. During this time, the patient had shoulder, elbow, and wrist. To a lesser degree,
also noted a stiffness of the right leg when rigidity was present in the right lower extremi-
walking. For one year prior to admission, since ty.
an alleged back injury, he had been unable to
e. Alternating movements were impaired
straighten up when walking and had had to
bilaterally (right more so than left).
walk in a very stooped position. During the 6
months prior to admission, the patient had 4. Reflexes:
experienced short episodes of subjective verti- a. Deep Tendon Reflexes: Biceps and tri-
go, resulting in a tendency to fall forward. ceps were more active on the left; patellar and
Past History: Achilles were more active on the right.
1. Poliomyelitis at age 2, with residual atrophy b. Plantar responses were extensor bilateral-
of left gastrocnemius muscle. ly.
2. Influenza at age 18. 5. Sensory system: Intact.
NEUROLOGICAL EXAMINATION: LABORATORY DATA:

1. Mental status: 1. Thyroid function normal.
a. Patient was depressed and anxious. 2. Cerebrospinal Fluid: Normal pressure, cells,
protein, and Hinton.
b. There was mild impairment of digit span
and of delayed recall, and an inability to retell 3. EEG: Normal
stories. Some evidence of confabulation was QUESTIONS:
present.
1. Indicate the diagnosis: provide a differential
2. Cranial nerves: A fixed facies with minor diagnosis.
facial asymmetry was present.
2. Where is the lesionr
3. Motor system:
3. What significance do you attach to the bilat-
a. Strength was intact, except for plantar eral Babinski signsr
flexion at left ankle, with associated atrophy of
4. What significance do you attach to the
gastrocnemius and shortening of the left
changes in mental statusr
Achilles tendon.
5. Indicate the pathophysiology and etiology.
b. Gait: The patient walked stooped over,
with slow short steps. He turned en bloc. 6. Outline current concepts of diagnostic and
There was a lack of associated movements of therapeutic management.
the arms, with greater impairment on the right 7. Indicate the prognosis.
side.
31-2 CHAPTER 31
Case 31-2: This 42 year-old woman reported (both eyes now demonstrated a full temporal
to the doctor with a complaint of "trouble with hemianopia). The patient was drowsy but
my eyes". At around the age of20, her menses could provide concise answers. Neurologic
ceased and never returned. The patient stated examination was otherwise normal. The
she had had an underactive thyroid for 20 patient was immediately admitted to the hospi-
years. Her menstrual symptoms did not tal. Laboratory studies in the hospital con-
respond to thyroid medication. During the firmed the clinical impression of hypothy-
past few years, the patient had had some auto- roidism. In addition, there was no FSH detect-
mobile accidents and had noted that these acci- ed on an assay of a 24 -hour urine specimen.
dents occurred when there were objects to her Plain skull films were positive and bilateral
right. During the month before entry, the carotid arteriograms were performed. Patient
patient felt excessively tired and was sleeping was started on endocrine therapy, and an oper-
more than usual but was able to go to work. ation was performed. Three days following
Her skin had become dry; she had gradually surgery, it was noted that the patient was com-
put on weight over the years; her hair was scant plaining of constant and excessive thirst and
with loss of underarm hair and scant pubic hair. was consuming huge quantities of fluids.
A bifrontal dull headache had been present for
one week.
QUESTIONS:
1. In this case, neurological evaluation many
PHYSICAL EXAMINATION: years previously would have established the
There was puffiness of hands and face and dry- diagnosis. Indicate the location of this
ness of the skin. Blood pressure was 108/72, lesion. Discuss the differences between this
pulse 82 and regular. Skin and mucous mem- lesion at onset and the lesion at the present
branes were pale, and there was bilateral pallor time.
of the optic discs. 2. Indicate the most likely pathology.
NEUROWGICAL EXAMINATION: Speculate as to the other possible causes of
this syndrome.
1. Mental status: Intact.
3. What happened the day after the initial
2. Cranial nerves: Intact except the visual
office evaluation?
fields showed a bitemporal upper quadrantic
field defect that was almost complete in the 4. Today, which neurodiagnostic study would
right eye and less marked on the left. There have best demonstrate the location and
was also bilateral pallor of the optic discs. nature of the pathology?
Pupils and ocular movements were normal. 5. This patient had 24-hour urine FSH levels
3. Motor system: No abnormalities noted. performed. Which additional endocrine
blood test would be performed today?
4. Reflexes: Within normal limits.
What are the causes of abnormalities in that
5. Sensory System: Normal. additional test?
SUBSEQUENT COURSE: 6. What is the localizing significance of the thy-
Patient returned the next day, having had an roid dysfunction?
emotional upset at work with the onset of a 7. What is the localizing significance of the
severe pressure headache. She complained of ovarian dysfunction?
sudden worsening of vision in the left eye and 8. Why did the patient have excessive thirst and
a film over the temporal fields. On examina- excessive consumption of fluids (polydipsia)
tion, she was pale and sweating. Blood pres- after surgery?
sure was 100/70; pulse was 100. There was
9. Why was the patient sleeping more than
more marked cutting of visual fields, particu-
usual and why was she markedly drowsy at
larly on the left, with a true hemianoptic defect
CASE HISTORY PROBLEM SOLVING PART V: GENERAL CASES 31-3
the time of admission? (Several explanations Cerebellar tests and gait were intact.
are possible in this case.) 4. Reflexes: Deep tendon reflexes were slightly
Case 31-3: Three weeks prior to admission, increased in the right arm compared to the
this 60 year-old right-handed white male had left. The Achilles' tendon reflexes were
the acute onset of clumsiness of his right hand. absent bilaterally.
Soon thereafter, he noticed weakness and 4. Sensory System:
numbness involving the right hand. He then
a. Vibration sensation was decreased bilater-
noticed that his right leg was weak., and he fell
ally at the toes.
to the floor. The weakness and numbness of
the hand and leg cleared in a matter of min- b. Occasional errors were made in letter and
utes. The patient, however, continued to have number recognition in the right hand
clumsiness of the right hand. On two subse- QUESTIONS:
quent occasions, he had a recurrence of weak.-
1. What is the diagnosis? Be specific as to the
ness of the right hand.
vessel and area involved, if vascular in nature.
The patient's history was also of significance in
2. Outline your diagnostic approach to this
that over a 2-month period, he had had 3
problem.
episodes, each 3 minutes in duration, of a
monocular blindness of the left eye. Diabetes 3. Indicate possible therapeutic measures.
mellitus had been present for approximately 20 4. What is the explanation for the absent
years. Six months before admission, the Achilles' deep tendon reflexes and the
patient had had a sudden onset of weakness decreased perception of vibration at toes?
and coldness of the right lower extremity, due
to sudden occlusion of the right femoral artery. Case 31-4: The patient was a 20 year-old,
Symptoms improved when a right femoral right-handed white housewife who was seen
endarterectomy with bypass was performed. initially in the 23rd week of her third pregnan-
The patient had had 5 to 10 minute episodes cy. The patient presented with a history of
of chest pain (angina pectoris) for a number of generalized convulsive (tonic clonic) seizures
years. beginning at age 7. These apparently would
occur once a month without warning. She was
Family history was significant in that the
patient's mother, father, daughter and son had begun on treatment with phenytoin and phe-
all experienced severe diabetes mellitus. nobarbital about age 8. She had had recur-
rences of seizures two years prior to the visit
GENERAL PHYSICAL and one year prior to the visit. On each occa-
EXAMINATION: sion, these seizures related to her omission of
1. Blood pressure was 130/80 in both the medication for several days. Her medications
right and left arms. at the time of the initial visit were phenytoin,
2. light pressure on the left eyeball led to a 100 mg a day and phenobarbital, 15 mg a day.
blackout of vision; similar symptoms were FAMILY HISTORY:
not produced on the right side. A maternal grandfather had convulsions and
NEUROWGIC EXAMINATION: staring spells. Two cousins also had a seizure
disorder, manifested by staring spells.
1. Mental status: The patient was oriented for
time, place, and person. NEUROWGICAL EXAMINATION:
2. Cranial nerves: No significant findings. In detail, the entire examination was normal.
3. Motor system: Strength was intact, except for
LABORATORY DATA:
a minimal drift downward of the outstretched
right arm when both arms were outstretched. 1. Electroencephalogram: The patient had bilat-
31-4 CHAPTER 31
eral, relatively synchronous bursts of poly found in his bed, unresponsive and he was
spikes -slow waves complexes most promi- found to have been incontinent of urine and
nent in the frontal recording areas. At times, feces.
the bursts would continue for 2 to 3 sec-
onds. No clinical phenomena were noted
GENERAL PHYSICAL
EXAMINATION:
during the discharges.
1. The patient was febrile with a temperature
2. Blood Levels: Dilantin blood level was less
of 102 to 103ooF. Blood pressure was
than 2.5 uG/ml.; Phenobarbital was 5
130/70; pulse was 96.
uG/ml.
2. There was a marked degree of nuchal
SUBSEQUENT COURSE: rigidity.
The patient agreed to increase her intake of 3. Examination of the skin revealed a diffuse
Dilantin to 200 mg a day and to increase her petechial rash with a number of ecchymotic
intake of Phenobarbital to 15 mgs. two times a areas on the extremities. Some of these areas
day. The blood levels were checked again had apparent necrotic centers.
approximately 3.5 weeks later. Her phonation
level was still low at 2.8 ug/ml., her phenobar- NEUROWGICAL EXAMINATION:
bital was 4.5 ug/ml. The patient did not 1. Mental status: The patient was in a coma; he
return again for follow up until 17 months responded to painful stimuli by withdrawing
later. In the interim, she had had no additional his extremities.
seizures of either a major or minor type. Her 2. Cranial nerves:
infant and previous offipring were normal.
a. The pupils were midposition and
1. Classify these seizures. If possible be spe- responded very poorly to light.
cific.
b. Funduscopic examination was not
2. What other types of seizures might be remarkable.
expected in this syndrome?
3. Motor system There was no definite lateral-
3. What would be the most appropriate ized weakness. Cerebellar system and gait
anticonvulsant? could not be tested.
4. What would neuro imaging studies 4. Reflexes:
demonstrate?
a. Deep tendon reflexes were equal but
5. Discuss the relationship between epilepsy hyperactive throughout.
and pregnancy.
b. An extensor plantar response was present
6. Discuss the relationship between anti- on the left side.
convulsants and pregnancy.
5. Sensory System: Could not be adequately
7. Discuss the role of anticonvulsants and tested.
related drugs in teratogenesis.
QUESTIONS:
8. Discuss the interaction of anticonvul-
sants and birth control pills. 1. What is your diagnosis?
2. Which studies must be performed and when
Case 31-5: This 23 year-old white right-hand- must they be performed?
ed, army recruit private, on the day prior to 3. When must treatment be started? Which
admission, was evaluated on sick call for an treatment would be most appropriate?
apparent upper respiratory infection. The
patient was given a day of barracks rest. Early LABORATORY DATA:
on the morning of admission, the patient 1. CBC: White blood count was markedly ele-
apparently vomited. At reveille, the patient was vated to 42,000, with a differential count of
64% neutrophils, 31% bands, and 5% lym- described in the past as a bright, alert and intel-
phocytes. Platelets were decreased to 95,000 ligent lady. The patient was unable to provide
per mm3. Blood serology was negative. a history. She showed little insight into her
2. Spinal fluid examination revealed a marked problem and seemed unaware of any reason for
increase in pressure (>600mm of CSF) The her neurological evaluation. The patient's son
fluid was grossly cloudy. There were 7250 indicated that she had begun to show some
white blood cells per cubic mm; 100% of decline in intellectual capacity as long as 3 or 4
these were polymorphonuclear leukocytes. years prior to admission. During the preceding
Spinal fluid sugar was 6-mg/100 ml (blood 12 months, a more marked change had
sugar was within normal range); spinal fluid occurred, particularly with regard to memory.
protein was increased to 314-mg/100 ml. In more recent months, a lack of concern for
her personal appearance and a lack of spon-
4. Smears and eventually cultures of spinal fluid
taneity had developed. She had lost interest in
and blood were consistent with the clinical
her home, friends, and activities.
diagnosis.
Past history was unremarkable as regards car-
SUBSEQUENT COURSE: diovascular disease, diabetes or alcohol or drug
The patient was begun on specific therapy. As and ingestion.
the patient's level of consciousness began to
improve, on the second hospital day it was
GENERAL PHYSICAL
EXAMINATION:
apparent that a left facial weakness was present.
On the fourth hospital day, as the patient Blood pressure was 140/96; cardiac status was
began to respond to questions by opening his normal.
eyes and moving his right hand, it became NEUROLOGICAL EXAMINATION:
apparent that he had a left facial weakness, a
1. Mental status:
weakness of the left arm and leg, and a left
Babinski response. On the sixth hospital day, a. The patient was pleasant and well man-
even though the patient was continuing to nered.
improve, he had the onset of focal seizures b. She was disoriented for the day of the
beginning on the left side of the body. Some week, for the day of the month, for the month
remained localized to the left side; some and for the year.
became generalized. Following readjustment c. She was unable to remember any of four
of therapy, seizures disappeared. With physio- test objects after a 5-minute period.
therapy, a significant improvement in function
d. The patient was unable to remember the
of the left arm and left leg occurred.
year she was born.
QUESTIONS: e. She was unable to recall any president but
4. Do you wish to modify your diagnosis and Kennedy.
proposed treatment based on the CSF find- f. She was able to follow very simple direc-
ings? What do you expect the cultures of tions, but was unable to remember any instruc-
blood and CSF to indicate? tions beyond these.
5. Indicate the pathophysiology involved in the g. She was unable to comprehend subtrac-
complications that developed during the tion of serial 7s and could not do even simple
patient's hospitalization. additions. She was unable to repeat numbers
in reverse.
Case 31-6: This 62 year-old white divorcee
h. She was unable to draw a triangle but did
was referred for evaluation of memory subse-
recognize a circle.
quently of personality change. The patient had
a high school education and had been i. There was a severe dysnomia for even
31-6 CHAPTER 31
common objects. 7. What cerebrospinal fluid findings are to be

2. Cranial nerves: expected?
a. Pupillary reactions were normal. 8. What is the natural history and prognosis?
b. At times, the patient had extinction of 9. What more restricted mental status changes
simultaneously presented visual objects in the might have been present early in the disease
left or right visual field. course? What would be a more likely diag-
nosis ifpersonality changes had been the pri-
3. Motor system:
mary early symptoms? Ifbasal ganglia symp-
a. Strength and gait were intact. toms had been present early in the course of
b. Minor tremulousness was present in the the disease, which diagnoses might have
performance of hand and arm movements. been considered.
c. Minor variable resistance on passive
motion existed and was described as Case 31-7 (Patient of Doctor John Sullivan
Gegenhalten. and Doctor Huntington Porter): This 67-year-
old white right-handed retried schoolteacher
4. Reflexes:
awoke one morning with numbness over the
a. Deep tendon reflexes were symmetric entire right side of her body. The right corner
and physiologic. of her mouth drooped. She was able to go to
b. Plantar responses were flexor bilaterally. a fumily physician but was unsteady on her feet.
c. Grasp was absent. She had no diplopia or aphasia. Numbness on
the right side disappeared gradually over a two-
5. Sensory system: Normal.
week period, but then appeared in the left foot.
QUESTIONS: The left hand became restless and would more
1. Does this patient have focal disease or a in a jerky up-and-down movement. The hand
more generalized disease? If the latter, which and arm would take on abnormal postures and
areas are predominantly affected? What is tend to trail behind her. One week later, this
the significance of the dysnomia in this case? involuntary movement began to affect the left
Which diagnosis would you assign to this foot, which became restless. Its constant
case? motion seriously interfered with her ability to
walk. Over the next several weeks, the move-
2. Describe the most likely pathology in this
ment disorder in the left hand disappeared.
case. Present a differential diagnosis.
Past History was not remarkable except for
3. What treatable causes of this progressive
menopause at age 30. Family history indicated
syndrome much be considered? Discuss in
that her mother died at age 63 of a "heart
terms of:
attack" . Father died at age 72 of a "shock".
a. Infections
b. Nutritional diseases
GENERAL PHYSICAL
EXAMINATION:
c. Metabolic diseases
Blood pressure was 160/100, with a normal
d. Intoxications cardiac examination.
e. Other treatable etiologies For each entity
indicate the appropriate diagnostic tests.
1. Mental Status: All areas were intact, with no
4. How would you manage this patient as
evidence of aphasia.
regards diagnosis and treatment?
2. Cranial Nerves:
5. What would an electroencephalogram
demonstrate? a. A slight droop of the left corner of the
mouth was present.
6. What would a CT scan demonstrate?
b. There was an unsustained nystagmus on month. Then she began to have sudden "jerky
far lateral gaze. movements" of the left hand, causing the arm
3. Motor System: to strike her in the face. The left arm also
began to posture in a position of relative flex-
a. Strength was intact, with good retention
ion at the elbow, wrist, and fingers. The
of skilled movements of the hands.
patient also reported occasional violent flinging
b. In the left leg, there was an almost con- movements of the arm. To some extent,
stant play of movement, smooth and rhythmi- numbness had returned to the right upper
cal, consisting of eversion/inversion of foot extremity.
and ankle with flexion/extension movements
When she was re-examined 4 months after the
of the toes. In the left arm, the same type of
initial episode, certain changes had occurred in
movement was present. This movement was
the movement disorder. A distal fluid, flowing
not synchronized with that in the foot and was
2 to 4 Hz movement was still noted at the fin-
often absent for periods of time. As the patient
gers, toes, hand, and foot, alternating between
used the right arm, the movement disorder
flexion/supination and extension/pronation.
became apparent in the left hand. When the
This movement had now appeared at more
patient performed repetitive movements of the
proximal joints, and some spread of movement
left fingers, mirrored movements of the right
into the face was reported. In addition, there
fingers occurred.
were sudden pronation and posterior rotatory
c. Gait: The body was twisted to the left. movements at the shoulder. At times, this was
The left hand trailed behind, with the index described as a wild swinging or flinging move-
finger pointing down and the other fingers ment of the left upper extremity. At the time of
clenched. The gait was unsteady. Walking did a visit 5 months later, significant improvement
not dampen the movement in the left leg. At had begun to occur. By the time of a follow-
times, the left leg would suddenly buckle. up 2 months later, approximately one year after
4. Reflexes: onset of symptoms, there was little evidence of
a. Deep tendon reflexes were symmetric any movement disorder. Occasional distal
and physiologic. movements occurred only when the patient
was emotionally excited.
b. Plantar responses were flexor bilaterally.
c. There was no release of the grasp reflex QUESTIONS:
and no repellent apraxia. 1. Provide a diagnostic label for the abnormal-
5. Sensory System: Pain, touch, position, and ity of movement noted on the initial neuro-
other discriminative modalities were intact. logic examination.
There was a slight decrease in vibration sen- 2. Provide a diagnostic label for the movement
sation at the toes. disorder that subsequently evolved.
LABORATORY DATA: 3. Discuss the neuroanatomic basis of these
disorders.
1. Fasting blood sugar was elevated to 250-
mg/100mI. 4. Discuss diagnostic and management
approaches.
2. Cerebrospinal fluid: Opening pressure was
60; no cells; protein was 45-mg/100 mI.
Case 31-8: One week prior to admission, this
3. Chest and skull X -rays were negative, except 51-year-old white housewife, developed
for calcification of the carotid siphon. episodic posterior headaches beginning in the
4. Sedimentation rate was 17 mm in one hour. neck and radiating to the vertex of the head.
The headaches were usually related to and
SUBSEQUENT COURSE: were definitely exacerbated by straining or
The patient did well for approximately one
31-8 CHAPTER 31
coughing. At the same time, the patient noted 5. Sensory J)'stem: All modalities were intact,
clumsiness of the left hand, and a tendency to except for a minimal decrease in vibratory sen-
fall to the left side. During the week prior to sation at the toes.
admission, a progressive gait ataxia also had
LABORATORY DATA:
developed.
The results of specialized studies were consis-
PAST mSTORY:
tent with the clinical diagnosis.
Eight months previously, the patient had been
admitted to the gynecology service before with QUESTIONS:
a 10-week history of postmenopausal vaginal 1. Where is the lesion? Be specific.
bleeding. She was found to have an infiltrative 2. What pathological process is to be expected?
anaplastic carcinoma of the uterine cervix. The
3. Outline your diagnostic and therapeutic
patient was treated with radiotherapy (4000R
approach for this case.
to the pelvis), followed by vaginal insertion of
radium. Re-evaluation one month prior to the 4. Which is the appropriate neuroimaging
present admission had revealed that this study?
anaplastic epidermoid carcinoma of the cervix 5. Should a lumbar puncture be performed?
had spread to the anterior vaginal wall. In Indicate why or why not.
addition, metastatic nodules were now present Case 31-9: A 21-year-old white right-handed
in the lung. wife of an air force enlisted man had been mar-
NEUROLOGIC EXAMINATION: ried for two months and had just moved from
her home in the south to an air force base in
1. Mental status: The patient was an anxious
New Jersey. She had been complaining of
white female who was cooperative, alert and
increasingly severe right frontal temporal or
well oriented.
bifrontal headaches for three to four weeks.
2. Cranial nerves: During the 10 days prior to admission, she had
a. There was coarse nystagmus on gaze to been treated on several occasions at the base
the left. dispensary for these headaches, which were rel-
b. There was a minor dysarthria for lingual atively constant and were now accompanied by
and guttural sounds. blurring of vision and frequent vomiting.
Various medications had been prescribed for an
3. Motor J)'stem:
upper respiratory infection or sinusitis. In the
a. Strength was intact. 48 hours prior to admission, the patient had
b. Gait was unsteady, with tendency to fall become increasingly confused and ataxic. Her
to the left, especially when turning to the left. past history was otherwise negative as regards
On a narrow base, the patient tended to fall head injury or pulmonary and ear infection.
backwards.
GENERAL PHYSICAL
c. Cerebellar tests revealed no definite trun-
EXAMINATION:
cal ataxia. There was a marked Appendicular
1. The patient was dehydrated and somewhat
ataxia on the finger-to-nose test in the left
lethargic.
upper extremity and the heel-to-shin test in the
left lower extremity. 2. She was complaining of severe headache,
particularly on head movement.
4. Reflexes:
3. There was a moderate degree ofhyperventi-
a. Deep tendon reflexes were active bilater-
lation.
ally. This, however, was felt to be consistent
with the patient's degree of anxiety. 4. No otitis media was present.
NEUROLOGICAL EXAMINATION: ize the primary location of the pathology.
I.Mental status: The patient was disoriented 2. Indicate what secondary complications have
for time and place. She was unable to pro- occurred.
vide a history and was unable to cooperate 3. The nature of the pathology may be some-
for the examination. She was impersistent in what uncertain to you. However, you
fixing gaze or in maintaining eyes in open should be able to present a differential diag-
position. nosis and then to indicate the most likely
2. Cranial nerves: diagnosis. Keep in mind that the headaches
a. On funduscopy, bilateral papilledema was had been present for only 3-4 weeks and the
present, with 2 to 3 diopters of disc elevation, additional symptoms for only 2-10 days.
accompanied by fresh hemorrhages and venous 4. Was the papilledema long-standing?
engorgement. 5. What is the significance of the pupillary
b. The right pupil was dilated and fixed in findings?
response to light. Extraocular movements 6. Assuming a cerebral hemisphere lesion, why
were otherwise intact. was the patient ataxic in sitting and standing
c. A left central facial weakness was present when examined late in her course?
to a marked degree. 7. Which diagnostic studies would you per-
3. Motor system: form in this case, and when would you per-
a. All limbs were moved spontaneously, but form these?
there was a downward drift of the outstretched 8. Which diagnostic studies would you not
left arm. perform? State reasons.
b. The patient was ataxic in a sitting posi- 9. How would you manage this problem from
tion and in attempting to stand, even on a a therapeutic standpoint? Indicate when you
broad base. would institute this therapy.
c. There was a tremor of the outstretched
hands, increasing to a minor degree on move- Case 31-10: This 55-year-old white widow, 6
ment and intention. to 8 years prior to admission, had the onset of
a peculiar reeling gait. At the same time, she
4. Reflexes:
was noted to be ''very nervous", having many
a. Deep tendon reflexes were increased on peculiar restless movements. At other times,
the left in the upper and lower extremities. she was described as constantly fidgeting. The
b. Plantar response was extensor on the left, patient's children felt that in recent years, she
equivocal on the right. had not been thinking as clearly as she once
c. Grasp reflex was present bilaterally. did. A personality change had also occurred.
5. Sensory system: Pain sensation was intact; FAMILY mSTORY:

modalities could not be tested. The patient's mother died in her sixties with a
6. Neck: Minor resistance to passive motion. disorder that had been labeled as Parkinsonism.
From the description of relatives, however, it
LABORATORY DATA:
was evident that the mother had restless move-
1. Skull and chest X -rays were negative. ments that were similar to the patient's.
3. EEG demonstrated almost continuous focal
1 to 2 Hz slow-wave activity.
NEUROLOGICAL EXAMINATION
1. Mental status: The patient was oriented and
QUESTIONS: alert with an intact general store of informa-
1. This patient was seen relatively late in her tion. Object recall was three out of four in
disease course. You should be able to local- 10 minutes. Digit span was six forward and
31-10 CHAPTER 31
three in reverse confused and this confusion increased on the

2. Cranial nerves: Intact. day of admission.
3. Motor system: NEUROLOGIC EXAMINATION:
a. Strength was intact with no significant This was a thin man with normal vital signs
spasticity or rigidity. who answered questions quickly but often
b. Gait showed a swooping quality of vari- incorrectly. In addition to the confusion,
able degree; there was also a decrease in associ- drowsiness and problems in memory, pertinent
ated arm movements. findings included the following: Extraocular
movements were limited in all directions, and
c. As the patient sat, she would move her
there was horizontal and vertical nystagmus.
head, neck, and feet almost constantly.
The gag reflex was diminished bilaterally.
d. The patient was able to walk a tandem Finger-to-nose and heel-to-shin tests showed a
gait, and there were no abnormalities of cere- mild deficit. The patient had an unsteady,
bellar function. broad-based gait. No other motor findings
4. Reflexes: Deep tendon reflexes were sym- were present
metric. Plantar responses were flexor. No
grasp reflex was present. QUESTIONS:
1. Do you require more historical information?
5. Sensory system: Intact.
If so, indicate what is required.
LABORATORY DATA: 2. Present a differential diagnosis.
1. Routine laboratory studies were not remark- 3. What is the most likely diagnosis?
able.
4. In a general sense what is the localization of
2. Specialized neuroradiology studies were con- lesions in this disease. What is the localiza-
sistent with the clinical diagnosis. tion for each specific symptom or sign
QUESTIONS: (confusion and impairment of new learning,
lethargy, impairment of extraocular move-
1. Present a differential diagnosis of this prob-
ment and ataxia?
lem and indicate the most likely diagnosis.
6. How could your suspected diagnosis be
2. Outline your diagnostic and therapeutic
confirmed?
approach to this problem.
7. How and when would you treat this patient?
3. What did the specialized neuroradiology
Which findings would rapidly resolve over
studies reveal?
the next 1-2 days?
4. Which neurodiagnostic study would be
8. You administer specific treatment but the
most cost-effective and specific in establish-
difficulties with memory fail to clear and one
ing the diagnosis today?
year later the patient is still confused and
5. Discuss the underlying molecular basis of confabulating. How do you modifY your
this disorder. diagnosis?
Case 31-11 (patient of Dr.Thomas Sabin): A 9. You administer specific treatment but one
50-year-old white man was admitted to the year later, the patient is still ataxic. How do
hospital because of drowsiness and confusion you modifY your diagnosis?
of 5 days duration. His wife stated that he was
Case 31-12: This 60-year-old right-handed
in good health until that time. For 4 days prior
retired priest was referred for evaluation of
to admission, he merely slept more than usual
problems in walking. The history was not pre-
and napped during the day, but while awake,
cise. Two and a half years previously, he had
was lucid. The day before admission, he was
been admitted to his local hospital, for severe
diabetic coma. Although he recovered, he had and urine immuno-electrophoresis, ESR,
some difficulty with memory thereafter. He and ANA were normal. Serological tests
began to full. Problems in walking had pro- (RPR and PTA) were negative. Liver func-
gressed, particularly in the last 6 to 8 months, tion studies had been previously elevated
so that he was no longer able to walk without but now, except for alkaline phosphatase,
assistance. His memory problems had pro- were normal.
gressed over the last year. He denied numb- 2. Electromyogram and nerve conduction stud-
ness in his extremities but was aware of ies indicated a severe sensory-motor periph-
"twitching" of his extremities. He denied any eral neuropathy, primarily axonal in type, as
significant family history. He indicated he had well as left median nerve (carpal tunnel) and
been a very heavy drinker and had been hospi- right ulnar nerve (olecranon groove) entrap-
talized once in the previous year for treatment ment neuropathies.
of alcoholism. Admitted intake was at least half
6. MRI demonstrated:
a liter (500 cc) of gin per day.
a. Prominence of cerebellar folia, particular-
NEUROLOGIC EXAMINATION: ly of the superior vermis;
1. Mental status: He was very vague about the b. Moderate cerebral cortical atrophy;
date. Delayed recall was limited to two out
c. Periventricular white matter involvement
of five objects in five minutes.
(leukoariosis ).
2. Cranial nerves: All were intact, except for a
tremulous voice. SUBSEQUENT COURSE:
3. Motor system: An alcoholism program with discontinuation
of all alcohol intake and administration of mul-
a. The patient stood on a broad base and
tiple B vitamins was recommended. When last
was very unsteady standing on a narrow base,
seen in follow-up, the patient was consuming
requiring support. This unsteadiness slightly
at least 500 cc of vodka per day. His neuro-
worsened with eye closure.
logic examination was unchanged except that
b. He had been brought into the office in a pain sensation was now intact. He refused
wheelchair. He walked with assistance with additional neurologic followup.
small steps but was very ataxic.
c. There was no impairment on finger-to- QUESTIONS:
nose testing but there was dysmetria on heel- This patient had several neurologic problems:
to-shin test. At least five can be specified.
4. Reflexes: Discuss in terms of:
a. Deep tendon reflexes were everywhere a. Ataxia
absent. b. Memory changes
b. Plantar responses were not responsive. c. Peripheral nerve disorders
5. Sensory system: d. Toxic and metabolic diseases
a. Pain sensation was absent to the level of
the knees.
b. Position sense was intact.
c. Vibration sensation was markedly
decreased at the toes and moderately decreased
at the ankles.
LABORATORY DATA:
1. Blood studies: Folic acid, B12 levels, serum
CHAPTER 31A
Case History Problem Solving: Part II
General Case History Review with
Correlation to Illustrations
PHOTO SERIES
Each series of photos is derived from a partic-
ular case history. Indicate the most likely diag-
nosis in terms of localization and pathology.
Then use the photos for the following

problem solving case histories.
Figure 31-2A. LtohJique
Figure 31-1.
Figure 31-2B. RtohJique

31A-2 CHAPTER31A
Figure 31-3B.
Figure 31-3A.
Figure 31-4B.
Figure 31-4A
Fif{ure 31-4C.
CASE HISTORY PROBLEM SOLVING PART V-A: IMAGING CORRELATION 31A-3
Figure 31-SA.
Figure 31-SB.
Figure 31-SC.
Figure 31-SD.
31A-4 CHAPTER31A
Figure 31-6A.
Figure 31-6B.
Figure 31-7.
Figure 31-8.
Figure 31-9.
31A-6 CHAPTER31A
Figure 31-12.
Figure 31-1OA and lOB..

Case 31A-l: This 43-year-old right-hand- NEUROLOGIC EXAMINATION:
ed white male, two months prior to admission I. Mental status: The patient was oriented
had the acute onset of blurring of vision and to time, place and person. Delayed recall was
possible diplopia. Two weeks prior to admis- o/ 5 in 5 minutes without assistance: 4 /5
sion, he had the acute onset of ataxia, vomit- with assistance.
ing, dizziness, and left face numbness. He 2. Cranial nerves: the following findings
improved, then developed severe problems were present:
with balance, slurring of speech and difficulty a. Tremor of head.
in the use of the left arm, which he labeled as b. Hyperactive jaw jerk.
"weakness". The patient was also aware that c. Positive glabellar sign.
he had become emotionally labile. Cranial 3. Motor system: the following findings
nerve examination demonstrated a paralysis of were present:
conjugate lateral gaze to the left. A marked a. Variable generalized weakness that at
left peripheral facial weakness was present. He times disappeared.
had a marked decrease in whisper perception b. Gait: Small steps, at times waddling,
in the left ear. Strength was actually intact. unsteady on the turns.
There was a marked dysmetria on the left fin- c. Sitting: Often tended to fall backwards
ger-to-nose and left heel-to-shin tests. The on the examining table.
patient was ataxic in walking. Deep tendon 4. Reflexes:
reflexes were symmetric, plantar responses a. Deep tendon reflexes were everywhere
were extensor bilaterally. Sensory examination hyperactive.
was normal. b. Plantars responses were equivocally
QUESTIONS: extensor bilaterally.
I. What is the most likely diagnosis in c. Grasp reflex was released bilaterally.
terms of localization and pathology d. Palmomental responses were positive
2. What study would be most diagnostic or bilaterally.
confirmatory of your clinical diagnosis? 5. Sensory system: Intact.
3. Select the most appropriate photograph. QUESTIONS:
Case 31A-2: This 68-year-old right-hand- I. Considering the combination of ataxia
ed married white female and retired clerical of gait, impairment of memory, and urinary
worker was referred for evaluation of "weak- incontinence, indicate the most likely
ness in both lower extremities" of approxi- syndrome.
mately two years duration. She had been 2. How do you interpret the bilateral
falling for at least one year. Although the release of grasp, the palmomental reflex, the
patient and her husband initially denied any bilateral extensor plantar responses, and the
bladder symptoms, her daughter, a nurse, was hyperactive jaw jerk?
able to indicate that urinary incontinence had 3. Provide a differential diagnosis of this
occurred on several occasions during the last syndrome.
year. The patient indicated her memory had 4. Which study or studies would you
been "bad" for I to 2 years. Her husband obtain to confirm your diagnosis?
minimized this symptom. Her daughter sub- 5. Select appropriate illustrations (several
sequently was able to relate a more significant may be appropriate).
impairment in mental functions. The 6. If this patient also had severe impair-
patient's mother, age 88, had senile dementia ment of upward gaze and headache, what
and problems walking. would be the most likely diagnosis and which
would be the most appropriate illustration.
31A-8 CHAPTER31A
7. If this patient also had a past history of Case 31A-4: This 70-year-old right-hand-
head trauma with resultant coma and recovery ed white widow and retired telephone compa-
10 years previously, what would be the most ny clerk was referred for evaluation of
likely clinical diagnosis and which illustration unsteadiness in walking, which had been pre-
would then best correspond? sent for 23 years. The symptom had begun in
8. What is the most appropriate therapy? relationship to a hospitalization for a myelo-
gram. At that time, the patient had been
Case 31A-3: This 47-year-old right-hand- involved in an automobile accident and had
ed married white female farm manager awoke developed lumbar radicular pain. The evening
one week before evaluation with numbness after the myelogram, she had developed
and "novocaine-like" sensation involving the "coma, convulsions, and a temperature of
entire trigeminal distribution on the right, llO°.
including the tongue, lip, mucosa, etc. She The medical records of that hospitalization
had no pain and no other neurologic symp- were not complete but did indicate she had a
toms. Five to six years previously, she had prolonged, markedly elevated temperature (>
intermittent unsteadiness that was attributed 104°F.) secondary to meningitis.
to an "inner ear infection". She also was aware At that time, the patient also had the onset
that during the last year, if she sat in a hot tub, of episodes of tinnitus, vertigo, olf.tctory hal-
she would be totally exhausted. lucinations of roasting meat, a sense of de'ja vu
and the sensation of hearing a symphony. She
would be observed to be glassy-eyed and inat-
This was entirely within normal limits
tentive.
except for a selective decrease in touch sensa- Past history indicated the following:
tion involving the entire distribution of the 1. Cervical disc surgery at age 30.
right trigeminal nerve, including mucous 2. Lumbar disc surgery at age 38 and
membranes, gums, upper and lower right half
age 60.
of the tongue and upper and lower lip. Touch 3. Hyperthyroidism had been treated with
sensation was also decreased over the right radioactive iodine. She was receiving thyroid
cornea. In all areas, pain sensation was intact. replacement.
Graphesthesia over the fuce was intact. 4. Diabetes mellitus had been treated with
SUBSEQUENT COURSE: insulin for 5 years.
All numbness disappeared approximately NEUROLOGIC EVALUATION:
two months after onset. She returned five 1. Mental status: Intact.
months later with complaint of one-week 2. Cranial nerves: Intact.
duration of "feeling slightly woozy".
3. Motor system:
Neurologic examination was not remarkable. a. Strength intact.
Symptoms were reproduced by rotation. b. Stance: Unsteady on a narrow base and
QUESTIONS: only slightly worse with eye closure.
c. Gait: Unable to walk a tandem gait,
1. What is the location of the lesion corre-
unsteady on the turns.
sponding to the sensory symptoms involving
d. Finger-to-nose test and heel-to-shin
the fuce?
tests were not remarkable.
2. What is the appropriate neurodiagnostic
study? What other studies might be obtained
4. Reflexes:
a. Deep tendon reflexes: Achilles reflexes
3. Select the appropriate illustration.
were absent bilaterally.
4. What is the most likely clinical
diagnosis?
5. Which therapy would you recommend!
5. Sensory system:
a. Pain sensation was decreased to the NEUROLOGIC EXAMINATION:
knees bilaterally. 1. Mental status: Oriented for time, place
b. Vibration sensation was absent at toes and person. Delayed recall without assistance
and decreased at ankles. oout of 5 objects in 5 minutes, with assistance
c. Position sensation was intact. 3 out of 5 objects.
2. Cranial nerves: Intact, including fundi,
SUBSEQUENT COURSE:
except for hyperactive jaw jerk.
The neurologic examination did not 3. Motor system:
change over the next two years. a. Strength intact.
QUESTIONS: b. Stance: He was relatively steady until he
closed his eyes.
1. As regards the ataxia of stance and gait
c. Gait: He walked on a broad base but was
present since the hospitalization 23 years pre-
able to do tandem gait. He was unsteady on
viously:
the turns.
a. Indicate the location oflesion.
d. Finger-to-nose test demonstrated a
b. Indicate the most likely pathology.
slight terminal tremor.
c. Indicate best study to demonstrate a.
4. Reflexes:
&b.
a. Deep tendon stretch reflexes were 2 in
d. Select the appropriate illustration.
the upper extremities, 3 at the patella, and 2-3
2. As regards the episodes characterized by
at Achilles tendon.
sensory perception of "roast meat odor" ,
b. Plantar responses were extensor
"music of a symphony", tinnitus and vertigo,
bilaterally
etc.:
c. There was no release of instinctive grasp.
a. Indicate diagnosis.
b. Indicate most likely etiology.
5. Sensory system:
a. Position sensation was intact at fingers
c. Select the best test to support diagnosis.
and toes.
d. Indicate the most appropriate
b. Vibration sensation was absent at toes,
treatment.
decreased at ankles, and markedly decreased at
3. As regards the absent Achilles reflexes,
fingers compared to wrist, and at wrist com-
the decreased vibratory sensation and distal
pared to elbows.
decrease in pain sensation:
c. Pain sensation was decreased at toes to
a. Indicate diagnosis.
mid arch and over fingers.
b. Indicate the most likely pathology.
QUESTIONS
Case 3IA-5: This 70-year-old single right-
1. As regards ataxia of stance and gait:
handed white male priest had been unsteady
Localize the lesion. Indicate the pathology.
for at least 1.5 years. He had been stumbling
2. Indicate best test to support the
over names for the same period but had no
diagnosis.
other problems in memory. Urinary symp-
3. Select the two best illustrations that
toms were denied.
would correspond to this case.
Past history indicated atrial fibrillation in
4. Does this patient also have another neu-
the past. Hypertension had been under treat-
rologic disorder?
ment for 10 to 20 years. There was no definite
history of cerebrovascular disease. SUBSEQUENT COURSE:
Family History: A niece had hydrocephalus The patient had periodic neurologic fol-
that was shunted when she was a child. Two low-up evaluations. He was relatively stable
of four sisters had cerebral aneurysms. over the next 4 years; then he reported a
3IA-IO CHAPTER 31A
minor increase in the degree of unsteadiness. lar reflex and a marked depression of both
Two years later, he developed a sudden onset Achilles deep tendon stretch reflexes.
of diplopia in looking to the left and a minor 2. Back: The patient could forward flex to
ptosis of the left lid. Examination now 60° to the vertical plan, at which point he
demonstrated: complained of pain shooting down the left
1. Chronic atrial fibrillation. posterior thigh.
2. Moderate ptosis of the left lid. 3. Straight-leg-raising: This was limited to
3. Weakness of the left lateral rectus 50 to 60° on the left, with pain in the left pos-
movements. terior thigh. On the right, straight-leg-raising
4. Decreased hearing in the left ear. could be carried out to 90°.
5. Deep tendon reflexes increased on the 3. Sciatic nerve: Tenderness was present on
left. the left.
6. Pain sensation decreased over the entire
right side, including the face. QUESTIONS:
7. Patient stood on broad base and walked 1. What is the clinical diagnosis? Be specif-
with small steps on broad base. ic as to the localization and pathology.
His diplopia cleared, but previous neuro- 2. Assuming that this patient had not
logic symptoms and signs remained. responded to "conservative" measures, which
diagnostic study would you obtain? Be
QUESTIONS specific.
s. As regards this last sudden episode, 4. Select the illustration - corresponding to
localize the pathology. Indicate the nature of this case.
the pathology. 5. Define "conservative measures".
6. Indicate the best study to support the 6. What therapy would be recommended if
clinical diagnosis. these measures had failed and pain progressed?
7. Does any illustration correspond to this
episode? Case 31A-7: This 27-year-old right-hand-
ed female college maintenance worker devel-
Case 3IA-6: This 36-year-old right-hand- oped progressive numbness in the left arm
ed white male lecturer was referred for evalua- extending from the elbow to all of the fingers.
tion of symptoms related to a motor vehicle Initially, this was intermittent, but it soon
accident that occurred 2.5 years earlier. He became constant. She also developed persis-
had initially symptoms in the neck and right tent discomfort in the posterior cervical area
arm, but these essentially cleared. A more per- extending to the left supraclavicular area.
sistent area of symptomatology related to the There was no history of trauma. Her primary
lumbar area. Occasional sharp pains extended physician obtained initial X-ray studies and,
from the back to the left buttock, the left pos- subsequently, referred the patient to a neuro-
terior thigh, the posterior calf and the ankle. surgeon.
Back pain improved but left leg pain increased. QUESTIONS:
In addition to the shooting pains in the left 1. What is the differential diagnosis at this
leg, he complained of intermittent numbness time?
in the left posterior thigh. He denied weak- 2. What initial study would you, as the pri-
ness, bladder or sexual dysfunction. There mary physician, obtain?
were no symptoms in the right leg, except for 3. Select the appropriate illustration.
occasional burning in the anterior tibial area. 4. Based on that illustration, what is the
NEUROLOGIC EXAMINATION: most likely diagnosis?
Totally intact except for the following: SUBSEQUENT COURSE:
1. Reflexes: slight decrease in the left patel-
CASE HISTORY PROBLEM SOLVING PART V-A: IMAGING CORRELATION 3IA-11
The neurosurgeon found the deep tendon QUESTIONS:
reflexes absent at the left biceps and triceps. 7. What is the diagnosis of this new prob-
He requested a more definitive neuroimaging lem involving the right arm?
study. Based on that study, the neurosurgeon 8. Which diagnostic procedure would you
performed definitive neurosurgical proce- request?
dures. The patient had an excellent result, 9. What is the explanation for the smaller
except for residual numbness in the fingers of left pupil, mild left lid ptosis and decreased
the left hand and a left Horner's syndrome. sweating over the left side of the face?
10. What condition might concern you
QUESTIONS:
regarding the bilateral deficit in hearing? How
1. Which definitive study would you, as the
would you evaluate this problem?
neurosurgeon, have requested?
2. Select the appropriate illustration. Case 31A-8: This 20-year-old left-handed
3. Based on the illustration, what is the white male was the product of a prolonged
most appropriate diagnosis? delivery. The mother claimed, "the head was
4. Which neurosurgical approaches (proce- held back." The day after birth, a seizure
dures) were utilized? occurred. At age 10 months, he was noted to
5. Why did the patient have residual senso- have problems in movement of the right arm
ry deficit in the thumb and index finger? and leg. He was still unable to stand at 14
6. Why did the patient have a residual months of age. When he was evaluated at the
Horner's syndrome? Children's Hospital Medical Center at age 2
SUBSEQUENT COURSE: years, he was described as having a spastic and
dystonic right hemiparesis, with severe delays
Six months after her last surgery, she
in expressive speech. At age 4 to 5 years, he
returned to the neurosurgeon, complaining
began to have frequent seizures, which began
of burning pain in the right scapular area
with tingling of the right hand and face, and
and some intermittent tingling of the
focal movements of the right hand and lips.
fourth and fifth fingers of the right hand.
These would secondarily generalize 3 to 4
Examination 6 months later demonstrated: times per day.
1. Cranial nerves:
Family History:
a. Mild ptosis of the left eyelid, a smaller
pupil on the left, and decreased sweating over The mother had a long-standing mild right
the left side of the face. hemiparesis, with focal sensory seizures involv-
b. Whisper perception was decreased ing right face and arm. A brother carried a
bilaterally. diagnosis of schizophrenia.
2. Motor system: There was mild weakness QUESTIONS:
in the right triceps muscle.
1. What is your clinical diagnosis (location
3. Reflexes: The triceps and biceps deep
of lesion, type of pathology) at this point?
tendon reflexes were decreased on the left, but
2. What study would have best demon-
the radial and finger jerks were increased on
strated the location and nature of the patholo-
the left. Plantar responses were flexor.
gy?
4. Sensory system: Pain sensation was
3. How would you manage the seizures?
decreased over the thumb and index finger
4. How would you manage the spastic dys-
and to a lesser degree over the middle finger of
tonic right hemiparesis and expressive speech
the left hand.
delay?
5. Neck and supraclavicular areas: She was
tender over the right supraclavicular area, with SUBSEQUENT COURSE:
pain extending into the right arm. He had undergone, at age 11, a heel-cord-
31A-12 CHAPTER 31A
lengthening and toe-tendon-stretching right elbow.

operation. 4. Reflexes:
At school, he had achieved third grade pro- a. Deep tendon reflexes were increased on
ficiency in reading and writing and tenth grade the right.
proficiency in math. b. Plantar responses were extensor on the
The patient was seen again 10 years later right.
for a second opinion regarding seizure con- 5. Sensory system: Intact for all primary and
trol. Over the intervening years, seizures had cortical modalities.
occurred at variable frequency. His seizures QUESTIONS:
were primarily focal motor seizures beginning
5. Indicate your diagnostic approach.
in the right arm. At times, secondary gener-
6. Today, what would be the best study to
alization might occur, particularly when flur-
indicate the location, extent, and nature of the
ries offocal seizures occurred. Often a warn-
lesion?
ing occurred, which he could not precisely
7. What would you expect the electroen-
identify but which had components of a
cephalogram to demonstrate?
dreamy, strange, or familiar sensation. Over
8. Indicate your therapeutic approach at
the years, he had been treated with phenytoin,
this point.
phenobarbital, valproic acid, carbamazepine
6. Discuss the alteration in the spasticity of
and primidone. Despite this, seizures were still
flexors and extensors at the elbow on rotation
occurring in flurries 3 to 4 days per week.
of the neck.
1. Mental status: He was oriented for time , Case 3IA-9: This I8-year-old right-hand-
place and person. Delayed recall was five out ed white male was the product of a prolonged
of five in five minutes. Later, neuropsycholog- delivery that apparently was complicated by
ical testing indicated that visual non-verbal "umbilical cord around the neck". "He did
learning was performed at a much higher level not breathe well at birth and may have aspirat-
than auditory verbal learning. Reading, ed. " Three generalized convulsive seizures
spelling, and arithmetic were all severely occurred at birth, and generalized convulsive
impaired. seizures recurred with vaccination at 9 months
2. Cranial nerves: There was smallness of of age and then once every 6 to 12 months.
the right side of the face. No seizures occurred from age 7 to age 15
3. Motor system: years. Seizures then recurred in relation to
a. There was smallness of the right hand, reduction of medication. Warning symptoms
thumb, arm, and foot. preceded most seizures. He would sense a
b. There was a right-sided weakness of the trembling of the extremities, and then vision
distal hand muscles, wrist extensor, and tri- would black out for 1 to 2 minutes while he
ceps. was still standing and able to think. Then he
c. Patient walked with a hemiplegic pos- would fall down and would be tonic/clonic
ture. The right arm was flexed at elbow and for 1 to 2 minutes, with grater involvement of
there were dystonic movements of the right the left side. He would be "sleepy and con-
hand. The leg was extended at hip, with exter- fused afterwards". He was described as having
nal rotation and circumduction. average performance in school but reading
d. There was marked resistance to passive had always been slow.
motion at the right shoulder and ankle ("tight NEUROLOGICAL EXAMINATION:
Achilles tendon"). With rotation of the head, Intact except for:
significant alterations occurred in the degree 1. Slight clumsiness in movements of the
of spasticity in the flexors and extensors at the left hand.
2. Deep tendon reflex increased on the left.
SUBSEQUENT COURSE:
The patient did well with no seizures for
five years. Then he had the onset of "trance-
like episodes." According to the patient, he
would note slurring of speech and then would
be unaware of the environment. According to
his father, he would appear to stare for one
minute and would not speak for one minute.
There would be slight rigidity of both arms,
but he would not fall to the ground, and there
would not be a genera1ized convulsive seizure.
At the end of the episode, he would be "fully
aware of his environment." No automatisms
would be noted during or after the episode.
With adjustment of medications, the episodes
were again controlled. Episodes recurred
seven years later and then, after eight more
years, more frequently (one to three episodes
per week).
Several years later, he had a more pro-
longed episode, beginning with a "seasick sen-
sation and problem with vision of the left eye"
and continuing with prolonged confusion. He
was "incoherent for 30 minutes and confused
for an additional 30 minutes." Eventually,
with additional adjustment of medication, con-
trol was again eventually achieved.
QUESTIONS:
1. What is your diagnosis?
2. Where is the pathology located?
3. What is the nature of the pathology?
4. This patient had multiple electroen-
cephalograms. Indicate the possible findings.
5. Which medication would you utilize in
management of this patient?
6. Which neuroimaging study would best
demonstrate the location and nature of the
pathology?
7. Select the illustration, which best
correlates with this case.
Index
INDEX Limbic nuclei 22-6

A Central
Abnormal Development of the Nervous System Basolatera1
4-15 Ventral amygdalofugal pathway 22-7,
Malformations resulting from abnormalities in 22-14
growth and migration Amyotrophic lateral sclerosis, 9-19
Anencephaly 4-17 Aneurysms, 13-7,26-26,26-27,26-28
Agenesis of corpus callosum 4-19, Anticonvulsant medications
Clinical Case 4-1: bilateral subcortical Choice of medication, 29-22
band heterotopias; double cortex 4-17. Molecular basis, 29-21
Clinical Case 4-2: Agenesis of the corpus Pharmacologic properties, 29-21
callosum 4-19 Side effects, 29-19
Heterotopias 4-15 Teratogenic effects, 29-19
Holoprosencephaly 4-19 4-17 Aphasia and related disorders, 24-3,24-3
Lissencephaly 4-18 Alexia without agraphia
Micropolygri 4-18,4-14 anomic or amnesic or nominal aphasia,24-14
Macrogyria 4-18 anterior type aphasia, 24-6
Microencephaly 4-19 Broca's area and Broca's aphasia, 24-6
Porencephaly 4-19 transcortical motor aphasia, 24-15
Schizencephaly 4-19, 4-15 Clinical cases
Cerebellar Agenesis 4-19 Case 24-1, acute anterior (Broca's), 24-7
Malformations Resulting from Case 24-2, chronic anterior (Broca's), 24-8
Chromosomal Trisomy and Translocation 4-20 Case 24-3, chronic nonfluent &apraxia, 24-
Malformations resulting from defective fusion 9,24-9
of dorsal structures 4-20 Case 24-4, fluent, Wernicke's, 24-10
Spinal Bifida 4-20 Case 24-5, fluent, disconnection,&
Cranial Bifida 4-20 Gerstmann's,24-12
Arnold Chiari 4-21 Case 24-6, fluent, disconnection (conduction
Acetylcholine, or repetition type), 24-13
basal ganglia 19-2, 19-5 Case 24-7, dyslexia due to AVM, 24-15
Action Potential 5-12, 5-13 Fluent aphasias, 24-6
Ionic mechanisms 5-13, 5-12 conduction type fluent aphasia, 24-11
Action potential cycle 5-18 disconnection type fluent aphasia,24-11
Active Transport 5-8, 5-21 dominant inferior parietal type fluent aphasia,
Agnosia, 24-15 24-11
Akinetic (atonic seizures), 29-12 dysgraphia, 24-12
Akinetic mutism, 29-2 dyslexia, 24-12
Alcoholic cerebellar atrophy, 20-8 Gerstmann's syndrome, 24-12
Alzheimer's disease, 30-12 pure word deafness, 24-10
and Down's syndrome, 30-15 transcortical sensory aphasia,24-15
and basal nucleus ofMeynert, 30-18 Wernicke's area and Wernicke's type of
cholinergic hypothesis ,30-18 fluent aphasia, 24-9
clinical fmdings and course, 30-17 global aphasia, 24-14
evaluation, 30-18 isolation of speech areas aphasia, 24-14
genetics, 30-15 mixed transcortical aphasia (isolation of
hippocampus , 30-14 speech areas ),24-14
prevalence, 30-12 selective dyslexia (a type of disconnection),24-
pathology, 30-13 15
treatment, 30-19 visual agnosia, 24-1
Amnesia Apo E, 30-17
Amnestic-confabulatory syndrome, 30-5 Apoptosis 4-4
Traumatic, 30-11 Apraxia, 24-17
Amygdala 22-6, 22-8 Arcuate fasciculus and role in language function,
Olfactory nuclei 22-6 24-5
Corticomedial Arsenic, 8-17, 27-28, and chapter 27 on CD
Basolateral ROM supplement
2 Index
Arteries Case 19-5, Huntington's disease, 19-21 (CD

Vertebral 1-17 ROM)
Basilar 1-17 Case 19-6, hepatolenticular degeneration,
Arterial supply 1-16, 1-19, table 1-13 19-22 (CD ROM)
Anterior circulation-Internal carotid, directpathway,19-1,19-2
Middle cerebral, anterior cerebral 1-16 indirect pathway, 19-1, 19-3
Posterior circulation-Vertebral, Basilar, microanatomy of striatum, 19-4,19-5
Posterior cerebral 1-16 symptoms of dysfunction :akinesia ,
Circle of Willis 1-171-19 dyskinesia, 19-4
Arteriovenous malformations, 26-31 Syndromes of dysfunction, 19-7
Ataxia of standing body posture, 20-10 chorea, 19-14
Ataxia telangiectasia, 20-18 double athetosis, 19-21
Atrophic changes 3-21 dystonia, 19-22
Autonomic Nervous System 16-10, 16-12 familial paroxysmal dyskinesia, 19-24
Cutaneous & deep vessels, glands and generalized chorea, 19-17
hair. 16-15 hemiballism, 19-15,19-16,19-19
Dual Innervation of Specific Structures hemichorea, 19-15, 19-16,19-18
16-14 to 16-15 hepatolenticular degeneration, 19-21
The Eye 16-14 Huntington's disease, 19-18,19-19,19-21
Lacrimal Glands 16-14 neuroleptic induced movement disorders,19-
Salivary Glands 16-14 23
The Heart 16-14 Parkinsonian syndrome, 19-7, 19-4
The Lungs 16-14 Parkinson's disease, 19-7,19-9
Abdominal Viscera 16-15 Parkinsonism plus syndromes, 19-14, 19-15
Pelvis 16-15 secondary Parkinsonism, 19-14
Enteric Nervous System 16-11 tics,19-24
Localization of preganglionic para-and Wilson's disease, 19-21
sympathetic neurons 16-11 transmitters, 19-1, 19-2, 19-1
Parasympathetic Nervous System and Basal nucleus ofMeynert, 30-18
the Cranial Nerves 16-11 Bacterial endocarditis, 26-30
Parasympathetic Nervous System and Basilar artery syndromes,13-13,13-14,13-15,13-
the Sacral Plexus 16-11 16
Postganglionic Neuron 16-10 Beta amyloid, 30-15
Preganglionic Neuron 16-10 Bladder, 9-2,18-3
Sympathetic Ganglia Autonomic bladder 16-16
Cervical Sympathetic Ganglia 16-13 Sensory paralytic bladder 16-16
Lumbar Sympathetic Ganglia 16-14 Reflex bladder 16-16
Thoracic Sympathetic Ganglia 16-13 Blood-Brain Barrier 3-24
Autosomal dominant cerebellar ataxias (ADCA), Brain abscess, 27-22, 27-23,27-24
20-19 Brain death, 29-2
Autosomal recessive cerebellar ataxias, 20-17 Brain stem, 13-1 Brain stem 11-1 11-1, 11-2 rnri
Axon and Axon Origin 3-8 Brain stem and eye movements 11-30
Axon hillock 3-8,3-16 Cases effecting eye movement 11-31
Axonal Guidance 3-24 Case 11-1 tumor in pons 11-31
Nerve Growth Factors 3-24 Case 11-2 pineal tumor 11-33
Azorean disease, 20-20 Tegmentum 11-1
B Zones 11-2
Babinski Response 7-22, 9-2 Ventricular
Basal ganglia, 19-1 Lateral
anatomy, 19-1,19-1 Medial
circuits, 19-1,19-3,19-1 Central
Clinical cases Basilar
Case 19-1, Parkinson's disease, 19-12 Clinical signs after lesions in
Case 19-2, hemichorea, 19-16, 19-18 tegmentum of brain stem 11-29
Case 19-3, hemiballismus, 19-17 Tectum 11-2
Case 19-4, Huntington's disease, 19-20 Medulla 11-3
Index 3
Level: Case 10-3, Guillain Barre syndrome,

Spinomedullary junction & motor 10-4
decussation 11-4, 11-4 Case 10-4, Cervical spondylosis with
Lower medulla at sensory decussation C7 cord compression, 10-S
11-4,11-S Case 10-S, Combined system disease,
Inferior olive, 11-7, 11-6 B 12 deficiency myelopathy and
Pons 11-10 peripheral neuropathy, 10-S
Level: Case 10-6, Glioma of cervical spinal
Lower pons at Facial colliculus 11-10, cord,10-6
11-7 Case 10-7, polymyositis, 10-7
Upper pons at motor and main sensory of Case 10-8, syringomyelia, 10-8
V 11-13, 11-8
Midbrain II-IS CHAPTER 14: BRAIN STEM AND
Level: CRANIAL NERVES
Inferior colliculus 11-1S, 11-9
Superior colliculus and pontine basis Case 14-1, Amyotrophic lateral
11-18, 11-18 sclerosis (classical), 14-2
Cerebral peduncles 11-21 11-11 Case 14-2, Lateral (dorsolateral)
Clinical cases in Brain Stem medullary syndrome, 14-3
Case 13-1, platybasia, 13-7 (CD ROM) Case 14-3, Pretectal-midbrain
Case 13-2, total infarct PICA, 13- 11 syndrome, lacunar, 14-4
Case 13-3, lateral medullary infarct, 13-11 Case 14-4, brain stem infarct lower
(CD ROM) pons primarily territory of anterior
Case 13-4, anterior inferior cerebellar artery inferior cerebellar artery (Plus) due to
territory infarct, 13-14, (CD ROM) vertebral basilar ischemia, 14-S
Case 13-S, paramedian pontine infarct, 13- Case 14-S, Cerebellar pontine angle
IS,13-16 tumor, vestibular Schwannoma, 14-6
Case 13-6, Weber's syndrome, paramedian Case 14-6, Weber's syndrome with
midbrain infarct, 13-17 prior basilar vertebral TIA's and
Case 13-7, extensive posterior cerebral artery ischemia, 14-7
infarct, 13-17, (CD ROM) Case 14-7, Myasthenia gravis, 14-8
Case 13-8, basilar artery thrombosis, 13- Case 14-8, Syringomyelia and
17,13-1S (CD ROM) syringobulbia. Coma due to C02
Case 13-9, brain stem glioma, 13-19,13-24 retention and low 02 saturation
Case 13-10, brain stem glioma, 13-19 (CD
ROM) CHAPTER 2S: CEREBRAL CORTEX:
Case 13-11, multiple sclerosis, brain stem- CORTICAL LOCALIZATION
cerebellum predominant, 13-20,13-21
Brain tumors, 27-7 (see ependymomas, Case 2S-1, Glioblastoma rt. occipital
glioblastomas, gliomas, lymphomas, extending to right parietal, 2S-1
meningiomas, medulloblastomas, metastatic Case 2S-2, Glioma right parietal, 25-2
tumors ,neoplasms) Case 2S-3, PrefrontaVpremotor
Brown Sequard syndrome, 9-2 metastatic tumor, 2S-3
C Case 2S-4, Embolus inferior division
Ca Channels S-9 Rt. MCA, Non dominant syndrome,2S-
CASE HISTORY PROBLEM SOLVING 4
CHAPTER 10:SPINAL CORD, Case 2S-S, Focal seizure Rt
NERVE ROOT, PERIPHERAL motor/sensory cortex secondary to
NERVE AND MUSCLE: metastatic tumor. Jacksonian march,
Case 10-1, cervical 7 radiculopathy and Todd's postictal palsy, 2S-S
secondary to acute ruptured disc, 10-2 Case 2S-6, Right temporal lobe seizures
Case 10-2, T3-4 spinal cord simple and complex partial. Epidural
compression extrinsic tumor hematoma at age 18 months, 2S-6
(meningioma) left lateral producing a Case 2S-7, Onset of seizures in left
partial Brown Sequard syndrome, 10-3 premotor cortex(tonic abduction of arm
4 Index
with head and eye turning). Stroke at Case 31-11, Wernicke's

age 9 months? arterial occlusion, 25-7 encephalopathy, 31-10
Case 25-8, Glioma left orbital frontal- Case 31-12, Multiple complications of
anterior temporal. Ictal aggression. 25-8 alcoholism and diabetes: cerebellar
degeneration and peripheral
CHAPTER 28: DISEASES OF THE neuropathy,31-12
CEREBRAL HEMISPHERES:
Case 28-1, Posterior communicating CHAPTER 31 PART I GENERAL
aneurysm with subarachnoid CASE HISTORY WITH
hemorrhage, 28-3 ILLUSTRATION CORRELATION
Case 28-2, Carotid TIA's involving Case 31Al, Acute intrinsic lesion of
retina and carotid border zone, 28-4 multiple sclerosis at left cerebellar
Case 28-3, MCA aneurysm with SAH. inferior pontine angle, 31-A7
Post op bacterial meningitis and focal Case 31A2, Hydrocephalus (secondary
seizures, 28-4 to a pineal region tumor), 31A-7
Case 28-4, Subacute right sided Case 31A3, Multiple sclerosis right mid
subdural hematoma, 28-6 pons, 31A-8
Case 28-5, Glioma with seizures Case 31A4, cerebellar atrophy due to
originating right Rolandic area, 28-7 hyperthermia, temporal lobe seizures,
Case 28-6, MCA lenticulostriate diabetic peripheral neuropathy, 31A-8
penetrating branch infarct left internal Case 31A5, hydrocephalus, peripheral
capsule. Pontine lacune is less likely. neuropathy, inferior pontine tegmental
28-8 infarct, 31A-9
Contrast case #1 Carotid TIA's Case 31A6, Ruptured lumbar disc ?L5-
borderzone and retina 28-8 SI 31A-1O
Contrast case #2 cardiogenic embolus Case 31A7 cervical radiculopathy,
main stem MCA 28-9 Schwannoma, 31A-I0
Case 28-7, Brain abscess, left temporal Case 31A8 porencephaly left Sylvian,
plus left peripheral facial paralysis, 28- 31A-11
9 Case 31A9 seizure disorder offocal
Case 28-8, Emboli left MCA and left origin right occipital, 31A-12
arm, 28-10
KEY TO THE PHOTOGRAPHS FOR
CHAPTER 31 GENERAL CASE CHAPTER 31
HISTORY PROBLEM SOLVING:
31-1 Ruptured disc LS-Sl, 31A1
Case 31-1, Parkinson's disease, and 31-2 Enlarged LT cervical neuro
dementia plus old polio, 31-1 foramina at C5-C7, probable
Case 31-2, Pituitary adenoma with Schwannoma 31Al
extrasellar compression of optic chiasm, 31-3 SchwannomaLTC6-C7,31-A2
post op diabetes insipidus, 31-2 31-4 Multiple sclerosis, major lesion
Case 31-3, Carotid TIA's hemisphere left pontine tegmentum, 31-A2
and retinal, 31-3 31-5 Multiple sclerosis Right mid
Case 31-4, Idiopathic epilepsy (primary pontine tegmentum and corpus
generalized epilepsy),31-3 callosum 31-A3
Case 31-5, Meningococcal meningitis 31-6 Pineal region tumor producing
with infarct right hemisphere and focal hydrocephalus, 31-A4
seizures, 31-4 31-7 Hydrocephalus, possible
Case 31-6, Alzheimer's disease, 31-5 aqueductal stenosis, 31-A4
Case 31-7, Hemichorea and 31-8 Atrophy right occipital, 31-A5
hemiballismus,31-6 31-9 Atrophy left peri sylvian, 31-A5
Case 31-8, Left cerebellar metastatic 31-10 Cerebellar atrophy, 31-A6
tumor, 31-7 31-11 Glioma (Glioblastoma) of right
Case 31-9, Right temporal lobe mass thalamus, 31-A6
with herniation: brain abscess, 31-8 31-12 Left frontal subdural hematoma,
Case 31-10, Huntington's chorea, 31-9 3 I-Ali
Index 5
Visual defects 22-19

Kluver-Bucy Syndrome 22-
Cell Membrane 5-1, 5-1 19
Chemical potential 5-2 Memory 22-21
Osmotic strength 5-2 Psychiatric Disturbances 22-20, 22-
Osmolarity 5-4 26 (Table 22-6), Supplemental CD
Osmotic Pressure 5-4 Aggressive behavior 22-20
Diffusion 5-3 Clinical Cases from the
Central Nerve Regeneration 3-23 temporal lobe:
Cerebral Hemispheres 1-9 1-8, 1-9 Case 22-1 Simple and complex
Correlation of Structure and Function 17-10, seizures from left temporal 22-17
17-10, 17-11,22-20 Case 22-2 focal seizures
Frontal lobe 1-9 1-10 originating in right temporal
Motor Areas, 17-11 lobe 22-18
4 17-11 Case 22-3 Complex partial
6 17-11 seizures 22-19 Occipital Lobe
8 17-13 17-16
44&45 17-13 Visual receptive (calcarine
Lateral surface 22-21 cortex) area 17 17-16
Orbital surface 22-21 Visual associational areas 18,
Clinical Case 22-4 Right frontal lobe 19 17-16
tumor 22-4 , 22-24 Conftrmation of Location of
Parasagittallesions pathology 17-10
Prefrontal 22-21 Occipital lobe 1-10 1-12
Prefrontal lobotomy 22-23 22-19 Anatomy
Parietallobe 1-9 1-11,17-14 Functional localization
Postcentral areas 3,1, 217-14 Cingulate gyrus 1-11 1-13
Functional localization Anatomy
Temporal lobe 1-10 1-12 Functional localization
Temporal Lobe Overview 17-14 Insular Gyri 1-11 1-14
Cytoarchitecture 17-1 Basal nuclei 1-11 1-15
Study of Functional Localization white matter
Stimulation 17-8 Association ftbers 11-12
Ablation 17-9 Commissural ftbers 11-12
Auditory Associational areas Subcortical fibers 11-12
42 & 22 17-14, 17-15 Corticofugal11-12
Wernicke's Areas area 22 17- Corticopetal11-12
15 Cerebral Neuron types 17-2
Middle temporal area 21 17- Spiny neurons 17-2
14 Pyramidal 17-2,17-2
Inferior temporal area 20 17- Stellate 17-3,17-2
14 Smooth neurons 17-3
Posterior temporal area 37 Fundamental Organization
17-14 Homogenetic 17-4
Entorhinal areas 27,28,35 17-14 Heterogenetic 17-4
Lateral neocortical areas 22- 6-layered = molecular, external
14 granular, external pyramidal, inner
Auditory and auditory granular, inner pyramidal, multiform
association area22-15 17-14, 17-4
17-15 Von Economo Categories; Agranular,
Symptoms following stimulation of Homotypical, Midpoint, Polar, Granular 17-6,
temporal lobe 22-17 17-5,17-6
Symptoms of disease of temporal lobe Cerebrum Subcortical white matter
22-15 Associational 17-17
Effects on hearing 22-19 Short subcortical 17-17
Aphasia 22-19 U fibers
6 Index
Long fiber bundles 17-18 Cerebellopontine Angle Syndrome

Uncinate fasciculus Case 12-7 on CD
Superior longitudinal Vestibular
fasciculus Case 12-8 Vestibular
Cingulum Schwanoma
Inferior longitudinal Jugular Foramen Syndrome
fasciculus Case 12-9 on CD
Inferior frontal Voluntary Control of Cranial Nerves
occipital fasciculus Corticobulbar-Voluntary Control of
Choroid plexus 3-30; fig 3-35 Cranial Nerves V, VII, IX-XII 12-23
Corticomesencephalic -Voluntary
Cingulum 22-14 Control of Eye movements via Cranial nerves
Circadian rhythms 16-10 III,IV and VI 12-23
Cordotomy 7-19 Motor nucleus
Corticofugal efferent fibers- Clinical Case 12-2 ;Trigeminal
corticospinal,corticobulbar Neuralgia 12-10
Corticopetal afferents -thalamocortical 17-16 Clinical Case 12-3 Ophthalamic Herpes
Cortical Commissural 12-11
Corpus callosum 17-17, 17-13,17-14 Cranial Nerve VI, Abducens 12- 11
Anterior comissure 12-4
Hippocampal Cranial Nerve VII, Facial 12-11 12-6
Cortical Projectional 17-16 Parasympathetic ganglia 12-13
CRANIAL NERVES Submandibular
Components 12-2 Pterygopalatine
Cranial Nerve I, Olfactory 12-2, 12-2 Clinical Case 12-5: Bell'sPalsy 12-
Cranial Nerve II, Optic 12-4, 12-3 14
Cranial nerve ill, Oculomotor Cranial nerve VIII,
12-4, 12-4 Vestibuloaccoustic 12-15, 12-7
Clinical Case 12-1; 12-6 12-4 Cochlear 12-15, 12-8
Cranial Nerve IV, Trochlear 12-7 12-4 Olivocochlearbundle 12-16
Cranial Nerve V, Trigeminal 12-7, 12- Vestibular 12-17, 12-7
Trigeminal 15-10 Vestibular nuclei 12-9
Ganglia Cranial Nerve IX, Glossopharyngeal
Descending/spinal 12-18 12-10
nucleus Cranial Nerve X, Vagus 12-19, 12-11
Chief sensory nucleus Motor nuclei
Mesencephalic Dorsal motor nucleus of X 12-
nucleus 20
Sensory nuclei Ambiguous nucleus
Taste solitary nucleus 12-20 of X 12-20
General sensation 12-20 Cranial Nerve Differentiation 4-10
Lesions of Peripheral Branches of Innvervation of muscles of somite
Vagus origin CN ill, N, VI, XII 4-9
Superior laryngeal 12-21 Innervation of muscles originating in
Recurrent laryngeal 12-21 pharyngeal arches 4-9
Supranuclear lesion 12-21 First arch -trigeminal 4-10
Cranial Nerve XI, Spinal Accessory 12-21, Second arch - facial 4-10
12-12 Third arch - glossopharyngeal
Cranial Nerve XII, Hypoglossal 12-22, 12-13 4-10
Dysfunction of cranial nerves Arches 4-6 vagus 4-10
Motor 11-28 Innervation of preganglionic
Sensory 11-28 parasympathetic smooth muscles 4-10
Effects of Extrinsic Lesions on Cranial Cranial nerves III, VII, IX, X
Nerves 12- Table 12-5 &Cases on CD Innervation of Special Sense organs 4-
Cavernous Sinus syndrome 10
Case 12-6 on CD Cranial nerves I, II, VIII
Index 7
Extrinsic syndromes, 13-2 Case 20-5, lateral hemisphere syndrome,

Cerebellar pontine angle, 13-2 hemangioblastoma, 20-5, (CD ROM)
Developmental abnormalities at the foramen Case 20-6, cerebellar infarct, (PICA), 20-16
magnum, 13-7 Case 20-7, arteriovenous malformation, 20-16,
Foramen magnum syndromes, herniations CD ROM)
meningiomas, 13-7 effects of disease, 20-5
Lateral cerebellum, 13-4 functional correlations, 20-4
Midbrain, pretectal, pinealoma, 13-5 major syndromes, 20-6
Midbrain, tentorial syndromes, herniations alcoholic cerebellar atrophy, 20-8
meningiomas, 13-5 anterior lobe, 20-8
Midline cerebellum, 13-3 atrophy related to fever and status
Intrinsic syndromes epilepticus,20-9
Gliomas of brain stem, 13-19 floccular-nodular lobe, 20-6
Multiple sclerosis, 13-19,13-20, 13-21 hemorrhage, 13-8
Pontine hemorrhage, 13-18 lateral cerebellar hemisphere, 20-10
Vascular syndromes, 13-8 midline cerebellar tumors, 20-7
Brain Stem Centers nuclei, 20-1
Respiration 11-23 neocerebellar or middle-posterior lobe, 10-10
Cardiovascular 11-23 paraneoplastic subacute cerebellar
Coughing 11-25 degeneration, 20-21
Deglutition 11-24 peduncles, 20-13
Vomiting 11-24 spinocerebellar degenerations, 20-9,20-16
Emetic 11-24 vascular syndromes,20-14, 20-17
CAG trinucleotide repeats Topography of representation,20-4
in Huntington's disease, 19-19 Cerebellar ataxia with myoclonus, 20-17
in spinocerebellar atrophy (SCA), 20-19 Cerebral dominance, 24-1
in x linked recessive bulbospinal Cerebral embolism, 26-20
neuronopathy, 9-18 Cerebrospinal fluid,
Carcinomatosis of the meninges, 27-18,27-22 content, 2-26
Cataplexy, 29-26 examination, (lumbar puncture),2-26
Caudate nucleus, 19-1 Cervical spondylosis, 9-4
Central pattern generators, 18-1 Chiari ,(Arnold Cbiari) malformation, 9-15,9-16
Central pontine myelinolysis, 27-27, (see fig 13- Chorea, 19-14
28 on case history CD ROM) Claustrum (norepinepbirine) 17-9
Cerebellar peduncles Climbing fibers, 20-2,20-3
Superior cerebellar peduncle 15-16 Cocaine, 27-27,26-6, (see chapter 27 supplement
Middle cerebellar peduncle 15-16 on CD ROM)
Inferior cerebellar peduncle 15-16 Colloid cyst of third ventricle, 27-18,27-19,27-
Lesions of cerebellar peduncles 11-27 20
Cerebellum, 20-1 Columnar organization of cerebral cortex, 21-1
anatomy, 20-1 Coma, 29-1,29-28
afferents,20-3 Acute onset 29-27,29-28
cytoarchitecture, 20-2 Care of comatose patient, 29-28
Dysfunction 11-26 Prognosis,29-28
efferents, 20-3 Prolonged disturbance of consciousness, 29-28
longitudinal divisions, 20-1 Compression fractures, 9-3
transverse divisions, 20-1,20-2 Computerized axial tomography scanning, (CT
Cerebellum Clinical Cases scans), 2-13, 2-16, 2-17,2-19,2-28
Case 20-1, medulloblastoma, floccular nodular Concept oflevel oflesion at spinal cord level,
syndrome, 20-7 2-3
Case 20-2, midline, metastatic, 20-7 Concept of extrinsic versus intrinsic, 2-8,9-1,9-
Case 20-3, alcoholic cerebellar degeneration, 10,13-1,13-2
20-9, (CD ROM) Confusion, 29-2
Case 20-4, anterior lobe syndrome, Consciousness,29-1
spinocerebellar degeneration, 20-9 Corpus callosum
Role in learning, 30-4
8 Index
transfer of information,24-18 Positron emission tomography (PET scan), 2-

Cortical shock, 18-12 20,2-22
Corticobasal degeneration (CBD), 19-14,19-15 Radioactive brain scans and flow studies, 2-20
Corticorubral spinal system, 18-16 Single photon emission computed tomography,
Craniopharyngioma, 27-18,27-19 (SPECT),2-20,2-21
Creutzfeldt-lakob disease, 30-18,30-20 Transcranial doppler, 2-26
D Ventriculography, 2-18
Decerebrate rigidity 11-27 X-rays, 2-13,2 -15
Deep tendon stretch reflexes, 2-4 Degenerations,27-26, see each clinical chapter and
Degeneration 3-20 chapter 27 on CD ROM supplement
Delayed or disordered motor development, 18-25 Devic's syndrome, 9-13
Delayed response test and delayed alternation, DIENCEPHALON
18-24 Epithalamus 16- 7
Delirium, 29-2 Metathalamus 15-8
Dementia, 30-1,30-11 Thalamus 15-3
Alzheimer's disease30-12 Anterior nuclei 15-3
Creutzfeldt-lakob, 30-18,30-20 Anterior tubercle 15-4, 15-2
Frontal-temporal,30-20 Medial nuclei 15-3
General paresis, 30-19 Magnocellular 15-4
Lewy body, 30-20 Parvicellular 15-4
Dentate gyrus 22-11 Midline nuclei 15-3, 15-4
Cytoarchitecture 22-11, 22-12A Intralaminar 15-3, 15-5
Pick's, 30-20 Parafascicular 15-5
Dermatomes - radicular patterns, 2-2, 2-4, 2-5,2- Lateral nuclei
6 Ventrobasal 15-3
Dermoids, 27-18 Development of Blood vessels Pulvinar 15-5
in the brain 4-4 Medial division
Development !Differentiation 4-5,4-4 Lateral division
of ventricular system 4-5 Inferior division
Spinal Cord 4-5 Differential diagnosis, 2-1
Mesencephalon 4-7 Clinical case
Prosencephalon 4-8 4-8, 4-9 Case 2-1, amyloid angiopathy leg area 2-27
Rhombencephalon 4-7 Location of lesion, overview 2-1
Development of dominance, 24-2 basal ganglia, 2-7
Development of motor function, 18-9, 18-25 brain stem, 2-4
Development of speech, 24-3 cerebellum, 2-8
Diagnostic studies in neurology, 2-12 cerebral cortex, 2-7
Angiography, (arteriography), 2-25 muscle, 2-1
Cerebrospinal fluid examination, 2-26 nerve root, 2-2
Computerized axial tomography scanning, (CT neuromuscular junction. 2-2
scans), 2-13, 2-16, 2-17,2-19,2-28 peripheral nerve, 2-2
Duplex scans, 2-26 spinal cord, 2-2
Electroencephalography, (EEG), 2-21 Type of pathology, 2-8
Electromyography, (EMG), 2-13 Disc disease, 8-21
Evoked potentials, 2-15,2-17,2-19, 2-25 Cervical, 8-19,8-22,9-4
F response or wave, 2-15 Lumbar, 8-19, 8-20
FunctionalMRl,2-21 Diseases of Muscle
H reflexes, 2-15 Muscular Dystrophies 6-11
Lumbar puncture, 2-26 Duchenne' Muscular Dystrophy 6-11 ,6-14,
Magnetic resonance angiography, (MRA), 2- Case 6-1 pp 6-5
26,2-26,2-27 Becker's Muscular Dystrophy 6-11
Magnetic resonance imaging, (MRJ scans), 2- Myotonic Myopathies 6-13
13,2-16,2-18,2-20 Congential myopathies 6-14
Myelography, 2-14 Metabolic Myopathies 6-14
Nerve conduction velocity, 2-13,2-14 Periodic Disorders of Muscles
Pneumoencephalography. 2-17.2-19
Index 9
Familial Periodic Paralysis 6-15, Case Generalized seizure discharges, 29-4,29-7, 29-
6-2pp 6-15 9,29-10,29-13,29-17,29-18,
Acquired Disorders of Muscle 6-16 Generalized burst suppression and isolated
Polymyositis 6-16, 6-15, Case 6-3 ; pp 6-17 cortex, 17-20
Disease of the Neuromuscular Junction Generalized suppression, see brain death and
Postsynaptic Disorders neocortical death
Myasthenia gravis 6-17,Case 6-4; pp 6-20 Electromyography, (EMG), 2-13
Anti cholinesterases, Encephalitis, 27-26,27-26 (see chapter 27 on CD
Thymectomy 6-20 ROM Supplement)
Pharmacological & toxic 6-21 Encephalomalacia, (infarction), 26-3,26-4
Reversible agents 6-21 Endocrine disorders affecting nervous system,
Neurotoxic agents 6-22 27-27( see chapter 270n CD ROM supplement)
pesticides organophosphates 6-22 Enteric Nervous System 16-11
snake toxins 6-22 Entorhinal region 22-10
Pre Synaptic Disorders 6-22 Ependymal Cells 3-19,3-27
Eaton-Lambert 6-22 Epidermoids,13-3,27-18
Botulism 6-23 Epilepsy and seizures, focal or partial, 29-4,29-5
Antibiotics 6-23 Causes, 29-5
Spider venom (black widow) Multifocal discharges, 29-6
6-23 Pathophysiology, 29-5
Disorders of the Autonomic Nervous System Regional variations in capacity for discharge
Eye - Edinger-Westphal nucleus, 29-5
Homer's, Argyll-Robertson pupil 16-15 Secondary epileptogenesis,29-6
Blood Vessels- Raynaud's 16-15 Spread of discharge, 29-6
Heart & GI 16-15 Epilepsy, management, 29-19
Bladder 16-15 to 16-16 Use of and side effects of anticonvulsant
Micturition 16-16 medications, 29-19, 29-20,29-2129-22,
Uninhibited bladder 16-16 Epilepsy, status, 29-19 ,29-22
Dissociated sensory loss in syringomyelia,9-14 Epilepsy, primary generalized or idiopathic, 29-
Domoic acid, 30-10 7,29-8
Dopamine receptors, 19-1, 19-3 Classification 29-7
Dopaminergic systems, 19-2,19-5 Childhood absence epilepsy, 29-8
Double athetosis, 19-21 Generalized tonic clonic, 29-12,29-14
Drop attacks, 29-12 Juvenile absence epilepsy, 29-9
Duplex scans, 2-26 Juvenile myoclonic epilepsy(JME),29-9
Dysarthria, 24-1,20-13 Overlap of syndromes, 29-15
Dyssynergia cerebellaris myoclonica, 20-17 Photosensitivity and genetics, 29-10,29-11
Dystonia, 19-22 Molecular biology, 29-13,29-17
Dysthrophic neurites, 30-14 Neuropathology, 29-15
E Pathophysiology, 29-15,29-16,29-18
Early experience and brain development, 30-4
Effectors 3-15 Epilepsy, secondary or symptomatic generalized,
Eye movements 11-30 29-7
Clinical Cases effecting eye movements Ependymoma, 20-7,13-4,27-14
11-31 Epidural abscess, 9-7
Case 11-1 tumor in pons 11-31 Evoked potentials, 2-15,2-17,2-19, 2-25
Case 11-2 pineal tumor 11-33 Excitatory Postsynaptic Potential EPSP 7-8, 7-
Electroencephalography, (EEG), 2-21 16, 7-17
EEG normal, 2-21,2-22 and CD ROM Extracellular Space 3-25
supplement Eye
EEG abnormalities, 2-21,2-22,2-23,2-24,29-3 Structure of Eye 23-1, 23-1
Focal slow waves, 2-21,2-23 Outer tunic cornea and sclera
Focal spikes and sharp waves, 29-3,29-4,29-5 Middle tunic vascular and pigmented
Focal voltage suppression, 2-21,2-23 Inner neural tunic 22-3
Generalized slow wave activity, 2-22,2-24 Photoreceptors 23-3 23-2
10 Index
Rods - vision in dim light Granule cells of cerebellum,20-2

and night vision 23-4 Guidelines
Cones - color vision 23-5 Localizing disease in brain stem 11-25
Lens 22-3 H
Pupil H reflexes, 2-15
Pupillary muscles 23-2 Hallervorden Spatz disease, 19-14
Pupillary reflexes 23-2 Headaches, 27-8
Light reflex Brain tumOfS, 27-8
Accommodation Cluster, 27-8
Fixed pupil Migraine, 27-8
F Muscle tension, 27-8
Fetal Alcohol Syndrome 4-20 Occipital/cervical neuralgia, 27-8
F response or wave, 2-15 Hemangioblastoma, 20-12, 20-13
Familial paroxysmal dyskinesia, 19-24 Hemorrhage, intra cerebral, 2-28,13-18
Fixation system for eye movement, 18-20 Hemiballism, 19-15,19-16,19-19
Fornix 22-13,22-14 Hemichorea, 19-15, 19-16,19-18
Fimbria 22-14 Hereditary spastic paraplegia, 9-21
Portio alveus 22-14 Herpes simplex
Portio tenia 22-14 Encephalitis, 30-11
Portio corpus 22-14 Sensory ganglion, 8-24
Portio columnaris 22-14 Herpes zoster .
Fracture dislocations, 9-3 Dorsal root ganglion, 8-23
Friedreich's ataxia, 20-17 Hippocampus 22-8 22-10
Frontal eye fields,18-19, 18-21 Cytoarchitecture 22-11
Functional MRI, 2-21 And dementia
G And memory, 30-7
Gait disorders of the elderly, 18-25 Herpes simplex encephalitis, 30-11
Gamma System 7-12 to 7-14, 7-23, 7-24 Selective vulnerability, 30-10
Generalized chorea, 19-17 Stimulation, 30-10
Glands Associated with the Brain ,Pineal and Vascular syndromes, 30-8
Pituitary 1-14 Vulnerability 22-11
Glia-Supporting cells of the CNS 3-16 and Memory 22-13
Astrocytes 3-17, 3-23, 3-24 and Cingulate gyrus 22-13
Oligodenrocytes 3-17, 3-23, 3-24 Histogenesis 4-2
Endothelial cells 3-17 Hensen's node 4-1
Ependymal Cells 3-19,3-27 Primitive streak
Microglia 3-18, 3-26 Neuroblasts 4-1,4-2
Ameboid microglia 3-18 Neural plate 4-1
Resting microglia 3-18 Neural tube 4-2
Activated microglia 3-18 Spinal cord 4-3
Reactive microglia 3-18 Brain stem 4-5
Multinucleated cells 3-18, 3- Marginal zone 4-2
31 Hormones & Releasing factors produced in
Mononuclear cells 3-18; table 3- 10 Hypothalamus 16-7; table 16-2
Monocytes 3-18 Adrenocorticotropic Hormone ACTH
Pericytes 3-18 16-7
Golgi neuron method 3-13-1,3-2 Corticotropin releasing factor 16-7
Golgi Tendon Organs 7-14 Growth Hormone -Somatotropic factor
Golgi type I neuron 1-2, 3-1 16-7
Golgi type II neuron 1-2, 3-2 Lactogenic Hormone (Prolactin) 16-7
Gliomas and glioblastoma multiforme, 18-18,27- Lactogenic inhibitory hormone 16-7
10,27-11,18-19,27-12,27-13,27-14 Leutinizing releasing factor 16-7
Globus pallidus, 19-1 Melanocyte Stimulating Hormone 16-7
Goldman Equation 5-7 Melanocyte Inhibitory Hormone 16-7
Golgi cells of cerebellum. 20-2 MSH releasing factor 16-7
MSH inhibitory factor 16-7
Index 11
Thyrotropic releasing factor 16-7 Tuberoinfundibular pathway and

Hormones Produced in Hypothalamus releasing factors 16-5, 16- 6
Vasopressin (supraoptic) anti ADH 16- Ventromedial hypothalamic nuclei and
6 feeding 16-3, 16-9
Oxytocin (periventricular nucleus) Hypothalamic Pathways
16-6 Medial forebrain bundle 16-4, 16-5
Hormones Produced in Adenohypophysis Dorsal longitudinal fasciculus 16-4
adenohypophysis 16-7; 16-11 Retinohypothalamic fibers to
Gonadotropins; leutinizing hormone LH supracbismatic nucleus 16-4
16-7 Fornix to mammillary nuclei 16-4
Follicle stimulating hormone 16-7 Periventricular system 16-4
Growth hormone somatotropin(STH) Mammillotegmental tract 16-4
16-7 Hypophysiotropbic area 16-6
Thyrotropic Stimulating Hormone Hypothalamus and body temperature 16-8
16-7 Hypothalamus center for heat loss 16-8
Thyrotropic Inhibitory Hormone 16-7 Hypothalamus center for heat production and
Intermediate/mantle zone 4-3 conservation 16-8
Subventricular zone 4-2 And Water Balance and Neurosecretion 16-9
Ventricular zone 4-3 And Food intake 16-9
Germinal Cells 4-3 And Sexual Behavior 16-9
Growth Cone guidance 4-3 And Sleep Cycle 16-9
Progranuned Cell Death 4-4 and Emotions 16-9
Huntington's disease, 19-18,19-19,19-21, and light levels 16-10
Hydrocepahlus 4-22, 4-19 Clinical Case 16-1.Adenoma of pituitary gland
Hypothalamic nuclei with acromegalic features 16-1, 16-1
Anterior region: 16-2, 16-3 Hypothalamic dopaminergic system, 19-6
Preoptic, I
Supraoptic Imprinting, 30-1
Pariventricular Inhibitory Postsynaptic Potentials IPSP 7-9, 7-16
Anterior Infections of the cerebral hemispheres, 27-18
supracbiasmatic Clinical cases
Middle region: 16-2 Case 27-5, 27-22, subdural empyema (CD
Dorsomedial ROM)
Ventromedial Focal, 27-19, acute (See Brain abscess,
Lateral subdural empyema)
Arcuate Focal chronic 27-23
Lateral zone Diffuse ,generalized, 27-23 (See meningitis and
Lateral nucleus encephalitis)
Lateral tuberal Inhibitory surround (surround inhibition), 29-6
nucleus Instinctive behavior, 30-1
Posterior region INTERNAL CAPSULE 15-5, 15-6
Posterior Anterior limb
Mammillary nuclei Genu
Hypothalamic-Hypophyseal tract 16-5, 16-8 Posterior limb
Supraoptic andparaventriuclar origin Retrolenticular 15-7
16-3 Sublenticular portion 15-7
Hypothalamic-Hypophyseal portal system 16-5, Thalamolenticular portion 15-7
16-10 Thalamic radiations
Supraoptic nucleus of hypothalamus, and Anterior radiations 15-8
osmoregulation 16-5 Inferior radiations 15-8
ADH and vasopressin 16-3 Posterior radiations 15-8
Supracbisamatic nucleus of Superior radiations 15-8
hypothalamus and biological clock 16-
3
Tuberal nuclei of the hypothalamus
forms tuberoinfundibular pathway
12 Index
Interrelation primary motor, premotor, Case 30-3, temporal lobe seizures, 30-10 (CD
prefrontal, 18-9 ROM)
K Case 30-4, Alzheimer's disease, 30-17
Kindling, 30-4 Case 30-5, general paresis, 30-19 (CD ROM)
L Case 30-6, probable Lewy body dementia, 30-
Lamination of major pathways 7-20 20 (CD ROM)
Language function evaluation, 24-4 Case 30-7, thalamic dementia -glioblastoma,
Lateral (dorsolateral) medullary syndrome, 13-10 30-18
Lateral premotor area (PMA), 18-17 Neurobiological mechanisms, 30-3
Lead toxicity,8-17, 27-28 and chapter 27 on CD read out phase, 30-2
ROM supplement stages of human memory, 30-2
Learning,30-1 immediate -short term, 30-2
declarative (explicit), 30-1 long term -labile stage, 30-2
non declarative (implicit), 30-1 long term -remote stage, 30-2
Leptomeningeal anastomosis, 26-3 disorders,30-4
Leukodystrophies, See chapter 27 on CD ROM recent memory, 30-4
supplement Meningiomas, 27-15,27-17,27-16,27-18
Lhermitte's sign, 9-29 Cerebellar pontine angle,2-18 13-3
Limbic system 22-1,22-3,22-4,22-5 convexity, 27-16
Lipidosis, See chapter 27 on CD ROM foramen magnum13-6
supplement intradural, ,compressing spinal cord, 9-8,9-5
Localization of disease process, 2-1 parasagittal,l- ,18-13,18-14,18-15
Locked in syndrome,( pseudo akinetic mutism or tentorial, 13-5
pseudo coma), 29-2 Mental retardation, 30-1
Long term potentiation, 30-4 Meningitis, bacterial 27-23,,27-25,27-26,27-24
Lumbar puncture, 2-26 Meningitis ,carcinomatous,,27-18, 27-22
Lymphomas, primary central nervous system, Meningitis ,non bacterial, (see chapter 27 on CD
27-15 ROM supplement)
M Mercury, 27-28 and chapter 27 on CD ROM
Machado-Joseph disease, 20-20 supplement
Magnetic resonance angiography, (MRA), 2-26 MERRF(myoclonus epilepsy with ragged red
Magnetic resonance imaging, (MRI scans), 2- fibers), 20-18
13,2-16,2-18,2-20 Mesolimbic dopaminergic system, 19-5
Malformations Mesocortical dopaminergic system, 19-5
-characterized by excessive growth of Metastatic tumors, 27-17,27-20, 27-21,27-22
ectodermal and mesodermal tissue Micturition 16-16
affecting skin, nervous system and other tissues Midbrain vascular syndromes, 13-15,13-16,13-
Tuberous sclerosis 4-21 17
Neurofibromatosis 4-21 Mini-mental status examination (MMSE), 2-12
Cutaneous angiomatosis with associated Mirror focus, 30-4
Malformations of the CNS 4-21 Mononeuropathies, 8-4, (see under nerve), (for
Sturge-Weber Syndrome 4-22 cases see peripheral nerve)
Malformations resulting from abnormalities in Mossy fiber, 20-2
the ventricular system Motivational drives and learning, 30-3
Syringomyelia 4-22 Motor cortex, 18-9,18-10
Syringobulbia 4-22 recovery of function after damage, 18-12
Mammillothalamic pathway 16-4 Motor development, 18-9
Manganese toxicity producing Parkinsonian Motor Pathways in Spinal Cord 7-19
syndrome, 19-10 Upper Motor Neuron Syndrome 7-19
Medullary vascular syndromes, 13-10 Babinski respone 7-32
Medulloblastoma, 13-3,20-7,13-4,20-8,27-10 Lower Motor Neuron Syndrome 7-19
Membrane Basis of Integration 7-8 Motor system, 18-1
Memory, 30-1 Clinical cases:
Clinical cases Effecting Memory Case 18-1, focal seizures -parasagittal
Case 30-1, Wernicke Korsakoff, 30-5 meningioma. 18-13
Case 30-2, transient global amnesia, 30-9
Index 13
Case 18-2, focal seizures-premotor- Neurulation 4-1,4-1

oligodendroglioma, 18-18 Neurofibrillary tangles, 30-13,30-14 30-15
Case 18-3, normal pressure Neurofibromatosis, (von Recklinghausen's
hydrocephalus 18-21, (CD ROM) disease), 9-10
MPTP induced Parkinson syndrome, 19-10 Neuroleptic induced movement disorders, 19-23
Multiple sclerosis Neurological history in diagnosis, 2-9
Spinal cord9-27, 9-28,9-29 Neurological examination, abbreviated, 2-12
Brain stem, 13-19,13-20,13-21 Neurological examination, detailed, 2-9
Cerebral hemispheres,27-27,27-27,27-28 and Neuromyelitis optica, 9-13
CD ROM supplement for Chapter 27 Neurosyphilis, 9-22, 9-23
Multisystem atrophy (MSA), 19-15 Neurofibrillar tangles. 3-8
Myelography, 2-14 Neuron
Myelin sheath 3-9, 3-17,3-28 Dendrites 3-2
Myelination 3-9 Soma 3-2
Muscle spindle 7-11, 7-20 Nucleus 3-7,3-8,3-9
Myoclonus Barr Body 3-9
Anatomical basis,29-1O Endoplasmic reticulum 3-4
Etiological and prognostic classification, 29-10 Rough Endoplasmic reticulwn! Nissl
N Substance 3-10,3-11. 3-12
Narcolepsy, 29-26 Smooth endoplasmic reticulum 3-4 3-
Negative motor response, 18-23 10
Neglect syndrome, 21-8 Lysosomes 3-4,3-10,3-11
Neocortical death, 29-3 Perixosomes 3-5
Neoplasms of the cerebral hemisphere, 27-7(see Mitochondria 3-5,3-10,3-11,3-12
gliomas, glioblastomas ,meningiomas, metastatic Centrosomes 3-6
tumors, oligodendrogliomas) Inclusions 3-6 3-11A
Clinical cases Glycogen 3-6, 3-11B
Case 27-3, grade 2 astrocytoma,27-11 (CD Lipid Droplets 3-6, 3-11
ROM) Neurosecretory Granules 3-6, 3-13B
Case 27-4, Glioblastoma multiforme,27- Neuronal Cytoskeleton 3-7,3-15
14,27-12,27-13 Microtubules 3-7
Nernst Equation 5-6 Microfilaments 3-7
Nerve conduction velocity, 2-13,2-14 Intermnediate filaments 3-7
Nerves Neuronal migration 4-14
brachial plexus, 8-4 Neuronal Organelles 3-8
lateral femoral cutaneous nerve of thigh, 8-8 Neuron types
long thoracic, 8-7 Unipolar, Bipolar,Multipolar 1-1, 1-1
lumbar plexus, 8-8,8-9,8-12 Pyramidal 17-2, 17-2
median, 8-7 Smooth neurons 17-3
obturator, 8-9 Spiny neurons 17-2
peroneal, 8-10,8-14 Stellate 17-3,17-2
radial, 8-8 Neurophysiology of Cerebral Cortex 17-21
sacral plexus, 8-8,8-10,8-13 Basis of EEG found on CD Rom for
sciatic, 8-9,8-14 chapter 17
tibial, 8-11,8-14 Activity ofIsolated Thalamus 17-21
ulnar, 8-7 Activity ofIsolated Cerebral Cortex 17-21
Nerve Growth Factors 3-24 Evoked Potentials 17-21, 17-17
Nerve Muscle Junction Primary evoked response
Endplate 6-7, 6-10 Augmenting response
Acetylcholine, Ach 6-8 Recruiting response
Denervation sensitivity 6-9 Arousal 17-22
Anticholinesterase, neostigmine, Capacity for Focal Discharge 17-24, 17-
endrophonium, eserine 6-9 21
Reinnervation 6-10 Capacity for Contralateral spread of
Nerve root, 8-19 discharge 17-25, 17-22
Neural Crest cells 3-20, 4-2
14 Index
Capacity for bilateral synchronous Patch Clamp S-9

discharge, experimental epilepsy 17-27 , Pathways
17-26,17-27 Basic organization of pathways 12-13
Neurotransmitters 3-lS Cells of origin
Nigral striatal dopaminergic system, 19-2 Location of tract in the brain
Nociception and Pain 7-17 to 7-18 Site of termination of pathway Function
Receptors 7-17 Motor control of hand the corticospinal
Modulation of pain transmission 7- 18 pathway 1-13
Chordotomy to relieve pain 7-18, 7-29 Motor
Nondominant hemisphere functions, 24-17,21-8 Corticobulbar IS-9, effects of
Normal pressure hydrocephalus, 18-26 disruption 11-2S
Nucleus acumbens 22-S Corticonuclear IS-9)
Nutritional disorders, 27-26,27,27 See chapter 27 Corticospinal IS-9 effects of
on CD ROM Supplement disruption 11- 2S
o Descending autonomics IS-9
Olfactory system 22-2, 22-2 Dorsal longitudinal fasciculus IS-9
Hypothalamus Medial longitudinal fasciculus (MLF)
Mammillary nuclei 22-S Monoamine containing IS-19
Mammillothalamic tract Rubrospinal 11-9
Epithalamus 22-S Tectospinal II-IS
Olivopontocerebellar atrophy (OPCA), 19-1S Sensory-
P AnterolaterallS-11
Pain IS-IS IS-II Auditory IS-17
From the body IS-IS Laterallemniscus IS-17
From the head IS-11 Cuneocerebellar IS-16
Gate 7-14 Spinothalamic IS-IS IS-II
Referred pain from the viscera Effects of disruption 11-27
IS-IS Solitary tract
Papez Circuit IS-IS, IS-42, 2-13 Dorsal spinocerebellar
Parallel fibers, 20-2 Ventral spinocerebellar
Paraneoplastic subacute cerebellar degeneration, Mediallemniscus IS-12 IS-9
20-21 Effects of disruption 11-27
Parietallobe,21-1 Pain IS-IS IS-II
Clinical cases From the body IS-IS
Case 21-1, focal sensory seizure in face From the head
secondary to a glioblastoma, 21-3,21-4,21-5 Referred
Case 21-2, metastatic tumor to postcentral Posterior columns IS-12
gyrus with pain syndrome, 21-S Fasciculus gracilis IS-12
Case 21-3, metastatic to non dominant parietal Fasciculus cuneatus IS-12
lobe with nondominant syndrome ,21-8,21-9,21- Trigeminal
10 Thalamic IS-14
Post central gyrus, 21-1,21-3,21-2 Vestibular IS-17
Parietal lobules, dominant, 21-7 Spinocerebellar IS-12
Parietal lobules, non dominant, 21-8 proprioception IS-12
Parieto-occipital eye fields, 18-19 tactile discrimination IS-12
Parkinsonian syndrome, 19-7, 19-4 Hemiballismus IS-9
Parkinson's disease, 19-7 Subthalamus IS-12
clinical symptoms and signs, 19-8 Ansa lenticularis IS-12
Clinical Case 1-1 parasagittal Subthalamic fasciculus IS-12
meningioma 1-17 Thalamic fasciculus IS-12
differential diagnosis, 19-13 Peripheral vs Central Nerve Structure 3-11, 3-19
etiology, 19-9 Perineurium 3-11
management, 19-11 Epineurium 3-11
pathology, 19-8,19-9. Endoneurium 3-11
Parkinsonism plus syndromes, 19-14, 19-1S Sheath of Schwann 3-11
Parkinsonism-dementia -ALS complex, 19-14 Central Nerve Structure 3-12
Index 15
Peripheral nerves and nerve roots, chapter 8 Refsum, 8-18

Clinical cases Remote effect of malignancy, 8-18
Case 8-1, brachial plexopathy, Pancoast Thalidomide, 8-17
tumor, 8-6 Trichloroethylene, 8-17
Case 8-2, long thoracic nerve, 8-7, (CD ROM) Tri ortho cresyl phosphate, 8-17
Case 8-3, median nerve, carpal tunnel, 8-7 Uremic, 8-17
Case 8-4, diabetic mononeuropathy, lumbar- Pontine vascular syndromes, 13-13,13-14,13-
sacralplexopathy,8-12 15,13-16
Case 8-5, GuillainBarre syndrome, 8-16 Positron emission tomography (PET scan), 2-
Case 8-6, Charcot Marie Tooth disease, 20,2-22
HMSN type 1,8-18, (CD ROM) Post central gyrus and sensory representation,
Case 8-7, lumbar radiculopathy, 8-20 21-1,21-2
Case 8-8, cervical radiculopathy, 8-22 Posterior inferior cerebellar artery syndrome, 13-
Disorders of, 8-1 (see mononeuropathies and 10,13-12
polyneuropathies) Posterior Root fibers 7-16
Distribution, compared to radicular segmental, Potassium Channels
2-5,2-6 Chemically controlled 5-9,5-10
Peripheral Nerve Regeneration 3-22, 3-34 Inactivation 5-16
Perfusion, 26-2 Refractory Period 5-20
Pes cavus, 9-26 Equilibrium potential 5-5 .
Physiology of Dendrites and cell body Resting membrane voltage 5-5
Decremental conduction 5-22, 5-22 Control 5-8, 5-4
Calcium channels 5-22 Chemically controlled 5-9,5-10
Transient calcium channels 5-23 Threshold 5-15
Long lasting calcium channels 5-23 Prefrontal cortex, 18-23
Ligand gated calcium channels 5-24 Premotor cortex, 20-16
Regulation 5-24,5-24 Presenilin, 30-16
Pineal body 16-10 Primary motor cortex, 18-9,18-10
Pinealoma, 13-5, 13-5 Primary lateral sclerosis, 9-20
Pituitary tumors, 27-16,23-10,2-18 Progressive bulbar palsy, 9-20
Plasticity of motor and sensory cortex, 18-12,30- Progressive muscular atrophy, 9-20
4 Progressive pseudobulbar palsy, 9-20
Pneumoencephalography, 2-17,2-19 Progressive supranuclear palsy (PSP), 19-15
Poliomyelitis, 9-17 Proprioception 15-16
Polyneuropathies, 8-15, (for cases, see peripheral Purkinje cell, 20-2
nerve) Putamen, 19-1
Acrylamide, 8-17 Pyramidal tract, 18-14
Amyloid, 8-18 R
Antineoplastic, 8-17 Radiculopathies, 8-19,(for cases see peripheral
Arsenic, 8-17 nerve)
Charcot Marie Tooth disease, 8-18 Radioactive brain scans and flow studies, 2-20
Chronic inflammatory demyelinating, (CIDP) Receptors
Diabetic, 8-17 Sensory endings 3-15
Diphtheritic, 8-17 Free nerve endings 3-15
Familial dysautonomia, 8-18 Encapsulated sensory endings 3-16
Guillain Barre syndrome, 8-15 Meissner's corpuscles 3-16
Hereditary sensory motor, (HMSN), 8-18 Pacinian copuscles 3-16
Hexa carbon industrial solvents, and other End Bulb of Krause and Golgi-Mason
agents, 8-17 3-16
HIV, 8-18 (see also chapter 27) Muscle and tendon spindles 3-16
Isoniazid, 8-17 Reciprocal Innervation of a Joint 7-7
Miller Fisher variant or syndrome, 8-15 Reflexes, 18-2
Lead, 8-17 developmental changes, 18-8, 18-9
Monoclonal gammopathy, 8-18 extension or extensor, 9-2,18-2
Nutritional deficiencies of B vitamins, 8-17 flexion, 18-2,18-3
Porphyria, 8-17 grasp, 18-6
16 Index
instinctive tactile avoiding reaction, 18-7, 18-8 Aristotles five senses - balance,
instinctive tactile grasp reaction, 18-6,18-7 hearing, smell, sight, taste 1-2
instinctive visual grasp and avoiding General senses - pain, temperature,
Reactions, 18-8 touch, pressure 1-2
interlimb, 18-4,18-5 Special senses - balance, vision,
local sign in flexion reflexes, 18-3 hearing, taste, smell 1-2
mass reflex, 9-2, 18-2 Sensory receptors 1-2
optical righting, 18-5 SeIIBory receptors and effectors in skin 1-3
placing reaction (visual and tactile), 18-6 Sensory modalities, primary compared to
righting, 18-4,18-5,18-6 corticaVdiscriminative,21-2,21-3
stretch, 9-2, Septum 22-5
tonic labyrinthine, 18-3 Shy-Drager syndrome, 19-15
tonic neck, 18-2 Single photon emission computed tomography,
Reflexive Response to Pain 7-6 (SPECT),2-20,2-21
Remote effects of malignancy, 20-21, 27-27, Skeletal muscles 6-1
(See chapter 27 on CD ROM supplement) Contraction 6-1
Response of the Nervous System to Injury 3-20 Molecular Architecture of Contraction
Reticular Formation 11-21 6-5
Non-cerebellar nuclei 11-21 Muscle proteins 6-5
Raphe Actin 6-5
Central Mysoin6-5
Lateral Sarcomeres 6-2 6-4
Cerebellar nuclei 11-21 Motor units 6-1, 6-1
Lateral of medulla Filaments 6-2
Paramedian of medulla Excitation-Contraction Coupling 6-2
Tegmental of pons Filament interaction 6-5
Cholinergic nuclei 11-23 Cross Bridges 6-5
Monoamine nuclei Norepenephrine Force Velocity 6-6
Serotinergic 11-21 Active State 6-6
Pathways Reticular structures 6-2
Lateral reticu1ospina1 11-22 t-SR coupling
Medial reticulospinal 11-22 T system 6-5, 6-5
Cenral tegmental 11-22 Threshold 5-15
Ascending reticular 11-22 Toxins and local anesthetics 5-19
Retrograde changes 3-20, 3-30 Sleep, 29-23
Rexed's Lamina of the Spinal Cord 7-17,7-18 Anatomical basis, 29-23,29-24
Rhinencephalon 22-1 Multiple sleep latency test, (MSLT), 29-29,29-
Romberg sign, 9-23 27
S Polysomnography, 29-14
Saccadic eye movements, 18-19 Sleep stages, 29-23
Sacral sparing, 9-3 Rapid eye movement stage (REM), 29-23,29-
Saltatory Conduction 5-20 24
Schwannomas, Slow wave, 29-23,29-24
Intradural with spinal cord compression, 9-9,9- Abnormalities of sleep
9 Excessive daytime sleepiness, 29-26
Nerve root, 8-23,2-15,2-16,8-25 Insomnia, 29-25
Neurofibromatosis, 9-10 Narcolepsy, and narcolepsy/cataplexy
Vestibu1ar,13-2, 13-3,27-20 syndrome, 29-26
Secondary Parkinsonism, 19-14 Sleep apnea, 29-25
Segmental sensory patterns,2-3, Sleep paralysis and hypnagogic hallucinations,
Segmental motor innervations, 2-3 29-27
Segmental reflex innervation, 2-4 Smooth pursuit eye movements, 18-20
Seizures and seizure disorders, 29-1 ( refer to Sodium Channels 5-7, 5-13
epilepsy) Sodium selectivity 5-14
Senile plaques, 30-15, 30-14,30-16 Special Senses see CD
Senses Vestiuloacoustic
Index 17
Visual Gross Anatomy 7-1,7-2,7-3,7-5

Spinal cord, 9-1 Cross Section Anatomy 7-3, 7-6
Acute epidural abscess, 9-7 Anterior Hom Cells 7-4, 7-8
Amyotrophic lateral sclerosis (ALS), 9-19,9-16 Medial nuclear group 7-5
Anterior hom cell disorders, 9-17 Lateral nuclear group 7-5
Anterior poliomyelitis, 9-17 Preganglionic autonomic
Anterior spinal artery syndrome, 9-10 nuclei 7-5
Brown Sequard hemisection syndrome, 9-2,9,3 Intemeurons 7-14
Bulbospinal neuronopathy, Kennedy's disease Organization of Gray Matter -Rexeds
9-18 10 lamina 7-15 to 7-16, 7-28
Clinical cases, Lamina in Spinal Cord gray matter after
Case 9-1, ruptured cervical disc with Spinal Cord Pathways Table 7-1 7-21
compression, 9-4,9-6 Synaptic Mechanisms 7-10
Case 9-2, epidural carcinoma with T4-T5 Slow Potentials 7-11
compression, 9-6 Stretch Receptors 7-11
Case 9-3, Schwannoma with compression, 9- Stria terminalis 16-4 ,22-14
10, (CD ROM) Subacute combined degeneration, 9-23,9-24
Case 9-4, transverse myelitis, 9-13, (CD Supporting cells of the CNS 3-16
ROM) Oligodenrocytes 3-17, 3-23, 3-24
Case 9-5, syringomyelia, 9-16 Endothelial cells 3-17
Case 9-6, syringomyelia and syringobulbia, 9- Mononuclear cells 3-18;table 3- 10
16,9-17, (CD ROM) Microglia 3-18, 3-26
Case 9-7, poliomyelitis in a non immunized Ameboid microglia 3-18
adult, 9-18, (CD ROM) Resting microglia 3-18
Case 9-8, classical amyotrophic lateral Activated microglia 3-18
sclerosis, 9-20 Reactive microglia 3-18
Case 9-9, tabes dorsalis, 9-22 Multinucleated cells 3-18,3-31
Case 9-10, combined system disease, 9-25 Astrocytes 3-17, 3-23, 3-24
Case 9-11, Friedreich's ataxia, 9-27, (CD Endothelial cells 3-17
ROM) Mononuclear cells 3-18;table 3- 10
Case 9-12, multiple sclerosis with cervical Oligodenrocytes 3-17, 3-23, 3-24
myelopathy onset, 9-29 Pericytes 3-18
Case 9-12, multiple sclerosis, 9-13, (CD Synapse 3-14 ;fig 3-17
ROM) Synaptic transmission 3-14
Cervical spondylosis, 9-4 Synaptic Types
Compression, acute, 9-1,9-6 Electrical synapses 3-13
Compression, chronic, anterior midline, 9-2 Chemical synapses 3-13
Compression fractures and fracture Synaptic Vesicles 3-14, 3-17, table 3-18
dislocations, effects on, 9-3,9-4 Syringomyelia, 9-14,9-16,9-17
Compression from epidural metastatic Stretch reflexes, 7-6, 7-10, 7-11, 9-2
carcinoma and lymphoma, 9-5 Stimulation of cerebral cortex: focal seizures
Compression from vertebral tuberculosis, 9-7 frontal eye fields, 18-21, 18-22
Dissociated sensory loss, 9-11 hippocampus or temporal lobe, 30-10,30-10
Friedreich's ataxia, 9-25,9-26 occipital eye fields, 18-21,24-16
Hematomyelia,9-3 post central gyrus, 21-2
Hereditary spastic paraplegia, 9-21 premotor, 18-17, 18-17
HTLV associated progressive myelopathy, 9-13 primary motor, 18-10, 18-14, 18-15
Multiple sclerosis, 9-27,9-28,9-29 speech areas, 24-5
Neuromyelitis optica, Devic's syndrome, 9-13 Striatal-nigral degeneration, 19-15
Primary lateral sclerosis, 9-20 Subarachnoid hemorrhage, 26-26
Progressive muscular atrophy,9-20 Substantia nigra, 19-1,19-2
Spinal muscular atrophies,9-18 compacta, 19-1, 19-2
Spinal shock, 9-1,18-2,18-3 reticularis, 19-1, 19-3
Satellite Cells 3-19, 3-28 Subthalamic nucleus, 19-1, 19-3
Schwann Cells 3-19,3-29 Supplementary motor cortex (SMA), 18-17
Spinal Cord 7-1 Suppressor areas for motor activity. 18-23
18 Index
Syncope, 29-1 Transient global amnesia syndrome, 30-9

Syphilis, 9-22 Trauma, brain 27-1,27-1,27-4
Syringomyelia, 9-14 Clinical cases
Syringobulbia, 9-15 Case 27-1, epidural hematoma, 27-2
T Case 27-2, subdural hematoma,27-5
Tabes dorsalis, 9-22,9-24 Concussion, 26-1
Transverse myelitis, 9-12,9-13 Contusions, 26-1
Tumors, epidural, metastatic, 9-5 Epidural hematoma, 27-2
Tumors, intradural, meningiomas and Lacerations, 27-2
Schwannomas, 9-8 Late effects ,27-6
Tumors, intrinsic, astrocytomas and Management of severe head trauma, 27-5
ependymomas, 9-13 Prevention,27-6,27-7
Tactile Discrimination-posterior columns 7-18 Skull fractures,27-2
Telencephalon 4-11 Subdural hematoma, 27-3, 27-4
Differentiation of primary sulci 4-12,4-11 Tremors, 20-21
Development of Cerebral cortex 4-12 Trimesters
Gray matter differentiation via First 4-1
migration of neuroblasts 4-13 Second Trimester 4-1
Commissures 4-14 Third trimester 4-1
Myelination 4-14 Toxic disorders 27-26,27-28 ( see chapter 27 on
Migration Disorders of cerebral cortex CD ROM supplement),
X-linked 4-16 V
Miller-Dieker 4-16 Vascular disease, 26-1
Bilateral nodular Brain stem, 13-8, (see under brain stem)
periventricular heterotopias 4-16 Cerebral hemispheres, 26-1
Microdysgensis 4-16 Anterior cerebral artery (ACA) syndromes,
Neuronal maturation 4-15 26-17,26-17
Tentorial herniation, 13-5,13-6 Anterior choroid artery syndrome, 26-18
Teratomas, 27-18 Anterior communicating artery (ACOM), 26-
Thalamus 18
Thalamic Afferents 15-7, 15-8 Border zone, 26-5,26-6
Ventral anterior 15-3 Cerebral embolism, 26-20,26-20
Ventral lateral 15-3 Clinical cases
Ventral posterior 15-3 Case 26-1, infarct MCA, ACA territory,
Medial nucleus 15-4 following ICA stenosis,26-6,26-7
Lateral nucleus 15-4 Case 26-2, carotid TIA's
Lateral dorsal 15-4 Case 26-3, internal carotid occlusion, infarct,
Lateral posterior 15-3 MCA,PCA 26-9,26-10,26-12
Reticular 15-4 Case 26-4, total territory MCA infarct, 26-
Metathalmus 15,26-16
Medial geniculate nucleus Case 26-5, embolic occlusion calcarine
Audition 15-6 branch PCA, 26-19,26-20
Lateral geniculate nucleus Case 26-6, cortical posterior cerebral artery
Vision 15-6 syndrome, embolic, 26-20 (CD ROM)
Posterior 15-3 Case 26-7, intracerebral hemorrhage, 26-23
Dorsal thalamus (CD ROM)
Specific nuclei 15-3 Case 26-8, subarachnoid hemorrhage, PCOM
Non-specific nuclei 15-4 aneurysm, 26-27 (CD ROM)
Thalamic Input: Noradrenergic, Serotoninergic, Case 26-9, subarachnoid hemorrhage, MCA
Dopaminergic,Cholinergic, GABAergic 15-8 aneurysm, 26-27 (CD ROM)
And dementia, 30-19 Case 26-10, subarachnoid hemorrhage,
And memory, 30-6 ACOM aneurysm, 27-27 (CD ROM)
Thalamic Syndrome (ofDejerine) 15-9 Case 26-11, bacterial endocarditis, mycotic
Tonsillar herniation, 13-6 aneurysm, ICH, 26-30 (CD ROM)
Tics,19-24 Case 26-12, arteriovenous malformation, 26-
Transcranial doppler, 2-26 31 (CD ROM)
Index 19
Ischemic occlusive, 26-1 Vitamin E deficiency and cerebellar ataxia, 20-

Internal carotid artery syndromes, 26-S,26- 18
6,26-7,26- 10,26,12 Von Economo's encephalitis and Parkinson's
Intracerebral hemorrhage (ICH) 26-22, 26- disease, 19-11
23,26-22,26-24,26-25 w
Lacunar Ipenetrating branch syndromes, 26- Wallenberg syndrome, 13-10
11,26-13,26-12,26-13,26-14 Wallerian Degeneration 3-21,3-32,3-33
Middle cerebral artery (MCA) syndromes, 26- Watershed,26-S
11,26-12,26-13,26-14,26-15,26-16 Weber's syndrome, 13-19
Posterior cerebral artery (PCA) syndromes, Wernicke's encephalopathy, 30-S
26-18,26-19,26-19,26-20 Wernicke-Korsakoff syndrome, 30-S
Subarachnoid hemorrhage, 26-26,26-27,26- Wilson's disease, 19-21
30,26-31,26-28,26,2,26-32 Working memory, 18-24
Vascular supply, 9-10,9-11 X
Vegetative state, persistent, 29-3 X-rays, 2-13,2 -IS,
Ventriculography, 2-18
Vertebral artery syndromes, 13-9,13,10,13-11,
Vertebral tuberculosis, 9-7
Visual System 23-1
Visual pathway 23-6
Lateral geniculate 23-11
Optic radiation 23-11
Occipital lobe
Area 17, 18, 1923-12
Ocular dominance columns 23-
12
Stimulation of areas 17,18,19
23-13
Occipital lobe and eye
movements 23-1S
Lesion in visual receptive
striate area 1723-16
Lesions of extrastriate areas 18
and 19 23-16
Effects of vascular lesions in
calcarine cortex 23-20
Physiology of visual system 23-13
Simple cell 23-13
Complex cell 23-13
Hypercomplex cell 23-13
Watershed, 26-S
Lesions in visual pathway 23-8, 23-7
Clinical Cases in visual system
Clinical Cases 23-1 subfrontal
meningioma compressing optic nerve
23-9
Case 23-2 pituitary adenoma
compressing optic chiasm 23-10
Case 23-3 mass lesion in right occipital
lobe 23-17
Case 23-4 seizures of focal origin left
occipital 23-18
Vitamin B 12, 9-23

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INTEGRATED NEUROSCIENCE

A Clinical Problem Solving Approach

Elliott M. Marcus, M.D.

Stanley Jacobson, Ph.D.

With Contributions by Brian Curtis, Ph.D.

Illustrations by Mary Gauthier Delaplane

SPRINGER SCIENCE+BUSDSfESS MEDIA, L L C

Marcus, Elliott M , 1932-

Copyright © 2003 by Springer Science+Business M e d i a N e w Y o r k

Permission for books published in Europe: [email protected]

Printed on acid-free paper.

II. Nerve Physiology 5-11

Functional Centers in the Brain Stem 11-20

12. Cranial Nerves 1-25

Gross Brain Labeled Levels

CASES IN LONG FORMAT - PDF Format

CRANIAL NERVE Illustrations in PDF Format

PATHWAYS IN THE CNS PDF Format

To our wives andfamilies who demonstrated infinite patience and support.

Introduction UNIPOLAR PSEUDOUNIPOLAR BIPOLAR

TABLE 1-1. TYPES OF NEURONS IN ganglia in autonomic chains or associated with

Class of Receptor Function Location See Chapter

NOCiceptor Pain Free nerve endings in skin and organs 5

Photoreceptor Vision and color Retina 22

ThermoreceptorTemperatureSkin, tissues, and organs 5

Archicerebellum Floccular, nodular, and uvula.

ing the functional divisions. Chapter 20 will dis-

Middle Receives input from all cerebral cortical

Superior Originates from dentate nucleus;

TABLE 1-8. DIVISIONS OF THE DIENCEPHALON

Division Subnuclei Functions

Epithalamus Habenula, stria medullaris, Similar to hypothalamus

Subthalamus Subthalamus and Subcortical unconscious center for movement

White maller, found Associational bundles

ry-motor information with emotional responses

Postcentral Gyrus (Sensory Stnp)

Supenor Parietal Lobule

:;r.J;::~- Infer or Par eta I Lobule

Figure 1-11. Parietal lobe of the Cerebral Cortex.

Supenor Tempora Gyrus

Figure 1-12, Temporal and occipital lobes of the cerebral cortex.

Figure 1-13. Medial surface of the cerebral hemispheres.

Figure 1-16. Medial surface of a cerebral hemisphere.

of the cerebral hemispheres. The posterior circu-

Middle Cerebral Artery

Vertebral Artenes --=========~~

Figure 1-19. Arterial circle of Willis.

Body of Lateral Posterior

a) Patients manifest lower motor neuron dis- Or 4) generalized type- polyneuropathy.

TABLE 2-3: DEEP TENDON STRETCH REFLEXES 6. Brain Stem

PERIPHERAL NERVES SPINAL (RADICULAR)

MEDIAL BRACHIAL CUT._-...,.......;+1\

POST. BRACH IAL CUT.

LAT. THORACIC RAMI

1oIfD. AHTEIlRACHIAL WI .. -t--~

LATERAL FEMORAL CU1.---.......-

ANTE RlOR FE IIOIIAL CU1~ --""""I\t'"'""

~ (RADICULAR) PERIPHERAL NERVES

LATERAL THORACIC RMII