Spinal Cord Pathology

Ronald C. Kim

T his chapter is structured to provide an overview of the

morphologic findings in those disorders that physicians
spinal canal (e.g., profound systemic circulatory impairment
[shock or cardiac arrest] or surgical cross-clamping or disease
engaged in the practice of spinal cord medicine are most likely of the aorta or its major branches).Under these circumstances
to encounter. It is written with an emphasis on clinicopathologic the most common pattern of damage is one that is limited
correlation and in such a manner as to provide the practitioner, largely to the gray matter from upper to mid-thoracic levels
where possible, with an insight into pathogenetic mechanisms. downward (Figure 2.1), presumably because of the protective
effect of the perimedullary anastomotic network exerted
on the spinal white matter (3). Clinically, there will be
SPINAL VASCULAR DISEASE persistent flaccid paraplegia (because of sparing of the corti-
Spinal Arterial Infarction cospinal tracts) and loss of pain and temperature perception
(because of interruption of the lateral spinothalamic path-
Although all of the arterial blood supply to the spinal cord is ulti- ways), with relative sparing of posterior column (propriocep-
mately derived from the aorta, it is provided by only seven to eight tive) function.
radiculomedullary branches (1). Because the cervical and upper Operative interruption of a major intercostal arterial feeder
two to three thoracic spinal segments are relatively richly sup- (such as ligation of the artery of Adamkiewicz during rib resec-
plied, arterial infarction in this region rarely occurs. The middle tion in preparation for thoracotomy for aortic surgery) will
thoracic (T4-T8) region, however, is typically dependent on a result in non-cavitary ischemic atrophy of the ventral portion
single radicular artery that usually enters the spinal canal near
the vertebral body of T7, and the thoracolumbar region is largely
dependent on a single major artery, the artery of Adamkiewicz,
which enters, usually on the left side, with the tenth, eleventh, or
twelfth thoracic nerve root or, less often, the first or second
lumbar nerve root. For this reason, the spinal cord from T5 down-
ward is particularly susceptible to arterial insufficiency.
The radiculomedullary arteries, upon entry into the spinal
canal, ramify over the surface of the spinal cord to form a per-
imedullary arterial network that coalesces into a single anterior
and two posterior spinal arteries that send centripetally directed
branches into the underlying white matter. The internal portion
of the spinal cord is supplied by sulcal arteries coursing through
the anterior median fissure and sending branches directed cen-
trifugally, predominantly into gray matter. Because of the
relatively rich anastomotic arterial network supplying the white
matter, in contrast to the end-arterial supply of the gray matter,
severe systemic circulatory impairment tends to produce dam- Figure 2.1 Spinal cord at S5 in a subject who became para-
age mainly to the gray matter (2). plegic after an episode of cardiac arrest and who died 9 weeks
Arterial infarction of the spinal cord develops most later. Tissue necrosis is limited almost exclusively to the gray
commonly as a consequence of factors arising outside of the matter.

22
 2 • Spinal Cord Pathology
23
paraplegia following atheromatous embolism to the
anterior spinal artery at spinal T10.

Figure 2.2 Ischemic atrophy of the ventral spinal cord at

T12 in a man who had become paraplegic 41⁄2 years earlier
following resection of the left ninth and tenth ribs for repair of
a thora-
coabdominal aortic aneurysm.

of the spinal cord (Figure 2.2) (4). In this situation lower

extremity weakness is usually of upper motor neuron type (i.e.,
with spasticity) because of damage to the lateral corticospinal
tracts.

Spinal Vascular Embolic Disease

Occlusion of the anterior spinal artery (ASA) with resultant cav-
itary infarction in its territory of supply is relatively uncommon
but, when it occurs, is usually the result of atheromatous or
fibrocartilaginous embolism (2). Atheromatous emboli (Figures
2.3 and 2.4) tend to appear in relatively elderly subjects with
severe atherosclerotic vascular disease, and may affect smaller
intramedullary arterial branches with resultant small infarcts,in
which case the clinical manifestations may vary, depending upon
their size and location. Fibrocartilaginous embolism (Figures 2.5
and 2.6), which may be observed on either the arterial or the

Figure 2.3 Cavitary necrosis of the tissue adjoining the

ante-
rior median fissure at spinal L4 in a man who developed sudden
 Figure 2.5 Coagulative necrosis within the lateral corti-
cospinal tract following fibrocartilaginous embolism to the spinal
circulation.

Figure 2.4 Atheromatous embolism to a dorsolateral spinal

arterial branch, from the same patient described in Figure 2.3.

Figure 2.6 Same patient as in Figure 2.5, showing fibrocarti-

lage embolus within a spinal vein.
24 I • Introduction and Evaluation

venous side of the spinal circulation, tends to occur in either

young adulthood or late middle life. A sizable proportion of
affected subjects have a history of minor traumatic injury or of
heavy lifting. It has been suggested that axial stress, such as that
which is associated with heavy lifting, may result in herniation
of fibrocartilaginous disc material into the bone marrow
(Schmorl’s nodes) and hence into the venous (and, if pressure
is high enough, into the arterial) circulation (5). As is the case
with atheromatous embolism, the neurologic manifestations will
vary according to the size and location of the ischemic lesions
produced.
Another form of spinal vascular embolism is that associ-
ated with decompression, either from ascending too quickly
after a deep dive or from loss of aircraft cabin pressure.Approx-
imately half of those afflicted have a patent foramen ovale (6).
For reasons not well understood, when neurologic manifesta- Figure 2.7 Spinal cord at T12 in a patient with an untreated
tions appear, spinal cord signs and symptoms tend to predom- dural AVF, showing ischemic atrophy and marked thickening of
inate,particularly those referable to the cervicothoracic region. the walls of spinal leptomeningeal veins.
In those subjects who have been examined postmortem, there
are multiple small infarcts within the spinal gray and white
matter. The pathogenesis of these lesions is poorly understood, The pathological picture is identical to that described by Foix and
but one group of observers noted, in an experimental model Alajouanine under the heading of “subacute necrotic myelitis,”
of decompression,the presence of gas bubbles within the spinal and it is generally accepted that the so-called Foix-Alajouanine
epidural veins (7). syndrome represents nothing more than the myelopathy associ-
ated with a spinal dural AVF (2).
Spinal Venous Infarction
Spinal venous thromboembolic occlusion is distinctly uncom- TRAUMATIC INJURY TO THE SPINAL CORD
mon and tends to occur in hypercoagulable states.Epidural,lep- Patterns of Injury
tomeningeal, or intraparenchymal veins may be affected.
Venous infarction of the spinal cord may be either hemorrhagic The varied clinical expressions of traumatic spinal cord injury
or non-hemorrhagic. Hemorrhagic infarction is characterized reflect the distribution and mechanism of damage (2). The ante-
by sudden onset with back pain, rapid progression, and short rior spinal cord syndrome (Figure 2.8) is typically the result of
survival, whereas non-hemorrhagic infarction is more insidi- hyperflexion injury and is characterized by spastic weakness and
ous and protracted, without back pain, and with relatively loss of pain and temperature perception with relative preserva-
longer survival (8). tion of posterior column (proprioceptive) sensation. The central
spinal cord syndrome (Figure 2.9) is ordinarily a consequence
of hyperextension injury (e.g., a diving accident) and is charac-
Spinal Vascular Malformations terized by spastic weakness, loss of pain and temperature
Arteriovenous malformations, which presumably are of vascular perception, and a variable loss of posterior column sensation. The
embryological origin, may involve either a portion of or the entire
cross-sectional extent of the spinal cord. They typically become
manifest acutely (due to hemorrhage) in young adults. Patho-
logically, the parenchyma of the spinal cord is replaced by a
network of abnormal, heavily collagenized vessels of greatly
varying mural thickness that cannot be identified as either arterial
or venous in nature.
Arteriovenous fistulas (AVFs) are acquired lesions that typ-
ically become manifest in middle life as slowly progressive lower
extremity weakness. The fistulous communication is most fre-
quently seen embedded within the dura ensheathing a nerve root
in the thoracolumbar region, although myelopathy may occa-
sionally be associated with fistulas at other sites, such as the pelvic
or retroperitoneal region or within the cranial cavity.
Pathologically, the walls of leptomeningal veins and of the spinal
intraparenchymal venocapillary network are greatly thickened,
an indication of venous hypertension and impairment of venous
drainage of the spinal cord. This results in a venocongestive Figure 2.8 Ventrally predominant damage to the spinal cord at
myelopathy, in which the cross-sectional area of the spinal cord L2 in a subject who had become paraplegic following a hyper-
may be reduced to one-half or less of its normal size (Figure 2.7). flexion injury in a motor vehicle accident 44 years earlier.
 2 • Spinal Cord Pathology
25
may in turn cause progression of the neurologic
deficit; in
extreme circumstances, for example, a paraplegic can,
with
upward extension of a syringomyelic cavity, become
quadriplegic
with a rising sensory level within a matter of hours, a
situation

Figure 2.9 Centrally predominant damage to the spinal

cord
at C7 in a man who had become quadriplegic following a div-
ing injury 27 years earlier. Note the large traumatic neuroma.

Brown-Séquard syndrome usually results from a stab wound and

is characterized by ipsilateral motor weakness, contralateral loss
of pain and temperature perception, and ipsilateral loss of pos-
terior column sensation. The complete spinal cord syndrome
results from crush injury or transection and is characterized by
spastic weakness and by complete sensory loss below the level of
the lesion.
Lesions developing directly as a result of the primary injury
(e.g., laceration or crush) are typically segmental and hemorrhagic.
Damage developing secondarily can be subdivided into early and
delayed complications. Within 8 to 24 hours the white matter and
the ascending and descending long spinal tracts contained therein
show massive edema and diminished vascular perfusion. Other fac-
tors that contribute to the spread of tissue damage include the
release of excitotoxic neurotransmitters, calcium and potassium
ion shifts, generation of oxygen free radicals, and activation of the
arachidonic acid cascade (2).
Weeks, months, or years after the injury, a number of addi-
tional morphologic alterations may appear. Traumatic
neuroma formation (Figure 2.9) may be massive at the
primary site of injury and is presumed to represent sprouting
from dorsal spinal afferents. Visible evidence of wallerian
degeneration of ascend-
ing tracts above and of descending tracts below the level of the
lesion does not appear until approximately 6 to 8 weeks have
elapsed. Chronic adhesive arachnoidopathy is an
invariable consequence of traumatic spinal cord injury.
The most dramatic late consequence of traumatic injury
with tethering of the spinal cord is delayed
traumatic
syringomyelia, in which, usually after several years have
elapsed,
one or more cavities appear within the spinal cord above or below
(without necessarily being directly contiguous with) the injury
site (9). Episodic elevation of venous back-pressure, such as that
which may occur during Valsalva maneuvers or while coughing,
sneezing, or straining at stool, may cause upward or downward
extension of these cavities within an immobile spinal cord. This
 Cervical Spondylosis
The most important vertebral column disease leading to struc-
tural damage to the spinal cord is cervical spondylosis. With
advancing age the intervertebral discs lose water and elasticity,
especially where spine mobility is greatest (i.e., at the C5-C6
and C6-C7 interspaces), and adjoining vertebral bodies may
come into direct contact with each other, leading to the for-
mation of bone spurs or osteophytes. When these bone spurs
form along the posterior margins of the vertebral bodies, they
may project into the spinal canal, thereby narrowing it.
Narrowing of the spinal canal in this manner will not
necessarily lead to symptomatic neurologic dysfunction in and
of itself, but it may increase an individual’s vulnerability to
spinal cord damage when there is a superimposed stressful
event, such as hyperextension of the neck after a rear-end
motor vehicle collision.
Figure 2.10 Delayed traumatic syringomyelia within the spinal The pattern of spinal cord damage that develops will vary
cord at C8 in a man who developed C5 quadriplegia after chiro- according to the location of the bone spurs. For example, if they
practic manipulation-associated vertebral osteomyelitis. Note the are laterally placed, they may encroach upon the neural foram-
adhesive arachnoidopathy, characterized by proliferation of collagen ina, resulting in a radiculopathy. A typical pattern of damage that
within the subarachnoid compartment. is seen relatively commonly is associated with a posteriorly
directed bone spur that is situated near the midline. In this
situation, the spinal cord, as seen in transverse section, assumes
that calls for immediate surgical intervention. Pathologically, the cavity, an ovoid shape with a “butterfly” distribution of damage that
which is typically asymmetrical and sometimes multiple, contains no affects both lateral corticospinal tracts (with resultant spastic
epithelial lining and is bordered by a zone of gliosis (Figure 2.10). lower extremity weakness and Babinski signs), the lateral spinal
gray matter, and the ventral portions of the posterior columns
(Figure 2.11) (2). The mechanism by which this pattern of
MYELOPATHY DUE TO VERTEBRAL
damage develops is unclear, but there is imaging evidence to
COLUMN DISEASE
26 I • Introduction and Evaluation

DEGENERATIVE AND DEMYELINATIVE SPINAL

CORD DISEASE
Friedreich’s Ataxia
Friedreich’s ataxia is the most common form of autosomal reces-
sive ataxia. It is due to a mutation of a gene on chromosome 9q13
that leads to markedly reduced expression of a protein (frataxin)
that appears to participate in the regulation of mitochondrial iron
efflux (12, 13). In the vast majority of instances, there is a GAA
trinucleotide repeat expansion.
The onset of illness usually occurs before the age of 20. The
cardinal clinical manifestations are progressive ataxia of gait, pes
cavus, kyphoscoliosis, hammer toes, areflexia, impaired propri-
oception, and hypertrophic or congestive cardiomyopathy with
interstitial myocarditis and granular iron deposits.
Figure 2.11 Cervical spondylotic myelopathy at spinal C5, showing flattening of the ventral surface and damage
within both gray and white matter.
showing pallor of myelin staining within the lateral and, to a
lesser degree, the dorsal white matter. Note the ovoid contour of
the spinal cord.

suggest that buckling of the ligamenta flava during hyperexten-

sion results in axonal disruption (10).

Rheumatoid Disease
Myelopathy may develop in subjects with rheumatoid disease,
either as a result of direct involvement of the spinal cord or its
coverings by the disease process (i.e., in the form of vasculitis or
of rheumatoid nodule formation), or, more commonly, as a result
of disease of the cervical spine (11). Vertebral column disease is
typically the result of subluxation, most frequently atlantoaxial
but sometimes subaxial. Atlantoaxial subluxation may occur
either in a forward or in an upward direction; in the former
circumstance the spinal cord may be pushed against the ante-
rior wall of the spinal canal, resulting in a triangular spinal cord
contour as seen in transverse sections, with a central pattern of
damage (Figure 2.12).

Figure 2.12 Spinal cord at C1 in a man with rheumatoid

dis-
ease who became quadriplegic after C1/C2 vertebral subluxation,
 The major neuropathologic findings are in the spinal cord
(14). There is degeneration of the entire peripheral propriocep-
tive pathway, with loss of posterior column fibers, shrinkage of
dorsal spinal nerve roots, loss of dorsal root ganglion cells, and
loss of large myelinated fibers within peripheral nerves that is
best seen in purely sensory nerves such as the sural nerve.Severe
nerve cell loss is observed within the nucleus dorsalis of
Clarke, with associated loss of nerve fibers from the dorsal
spinocerebellar tract. Nerve fibers are also lost from the ventral
spinocerebellar tracts and from the lateral and ventral corti-
cospinal tracts (Figure 2.13). The cerebellum usually shows
severe nerve cell loss within the dentate nuclei, with degenera-
tion of their efferent fibers coursing through the superior cere-
bellar peduncles.

Hereditary Spastic Paraplegia

The hereditary spastic paraplegias (HSPs) are a clinically and
genetically heterogeneous group of disorders characterized pre- Figure 2.13 Upper thoracic spinal cord in a patient with
dominantly by progressive spastic weakness of the lower extrem-
ities. Several dozen different genetic loci have been identified. Friedreich’s ataxia, showing systematized loss of myelinated
Most often the disorder is transmitted in autosomal dominant axons within the posterior columns, lateral and ventral corti-
fashion, but autosomal or X-linked recessive forms have also cospinal tracts, and dorsal and ventral spinocerebellar tracts.
 2 • Spinal Cord Pathology
27
dying-back degeneration of nerve fibers within the lateral
and

Figure 2.14 “Pure” hereditary spastic paraplegia, showing

loss of myelinated axons within the posterior columns and lateral
cor-
ticospinal tracts.

been described. Mutations in the spastin gene (SPG4, encoded

on chromosome 2p22) and in the atlastin gene (SPG3A, encoded
on chromosome 14q12-q21) account for more than half of the
autosomal dominant forms of HSP. The onset of illness may
occur at any age, depending on the mutation. Pure phenotypes
are characterized by spastic lower extremity weakness
alone, whereas complex phenotypes are associated with other
abnormalities, such as ataxia, dementia, seizures, visual dysfunc-
tion, or systemic manifestations (15, 16).
Pathologically, pure HSP is characterized by distally
predominant loss of myelinated axons with the lateral corticospinal
tracts and, sometimes, the posterior columns (Figure 2.14).

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is often included, together
with progressive muscular atrophy (PMA) and progressive bul-
bar palsy (PBP), under the broader heading of motor neuron dis-
ease (MND), and is characterized by degeneration of motor
neurons within motor cortex, brain stem, and spinal cord. This
is manifested clinically by the development, usually in older adult
life, of progressive weakness that leads, within 2 to 5 years, to
death from respiratory failure. Dementia of frontotemporal type
is seen in about 5% of cases (17).
A small proportion (5%-10%) are familial (usually autoso-
mal dominant), and of these, approximately 20% are associated
with mutations of the gene encoding copper/zinc superoxide
dismutase (SOD1) (17). Although classical sporadic ALS typically
begins in the limbs and is characterized, at some time during the
course of illness, by both upper motor neuron (UMN) and lower
motor neuron (LMN) signs, PMA, which initially appears to be
restricted to LMNs, and PBP, which seems at first to be limited to
the brain stem, both usually progress to UMN involvement, a find-
ing that is reflected in the distribution of CNS changes seen at
autopsy.
Pathologically, LMN disease is characterized by nerve cell
loss and astrocytosis within the spinal anterior horns and brain
stem motor (especially the hypoglossal) nuclei, with striking atro-
phy of motor nerve roots, and UMN disease is characterized by
 C-immunoreactive Bunina bodies, small hyaline inclusions, and
ubiquitin-immunoreactive skein-like inclusions may be observed
within the cytoplasm of surviving spinal and brain stem motor
neurons and are highly specific for ALS (17). Neurofilament-rich
axonal spheroids may be seen within the most proximal axonal
segments in the active stages of the disease. The familial forms
of ALS show similar pathological features, although some may
show either posterior column involvement or only minimal
corticospinal tract involvement. Skeletal muscle that is deprived
of its innervation will show denervation atrophy.

Primary Lateral Sclerosis

There is considerable debate as to whether or not primary lat-
eral sclerosis is an entity that is separate and distinct from other
forms of MND. Those who argue that it is describe a sporadic
motor disorder that is dominated clinically by UMN dysfunction
Figure 2.15 Amyotrophic lateral sclerosis, showing loss of
with little or no evidence of LMN involvement (i.e., spastic weak-
myelinated axons within the lateral and (on one side) ventral cor-
ticospinal tracts. Loss of spinal anterior horn cells (not pictured) was ness with no fasciculations). Survival may be considerably longer
also present. than for classical ALS, often for 10 years or more. A few undergo
progression into ALS. Pathologically, although damage to the
corticospinal tracts is striking, the presence, on occasion, of
ventral corticospinal tracts (Figure 2.15) (18, 19). With advanced some degree of loss of spinal anterior horn cells, together with
disease the motor cortex may also be affected. Although sensory the finding of ubiquitinated cytoplasmic inclusions, suggests that
fibers are not ordinarily affected, in those subjects who have been the disorder is a variant of ALS (21).
maintained for long periods of time (5 years or more) on assisted
ventilation, damage may be observed at sites that are typically Spinal Muscular Atrophy
spared, such as the lateral and ventral columns of the spinal cord
and the third, fourth, and sixth cranial nerve nuclei and the Spinal muscular atrophy (SMA) is a heterogeneous group of
nucleus of Onufrowicz in the sacral spinal cord (20). Cystatin autosomal recessive disorders due to homozygous deletions in
the survival motor neuron (SMN1) gene on chromosome 5q13
28 I • Introduction and Evaluation

(21, 22). All are characterized clinically by LMN weakness, are- in which case the myelin that is formed is of peripheral rather
flexia, fasciculations, absence of sensory signs, and EMG evidence than central type.
of denervation. The classical infantile type (type I SMA or
Werdnig-Hoffmann disease) is lethal and results in death at age
3 to 18 months. The chronic infantile type (type II SMA) is more Neuromyelitis Optica
slowly progressive and may be associated with survival into adult- Neuromyelitis optica (NMO) is a relapsing, polyphasic inflam-
hood. Patients with the chronic childhood type (type III SMA matory demyelinating disorder that appears to be separate and
or Kugelberg-Welander disease) progress very slowly and may distinct from multiple sclerosis. The vast majority (90%) of
have near-normal life expectancies. affected subjects are women, and the median age of onset is
Pathologically, in the severe infantile form, there is profound toward the end of the fourth decade. The optic neuritis and
nerve cell loss and astrocytosis within the spinal anterior horns myelitis may occur either sequentially or simultaneously, and over
and brain stem motor nuclei, with atrophy of motor nerve roots. half of patients develop permanent visual or ambulatory impair-
Skeletal muscle shows denervation atrophy. ment within 5 years of onset (24). A highly specific serum autoan-
tibody (NMO-IgG) has been identified that binds to the water
channel protein aquaporin 4, which appears to play a major role
Multiple Sclerosis in water homeostasis within the CNS.
The histopathologic substrate of NMO is a necrotizing optic
The vast majority of patients with multiple sclerosis will show neuritis and longitudinally extensive myelitis in which an admix-
clinical and pathological evidence of spinal cord involvement, ture of demyelination and cavitating necrosis, an inflammatory
usually in association with manifestations indicative of disease at infiltrate containing many neutrophils and eosinophils, and
other sites. In a sizable proportion, spinal cord dysfunction, in vasocentrically distributed immune complex deposition are typ-
the form of spastic ataxia, spastic paraparesis, or impaired pro- ically observed (25, 26). NMO also appears to occur in associa-
prioception or vibratory sensation, may predominate. tion with certain other autoimmune disorders, notably systemic
As is the case elsewhere in the CNS, the characteristic patho- lupus erythematosus and Sjögren’s syndrome.
logic finding is the presence of sharply circumscribed foci of
demyelination with relative sparing of axons (23). These lesions
may be visible on inspection of the surface of the spinal cord and TOXIC/METABOLIC MYELOPATHIES
may be associated with gross atrophy. As seen in transverse sec-
tion, their boundaries bear no relation to gray-white matter Postangiography Myelopathy
interfaces or to fiber pathways (Figure 2.16). Active plaques are Postangiography myelopathy is an uncommon event and is
typically associated with perivascular “cuffs”of lymphocytes and typically encountered following aortography or, less frequently,
plasma cells, axonal swellings, and lipid-laden macrophages. If vertebral angiography. It is a consequence of inadvertent admin-
several lesions are present, they may be in different histological istration of contrast material directly into the spinal circulation
stages of evolution. Within old plaques the concentration of through radiculomedullary feeding arteries. Clinical manifesta-
oligodendrocytes is sharply reduced.“Shadow plaques” are those tions (paraplegia or quadriplegia) appear within hours. Patho-
in which the staining density of the myelin is only partially logically, there is centrally predominant necrosis that damages
reduced, and they represent remyelination with formation of most of the gray matter (2). The arterial supply and venous
short, thin myelin internodes. Foci of demyelination near nerve drainage are intact. Margolis and his colleagues reproduced the
root entry zones may undergo remyelination by Schwann cells, myelopathy by injecting sodium acetrizoate (Urokon) into the
aortas of dogs and concluded, on the basis of this work, that dam-
age was the result of toxicity rather than ischemia (27).

Myelopathy after Intrathecal Injections

Myelopathy may follow the intrathecal administration of a wide
variety of agents, including spinal anesthetics, alcohols, hyper-
tonic saline, steroids, methylene blue, chemotherapeutic agents,
ammonium sulfate, or magnesium sulfate. Pathologically, the pat-
tern of damage is typically one of circumferentially distributed
loss of myelinated axons (Figure 2.17) (2). Later there may be
fibrous thickening of the leptomeninges. Bunge and his col-
leagues showed experimentally that simple CSF barbotage (i.e.,
slow, repeated withdrawal and reinjection of minute quantities
of CSF without administering any exogenous material) could
result in circumferential demyelination (28).

Figure 2.16 Sharply circumscribed plaques of Chronic Adhesive Arachnoidopathy

demyelination within the spinal cord at C6 in a quadriplegic with
long-standing multiple sclerosis. Note the presence of Fibrous thickening of the leptomeninges may result from a wide
demyelination with both gray and white matter. variety of causes, including the intrathecal administration of any
 2 • Spinal Cord Pathology
29
myelin lamellae progresses sequentially to the formation
of

Figure 2.17 Circumferential pallor of myelin staining

within the spinal cord at L4, following intrathecal
administration of hypertonic saline for pain relief.

one of a number of agents (particularly contrast media), tuber-

culous or pyogenic bacterial meningitis, traumatic injury or sur-
gical intervention, and hemorrhage into the spinal subarachnoid
compartment. In a sizable proportion of patients, the etiology
is unclear. Depending on the mode of development, the patho-
logic findings may range from mild leptomeningeal opacification
to dense collagenization within the subarachnoid compartment,
with entrapment of nerve roots and blood vessels and adherence
to the overlying dura (Figure 2.10) (2).

Vitamin B12 Deficiency Myeloneuropathy

The absorption within the distal ileum of vitamin B12 (cobal-
amin), which must be supplied by ingestion of meat and dairy
products, requires binding to Castle’s intrinsic factor, which is
elaborated by gastric parietal cells. Vitamin B12 deficiency may
therefore be induced in a variety of circumstances, including
autoimmune gastritis, gastric or distal ileal surgery, Crohn’s dis-
ease, tropical sprue, fish tapeworm infestation, dietary insuffi-
ciency (e.g., in vegeterians), or inborn errors of cobalamin
metabolism. Neurologically symptomatic patients may not be
anemic, although bone marrow examination will reveal the pres-
ence of megaloblasts. As the disease progresses over a period of
weeks or months, gait ataxia, impaired proprioception and vibra-
tory sensation, loss of deep tendon reflexes, and spasticity will
develop, as will an unexplained psychosis.
Pathologically, the disease typically begins at mid-thoracic
levels with small foci of ballooning degeneration of myelin
sheaths within the central portions of the posterior columns
and the peripheral portions of the lateral columns; these foci
eventually coalesce to form large areas of myelin destruction
(Figure 2.18) and secondary axonal damage, with permeation
by macrophages and reactive astrocytosis (29). Although the
terms “subacute combined degeneration” and “combined sys-
tems degeneration” are used to denote the pattern of damage,
the destruction is non-systematized and does not affect
entire
tracts in the manner that Friedreich’s ataxia or ALS do.Electron
microscopy of experimentally induced vitamin B12 deficiency
myelopathy in rhesus monkeys has shown that separation of
 Spinal Epidural Abscess
Spinal epidural abscess formation typically develops in the pres-
ence of one or more predisposing factors, such as diabetes melli-
tus, chronic alcohol abuse, HIV infection, a prior operative
procedure, placement of a stimulator or a catheter, or sepsis. It
occurs more frequently posteriorly than anteriorly and in the tho-
racolumbar than in the cervical region. Staphylococcus aureus
is the
etiologic agent in at least two-thirds of cases (32). Clinically, the
classical clinical triad consists of back pain, fever, and neurologic
deficit (weakness), although not all components are always pre-
sent. MRI is currently the most sensitive method of detection.
Hematogenous dissemination, seen in approximately half of the
affected subjects, typically results in an exudate in which neu-
trophils predominate, whereas contiguous spread from an adjoin-
ing focus of infection (such as vertebral osteomyelitis), which
Figure 2.18 Non-systematized pallor of myelin staining within accounts for another third of those affected, often results in a mixed
the dorsal and lateral white matter at spinal T8, in a patient with severe inflammatory response that contains an abundance of lympho-
vitamin B12 deficiency. cytes and plasma cells. The mechanism by which the spinal cord
is damaged is unclear. Although Feldenzer and colleagues (1988),
in their experimental animal model, found evidence of direct com-
intramyelinic vacuoles, degeneration of myelin sheaths, and pression (33), studies at autopsy have shown the presence, on occa-
degeneration of axons (30). Peripheral neuropathy appears in the sion, of thrombosis of small leptomeningeal arteries and veins (32).
majority of affected subjects,as evidenced by reduced nerve
conduction velocity, and has been associated with both demyeli- Spinal Subdural Abscess
nation and axonal degeneration.
Chronic exposure to nitrous oxide (NO) may produce a Spinal subdural abscess formation is considerably less common.
similar clinical and pathologic picture. NO appears to inactivate Most of these lesions occur at cervical or thoracic levels and,
methionine synthetase, a vitamin B12-dependent enzyme (31). as is the case with epidural infections, Staphylococcus
aureus is
INFECTIONS WITHIN THE SPINAL CANAL
30 I • Introduction and Evaluation

the most commonly isolated agent (34). Although in most

instances infection is believed to be the result of hematogenous
dissemination, a primary focus at another site is often not
found. Again, the mechanism of damage to the spinal cord is
debated (i.e., compression vs. vasculitis).

Spinal Intramedullary Abscess

Intramedullary abscess formation is also distinctly uncommon.
Such abscesses are usually solitary but may occur multiply. Most
have been described at mid- to low thoracic levels. Over half
appear to have resulted from hematogenous dissemination, and
about 20% develop contiguously from an adjoining site of infec-
tion, such as vertebral osteomyelitis (35). Staphylococcus aureus
is the most commonly isolated organism. The presence of a
capsule and the predominating inflammatory cell type (lym- philus influenzae in a 14-month-old child. The exudate
phoplasmacytic or neutrophilic) will depend on whether the is con-
infection is chronic or acute. fined within the subarachnoid compartment and is heavier
along the dorsal surface.

Suppurative Spinal Leptomeningitis

Spinal subarachnoid suppuration accompanies that seen
intracranially. Following upon large-scale immunization against
type b Hemophilus influenzae, bacterial meningitis is now
pre-
dominantly a disease of adults (36). In the post-neonatal period
Streptococcus pneumoniae accounts for approximately
one-half
and Neisseria meningitidis for one-quarter to one-third of
cases
(37, 38).
Pathologically, the exudate tends to localize by gravity along
the dorsal surface of the lower thoracic spinal cord (Figure 2.19).
It consists mainly of neutrophils for the first few days, after which
time lymphocytes and fibrin appear. After a week microglial cells
within the underlying parenchyma begin to proliferate. If the
exudate extends into the underlying neural parenchyma, the
result is a meningomyelitis. Healing is characterized by fibro-
blastic organization of the exudates. Local complications may
include occlusive vasculitis, abscess formation, or adhesive arach-
noidopathy.

Figure 2.19 Acute suppurative leptomeningitis due to

Hemo-
Figure 2.20 Tabes dorsalis within the cervical spinal cord, Many viral agents are capable of producing myelitis. Only a few
showing darkening within the posterior columns due to loss of will be described here.
myelinated axons. Poliovirus is a single-stranded RNA enterovirus that, on
the rare occasion when symptomatic CNS involvement occurs,
tends to damage spinal anterior horn cells and other motor
neurons, presumably because they bear relatively large numbers of
Other Bacterial Infections viral sur-
face receptors. Histologically, in the active phase of the disease, the
Tuberculosis of the spine may lead to vertebral body collapse, affected areas show the presence of many pleomorphic microglia
usually in the thoracic or lumbar region. Chronic epidural with evidence of neuronophagia. At later stages there is striking
abscess formation may also occur. Tuberculous spinal menin- focal tissue pallor (Figure 2.21) with nerve cell loss and astrocyto-
gitis is virtually always associated with concomitant intracranial sis and shrinkage of the ventral spinal roots.
infection. West Nile virus, a culex mosquito-borne member of the
Tabes dorsalis represents the classical spinal form of neu- fla-
rosyphilis and is rarely seen today. The lumbosacral region is most vivirus phylogenetic group, is harbored in birds but is capable
frequently affected. Pathologically, there is degeneration of the dorsal of infecting many animals. Symptomatic CNS involvement is
root ganglia, dorsal spinal roots, and posterior columns (Figure 2.20), uncommon but, when it develops, is seen in widespread distrib-
without evidence of infiltration by inflammatory cells or stainable ution. Pathologically, it is characterized by the presence of neu-
microorganisms. The pathogenesis of this con- ronal necrosis and neuronophagia, microglial nodule formation,
dition is not understood. and perivascular cuffing by mononuclear inflammatory cells. A
small subset of patients will develop a poliomyelitis-like syn-
Viral Infections of the Spinal Cord drome characterized by flaccid paralysis; in such cases, spinal
anterior horn pathology is strikingly similar to that observed with
poliovirus infection (39).
 2 • Spinal Cord Pathology
31

resembles that associated with vitamin B12-deficiency

myelopathy (40).
Other viral agents that may be associated with myelitis, such
as herpes simplex virus types 1 and 2, cytomegalovirus, and
human T-cell leukemia virus type I, typically produce necrotiz-
ing lesions.

NEOPLASMS WITHIN THE SPINAL CANAL

Although virtually any neoplasm that occurs within the cranial
cavity can be seen within the spinal canal, the most common
spinal neoplasms are nerve sheath tumors, meningiomas,
ependymomas, astrocytomas, and secondary (metastatic) tumors
(41, 42, 43).
Nerve sheath tumors are of two types, schwannomas and
Figure 2.21 Focal tissue pallor within the spinal anterior dorsal and lateral white matter. The pattern of damage
horns of a patient who had suffered paralysis after having suffered closely resembles that of vitamin B12-deficiency
acute anterior poliomyelitis 27 years earlier. myelopathy.

After varicella-zoster virus infection, the agent is

typically
stored within spinal dorsal root ganglia. In subjects who have
been immunosuppressed (particularly those with AIDS),
recrudescence of infection typically results in the appearance
of a dermatomal eruption. Pathologically, the dorsal root
ganglion at that level shows the presence of a ganglioradi-
culitis, sometimes with Cowdry type A intranuclear inclusion
body formation. On rare occasion this may lead to the devel-
opment of a granulomatous vasculitis or a focal necrotizing
myelopathy.
HIV-infected individuals may develop a symptomatic
myelopathy (vacuolar myelopathy of AIDS) that is
character-
ized clinically by spastic paraparesis, impairment of proprio-
ception, and posterior column ataxia, and pathologically
by non-systematized vacuolar degeneration, particularly
within the dorsal and lateral funiculi (Figure 2.22), that closely

Figure 2.22 AIDS-associated vacuolar myelopathy,

showing non-systematized microcystic rarefaction within the
neurofibromas.Schwannomas,which account for roughly 30% circumscribed extra-axial neoplasms, two-thirds of which are
of primary spinal neoplasms, are benign and tend to occur at extradural,are usually situated within dorsal spinal nerve roots
and below lumbar regions. When multiple, they should raise (Figure 2.23). They are composed of spindle-shaped cells
the suspicion that NF-2 may be present. These sharply

Figure 2.23 Schwannoma affecting a spinal nerve root.

32 I • Introduction and Evaluation

arranged in interlacing fascicles, and typically show both

compact (Antoni A) and loose-meshed (Antoni B) areas with
nuclear palisading and Verocay body formation, nuclear
atypia, vascular hyalinization, and immunoreactivity for
S-100 protein.
Neurofibromas, which are also of Schwann cell origin,
account for about 25% of primary spinal neoplasms. These
benign tumors are typically encountered within the intradural
portions of dorsal spinal nerve roots. They are usually solitary
and, when seen multiply, should raise the suspicion that the
patient may be suffering from NF-1. Pathologically, these
fusiform lesions tend to separate rather than displace nerve fibers.
Typically they are composed of spindle-shaped or stellate cells
in a loose connective tissue matrix and, like schwannomas, show
immunoreactivity for S-100 protein.
Meningiomas, which account for approximately 25% of pri-
mary spinal neoplasms, are benign intradural lesions that are most
commonly observed at thoracic levels (Figure 2.24). Roughly 80%
of affected subjects are women. When meningiomas occur mul-
tiply, the possibility of NF-2 should be considered. Pathologically,
these tumors, which are of arachnoidal cell origin, are composed

Figure 2.25 Filum terminale ependymoma.

of uniform, process-bearing cells with abundant cytoplasm and

round to oval vesicular nuclei, with a tendency toward whorling
and psammoma body formation.
Ependymomas are low-grade glial neoplasms that
are
observed most frequently within the cauda equina and the lum-
bosacral region. The most common site of origin is the filum ter-
minale (Figure 2.25), presumably because of the presence there
of residual nests of cells left by the embryonic ventriculus
terminalis. Ependymomas are well-circumscribed lesions com-
posed of process-bearing cells with uniform vesicular nuclei, a
tendency toward perivascular pseudorosette formation, and,
occasionally, the presence of ependymal rosettes. Most of the
neoplasms arising in the cauda equina are of myxopapillary type
and are characterized by the presence of tumor cells arranged
around blood vessels that are separated by a mucopolysaccha-
ride-rich stroma.
Some 80% to 85% of spinal astrocytomas arise in the
cervi-
cal or thoracic regions. These infiltrative neoplasms are typically
associated with fusiform enlargement of the spinal cord and are
composed of stellate or spindle-shaped, process-bearing cells
Figure 2.24 “Dumbbell” spinal meningioma with both with rounded or oval vesicular nuclei that show immunoreac-
extradural and intradural components. tivity for glial fibrillary acidic protein. Higher-grade neoplasms
 2 • Spinal Cord Pathology
33

References
1. Lazorthes G. Pathology, classification and clinical aspects of vascular
diseases of the spinal cord. In: Vinken PJ, Bruyn GW, eds. Handbook
of
Clinical Neurology, Vol. 12. Amsterdam: North Holland Publishing
Company, 1972:492-506.
2. Kim RC. Pathology of non-neoplastic, regional disorders of the spinal
cord. In Nelson JS, Mena H, Parisi JE, Schochet SS Jr, eds. Principles
and
Practice of Neuropathology. 2nd ed. New York: Oxford University
Press,
2003:459-496.
3. Kim SW, Kim RC, Choi BH, Gordon SK. Non-traumatic ischaemic
myelopathy: a review of 25 cases. Paraplegia 1988; 26:262-272.
4. Hughes JT, MacIntyre AG. Spinal cord infarction occurring during
thoracolumbar sympathectomy. J Neurol Neurosurg Psychiatry
1963;
26:118-121.
5. Tosi L, Rigoli G, Beltramello A. Fibrocartilaginous embolism of the spinal
cord: a clinical and pathogenetic reconsideration. J Neurol
Neurosurg
Psychiatry 1996; 60:55-60.
Figure 2.26 Spinal intramedullary metastasis of small cell
car-
cinoma of the lung.
Figure 2.27 Ischemic perivenous microcystic
rarefaction at
spinal T7, particularly dorsally and laterally, owing to
epidural
show a greater degree of nuclear pleomorphism, with a higher venous obstruction by metastatic prostatic
proliferation index, evidence of vascular hyperplasia, and tumor adenocarcinoma.
necrosis.
Metastases produce symptomatic spinal cord
dysfunction usually following involvement of the vertebral
column, especially in the thoracic region.Rarely,metastasis may
develop within the spinal leptomeninges or within the spinal
cord parenchyma (Figure 2.26). Lung and breast are the
most common primary sites.
In most cases of spinal cord “compression” due to metasta-
tic extradural disease, the spinal cord, when examined patho-
logically, typically does not show deformity of the type that
might be expected on the basis of direct compression. Rather,
there are wedge-shaped foci of perivenous microcystic rar-
efaction, often with hemorrhagic extravasation (Figure 2.27).
This finding,coupled with experimental evidence,suggests that
spinal cord damage associated with vertebral/epidural metasta-
tic disease is attributable largely to epidural venous obstruc-
tion (44).
 6. Wilmshurst PT, Byrne JC, Webb-Peploe MM. Relation between intera- of Dementia and Movement Disorders. Basel: ISN Neuropath
trial shunts and decompression sickness in divers. Lancet 1989; Press, 2003:350-368.
2:1302-1306. 18. Hays AP. The pathology of amyotrophic lateral sclerosis. In: Mitsumoto
7. Hallenbeck JM, Bove AA, Elliott DH. Mechanisms underlying spinal cord H, Przedborski S, Gordon PH, eds. Amyotrophic Lateral
damage in decompression sickness. Neurology 1975; 308-316. Sclerosis. New
8. Kim RC, Smith HR, Henbest ML, Choi BH. Non-hemorrhagic venous York: Taylor & Francis, 2006:43-80.
infarction of the spinal cord. Ann Neurol 1984; 156: 379-385. 19. Kim RC, Sung JH. Motor system degenerations. In: Duckett S, ed.
9. Barnett HJM, Jousse AT, Ball MJ. Pathology and pathogenesis of Pathology of the Aging Human Nervous System.
progressive cystic myelopathy as a late sequel to spinal cord injury. In: Barnett Philadelphia: Lea &
HJM, Foster JB, Hudgson P, eds. Syringomyelia. Philadelphia: WB Saunders, Febiger, 1991:159-171.
1973:179-219. 20. Bergmann M, Völpel M, Kuchelmeister K. Onuf ’s nucleus is frequently
10. Quencer RM, Bunge RP, Egnor M, Green BA, et al. Acute traumatic involved in motor neuron disease/amyotrophic lateral sclerosis. J Neurol
central cord syndrome: MRI-pathological correlations. Neuroradiology Sci 1995; 129:141-146.
1992; 34:85-94. 21. Swash M. Primary lateral sclerosis. In: Dickson D, ed.
11. Kim RC, Collins GH. The neuropathology of rheumatoid disease. Hum Neurodegeneration:
Pathol 1981; 12:5-15. The Molecular Pathology of Dementia and Movement
12. Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol 1998; Disorders. Basel: ISN
57:531-543. Neuropath Press, 2003: 369-371.
13. Albin RL. Dominant ataxias and Friedreich ataxia: an update. Curr Opin 22. Harding B. Spinal muscular atrophy. In: Dickson D, ed.
Neurol 2003; 16:507-514. Neurodegeneration: The Molecular Pathology of Dementia
14. Lamarche JB, Lemieux, Lieu HB. The neuropathology of “typical” and Movement Disorders. Basel: ISN Neuropath Press, 2003:372-
Friedreich’s ataxia in Quebec. Can J Neurol Sci 1984; 11:592-600. 375.
15. McDermott CJ, Shaw PJ. Hereditary spastic paraparesis. In: Eisen AA, 23. Prineas JW, McDonald WI, Franklin RJM. Demyelinating diseases. In:
Shaw PJ, eds. Handbook of Clinical Neurology, Vol. 12. Amsterdam: Graham DI, Lantos PL, eds. Greenfield’s Neuropathology. 7th ed.
Elsevier, 2007:329-352. London:
16. Depienne C, Stevanin G, Brice A, Durr A. Hereditary spastic paraplegias: Arnold, 2002:471-550.
an update. Curr Opin Neurol 2007; 20:674-680. 24. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker
17. Kato S, Shaw P, Wood-Allum C, Leigh PN, Shaw C. Amyotrophic lateral BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;
sclerosis. In: Dickson D, ed. Neurodegeneration: The Molecular 6:805-815.
Pathology 25. Mandler RN, Davis LE, Jeffery DR, Kornfeld M. Devic’s neuromyelitis
optica: a clinicopathological study of 8 patients. Ann Neurol 1993;

34:162-168.
34 I • Introduction and Evaluation

26. Lucchinetti CF, Mandler RN, McGavern D, Bruck W, et al. A role for 35. Menezes AH, Graf CJ, Perret GE. Spinal cord abscess: a review. Surg
humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica.
Brain 2002; 125:1450-1461. Neurol 1977; 8:461-467.
27. Margolis G, Tarazi AK, Grimson KS. Contrast medium injury to the 36. Schuchat A, Robinson K, Wenger JD, Harrison LH, et al. Bacterial menin-
spinal cord produced by aortography: pathologic anatomy of the exper- gitis in the United States in 1995. New Engl J Med 1997; 337:970-976.
imental lesions. J Neurosurg 1956; 8:349-365. 37. Swartz MN. Bacterial meningitis—a view of the past 90 years. New Engl
28. Bunge RP, Bunge MB, Ris H. Electron microscopic study of demyelina- J Med 2004; 351:1826-1828.
tion in an experimentally induced lesion in adult cat spinal cord. J 38. Van de Beek D, de Gans J, Spanjaard L, Weisfelt M, et al. Clinical features
Biophys and prognostic factors in adults with bacterial meningitis. New Engl J
Biochem Cytol 1960; 7:685-696. Med
29. Pant SS, Asbury AK, Richardson EP Jr. The myelopathy of pernicious 2004; 351:1849-1859.
anemia: a neuropathological reappraisal. Acta Neurol Scand 39. Fratkin JD, Leis AA, Stokic DS, Slavinski SA, Geiss RW. Spinal cord
1968; neuropathology in human West Nile virus infection. Arch Pathol Lab
44(Suppl 35):1-36. Med
30. Agamanolis DP, Victor V, Harris HW, Hines JD, et al. An ultrastructural 2004; 128:533-537.
study of subacute combined degeneration of the spinal cord in vitamin 40. Petito CK, Navia BA, Cho E-S, Jordan BD, et al. Vacuolar myelopathy
B12-deficient rhesus monkeys. J Neuropathol Exp Neurol pathologically resembling subacute combined degeneration in patients
1978; 37:273-299. with the acquired immunodeficiency syndrome. New Engl J Med
31. Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide. 1985; 312:874-879.
Lancet 1978; 2:1227-1230. 41. Slooff JL, Kernohan JW, MacCarty CS. Primary Intramedullary
32. Darouiche RO. Spinal epidural abscess. New Engl J Med 2006; Tumors of
355:2012-2020. the Spinal Cord and Filum Terminale. Philadelphia: WB Saunders,
33. Feldenzer JA, McKeever PE, Schaberg DR, Campbell JA, Hoff JT. Exper- 1964.
imental spinal epidural abscess: a pathophysiological model in the rabbit. 42. Coons SW. Pathology of tumors of the spinal cord, spine, and
Neurosurgery 1987; 20:859-867. paraspinous soft tissue. In: Dickman CA, Fehlings MG, Gokasian ZL, eds.
34. Levy ML, Wieder BH, Schneider J, Zee CS, Weiss MH. Subdural Spinal Cord and Spinal Column Tumors: Principles and
empyema of the cervical spine: clinicopathological correlates and mag- Practice. Stuttgart: Thieme, 2006:41-110.
netic resonance imaging; report of three cases. J Neurosurg 1993; 43. Byrne TN, Waxman SG. Spinal Cord Compression: Diagnosis
79:929-935. and
Principles of Management. Philadelphia: FA Davis Company, 1990.
44. Arguello F, Baggs RB, Duerst RE, Johnstone L, et al. Pathogenesis of
vertebral metastasis and epidural spinal cord compression. Cancer 1990;
65:98-106.