CHAPTER 419: CEREBROVASCULAR DISEASE

INTRODUCTION

- Standard definition of TIA = requires all neurologic signs and symptoms resolve within 24 hours regardless of whether
there is an imaging evidence of new permanent brain injury
- STROKE has occurred if the neurologic signs last for more than 24 hours
- The time of stroke is defined as the time the patient’s symptoms began or the time the patient was last seen as normal
- Migraine can mimic stroke, even in patients without a significant migraine history. When it develops without headache
(acephalic migraine), the diagnosis may remain elusive. A sensory deficit, as well as motor deficits, tends to migrate
slowly across a limb over minutes rather than seconds as with stroke
- CT imaging of the brain = the STANDARD imaging modality to detect the presence or absence of intracranial hemorrhage

ISCHEMIC STROKE

PATHOPHYSIOLOGY
- Decrease in cerebral blood flow to zero causes death of brain tissue within 4-10 minutes
- Ischemic penumbra = tissue surrounding the core region of infarction is ischemic but reversibly dysfunctional
- The penumbra may be imaged by using perfusion-diffusion imaging with MRI or CT
- The ischemic penumbra will eventually infarct if no change in flow occurs, and hence saving the ischemic penumbra is
the goal of revascularization therapies
- Edema PEAKS on the 2nd or 3rd day but can cause mass effect for 10 days.
- The larger the infarct, the greater the likelihood that clinically significant edema will develop.

TREATMENT
- There are no reliable clinical findings that conclusively separate ischemia from hemorrhage
- Because there is collateral blood flow within the ischemic brain is blood pressure dependent, there is controversy about
whether blood pressure should be lowered acutely.
- Blood pressure should be lowered if there malignant hypertension or concomitant myocardial ischemia or if blood pressure
is >185/110 mmHg and thrombolytic therapy is anticipated.
- Fever is detrimental and should be treated with antipyretics and surface cooling.
- Serum glucose should be monitored and kept at <6.1 mmol/L (110 mg/dL) using an insulin infusion if necessary.
- For edema, water restriction and IV mannitol may be used to raise the serum osmolarity, but hypovolemia should be
avoided as this may contribute to hypotension and worsening infarction.

Intravenous Thrombolysis

- Treatment with IV rtPA within 3 hours of the onset of ischemic stroke improved clinical outcome.
- rtPA: only approved for 0-3 hours in the US and Canada

Anti-thrombotic Treatment

- ASPIRIN = only antiplatelet agent that has proven effective for the acute treatment of ischemic stroke
- The glycoprotein IIb/IIIa receptor inhibitor abciximab was found to cause excess intracranial hemorrhage and
should be avoided in acute stroke.
- Clopidogrel is being tested as a way to prevent stroke following TIA and minor ischemic stroke
- Trials do not support the routine use of heparin or other anticoagulants for patients with atherothrombotic stroke
- Neuroprotection is the concept of providing a treatment that prolongs the brain’s tolerance to ischemia.
Hypothermia is a powerful neuroprotectant treatment in patients with cardiac arrest and is neuroprotective in
animal models of stroke, but has not been adequately studied in patients with ischemic stroke
- The use of restraint therapy (immobilizing the unaffected side) has been shown to improve hemiparesis
following stroke, even years following the stroke, suggesting that physical therapy can recruit unused neural
pathways
-
ETIOLOGY OF ISCHEMIC STROKE

A. Cardioembolic Stroke

o MOST significant cause of cardioembolic stroke in MOST of the world:

• Nonrheumatic (often called nonvalvular) atrial fibrillation
• MI
• Prosthetic valves
• RHD
• Ischemic cardiomyopathy
o Emboli from the heart MOST often lodge in the:
• MCA
• Posterior cerebral artery (PCA)
• One of their branches
o MOST common cause of cerebral embolism overall = nonrheumatic atrial fibrillation
o Recent MI may be a source of emboli, especially when trasnmural and involving the anteroseptal ventricular
wall, and prophylactic anticoagulation following MI has been shown to reduce stroke risk
o Right to left shunt is implied if immediately following IV injection of agitated saline, the ultrasound signature of
bubbles is observed during transcranial doppler insonation of the MCA; pulmonary AVMs should be considered if
this test is positive yet an echocardiogram fails to reveal an intracardiac shunt
o The appearance of multifocal symptoms and signs in a patient with stroke makes bacterial endocarditis more likely
 B. Artery to Artery Embolic Stroke
o Unlike the myocardial vessels, artery to artery embolism rather than local thrombosis, appears to be the
dominant vascular mechanism causing brain ischemia
o MOST common source of artery to artery embolism = carotid bifurcation atherosclerosis
o Atherosclerosis within the carotid artery occurs MOST frequently within the common carotid bifurcation and
proximal internal carotid artery

C. Other Causes of Artery-to-Artery Embolic Stroke

o Extracranial dissections do NOT cause hemorrhage because of the tough adventia of these vessels
o Intracranial dissections may produce SAH because the adventia of the intracranial vessels is thin and
pseudoaneurysms may form, requiring urgent treatment to prevent rerupture
o MOST dissections heal spontaneously and stroke or TIA is uncommon beyond 2 weeks

SMALL-VESSEL STROKE

• Lacunar infarction = refers to infarction following atherothrombotic or lipohyalinotic occlusion of a small artery (30-300 um)
• Small-vessel stroke = denotes occlusion of such a small penetrating artery and is now the preferred term
• MOST Common Lacunar Syndromes:
o Pure motor hemiparesis = infarct in the posterior limb of the internal capsule or basis pontis; the face, arm,
and leg are almost always involved
o Pure sensory stroke = infarct in the ventral thalamus
o Ataxic hemiparesis = infarct in the ventral pons or internal capsule
o Dysarthria and a clumsy hand = infarction in the ventral pons or genu of the internal capsule
• HERALD a small-vessel infarct = transient symptoms (small vessel TIA)

LESS COMMON CAUSES OF STROKE

A. Venous Sinus Thrombosis of the Lateral Sagittal Sinus or Small Cortical Veins
- Occurs as a complication of OCP use, pregnancy and the post-partum period, inflammatory bowel disease,
intracranial infections (meningitis), and dehydration
- Often, CT imaging is normal unless as intracranial venous hemorrhage has occurred, but the venous sinus
occlusion is readily visualized using MR- or CT-venography or conventional x-ray angiography
- IV heparin, regardless of the presence of intracranial hemorrhage, has been shown to reduce morbidity and
mortality, and the long-term outcome is generally good. Heparin prevents further thrombosis and reduced venous
hypertension and ischemia
- If an underlying hypercoaguable state is not found, many physicians treat with vitamin K antagonists for 3-6
months then convert to aspirin, depending on the degree of resolution of the venous sinus thrombosis
- Anticoagulation is often continued indefinitely if thrombophilia is diagnosed

B. Sickle Cell Anemia

o Common cause of stroke in children
o May be predicted by documenting high-velocity blood flow within the MCAs using transcranial Doppler
ultrasonography

C. Fibromuscular Dysplasia
o Affects the cervical arteries and occurs mainly in women
o Anticoagulation or antiplatelet may be helpful

D. Drugs
o In particular amphetamines and perhaps cocaine may cause stroke on the basis of acute hypertension or
drug-induced vasculopathy
o No data exist on the value of any treatment

E. Moyamoya Disease
o Poorly understood occlusive disease involving large cranial arteries, especially the distal internal carotid artery
and the stem of the MCA and ACA
o Vascular inflammation is absent
o The lenticulostriate arteries develop a rich collateral circulation around the occlusive lesion, which gives the
impression of a puff of smoke on conventional x-ray angiography
o Anticoagulation is risky because of the occurrence of intracranial hemorrhage from rupture of the transdural
and pial anastomotic channels
o Surgical bypass of extracranial carotid arteries to the dura or MCAs may prevent stroke and hemorrhage
F. Reversible Posterior Leukoencephalopathy

o Occurs in head injury, seizure, migraine, sympathomimetic drug use, eclampsia and the post-partum period
o The pathophysiology is uncertain but likely involves widespread cerebral segmental vasoconstriction and cerebral
edema
o Fluctuating neurologic symptoms and signs, especially visual symptoms

G. Leukoaraiosis or Periventricular White Matter Disease

o Pathophysiologic basis of the disease is lipohyalinosis of small penetrating arteries within the white matter, likely
produced by chronic hypertension
o May develop subcortical dementia syndrome
TRANSIENT ISCHEMIC ATTACK

- Episodes of stroke that lasts only BRIEFLY

- The STANDARD definition of duration is <24 hours, but MOST lasts < 1 hr
- Causes are similar to the causes of ischemic stroke, but because TIAs may herald stroke they are important risk factor
that should be considered separately
- Amaurosis fugax (transient monocular blindness) = occurs from emboli to the central retinal artery of one eye and may
indicate carotid stenosis as the cause or local ophthalmic artery disease
- The risk of stroke after TIA is 10-15% in the 1st 3 months, with most events occurring in the first 2 days
- The improvement characteristic of TIA is a CONTRAINDICATION to thrombolysis

TREATMENT: PRIMARY AND SECONDARY PREVENTION OF STROKE AND TIA

• Identification and control of modifiable risk factors is the best strategy to reduce the burden of stroke
• Hypertension = MOST significant of risk factors
A statin should be considered in ALL patients with PRIOR ISCHEMIC stroke

ANTI-PLATELET AGENTS

A. Aspirin
o MOST widely used antiplatelet agent
o Acetylates platelet cyclooxygenase which irreversibly inhibits the formation in platelets of thromboxane A2,
a platelet aggregating and vasoconstricting prostaglandin
o The effect is permanent and usually lasts 8 days
o Paradoxically, it also inhibits formation of prostacylin, an antiaggregating and vasodilating prostaglandin, in
endothelial cells

B. Ticlopidine and Clopidogrel

o Blocks the adenosine diphosphate (ADP) receptor on platelets and thus prevent the cascade resulting in the
activation of the glycoprotein IIb/IIIa receptor that leads to fibrinogen binding to the platelet and consequent
platelet aggregation
o Ticlopidene is MORE effective than aspirin; however, it has the disadvantage of causing diarrhea, skin rash,
and in rare instances, neutropenia and TTP
o Clopidogrel rarely causes TTP but does not cause neutropenia

C. Dipyridamole
o Inhibits the uptake of adenosine by a variety of cells, including those of vascular endothelium
o The accumulated adenosine is an inhibitor of aggregation
o PRINCIPAL side effect = HEADACHE

ANTICOAGULATION

• The decision to use anticoagulation for primary prevention depends on risk factors
• Anticoagulation reduces the risk of embolism in acute MI
• MOST clinicians recommend a 3-month course of anticoagulation when there is anterior Q-wave infarction, substantial left
ventricular dysfunction, congestive heart failure, mural thrombosis, or atrial fibrillation

TREATMENT OF CAROTID ATHEROSCLEROSIS

• Substantial benefit for surgery in patients with stenosis > 70%

• Endarterectomy = MOST beneficial when performed within 2 weeks of symptom onset – benefit is MORE pronounced in:
o > 75 years
o Men

STROKE SYNDROME
• Divided into:
- Large-vessel stroke within the anterior circulation
- Large-vessel stroke within the posterior circulation
- Small-vessel disease of either vascular bed

STROKES WITHIN THE ANTERIOR CIRCULATION

A. Middle Cerebral Artery

o Occlusion of the proximal MCA or one of its major branches is MOST often due to an EMBOLUS rather an
intracranial atherothrombosis
o The cortical branches of the MCA supply the lateral surface of the hemisphere EXCEPT for
 • The frontal pole and a strip along the superomedial border of the frontal and parietal lobes supplied by ACA
• Lower posterior occipital and temporal pole convolutions supplied by the PCA

o Block at the MCA origin/stem with limited distal collaterals ! contralateral hemiplegia, hemianesthesia,
homonymous hemianopsia, preferential gaze to the ipsilateral side
o Involvement of the dominant hemisphere ! global aphasia
o Involvement of the non-dominant hemisphere ! anosognosia, constructional apraxia, neglect
o Partial syndromes due embolic occlusions of a single branch include hand, or arm and hand, weakness alone
(brachial syndrome) or facial weakness with nonfluent (Broca) aphasia with or without arm weakness (frontal
opercular syndrome)
o Block at the inferior division of the MCA of the dominant hemisphere
o Fluent (Wernicke’s) aphasia
o Prominent features = jargon speech and inability to comprehend written and spoken language
o Contralateral homonymous superior quadrantanopia
o Block at the inferior division of the MCA of non-dominant hemisphere = hemineglect or spatial agnosia without
weakness
o Occlusion of a lenticulostriate vessel within the internal capsule ! pure motor stroke or sensory-motor stroke
contralateral to the lesion
o Ischemia within the genu of the internal capsule moving posteriorly
• Facial weakness followed by arm then leg weakness
• Ataxic contralateral hand
• Dysarthria
B. Anterior Cerebral Artery
o Divided into 2 segments: precommunal (A1) circle of Willis and postcommunal (A2) segment
o Profound abulia (delay in verbal and motor response) ! block of both A2 segments

C. Anterior Choroidal Artery

o Arises from the internal carotid artery and supplies the posterior limb of the internal capsule and the
white matter posterolateral to it, through which pass some of the geniculocalcarine fibers
o Complete syndrome of anterior choroidal artery:
• Contralateral hemiplegia, hemianesthesia, homonymous hemianopsia
• Because this territory is also supplied by penetrating vessels of the proximal MCA & the posterior
communicating and posterior choroidal arteries, minimal deficits may occur and patients frequently
recover substantially

D. Internal Carotid Artery

o The cortex supplied by the MCA territory is affected most often
o Also supplies the optic nerve and retina via the ophthalmic artery
o In 25% of symptomatic ICA disease, recurrent transient monocular blindness (amaurosis fugax) warns of the
lesion. Pt’s typically describe a horizontal shade that sweeps down or up across the field of vision

STROKES WITHIN THE POSTERIOR CIRCULATION

• Posterior circulation is composed of the paired vertebral arteries, the basilar artery, and the paired posterior cerebral arteries
• The vertebral arteries join to form the basilar artery at the pontomedullary junction
• The basilar artery divides into 2 posterior cerebral arteries in the interpeduncular fossa

P1 Syndrome

o Infarction at the ipsilateral subthalamus and medial thalamus and the ipsilateral cerebral peduncle and midbrain
o Claude’s syndrome ! third nerve palsy with contralateral ataxia
o Weber’s syndrome ! contralateral hemiplegia
o Subthalamic nucleus ! contralateral hemiballismus
o Occlusion of the Pecheron artery ! upward gaze paresis, abulia, drowsiness
o Thalamic Dejerine-Roussy syndrome ! contralateral hemisensory loss followed later by an agonizing, searing
or burning pain in the affected areas; persistent and responds poorly to analgesics; anticonvulsants or TCAs
may be beneficial

P2 Syndrome
o Occlusion of the distal PCA with resulting infarction of the medial temporal and occipital lobes
o Usual manifestation: contralateral homonymous hemianopoa with macula sparing
o Occlusion of posterior cerebral artery ! peduncular hallucinosis (visual hallucinations of brightly colored scenes &
objects)
o Anton’s syndrome:
• Cortical blindness
• Gun-barrel vision (loss of peripheral vision)
o Balint’s syndrome:
• Infarctions secondary to low flow in watershed areas between the distal PCA and MCA
• Disorder of the orderly visual scanning of the environment
o Palinopsia ! persistence of visual image for several minutes despite gazing at another scene
o Asimultanagnosia ! inability to synthesize the whole of an image
o HALLMARK of top of the basilar artery occlusion = sudden onset of bilateral signs, including ptosis,
papillary asymmetry or lack of reaction to light and somnolence

Vertebral and Posterior Inferior Cerebellar Arteries

 o Vertebral artery that arises from the innominate artery on the subclavian artery consists of 4 segments (V1-V4)
o Atherothrombotic lesions have a PREDILECTION for V1 and V4 segments
o HEMIPARESIS is NOT a feature of vertebral artery occlusion
o Quadriparesis may result from anterior spinal artery occlusion
o If the subclavian artery is occluded proximal to the origin of the vertebral artery, there is a reversal in the direction
of blood flow in the ipsilateral vertebral artery.
o Exercise of ipsilateral arm may increase demand on vertebral flow, producing posterior circulation TIA or subclavian
steal
Basilar Artery

o Atheromatous lesions can occur anywhere along the basilar trunk but are most frequent in the proximal basilar
and distal vertebral segments
o The picture of a complete basilar artery occlusion, however, is easy to recognize as a constellation of bilateral long
tract signs (sensory and motor) with signs of cranial nerve and cerebellar dysfunction
o The therapeutic goal is to identify impending basilar occlusion before devastating infarction occurs
o A series of TIAs and a slowly progressive fluctuating stroke are extremely significant, as they often
herald an atherothrombotic occlusion of the distal vertebral or proximal basilar artery
o Herald hemiparesis has been emphasized as an initial symptom of basilar occlusion
IMAGING STUDIES

I. CT SCAN
• Brain CT scans obtained in the first several hours after an infarction generally show NO abnormality
• Infarct may NOT be seen reliably for 24–48 hours
• May FAIL to show:
o Small ischemic strokes in the posterior fossa because of bone artifact
o Small infarcts on the cortical surface
• Contrast-enhanced CT scans add specificity by showing:
o Enhancement of subacute infarcts
o Allow visualization of venous structures
• Also sensitive for detecting SAH
• Non-Contrast head CT = Imaging modality of CHOICE in patients with ACUTE STROKE

II. MRI
• Reliably documents the extent and location of infarction in ALL areas of the brain, including the posterior
fossa and cortical surface
• LESS SENSITIVE than CT for detecting ACUTE blood
• Ischemic penumbra: brain regions showing poor perfusion but no abnormality on diffusion
• MR angiography: highly sensitive for stenosis of extracranial internal carotid arteries + large
intracranial vessels ! overestimate the degree of stenosis when compared to conventional x-ray
angiography
• MRI with fat saturation: used to visualize extra or intracranial arterial dissection

III. CEREBRAL ANGIOGRAPHY

• Conventional X-ray cerebral angiography = GOLD standard for identifying and quantifying
atherosclerotic stenoses of arteries
• Endovascular techniques:
o Deploy stents within delicate intracranial vessels
o Perform balloon angioplasty of stenotic lesions
o Treat intracranial aneurysms by embolization
o Open occluded vessels in acute stroke with mechanical thrombectomy devices
• Comprehensive stroke center: centers capable of thrombolytic agents delivered intraarterially in patients
with acute MCA stroke

IV. ULTRASOUND TECHNIQUES

• Transcranial Doppler (TCD) assessment of MCA, ACA, and PCA flow and of vertebrobasilar flow is also
useful.
• This latter technique can detect stenotic lesions in the large intracranial arteries because such lesions
increase systolic flow velocity.

V. PERFUSION TECHNIQUES
• These tools are generally used for research but can be useful for determining the significance of
arterial stenosis and planning for revascularization surgery
•

INTRACRANIAL HEMORRHAGE
• Bleeding into subdural and epidural spaces = PRINCIPALLY produced by TRAUMA
• SAHs are produced by trauma and rupture of intracranial aneurysm

I. DIAGNOSIS
• Often discovered on noncontrast CT imaging of the brain during acute evaluation of stroke
• CT-imaging = PREFERRED method for acute stroke evaluation

II. EMERGENCY MANAGEMENT

• It is RECOMMENDED to keep the MAP <130 mmHg unless an increase in ICP is suspected
• In patients with ICP monitor in place, current recommendations are to keep the cerebral perfusion pressure
above 60 mmHg
• Blood pressure should be lowered with nonvasodilating IV drugs such as nicardipine, labetalol or esmolol
II. INTRAPARENCYMAL HEMORRHAGE
• ICH = MOST common type of intracranial hemorrhage
• Hypertension, trauma, and cerebral amyloid angiopathy cause the MAJORITY of these hemorrhages

A. Hypertensive Intraparenchymal Hemorrhage

o MOST common sites = basal ganglia (especially putamen), thalamus, cerebellum, pons
o MOST develop over 30-90 minutes (whereas those associated with ANTICOAGULANT
therapy may evolve for as long as 24-48 hours)
o PUTAMEN = MOST common site of hypertensive hemorrhage – SENTINEL sign = contralateral
hemiparesis
o Thalamic hemorrhages:
• Deviation of the eyes downward and inward, unequal pupils with absence of light
reaction, skew deviation with the eye opposite the hemorrhage displaced downward and
medially, ipsilateral Horner’s syndrome, absence of convergence, paralysis of vertical
gaze, retraction nystagmus
o Pontine hemorrhages:
• Prominent decerebrate rigidity and pinpoint (1 mm) pupils that react to light

B. Lobar Hemorrhage
- MAJOR neurologic deficit with an occipital hemorrhage = hemianopia
- MAJOR neurologic deficit with a left temporal hemorrhage = aphasia, delirium
- MAJOR neurologic deficit with a parietal hemorrhage = hemisensory loss
- MAJOR neurologic deficit with a frontal hemorrhage = arm weakness

C. Other Causes of Intracerebral Hemorrhage

1. Cerebral Amyloid Angiopathy
• Causes single and recurrent lobar hemorrhages
• MOST common cause of lobar hemorrhage in the ELDERLY
• Suspected in patients who present with multiple hemorrhages (or infarcts) over
several months or years, or in patients with “micro-bleeds” seen on brain MRI
sequences sensitive for hemosiderin
• Definitively diagnosed by pathologic demonstration of Congo red staining of amyloid in
cerebral vessels
• Markers of amyloid angiopathy: έ2 and έ4 allelic variations of the apolipoprotein E gene

2. Cocaine and Methamphetamine

• Frequent causes of stroke in young (age <45 years) patients
• Angiographic findings vary from completely normal arteries to large-vessel occlusion
or stenosis, vasospasm, or changes consistent with vasculopathy
• Mechanism of sympathomimetic-related stroke is not known, but cocaine enhances
sympathetic activity causing acute, sometimes severe, hypertension, and this may
lead to hemorrhage

3. Head Injury
• Common sites are intracerebral (especially temporal and inferior frontal lobes) and into
the subarachnoid, subdural and epidural spaces
4. Anticoagulant-related ICH
• Can occur at any location
• Often lobar or subdural
• May evolve SLOWLY, over 24–48 hours.

5. ICH associated with Hematologic Disorders (Leukemia, Aplastic Anemia, Thrombocytopenic

Purpura)
• Can occur at any site
• May present as multiple ICHs
• Skin and mucous membrane bleeding is usually evident
 6. Hypertensive Encephalopathy
• Complication of malignant hypertension
• In MOST cases ICP and CSF protein levels are elevated.
• MRI brain imaging: pattern of typically posterior (occipital > frontal) brain edema that is
reversible and termed
reversible posterior leukoencephalopathy

• Lowering the blood pressure reverses the process, but stroke can occur, especially if
blood pressure is lowered too rapidly
• Neuropathologic examination: multifocal to diffuse cerebral edema and
hemorrhages of various sizes from petechial to massive
• Microscopically, there are necrosis of arterioles, minute cerebral infarcts, and
hemorrhages

7. Hemorrhage into a Brain Tumor

• May be the first manifestation of neoplasm
• MOST common metastatic tumors associated with ICH:
• Choriocarcinoma
• Malignant melanoma
• Renal cell carcinoma
• Bronchogenic carcinoma

III. LABORATORY AND IMAGING EVALUATION

• CT imaging reliably detects acute focal hemorrhages in the supratentorial space.
• Small pontine hemorrhages may NOT be identified because of motion and bone-induced artifact
that obscure structures in the posterior fossa.
• After the first 2 weeks, x-ray attenuation values of clotted blood diminish until they become isodense with
surrounding brain.
• Postcontrast CT imaging may reveal acute hematoma enhancement signifying bleeding at the time
of imaging; this "DOT-SIGN" portends increased mortality
• A lumbar puncture should be AVOIDED as it may induce cerebral herniation.

IV. TREATMENT OF INTRACEREBTAL HEMORRHAGE

• For patients taking VKAs, rapid reversal of coagulopathy can be achieved by infusing prothrombin
complex concentrates which can be administered quickly, followed by FFP and Vitamin K
• When ICH is associated with thrombocytopenia (plt count <50,000/uL), transfusion of fresh platelets is
indicated
• Evacuation of SUPRATENTORIAL hematomas does NOT appear to improve outcome
• For CEREBELLAR hemorrhages, a neurosurgeon should be consulted immediately to assist with the
evaluation
o MOST cerebellar hematomas >3 cm in diameter will REQUIRE surgical evacuation
o If alert without focal brainstem signs and if hematoma is <1 cm in diameter = surgical removal is
usually UNNECESSARY.
o Patients with hematomas between 1 and 3 cm require careful observation for signs of impaired
consciousness and precipitous respiratory failure
• Since hyperventilation may actually produce ischemia by cerebral vasoconstriction, induced
hyperventilation should be LIMITED to ACUTE resuscitation of the patient with presumptive high ICP and
eliminated once other treatments (osmotic therapy or surgical treatments) have been instituted
• Glucocorticoids are NOT helpful for the edema from intracerebral hematoma
• Patients with amyloid angiopathy should avoid antithrombotic age
CONGENITAL VASCULAR MALFORMATIONS

I. CONGENITAL AVM
• True AVMs are congenital shunts between the arterial and venous systems that may present as
headache, seizures, and intracranial hemorrhage.
• Consist of a tangle of abnormal vessels across the cortical surface or deep within the brain substance.
 • Vary in size: from a small blemish a few millimeters in diameter to a large mass of tortuous channels
composing an arteriovenous shunt of sufficient magnitude to raise cardiac output and precipitate heart
failure
• Occur in ALL parts of the cerebral hemispheres, brainstem, and spinal cord, but the largest ones are MOST
frequently in the
posterior half of the hemispheres, commonly forming a wedge-shaped lesion extending from the cortex
to the ventricle

• Bleeding, headache, or seizures are MOST common between the ages of 10 and 30, occasionally as late
as the fifties
• More frequent in men
• Familial AVM may be a part of the autosomal dominant syndrome of hereditary hemorrhagic
telangiectasia (Osler-Rendu-Weber) syndrome due to mutations in endoglin (chromosome 9) or
activin receptor-like kinase 1 (chromosome 12).
• In MOST, the hemorrhage is mainly intraparenchymal with extension into the subarachnoid space in some
cases.
• Blood is usually NOT deposited in the basal cisterns
• Symptomatic cerebral vasospasm is RARE
• Risk of rerupture: 2–4% per year
• May be large enough to steal blood away from adjacent normal brain tissue or to increase venous
pressure significantly to produce venous ischemia locally and in remote areas of the brain seen MOST
often with large AVMs in the territory of the MCA
• Large AVMs of the anterior circulation: may be associated with a systolic and diastolic bruit (sometimes
self-audible) over the eye, forehead, or neck and a bounding carotid pulse
• Conventional x-ray angiography: gold standard for evaluating the precise anatomy of the AVM
• Asymptomatic AVMs: 2–4% per year risk for hemorrhage
• Paradoxically, smaller lesions seem to have a higher hemorrhage rate.
• The impact of recurrent hemorrhage on disability is relatively modest, so the indication for surgery in
asymptomatic AVMs is debated.

II. VENOUS ANOMALIES

• Result from the development of anomalous cerebral, cerebellar, or brainstem venous drainage
• Unlike AVMs, functional venous channels
• Little clinical significance and should be ignored if found incidentally on brain imaging studies
• Surgical resection of these anomalies may result in venous infarction and hemorrhage
• May be associated with cavernous malformations

III. CAPILLARY TELANGECTASIAS

• Pons and deep cerebral white matter are typical locations
• Seen in hereditary hemorrhagic telangectasia (Osler Weber Rendu)
• No treatment options exist

IV. DURAL ATRIOVENOUS FISTULAS

• Acquired vascular lesion
• Usually from a dural artery to a dural sinus
• Complains of a pulse-synchronous cephalic bruit (pulsatile tinnitus) and headache
• Surgical and endovascular techniques are usually curative

ACQUIRED VASCULAR LESIONS

CAVERNOUS ANGIOMAS

- Tufts of capillary sinusoids that form within the deep hemispheric white matter and brainstem with
no normal intervening neural structures Typically <1 cm in diameter and are often associated with a
venous anomaly
- Bleeding is usually of small volume, causing slight mass effect only.
- Bleeding risk for single cavernous malformations: 0.7–1.5% per year
- May occur if the malformation is located near the cerebral cortex
- Surgery reserved for those malformations that form near the brain surface
- Radiation treatment has not been shown to be of benefit
DURAL ARTERIOVENOUS FISTULAS

- Acquired connections usually from a dural artery to a dural sinus

- May complain of a pulse-synchronous cephalic bruit ("pulsatile tinnitus") and headache
- Surgical and endovascular techniques are usually curative.
- May form because of trauma, but MOST are idiopathic
Fistulas have been observed to appear months to years following venous sinus thrombosis, suggesting that
angiogenesis factors elaborated from the thrombotic process may cause these anomalous connections to form.

CHAPTER 86: PRIMARY AND METASTATIC TUMORS OF THE NERVOUS SYSTEM

INTRODUCTION

• Primary brain tumors, at least one-half of these tumors are malignant and associated with a high mortality
rate.
• Meningiomas account for 35%, vestibular schwannomas 10%, and central nervous system (CNS)
lymphomas about 2%.
• Brain metastases are three times more common than all primary brain tumors combined.
• Metastases to the leptomeninges and epidural space of the spinal cord each occur in approximately 3–5%
of patients with systemic cancer and are also a major cause of neurologic disability in this population.

APPROACH TO THE PATIENT: Primary and Metastatic Tumors of the Nervous System

I. CLINICAL FEATURES
• General or nonspecific symptoms include headache, cognitive difficulties, personality change, and gait
disorder.
• Generalized symptoms arise when the enlarging tumor and its surrounding edema cause an increase in
intracranial pressure or direct compression of cerebrospinal fluid (CSF) circulation leading to
hydrocephalus.
• Occasionally, headaches have features of a typical migraine with unilateral throbbing pain associated with
visual scotoma.
• Personality changes may include apathy and withdrawal from social circumstances, mimicking depression.
• Focal or lateralizing findings include hemiparesis, aphasia, or visual field defect.
• Seizures are common, occurring in 25% of patients with brain metastases or malignant gliomas.
• CLASSIC headache associated with a brain tumor = MOST evident in the morning and improves during
the day

Table 379-1: Symptoms and Signs at Presentation of Brain Tumors

II. NEUROIMAGING
A. Cranial MRI
o PREFERRED diagnostic test for any patient suspected of having a brain tumor, and should be
performed with gadolinium contrast administration
o Malignant brain tumors—whether primary or metastatic—typically enhance with gadolinium and
may have central areas of necrosis; they are characteristically surrounded by edema of the
neighboring white matter.
B. Functional MRI
o Useful in presurgical planning and defining eloquent sensory, motor, and language cortex.
C. Positron emission tomography (PET)
o Useful in determining the metabolic activity of the lesions seen on MRI;
D. MR perfusion and spectroscopy
o Provide information on blood flow or tissue composition: these techniques may help distinguish
tumor progression from necrotic tissue as a consequence of treatment with radiation and
chemotherapy or identify foci of high-grade tumor in an otherwise low-grade-appearing glioma.
E. CT Scan
o Should be reserved for those patients unable to undergo MRI (e.g., pacemaker)

F. Other Tests:
o Neuroimaging is the ONLY test necessary to diagnose a brain tumor
o Laboratory tests are rarely useful, although patients with metastatic disease may have elevation of
serum tumor markers.

III. TREATMENT: BRAIN TUMORS

• Therapy of any intracranial malignancy requires both symptomatic and definitive treatments.
o Definitive treatment is based upon the specific tumor type and includes surgery, radiotherapy (RT),
and chemotherapy
o Symptomatic treatments apply to brain tumors of any type

A. Glucocorticoids
o Highly effective at reducing perilesional edema and improving neurologic function, often within
hours of administration.
o DEXAMETHASONE = glucocorticoid of CHOICE because of its relatively low mineralocorticoid
activity.
• Initial doses are typically 8 mg to 16 mg/dl
• WOF: long-term use causes substantial toxicity including insomnia, weight gain, diabetes
mellitus, steroid myopathy, and personality changes. Consequently, a taper is indicated
as definitive treatment is administered and the patient improves

B. Anticonvulsant Drug Therapy

o NO role for prophylactic anticonvulsant drugs in patients who have not had a seizure.
o The agents of choice are those drugs that do not induce the hepatic microsomal enzyme system.
o Ex. levetiracetam, topiramate, lamotrigine, valproic acid, or lacosamide
o Other drugs such as phenytoin and carbamazepine are used less frequently because they are
potent enzyme inducers that can interfere with both glucocorticoid and chemotherapy metabolism.

C. Anticoagulants
o Venous thromboembolic disease occurs in 20–30% of patients with high-grade gliomas and brain
metastases.
o Used prophylactically during hospitalization and in patients who are nonambulatory.
o Deep vein thrombosis or pulmonary embolus can receive therapeutic doses of anticoagulation
 safely and without increasing the risk for hemorrhage into the tumor.
o IVC filters are reserved for patients with absolute contraindications to anticoagulation such as
recent craniotomy.

PRIMARY BRAIN TUMORS

I. PATHOGENESIS
o The ONLY established risk factors are:
o Exposure to ionizing radiation = meningiomas, gliomas, and schwannomas
o Immunosuppression = primary CNS lymphoma
o Molecular pathogenesis
o Loss of tumor suppressor genes (e.g. p53, cyclin-dependent kinase inhibitor 2A and 2B, and PTEN)
o Amplification and overexpression of protooncogenes (e.g. EGFR and PDGFR)

INTRINSIC "MALIGNANT" TUMORS

I. DIFFUSE GIOMAS
• Most common type of malignant primary brain tumor and are derived, into astrocytomas and
oligodendrogliomas.
II. ASTROCYTOMAS
• Infiltrative tumors with a presumptive glial cell of origin.
• World Health Organization (WHO) classifies astrocytomas into FOUR prognostic grades based on histologic
features:
o Grade I (pilocytic astrocytoma, subependymal giant cell astrocytoma)
o Grade II (diffuse astrocytoma)
o Grade III (anaplastic astrocytoma)
o Grade IV (glioblastoma)
• Grades I and II are considered low-grade
• Grades III and IV high-grade

A. Low-Grade Astrocytoma (tumors occur predominantly in children and young adults)

1. Grade I Astrocytomas
o Pilocytic Astrocytomas (WHO grade I) are the MOST common tumor of CHILDHOOD
o Occur typically in the cerebellum but may also be found elsewhere in the neuraxis,
including the optic nerves and brainstem.
o Appear as cystic lesions with an enhancing mural nodule.
o Often have BRAF fusions or mutations.
o Well demarcated lesions that are potentially curable if they can be completely resected.
o Giant cell subependymal astrocytomas are usually found in the ventricular wall of patients
with tuberous sclerosis.
o Do NOT require intervention but can be treated surgically or with inhibitors of the
mammalian target of
rapamycin (mTOR)

2. Grade II Astrocytomas
o Infiltrative tumors that usually present with SEIZURES in young adults.
o Appear as nonenhancing tumors with increased T2/FLAIR signal
o Should undergo maximal surgical resection
o Radiotherapy is helpful, but there is no difference in overall survival between
radiotherapy administered postoperatively or delayed until the time of tumor progression.
o Chemotherapeutic agents such as TEMOZOLOMIDE, an oral alkylating agent, can be
helpful in some patients.

B. High-Grade Astrocytoma
1. Grade III (Anaplastic) Astrocytoma
o Account for approximately 15–20% of high-grade astrocytomas.
o Generally present in the fourth and fifth decades of life
o Treatment is the same as for glioblastoma, consisting of maximal safe surgical resection
followed by radiotherapy with concurrent and adjuvant temozolomide, or with
radiotherapy and adjuvant temozolomide alone.
 2. Grade IV Astrocytoma (Glioblastoma)
o MAJORITY of high-grade astrocytomas
o 10% have IDH mutations.
o Most common malignant primary brain tumor.
o Present in the sixth and seventh decades of life with headache, seizures, or focal
neurologic deficits.
o Appear as ring-enhancing masses with central necrosis and surrounding edema
o These are highly infiltrative tumors, and the areas of increased T2/FLAIR signal
surrounding the main tumor mass contain invading tumor cells.
o Treatment involves maximal surgical resection followed by partial-field external beam
radiotherapy (6000 cGy in thirty 200-cGy fractions) with concomitant temozolomide,
followed by 6–12 months of adjuvant temozolomide.
o ADVERSE prognostic factors in patients with high-grade astrocytomas are:
• Older age
• Absence of IDh mutations
• Unmethylated mGMT promotor
• Poor Karnofsky performance status
• Unresectable tumor.

III. OLIGODENDROGLIOMA (approximately 15–20% of gliomas)

• Classified by the WHO into:
o Well-differentiated oligodendrogliomas (grade II)
o Anaplastic oligodendrogliomas (grade III)
• Distinctive features:
o Perinuclear clearing—giving rise to a "fried-egg" appearance
o Reticular pattern of blood vessel growth.
o Some tumors have both an oligodendroglial as well as an astrocytic component.

A. Grade II Oligodendrogliomas
o Generally more responsive to therapy and have a better prognosis than pure astrocytic tumors.
o Present similarly to grade II astrocytomas in young adults.
o The tumors are nonenhancing and often partially calcified
o Treated with surgery and, if necessary, radiotherapy and chemotherapy.

B. Anaplastic Oligodendrogliomas
o present in the fourth and fifth decades as variably enhancing tumors.
o More responsive to therapy than grade III astrocytomas.
o Treatment involves maximal safe resection followed by RT and PCV or temozolomide
chemotherapy.
o Median survival of patients with AO is in excess of 10 years.

IV. EPENDYMOMA
• Tumors derived from ependymal cells that line the ventricular surface.
• Approximately 5% of childhood tumors and frequently arise from the wall of the fourth ventricle in the
posterior fossa.
• Adults can have intra-cranial ependymomas, they occur MORE commonly in the SPINE, especially in the
filum terminale of the spinal cord where they have a myxopapillary histology.
• Ependymomas that can be completely resected are potentially curable.
• Less common anaplastic ependymoma is more aggressive and is treated with resection and RT
(chemotherapy has limited efficacy)
• Subependymomas are slow growing benign lesions arising in the wall of ventricles that often do not require
treatment.

V. PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

• RARE Non-Hodgkin's lymphoma accounting for less than 3% of primary brain tumors.
• In immunocompetent = usually consists of diffuse large B-cell lymphomas
• Epstein-Barr virus (EBV) frequently plays an important role in the pathogenesis of HIV-related PCNSL.
• Immunocompetent patients are older (median 60 years) compared to HIV-related PCNSL (median 31 years).
• PCNSL usually presents as a mass lesion, with neuropsychiatric symptoms, symptoms of increased
intracranial pressure, lateralizing signs, or seizures.
• Contrast-enhanced MRI, PCNSL usually appears as a densely enhancing tumor
• Immunocompetent patients have solitary lesions more often than immunosuppressed patients.
 • Stereotactic biopsy is necessary to obtain a histologic diagnosis.
• Glucocorticoids should be withheld until after the biopsy has been obtained, since they have a cytolytic
effect on lymphoma cells and may lead to nondiagnostic tissue.
• Patients should be tested for HIV
• Extent of disease assessed by performing positron emission tomography (PET) or computerized
tomography (CT) of the body, MRI of the spine, CSF analysis, and slit-lamp examination of the eye.
• Bone marrow biopsy and testicular ultrasound are occasionally performed.

A. Treatment: Primary Central Nervous System Lymphoma

o PCNSL is relatively SENSITIVE to glucocorticoids, chemotherapy, and radiotherapy.
o High-dose methotrexate, a folate antagonist that interrupts DNA synthesis, produces response
rates ranging from 35 to 80% and median survival up to 50 months.
o High-dose chemotherapy with autologous stem cell rescue = may offer the BEST chance of
preventing relapse.
o Treatment options include radiotherapy for patients who have not had prior irradiation, re-
treatment with methotrexate, as well as other agents such as temozolomide, rituximab,
procarbazine, topotecan, and pemetrexed

B. PCNSL in Immunocompromised Patients

o Often produces multiple-ring enhancing lesions that can be difficult to differentiate from
METASTASES and infections such as TOXOPLASMOSIS.
o The diagnosis is usually established by examination of the cerebrospinal fluid for cytology and
EBV DNA, toxoplasmosis serologic testing, brain PET imaging for hypermetabolism of the lesions
consistent with tumor instead of infection, and, if necessary, brain biopsy.
o Since the advent of highly active antiretroviral drugs, the incidence of HIV-related PCNSL has
declined.
o Patients are preferably treated with high-dose methotrexate-based regimen nad initiation of highly
active antiretroviral therapy
o Whole brain RT is reserved for those who cannot tolerate systemic chemotherapy

VI. MEDULLOBLASTOMAS
• MOST common malignant brain tumor of CHILDHOOD
• Arise from granule cell progenitors or from multipotent progenitors from the ventricular zone.
• Associated with inherited syndromes such as Gorlin, Turcot, or Li-Fraumeni.
• Appear as highly cellular tumors with abundant dark staining, round nuclei, and rosette formation (Homer-
Wright rosettes).
• Present with headache, ataxia, and signs of brainstem involvement.
• MRI: densely enhancing tumors in the posterior fossa, sometimes associated with hydrocephalus
• Treatment involves maximal surgical resection, craniospinal irradiation, and chemotherapy with agents
such as cisplatin, lomustine, cyclophosphamide, and vincristine.
VII. PINEAL REGION TUMORS
• Present with headache, visual symptoms, and hydrocephalus.
• Parinaud's syndrome = characterized by impaired upgaze and accommodation.

EXTRINSIC "BENIGN" TUMORS

I. MENINGIOMAS
• Now the MOST common PRIMARY brain tumor
• Incidence increases with age
• More common in WOMEN and in patients with neurofibromatosis type 2
• Occur more commonly in patients with a past history of cranial irradiation
• Can also present with headaches, seizures, or focal neurologic deficits.
• Meningiomas arise from the dura mater and are composed of neoplastic meningothelial (arachnoidal cap)
cells.
• MOST commonly located over the cerebral convexities, especially adjacent to the sagittal sinus, but can
also occur in the skull base and along the dorsum of the spinal cord
• Meningiomas are classified by the WHO into three histologic grades of increasing aggressiveness:
o Grade I (benign meningiomas)
o Grade II (atypical meningiomas)
o Grade III (malignant meningiomas)
• MAIN differential diagnosis for meningioma = Dural Metastasis
 • Syptomatic lesions should be resected. Incompletely resected tumors tend to recur.
• Tumors that cannot be resected can benefit from external beam RT or SRS

II. SCHWANNOMAS
• Generally benign tumors arising from the Schwann cells of cranial and spinal nerve roots.
• MOST common schwannomas = vestibular schwannomas or acoustic neuromas: arise from the
vestibular portion of the eighth cranial nerve and account for approximately 9% of primary brain tumors.
• Patients with neurofibromatosis type 2 have a high incidence of vestibular schwannomas that are frequently
bilateral.
• Schwannomas arising from other cranial nerves, such as the trigeminal nerve (cranial nerve V), occur with
much lower frequency.
• Neurofibromatosis type 1 = associated with an increased incidence of schwannomas of the spinal nerve
roots
• Vestibular schwannomas may be found incidentally on neuroimaging or present with progressive unilateral
hearing loss, dizziness, tinnitus, or less commonly, symptoms
• Differential diagnosis includes meningioma.

III. CRANIOPHARYNGIOMAS
• Rare, usually suprasellar, partially calcified, solid, or mixed solid-cystic benign tumors that arise from
remnants of Rathke's pouch
• Have a bimodal distribution, occurring predominantly in children but also between the ages of 55 and 65
years.
• Present with headaches, visual impairment, and impaired growth in children and hypopituitarism in adults.
• Treatment involves surgery, radiotherapy, or the combination of the two.

OTHER BENIGN TUMORS

I. DYSEMBRYOPLASTIC NEUROEPITHELIAL
• BENIGN, supratentorial tumors, usually in the temporal lobes.
• Occur in children and young adults with a long-standing history of seizures. If the seizures are refractory,
surgical resection is curative.

II. EPIDERMOID CYSTS

• Consist of squamous epithelium surrounding a keratin-filled cyst.
• Cerebellopontine angle and the intrasellar and suprasellar regions
• Present with headaches, cranial nerve abnormalities, seizures, or hydrocephalus.
• Imaging studies demonstrate extraaxial lesions with characteristics that are similar to CSF but have
restricted diffusion. Treatment involves surgical resection.

III. DERMOID CYSTS

• Arise from epithelial cells that are retained during closure of the neural tube.
• Contain both epidermal and dermal structures such as hair follicles, sweat glands, and sebaceous glands
• Unlike epidermoid cysts, these tumors usually have a midline location.
• MOST frequently in the posterior fossa, especially the vermis, fourth ventricle, and suprasellar cistern.
• Radiographically, dermoid cysts resemble lipomas, demonstrating T1 hyperintensity and variable signal on
T2. Symptomatic dermoid cysts can be treated with surgery.

IV. COLLOID CYSTS

• Arise in the anterior third ventricle
• Present with headaches, hydrocephalus, and very rarely sudden death.
• Surgical resection is curative or a third ventriculostomy may relieve the obstructive hydrocephalus and be
sufficient therapy.

NEUROCUTANEOUS SYNDROMES (PHAKOMATOSES)

I. NEUROFIBROMATOSIS TYPE 1 (NF1) (VON RECKLINGHAUSEN’S DISEASE)

• Autosomal dominant disorder with variable penetrance.
• Mutations of NF1 results in large number of nervous system tumors including neurofibromas, plexiform
neurofibromas, optic nerve gliomas, astrocytomas, and menigiomas.
• Cutaneous manifestations include café-au-lait spots and axillary freckling.
• Also associated with hamartomas of the iris termed Lisch nodules, pheochormocytomas,
 pseudoarthrosis of the tibia, scoliosis, epilepsy, and mental retardation.

II. NEUROFIBROMATOSIS TYPE 2 (NF2)

• Less common than NF1
• Autosomal dominant disorder with full penetrance
• Characterized by bilateral vestibular schwannomas in >90% of patients, multiple meningiomas, and
spinal ependymomas and astrocytomas.
• May also have diffuse schwannomatosis that may affect that cranial, spinal, or peripheral nerves;
posterior subcapsular lens opacities; and retinal hamartomas.

III. TUBEROUS SCLEROSIS (BOURNEVILLE DISEASE)

• Autosomal dominant disorder
• Patients may have seizures, mental retardation, adenoma sebaceum (facial angiofibromas), shagreen
patch, hypomelanotic macles, periungal fibromas, renal angiomyolipomas, and cardiac
rhabdomyomas.
• Frequently require anticonvulsants for seizures.

TUMORS METASTATIC TO THE BRAIN

• Brain metastases arise from HEMATOGENOUS spread and frequently arise from either a
LUNG primary or are associated with pulmonary metastases.
• MOST metastases develop at the gray matter–white matter junction in the watershed
distribution of the brain where intravascular tumor cells lodge in terminal arterioles.
• The distribution of metastases in the brain approximates the proportion of blood flow:
i. 85% of all metastases are supratentorial
ii. 15% occur in the posterior fossa
• MOST common sources of brain metastases:
i. LUNG carcinoma
ii. BREAST carcinoma
• MELANOMA = has the greatest propensity to metastasize to the brain, being found in 80% of patients
at autopsy
• Other tumor types such as ovarian and esophageal carcinoma RARELY metastasize to the brain.
• PROSTATE and BREAST cancer = propensity to metastasize to the DURA and can mimic
meningioma.
• Leptomeningeal metastases = common from HEMATOLOGIC malignancies and also BREAST and
LUNG cancers.
• Spinal cord compression = primarily arises in PROSTATE and BREAST cancer: strong propensity
to metastasize to axial skeleton.

I. DIAGNOSIS OF METASTASES
• Brain metastases = BEST visualized on MRI, where they usually appear as well-circumscribed lesions
• Occasionally, intracranial metastases will HEMORRHAGE (GREATEST propensity to hemorrhage):
o Melanoma
o Thyroid
o Kidney cancer
• MOST common cause of a hemorrhagic metastasis is LUNG cancer because it accounts for the majority of
brain metastases.
• Biopsy is rarely necessary for diagnosis in most patients because imaging alone in the appropriate clinical
situation usually suffices.
II. TREATMENT: TUMORS METASTATIC TO THE BRAIN
A. Radiation Therapy
o STANDARD treatment for brain metastases = whole-brain radiotherapy (WBRT) usually
administered to a total dose of 3000 cGy in 10 fractions.
o Stereotactic radiosurgery (SRS) delivered through a variety of techniques including the gamma
knife, linear accelerator, proton beam, and CyberKnife all can deliver highly focused doses of RT,
usually in a single fraction.
o Median survival = ONLY 4-6 months
o SRS can only be used for lesions 3cm or less in diameter, and should be confined to patients with
only 1-3 metastases

B. Surgery
o Useful in patients who have highly radioresistant lesions such as renal carcinoma.
o Surgical resection can afford rapid symptomatic improvement and prolonged survival.

C. Chemotherapy
o Becoming increasingly useful for brain metastasis.
o Metastases from certain tumor types that are highly chemosensitive, such as germ cell tumors or
small cell lung cancer
o EGFR mutations that sensitize them to EGFR inhibitors
o Antiangiogenic agents such as BEVACIZUMAB may also prove efficacious in the treatment of CNS
metastases.

LEPTOMENINGEAL METASTASES
• Carcinomatous meningitis, meningeal carcinomatosis, or in the case of specific tumors, leukemic or
lymphomatous meningitis
• ACUTE LEUKEMIA = MOST common to metastasize to the subarachnoid space (among hematologic
malignancies)
• Among solid tumors, BREAST and LUNG carcinomas and MELANOMA = MOST frequently spread in this
fashion
• Tumor cells reach the subarachnoid space via the arterial circulation or occasionally through retrograde
flow in venous systems that drain metastases along the bony spine or cranium.

I. CLINICAL FEATURES
• Leptomeningeal metastases are characterized clinically by multilevel symptoms and signs along the
neuraxis.
• Combinations of lumbar and cervical radiculopathies, cranial neuropathies, seizures, confusion, and
encephalopathy from hydrocephalus or raised intracranial pressure can be present.
• Focal deficits such as hemiparesis or aphasia are RARELY due to leptomeningeal metastases unless there
is direct brain infiltration and are more often associated with coexisting brain lesions.
• New onset limb pain in patients with breast, lung cancer, or melanoma should prompt consideration of
leptomeningeal spread.

II. LABORATORY AND IMAGING DIAGNOSIS

• MR imaging can be DEFINITIVE in patients when there are clear tumor nodules adherent to the cauda
equina or spinal cord, enhancing cranial nerves, or subarachnoid enhancement on brain imaging
• Demonstration of tumor cells in CSF = DEFINITIVE and often considered the GOLD STANDARD
• CSF cytologic examination = MOST useful in hematologic malignancies
• Flow cytometry within the CSF can also be definitive when present.
• CSF abnormalities include elevated protein concentration and elevated white count; hypoglycorrhachia is
noted in <25% of patients.

III. TREATMENT: LEPTOMENINGEAL METASTASES

• The treatment is PALLIATIVE as there is NO curative therapy.
• RT to the symptomatically involved areas, such as skull base for cranial neuropathy, can relieve pain and
sometimes improve function.
• Whole neuraxis RT has extensive toxicity with myelosuppression and gastrointestinal irritation as well as
limited effectiveness.
• Systemic chemotherapy with agents that can penetrate the blood-CSF barrier may be helpful
• Surgery has a limited role in the treatment of leptomeningeal metastasis, but placement of a
ventriculoperitoneal shunt can relieve raised intracranial pressure.
EPIDURAL METASTASIS
• Occurs in 3–5% with a systemic malignancy and causes neurologic compromise by compressing the spinal
cord or cauda equina.
• MOST common cancers that metastasize to the epidural space are those malignancies that spread to
BONE, such as:
o Breast
o Prostate
• Lymphoma can cause bone involvement and compression but it can also invade the intervertebral
foramens and cause spinal cord compression without bone destruction.
• Thoracic spine = affected MOST commonly, followed by the lumbar and then cervical spine

I. CLINICAL FEATURES
• BACK PAIN = presenting symptom of epidural metastasis in virtually ALL patients
• Leg weakness is seen in about 50% of patients as is sensory dysfunction.
• Sphincter problems are present in about 25% of patients at diagnosis.

II. DIAGNOSIS
• MRI of the complete spine = BEST test
• Contrast is not needed to identify spinal or epidural lesions.
• Plain films, bone scans, or even CT scans may show bone metastases, but only MRI can reliably delineate
epidural tumor.
• Differential diagnosis of epidural tumor include
o Epidural abscess
o Acute or chronic hematomas
o Rarely, extramedullary hematopoiesis.

III. TREATMENT: EPIDURAL METASTASIS

• Surgical procedure of CHOICE = complete removal of the mass, typically ANTERIOR to the spinal canal
• RT = MAINSTAY of treatment and can be used for radiosensitive tumors, such as lymphoma, or for those
unable to undergo surgery.
• Chemotherapy is rarely used for epidural metastasis unless the patient has minimal to no neurologic deficit
and a highly chemosensitive tumor such as lymphoma or germinoma.

NEUROLOGIC TOXICITY OF THERAPY

I. TOXICITY FROM RADIOTHERAPY

• Acute = occurring within days of RT
• Early Delayed = months
• Late Delayed = years
• Acute and early delayed syndromes RESOLVE and do NOT result in persistent deficits
• Late delayed toxicities are usually PERMANENT and sometimes progressive

A. Acute Toxicity
o Occurs during RT to the brain.
o RT can cause a transient disruption of the blood-brain barrier, resulting in increased edema and
elevated intracranial pressure
o Headache, lethargy, nausea and vomiting, and can be both prevented and treated with the
administration of glucocorticoids.
o There is NO acute RT toxicity that affects the spinal cord.

B. Early Delayed Toxicity

o Usually apparent weeks to months after completion of cranial irradiation and is likely due to focal
demyelination.
o Clinically it may be asymptomatic or take the form of worsening or reappearance of a preexisting
neurologic deficit
o Lhermitte symptom = paresthesias of the limbs or along the spine when the patient flexes the
neck.

C. Late Delayed Toxicity

o MOST serious as they are often IRREVERSIBLE and cause severe neurologic deficits.
o In the brain, late toxicities can take several forms, the most common of which include radiation
necrosis and leukoencephalopathy
 o Leukoencephalopathy = seen MOST commonly after WBRT
o Clinically, patients develop cognitive impairment, gait disorder, and later urinary incontinence.
o Peripheral nervous system is relatively resistant to RT toxicities.

II. TOXICITY FROM CHEMOTHERAPY

• NEUROTOXICITY = SECOND only to MYELOSUPPRESSION as the dose-limiting toxicity of
chemotherapeutic agents
• Chemotherapy causes peripheral neuropathy from a number of commonly used agents, and the type of
neuropathy can differ, depending upon the drug.
• Vincristine = paresthesias but little sensory loss and is associated with motor dysfunction, autonomic
impairment (frequently ileus), and rarely cranial nerve compromise.
• Cisplatin = large fiber sensory loss resulting in sensory ataxia but little cutaneous sensory loss and no
weakness.
• Taxanes = cause a predominately sensory neuropathy.
• Agents such as bortezomib and thalidomide also cause neuropathy.

ACUTE BACTERIAL MENINGITIS (CHAPTER 133)

o Acute purulent infection within the subarachnoid space, associated with a CNS inflammatory
reaction that may result in decreased consciousness, seizures, raised intracranial pressure (ICP),
and stroke
o Meninges, subarachnoid space, and brain parenchyma are all frequently involved in the inflammatory
reaction (meningoencephalitis).

I. EPIDEMIOLOGY
• MOST common form of suppurative CNS infection = BACTERIAL MENINGITIS
• Community-acquired bacterial
meningitis are:
o Streptococcus pneumoniae
(50%)
o Neisseria meningitidis (25%)
o Group B streptococci (15%)
o Listeria monocytogenes (10%)
o Haemophilus influenzae type b <10%

II. ETIOLOGY
A. S.pneumonia
o MOST common cause of meningitis in adults >20 years
o Risk factors include:
• Coexisting acute or chronic pneumococcal sinusitis or otitis media
• Alcoholism
• Diabetes
• Splenectomy
• Hypogammaglobulinemia
• Complement deficiency
• Head trauma with basilar skull fracture

B. N. meningitides
o Decreased with the routine immunization of 11- to 18-year-olds with the tetravalent
(serogroupd. s A, C, W-135, and Y) meningococcal glycoconjugate vaccine.
o The risk of invasive disease following nasopharyngeal colonization depends on both
bacterial virulence factors and host immune defense mechanisms
o IMPORTANT clue to diagnosis of meningococcal infection = PETECHIAL or PURPUTIC skin
lesions
o Causative organism of recurring epidemics of meningitis every 8-12 years

C. Others
o S. bovis, the HACEK group (Haemophilus sp., Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), or enterococci.
o Group B streptococcus, or S. agalactiae, was previously responsible for meningitis
predominantly in neonates, but it has been reported with increasing frequency in individuals >50
years of age, particularly those with underlying diseases.
o L. monocytogenes: increasingly important cause of meningitis in neonates (<1 month of age),
pregnant women, individuals
>60 years, and immunocompromised individuals of all ages. Infection is acquired by ingesting foods
o H. influenzae type b meningitis in children has declined dramatically since the introduction of
the Hib conjugate vaccine, although rare cases of Hib meningitis in vaccinated children have been
reported.
o Staphylococcus aureus and coagulase-negative staphylococci are important causes of
meningitis that occurs following invasive neurosurgical procedures, particularly shunting
procedures for hydrocephalus, or as a complication of the use of subcutaneous Ommaya
reservoirs for administration of intrathecal
III. CLINICAL PRESENTATION
• Can present as either an:
o Acute fulminant illness that progresses rapidly in a few hours
o Subacute infection that progressively worsens over several days.
• Classic clinical TRIAD of meningitis is fever, headache, and nuchal rigidity, but the classic triad may not
be present.
• Fever and headache, stiff neck, or an altered level of consciousness will be present in nearly every patient
with bacterial meningitis.
• Raised ICP is an expected complication of bacterial meningitis and the MAJOR cause of obtundation and
coma in this disease
• More than 90% of patients will have a CSF opening pressure >180 mmH 2O, and 20% have opening
pressures >400 mmH2O.
• Signs of increased ICP include a deteriorating or reduced level of consciousness, papilledema, dilated
poorly reactive pupils, sixth nerve palsies, decerebrate posturing, and the Cushing reflex (bradycardia,
hypertension, and irregular respirations).
• MOST disastrous complication of increased ICP = CEREBRAL HERNIATION
• Siezures occur as part o the initial presentation of bacterial meningitis or during the course of illness in 20-
40% of patients.

IV. DIAGNOSIS
• When bacterial meningitis is suspected, blood cultures should be immediately obtained and empirical
antimicrobial and adjunctive
dexamethasone therapy initiated without delay

• Diagnosis of bacterial meningitis = made by examination of the CSF

• The need to obtain neuroimaging studies (CT or MRI) prior to LP requires clinical judgment.
• Antibiotic therapy initiated a few hours prior to LP will NOT significantly alter the CSF WBC count or glucose
concentration, nor is it likely to prevent visualization of organisms by Gram's stain or detection of bacterial
nucleic acid by PCR assay

V. DIFFERENTIAL DIAGNOSIS
 • Viral meningoencehphalitis, and particularly Herpes simplex virus (HSV) encephalitis can mimic the clinical
presentation of bacterial meningitis.
• Ricketsiall disease can also mimic bacterial meningitis.
• Focal suppurative CNS inections, including subdural and epidural empyema and brain abscess, should also
be considered, especially when focal neurologic findings are present.
• MRI should be performed promptly in all patients who present with focal neurologic findings.
• A number of noninfectious CNS disorders can mimic bacterial meningitis including subarachnoid
hemorrhage.

VI. CLASSIC CSF ABNORMALITIES IN BACTERIAL MENINGITIS

• PMN leukocytosis >100cells/uL in 90%
• Decreased glucose concentration < 40mg/dL and/or CSF/serum glucose ratio < 0.4
• Increased protein concentration > 45mg/dL in 90%
• Increased opening pressure > 180mmH2O

TREATMENT: ACUTE BACTERIAL MENINGITIS

I. EMPIRICAL ANTIMICROBIAL THERAPY
• Bacterial meningitis is a medical emergency.
• The goal is to begin antibiotic therapy within 60 min of a patient's arrival in the emergency room.
• Empirical antimicrobial therapy is initiated in patients with suspected bacterial meningitis before the results
of CSF Gram's stain and culture are known.
• S. pneumoniae and N. meningitides = the MOST common etiologic organisms of community-acquired
bacterial meningitis.
• Due to the emergence of penicillin- and cephalosporin-resistant S. pneumoniae, empirical therapy of
community-acquired suspected bacterial meningitis in children and adults should include a combination of
dexamethasone, a third- or fourth-generation cephalosporin (e.g., ceftriaxone, cefotaxime, or cefepime),
and vancomycin, plus acyclovir, as HSV encephalitis is the leading disease in the differential diagnosis,
and doxycycline during tick season to treat tick-borne bacterial infections.
• Ceftriaxone or cefotaxime provide good coverage for susceptible S. pneumoniae, group B streptococci,
and H. influenzae and adequate coverage for N. meningitidis.
• Cefepime is a broad-spectrum fourth-generation cephalosporin with in vitro activity similar to that of
cefotaxime or ceftriaxone against
S. pneumoniae and N. meningitidis and greater activity against Enterobacter species and Pseudomonas
aeruginosa.
II. SPECIFIC ANTIMICROBIAL THERAPY

A. Meningococcal Meningitis
o Although ceftriaxone and cefotaxime provide adequate empirical coverage for N.
meningitidis, penicillin G remains the antibiotic of choice for meningococcal meningitis
caused by susceptible strains.
o A 7-day course of intravenous antibiotic therapy is adequate for uncomplicated meningococcal
meningitis.
o The index case and all close contacts should receive chemoprophylaxis with a 2-day regimen of
rifampin (600 mg every 12 h for 2 days in adults and 10 mg/kg every 12 h for 2 days in children
>1 year).
o Rifampin is not recommended in pregnant women.
o Alternatively, adults can be treated with one dose of azithromycin (500 mg), or one IM dose of
ceftriaxone (250 mg).
o Close contacts are defined as those individuals who have had contact with oropharyngeal
secretions, either through kissing or by sharing toys, beverages, or cigarettes.

B. Pneumococcal Meningitis
o Cephalosporin (ceftriaxone, cefotaxime, or cefepime) and vancomycin.
o All CSF isolates of S. pneumoniae should be tested for sensitivity to penicillin and the
cephalosporins.
o A 2-week course of intravenous antimicrobial therapy is recommended for pneumococcal
meningitis.
o S. pneumoniae meningitis should have a repeat LP performed 24–36 h after the initiation
of antimicrobial therapy to document sterilization of the CSF.
o Failure to sterilize the CSF after 24–36 h of antibiotics should be considered presumptive evidence
of antibiotic resistance.

C. Listeria Meningitis
o The intraventricular route of administration is preferred over the intrathecal route because
adequate concentrations of vancomycin in the cerebral ventricles are not always
achieved with intrathecal administration.
o Meningitis due to L. monocytogenes is treated with ampicillin for at least 3 weeks
o Gentamicin is added in critically ill patients (2 mg/kg loading dose, then 7.5 mg/kg per day given
every 8 h and adjusted for serum levels and renal function).
 D. Staphylococcal Meningitis
o Meningitis due to susceptible strains of S. aureus or coagulase-negative staphylococci is treated
with nafcillin
o VANCOMYCIN = drug of CHOICE for methicillin-resistant staphylococci and for patients allergic
to penicillin.

E. Gram-Negative Bacillary Meningitis

o The third-generation cephalosporins—cefotaxime, ceftriaxone, and ceftazidime—are equally
efficacious for the treatment of gram-negative bacillary meningitis, with the exception of
meningitis due to P. aeruginosa, which should be treated with ceftazidime, cefepime, or
meropenem
o 3-week course of intravenous antibiotic therapy is recommended for meningitis due to gram-
negative bacilli.

III. ADJUNCTIVE THERAPY

• Dexamethasone exerts its beneficial effect by inhibiting the synthesis of IL-1B and TNF-a at the level of
mRNA, decreasing CSF outflow resistance, and stabilizing the blood-brain barrier.
• First dose should ideally be started 20mins before, or not later than concurrent with, the first dose of
antibiotics.

IV. PROGNOSIS: Risk of Death INCREASES with:

• Decreased level of consciousness on admission
• Onset of seizures within 24 hours of admission
• Signs of increased ICP
• Young age (infancy) and age > 50
• Presence of comorbid conditions including shock and/or need for mechanical ventilation
• Delay in initiation of treatment
• Common sequelae include decreased intellectual function, memory impairment, seizures, hearing loss and
dizziness, and gait disturbances.

ACUTE VIRAL MENINGITIS

• Immunocompetent adult patients with viral meningitis usually present with headache, fever, and signs of
meningeal irritation coupled with an inflammatory CSF profile
• HEADACHE is almost invariably present and often characterized as frontal or retroorbital and frequently
associated with photophobia and pain on moving the eyes.
• Nuchal rigidity is present in most cases but may be mild and present only near the limit of neck anteflexion.
• Constitutional signs can include malaise, myalgia, anorexia, nausea and vomiting, abdominal pain, and/or
diarrhea. Patients often have mild lethargy or drowsiness; however, profound alterations in
consciousness, such as stupor, coma, or marked confusion do not occur in viral meningitis and suggest
the presence of encephalitis or other alternative diagnoses.
• MOST important agents are:
o Enteroviruses (including echoviruses and coxsackieviruses in addition to numbered enteroviruses)
o HSV type 2 (HSV-2)
o HIV
o Arboviruses
• CSF cultures are positive in 30–70% of patients, the frequency of isolation depending on the specific viral
agent.
• Approximately two-thirds of culture-negative cases of "aseptic" meningitis have a specific viral etiology
identified by CSF PCR
• All cases of viral meningitis is primarily symptomatic and includes use of analgesics, antipyretics, and
antiemetics.
• Fluid and electrolyte status should be monitored.
• Oral or IV acyclovir may be of benefit in meningitis caused by HSV-1 or -2 and in cases of severe EBV or
VZV infection.
• Intravenous acyclovir (15–30 mg/kg per day in three divided doses), which can be followed by an oral drug
such as acyclovir (800 mg, five times daily), famciclovir (500 mg tid), or valacyclovir (1000 mg tid) for a
total course of 7–14 days.

SUBACUTE MENINGITIS
• Typically have an unrelenting headache, stiff neck, low-grade fever, and lethargy for days to several
weeks before they present for evaluation. Cranial nerve abnormalities and night sweats may be
 present
• Common causative organisms include:
o M. tuberculosis
o C. neoformans
o H. capsulatum
o C. immitis
o T. pallidum.
• Initial infection with M. tuberculosis is acquired by inhalation of aerosolized droplet nuclei.
• Tuberculous meningitis in adults does not develop acutely from hematogenous spread of tubercle bacilli to
the meninges.
• Rather, millet seed–sized (miliary) tubercles form in the parenchyma of the brain during hematogenous
dissemination of tubercle bacilli in the course of primary infection.
• Fungal infections are typically acquired by the inhalation of airborne fungal spores. The initial
pulmonary infection may be asymptomatic or present with fever, cough, sputum production, and
chest pain. The pulmonary infection is often self-limited.
• MOST common pathogen causing FUNGAL meningitis = C. neoformans.
• Dexamethasone therapy is recommended for HIV-negative patients with tuberculous meningitis (dose 12-
16mg/d for 3 weeks then tapered over 3 weeks).
• Meningitis due to C. neoformans in non-HIV, non transplant patients is treated with induction therapy with
amphotericin B (0.7 mg/kg IV per day) plus flucytosine (100mg/kg per day in four divided doses) for at least
4 weeks if CSF culture results are negative after 2 weeks of treatment.
• Syphillitic meningitis is treated with aqueous penicillin G in a dose of 3-4 million units intravenously every 4
hours for 10-14 days.

CHRONIC AND RECURRENT MENINGITIS

INTRODUCTION

• Chronic inflammation of the meninges (pia, arachnoid, and dura) can produce profound neurologic disability
and may be fatal if not successfully treated.
• The condition is most commonly diagnosed when a characteristic neurologic syndrome exists for >4 weeks
and is associated with a persistent inflammatory response in the cerebrospinal fluid (CSF) (white blood cell
count >5/ L).
• Five categories of disease account for MOST cases of chronic meningitis
o Meningeal infections
o Malignancy
o Noninfectious inflammatory disorders
o Chemical meningitis
o Parameningeal infections.

I. CLINICAL PATHOPHYSIOLOGY
• Persistent headache with or without stiff neck, hydrocephalus, cranial neuropathies, radiculopathies, and
cognitive or personality changes are the cardinal features.
• Diagnosis of chronic meningitis is usually made when the clinical presentation prompts the astute physician
to examine the CSF for signs of inflammation.
• CSF is produced by the choroid plexus of the cerebral ventricles, exits through narrow foramina into the
subarachnoid space

II. APPROACH TO THE PATIENT: CHRONIC MENINGITIS

• The occurrence of chronic headache, hydrocephalus, cranial neuropathy, radiculopathy, and/or cognitive
decline in a patient
• Lumbar puncture for evidence of meningeal inflammation.
• Imaging study (CT or MRI) shows contrast enhancement of the meninges, which is always abnormal with
the exception of dural enhancement after lumbar puncture, neurosurgical procedures, or spontaneous CSF
leakage.
• Once chronic meningitis is confirmed by CSF examination, effort is focused on identifying the cause by:
o 1) Further analysis of the CSF
o 2) Diagnosis of an underlying systemic infection or noninfectious inflammatory condition
o 3) Pathologic examination of meningeal biopsy specimens.
• Empirical treatment generally consists of antimycobacterial agents, amphotericin for fungal infection, and/or
glucocorticoids for noninfectious inflammatory cause.
 • It is important to direct empirical therapy of lymphocytic meningitis at tuberculosis, particularly if the condition
is associated with low CSF glucose, since untreated disease can be devastating within weeks.

BRAIN ABSCESS AND EMPYEMA (CHAPTER 135)

BRAIN ABSCESS

• Focal, suppurative infection within the brain parenchyma, typically surrounded by a vascularized capsule.
• CEREBRITIS = employed to describe a nonencapsulated brain abscess.
• Etiology:
o 1) Direct spread from a contiguous cranial site, such as paranasal sinusitis, otitis media, mastoiditis,
or dental infection
o 2) Following head trauma or a neurosurgical procedure
o 3) Result of hematogenous spread from a remote site of infection
• In 25% of cases, no obvious primary source of infection is apparent (cryptogenic brain abscess)
• Otogenic brain abscesses occur predominalty in the temporal area and cerebellum
• Dental infections are associated with 2% of brain abscesses, although it is often suggested that many
cryptogenic abscesses are in fact due to dental infections.
• Hematogenous abscesses account for 25% of brain abscesses.
• Pathogenesis and Histopathology
o Early cerebritis stage (days 1-3) – perivascular infiltration of inflammatory cells, which surround a
centrale core of coagulative necrosis
o Late cerebritis stage (days 4-9) – pus formation leads to enlargement of necrotic center, which is
surrounded at its border by an inflammatory infiltrate of macrophages and fibrblasts
o Early capsule formation (day 10-13) – formation of a capsule that is better developed on the cortical
than on the ventricular side of the lesion. Appearance of ring enhancing capsule on neuroimaging
studies.
o Late capsule formation (day 14 and beyond) – well formed necrotic center surrounded by a dense
collagenous capsule

1.CLINICAL PRESENTATION

• MOST patients present to the hospital 11-12 days following onset of symptoms
• CLASSIC clinical triad = headache, fever, focal neurologic deficit (present in < 50%)
• MOST COMMON symptom = HEADACHE (75%)
• Fever is present in only 50% of patients at the time of diagnosis.
• New onset of focal or generalized seizure activity is presenting sign in 15-35%

II. DIAGNOSIS
• MRI better than CT for demonstrating abscesses in the EARLY (cerebritis) stages and is superior to
CT for identifying abscesses in the posterior fossa
• CT and MRI appearance, particularly of the capsule, may be altered by treatment with glucocorticoids.
• Microbiologic diagnosis of the etiologic agent is most accurately determinted by gram’s stain and culture
of abscess material obtained by CT-guided stereotactic needle aspiration
• LP should not be perfomed in patients with known or suspected focal intracranial infections such as
abscess or empyema

III. TREATMENT
• Optimal therapy = combination of high dose parenteral antibiotics and neurosurgical drainage
• Empirical therapy in immunocompetent patient = 3rd or 4th generation cephalosporin (cefotaxime,
ceftriaxone, cefepime) and metronidazole
• Medical therapy alone is not optimal for treatment of brain abscesses and should be reserved for
patients whose abscesses are nurosurgically inaccessible, for patients with small (<2-3cm) or
nonencapsulated abscesses (cerebritis).
• All patients should receive a minimum of 6-8 weeks of parenteral antibiotic therapy.
• Patients should receive prophylactic anticonvulstant therapy because of high risk of focal or
generalized seizures.
• Intravenous dexamethasone therapy (10mg every 6 hours) is usually reserved for patients with
substantial periabscess edema and associated mass effect and increased ICP.
• Serial MRI or CT scans should be obtained on a montly or twice-monthly basis to document
resolution of the abscess.
SUBDURAL EMPYEMA

o Collection of pus between the dura and arachnoid membranes.

o Rare disorder than accounts for 15-25% of focal suppurative CNS infections
o Sinusitis if the most common predisposing condition and typically involves the frontal sinuses,
either alone or in combination with the ethmoid and maxillary sinuses.
o Aerobic and anerobic streptococcis, staphylococci, Enterobacteriaceae, and anaerobic bacteria
are the most common causative organisms of sinusitis associated SDE.
o Staphylococci and gram negative bacilli are often the etiologic organisms when SDE follows
neurosurgical procedures or head trauma.
o Sinusitis associated SDE develops as a result of either retrograde spread of infection from septic
thrombophlebitis of the mucosal veins draining the sinuses or contiguous spread of infection to
the brain from osteomyelitis in the posterior wall of the frontal or other sinuses.
o May also develop from direct introduction of bacteria into the subdural space as complication of
neurosurgical procedure.
o Typically presents with fever and progressively worsening headache.
o Headache is the most common complaint at the time of presentation.
o Contralateral hemiparesis is the most common focal neurologic deficit and can occur from direct
oeffects of the SDE on the cortex or asa consequence of venous infarction.
o MRI is superior to CT in identifying SDE and any associated intracranial infections.
o SDE is a medical emergency. Emergent neurosurgical evacuation of the empyema, either through
craniotomy, craniectomy, or burr-hole drainage, is the definitive step in the management of this
infection.

CRANIAL EPIDURAL ABSCESS

o Suppurative infection occurring in the potential space between the inner skull table and the dura
o Develops as a complication of craniotomy or compound skull fracture or as a result of spread of
infection from the frontal sinuses, middle ear, mastoid, or orbit.
o Staphylococci or gram negative organisms are the usual cause of an epidural abscess that
develops asa complication of craniotomy or compound skull fracture
o Patients presents with fever, headache, nuchal rigidity, seizures and focal deficits.
o Diagnosis should be considered when fever and headache follow recent head trauma or occur in
the setting of frontal sinusitis, mastoiditis, or otitis media.
o Cranial MRI with gadolinium enhancement is the procedure of choice to demonstrate a cranial
epidural abscess.
o Immediate neurosurgical drainage is indicated.

SUPPURATIVE THROMBOPHLEBITIS

o Septic venous thrombosis of cortical veins and sinuses.

o May occur as a complication of bacterial meningitis, SDE, epidural abscesses, or infection in the
skin of the face, paranasal sinuses, middle ear, or mastoid
o Septic thrombosis of the superior sagittal sinus presents with headache, fever, nausea and
vomiting, confusion, and focal or generalized seizures.
o There may be rapid development of stupor and coma.
o Symptoms of septic cavernous sinsus thrombosis are fever, headache, frontal and retroorbital
pain, and diplopia. Classic signs are ptosis, proptosis, chemosis, and extraocular dysmotility due
to deficits of cranial nerves III, IV, VI.
o Headache and earache are most frequent symptoms of transverse sinus thrombosis.
o Diagnosis is suggested by an absent flor void within the affected venous sinus on MRI and
confirmed with magnetic resonance venography, CT angiogram, or the venous phase of cerebral
angiography.
o Treated with antibiotics, huydration, and removal of infected tissue and thrombus in septic lateral
or cavernous sinus thrombosis.
o Optimal duration of therapy is unknown but antibiotics are usually continued for 6 weeks or until
there is radiographic evidence of resolution of thrombosis.

PERIPHERAL NEUROPATHY
INTRODUCTION

• Peripheral nerves are composed of sensory, motor, and autonomic elements.

• Nerves can be subdivided into three major classes: large myelinated, small myelinated, and small
unmyelinated.

DIABETIC NEUROPATHY
• Diabetes mellitus (DM) = MOST common cause of peripheral neuropathy in developed countries.
• DM is associated with several types of polyneuropathy: distal symmetric sensory or sensorimotor
polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies, cranial
neuropathies, and other mononeuropathies.
• Risk factors for the development of neuropathy include long-standing, poorly controlled DM and the
presence of retinopathy and nephropathy.

I. DIABETIC DISTAL SYMMETRIC SENSORY AND SENSORIMOTOR POLYNEUROPATHY (DSPN)

• DSPN is the MOST common form of diabetic neuropathy
• Manifests as sensory loss beginning in the toes that gradually progresses over time up the legs and into the
fingers and arms

II. DIABETIC AUTONOMIC NEUROPATHY

• Autonomic neuropathy is typically seen in combination with DSPN.
• The autonomic neuropathy can manifest as abnormal sweating, dysfunctional thermoregulation, dry eyes
and mouth, pupillary abnormalities, cardiac arrhythmias, postural hypotension, gastrointestinal
abnormalities (e.g., gastroparesis, postprandial bloating, chronic diarrhea or constipation), and
genitourinary dysfunction (e.g., impotence, retrograde ejaculation, incontinence). T
• Tests of autonomic function are generally abnormal, including sympathetic skin responses and quantitative
sudomotor axon reflex testing. Sensory and motor NCS generally demonstrate features described above
with DSPN.
III. DIABETIC RADICULOPLEXUS NEUROPATHY (DIABETIC AMYOTROPHY OR BRUNS-GARLAND
SYNDROME)
• Presenting manifestation of DM in approximately one third of patients.
• Typically presents with severe pain in the low back, hip, and thigh in one leg.
• Atrophy and weakness of proximal and distal muscles in the affected leg become apparent within a few
days or weeks.
• Wekaness usually progresses over several weeks or months, but can continue to progress for 18 months
or more.
• Subsequently, there is slow recovery but many are left with residual weakness, senory loss, and pain.
• CSF protein is usually elevated, while the cell count is normal. ESR often increased.

IV. DIABETIC MONONEUROPATHIES OR MULTIPLE MONONEUROPATHIES

• The MOST common MONONEUROPATHIES are median neuropathy at the wrist and ulnar
neuropathy at the elbow, but peroneal neuropathy at the fibular head, and sciatic, lateral femoral,
cutaneous, or cranial neuropathies also occur.
• In cranial mononeuropathies, a seventh nerve palsy is MOST common, followed by third nerve, sixth
nerve, and, less frequently, fourth nerve palsies.
• Diabetic third nerve palsies are characteristically pupil-sparing

OTHERS

I. HYPOTHYROIDISM
• More commonly associated with proximal myopathy, but some patients deveoop neuropathy, most typically
CTS.
• Treatment is correction of the hypothyroidism.
II. SJÖGREN SYNDROME
• Sjögren syndrome, characterized by the sicca complex of xerophthalmia, xerostomia, and dryness of other
mucous membranes, can be complicated by neuropathy.
• Most common is a length-dependent axonal sensorimotor neuropathy characterized mainly by sensory loss
in the distal extremities

III. RHEUMATOID ARTHRITIS

• Peripheral neuropathy occurs in at least 50% of patients with rheumatoid arthritis (RA) and may be vasculitic
in nature
• Vasculitic neuropathy can present with a mononeuropathy multiplex, a generalized symmetric pattern of
involvement, or a combination of these patterns.
• Neuropathies may also be due to drugs used to treat the RA (e.g., tumor necrosis blockers, leflunomide).
Nerve biopsy often reveals thickening of the epineurial and endoneurial blood vessels

IV. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

• Between 2 and 27% of individuals with SLE develop a peripheral neuropathy.
• Affected patients typically present with a slowly progressive sensory loss beginning in the feet. Some
patients develop burning pain and paresthesias with normal reflexes, and nerve conduction studies suggest
a pure small-fiber neuropathy. Less common are multiple mononeuropathies presumably secondary to
necrotizing vasculitis.
• Patients with a GBS or CIDP-like neuropathy should be treated accordingly
V. SYSTEMIC SCLEROSIS (SCLERODERMA)
• A distal symmetric, mainly sensory, polyneuropathy complicates 5–67% of scleroderma cases
• Mononeuropathies can also develop, MOST commonly of the TRIGEMINAL NERVE, producing numbness
and dysesthesias in the face.
• Multiple mononeuropathies also occur.

VI. MIXED CONNECTIVE TISSUE DISEASE (MCTD)

• A mild distal axonal sensorimotor polyneuropathy occurs in approximately 10% of patients with MCTD.

VII. SARCOIDOSIS
• Peripheral or central nervous systems are involved in about 5% of patients with sarcoidosis.
• MOST common cranial nerve involved is the SEVENTH NERVE, which can be affected bilaterally.
• Some patients develop radiculopathy or polyradiculopathy.
VIII. HYPEREOSINOPHILLIC SYNDROME
• Eosinophilia associated with various skin, cardiac, hematologic, and neurologic abnormalities.
• Generalized peripheral neuropathy or a mononeuropathy multiplex occurs in 6-14% of patients

IX. CELIAC DISEASE (GLUTEN-INDUCED ENTEROPATHY OR NONTROPICAL SPRUE)

• Neurologic complications, particularly ataxia and peripheral neuropathy are estimated to occur in 10% of
patients with celiac disease.
• Generalized sensorimotor polyneuropathy, pure motor neuropathy, multiple mononeuropathy, autonomic
neuropathy, small-fiber neuropathy and neuromyotonia have all been reported in associated with celiac
disease or antigliadin/antiendomysial antibodies.

X. INFLAMMATORY BOWEL DISEASE

• Ulcerative colitis and Crohn's disease may be complicated by GBS, CIDP, generalized axonal sensory or
sensorimotor polyneuropathy, small-fiber neuropathy, or mononeuropathy.
• These neuropathies may be autoimmune, nutritional (e.g., vitamin B12 deficiency), treatment related (e.g.,
metronidazole), or idiopathic in nature.

XI. UREMIC NEUROPATHY

• Approximately 60% of patients with renal failure develop a polyneuropathy characterized by length-
dependent numbness, tingling, allodynia, and mild distal weakness.
• Rarely, a rapidly progressive weakness and sensory loss very similar to GBS can occur that improves with
an increase in the intensity of renal dialysis or with transplantation.
• Mononeuropathies can also occur, the MOST common of which is carpal tunnel syndrome.

XII. CHRONIC LIVER DISEASE

• Generalized sensorimotor neuropathy characterized by numbness, tingling, and minor weakness in the
distal aspects of primarily the lower limbs
• Sural nerve biopsy reveals both segmental demyelination and axonal loss.

XIII. CRITICAL ILLNESS POLYNEUROPATHY

• MOST common causes of acute generalized weakness leading to admission to a MICU = GBS and
myasthenia gravis
• Weakness developing in critically ill patients while in the ICU is usually caused by critical illness
polyneuropathy (CIP) or critical illness myopathy (CIM), or much less commonly, by prolonged
neuromuscular blockade

XIV. LEPROSY (HANSEN DISEASES)

• Caused by the acid-fast bacteria Mycobacterium leprae, is the most common cause of peripheral
neuropathy in Southeast Asia, Africa, and South America
• Clinical manifestations range from tuberculoid leprosy at one end to lepromatous leprosy at the other end
of the spectrum, with borderline leprosy in between. red- free in the endoneurium, within macrophages, or
within Schwann cells.
• Treated with multiple drugs: dapsone, rifampin, and clofazimine.

XV. LYME DISEASE

• Neurologic complications may develop during the second and third stages of infection.
• Facial neuropathy is omost common and is bilateral in about half of cases, which is rare for idiopathic Bell’s
palsy. Involvement of the nerves is frequently asymmetric.
• Some patients present with a polyradiculoneuropathy or multiple mononeuropathies.

XVI. DIPHTERITIC NEUROPATHY

• A generalized polyneuropathy may manifest 2 or 3 months following the initial infection, characterized by
numbness, paresthesias, and weakness of arms and legs occasionally ventilatory failure.
• The neuropathy usually resolves after several months.

XVII. HUMAN IMMUNODEFICIENCY VIRUS (HIV)

• Approximately 20% of HIV-infected individuals develop a neuropathy either as a direct result of the virus
itself, other associated viral infections (e.g., cytomegalovirus), or neurotoxicity secondary to antiviral
medications.
• The major presentations of peripheral neuropathy associated with HIV infection include (1) distal symmetric
polyneuropathy (DSP),
 (2) inflammatory demyelinating polyneuropathy (including both GBS and CIDP), (3) multiple
mononeuropathies (e.g., vasculitis, CMV-related), (4) polyradiculopathy (usually CMV-related), (5)
autonomic neuropathy, and (6) sensory ganglionitis.

A. HIV-Related Distal Symmetric Polyneuropathy (Dsp)

o DSP = MOST common form of peripheral neuropathy associated with HIV infection & usually seen
in patients with AIDS.

B. HIV-Related Inflammatory Demyelinating Polyradiculoneuropathy

o Both AIDP and CIDP can occur as a complication of HIV infection. AIDP usually develops at the
time of seroconversion.

C. HIV-Related Progressive Polyradiculopathy

o An acute, progressive lumbosacral polyradiculoneuropathy usually secondary to cytomegalovirus
(CMV) infection can develop in patients with AIDS.
o Patients present with severe radicular pain, numbness, and weakness in the legs, which is usually
asymmetric.

D. HIV-Related Multiple Mononeuropathies

o Multiple mononeuropathies can also develop in patients with HIV infection, usually in the context of
AIDS.
o Nerve biopsies can reveal axonal degeneration with necrotizing vasculitis or perivascular
inflammation.
o Glucocorticoid treatment is indicated for vasculitis directly due to HIV infection

XVIII. CYTOMEGALOVIRUS
• CMV can cause acute lumbosacral polyradiculopathy and multiple mononeuropathies in patients with HIV
infection and in other immune deficiency conditions.

XIX. EPSTEIN-BARR VIRUS

• EBV infection has been associated with GBS, cranial neuropathies, mononeuropathy multiplex, brachial
plexopathy, lumbosacral radiculoplexopathy, and sensory neuropathies.

XX. HEPATITIS VIRUSES

• Hepatitis B and C can cause multiple mononeuropathies related to vasculitis, AIDP, or CIDP.

NEUROPATHIES ASSOCIATED WITH MALIGNANCY

• Patients with malignancy can develop neuropathies due to
o 1) A direct effect of the cancer by invasion or compression of the nerves
o 2) Remote or paraneoplastic effect
o 3) A toxic effect of treatment
o 4) As a consequence of immune compromise caused by immunosuppressive medications.

• The MOST common associated malignancy is LUNG CANCER, but neuropathies also complicate
carcinoma of the breast, ovaries, stomach, colon, rectum, and other organs, including the
lymphoproliferative system

I. PARANEOPLASTIC SENSORY NEURONOPATHY / GANGLIONOPATHY

• Paraneoplastic Sensory Neuronopathy/Ganglionopathy Paraneoplastic encephalomyelitis/sensory
neuronopathy (PEM/SN) usually complicates small cell lung carcinoma

II. NEUROPATHY SECONDARY TO TUMOR INFILTRATION

• Malignant cells, in particular leukemia and lymphoma, can infiltrate cranial and peripheral nerves, leading
to mononeuropathy, mononeuropathy multiplex, polyradiculopathy, plexopathy, or even a generalized
symmetric distal or proximal and distal polyneuropathy.

III. NEUROPATHY AS A COMPLICATION OF BONE MARROW TRANSPLANTATION

• Neuropathies may develop in patients who undergo bone marrow transplantation (BMT) because of the
toxic effects of chemotherapy, radiation, infection, or an autoimmune response directed against the
peripheral nerves.
• Peripheral neuropathy in BMT is often associated with graft-versus-host disease (GVHD).
 • Chronic GVHD shares many features with a variety of autoimmune disorders, and it is possible that an
immune-mediated response directed against peripheral nerves is responsible. of the GVHD.

IV. LYMPHOMA
• Lymphomas may cause neuropathy by infiltration or direct compression of nerves or by a paraneoplastic
process.
• The neuropathy can be purely sensory or motor, but most commonly is sensorimotor.

V. MULTIPLE MYELOMA
• Presents in the fifth to seventh decade of life with fatigue, bone pain, anemia, and hypercalcemia.

VI. TOXIC NEUROPATHIES SECONDARY TO CHEMOTHERAPY

• Many of the commonly used chemotherapy agents can cause a toxic neuropathy
• The mechanisms by which these agents cause toxic neuropathies vary as can the specific type of neuropathy
produced.

OTHER TOXIC NEUROPATHIES

I. CHLOROQUINE AND HYDROXYCHLOROQUINE

• Can cause a toxic myopathy characterized by slowly progressive, painless, proximal weakness and
atrophy, which is worse in the legs than the arms.

II. AMIODARONE
• Nerve biopsy demonstrates a combination of segmental demyelination and axonal loss.

III. COLCHICINE
• Inhibits the polymerization of tubulin into microtubules. The disruption of the microtubules probably leads
to defective intracellular movement of important proteins, nutrients, and waste products in muscle and
nerves.

IV. THALIDOMIDE
• An immunomodulating agent used to treat multiple myeloma, GVHD, leprosy, and other autoimmune
disorders. Thalidomide is associated with severe teratogenic effects as well as peripheral neuropathy that
can be dose-limiting.
• Patients develop numbness, painful tingling, and burning discomfort in the feet and hands and less
commonly muscle weakness and atrophy.

V. PYRIDOXINE (VITAMIN B6) TOXICITY

• An essential vitamin that serves as a coenzyme for transamination and decarboxylation. However, at high
doses (116 mg/d),
• Patients can develop a severe sensory neuropathy with dysesthesias and sensory ataxia.

VI. ISONIAZID
• One of the most common side effects of isoniazid (INH) is peripheral neuropathy.
• Standard doses of INH (3-5 mg/kg per day) are associated with a 2% incidence of neuropathy, whereas
neuropathy develops in at least 17% of patients taking in excess of 6 mg/kg per day.
• Elderly, malnourished, and “slow acetylators” are at increased risk for developing the neuropathy.
• Prophylactic administration of pyridoxine 100 mg/d can prevent the neuropathy from developing

VII. ANTIRETROVIRAL AGENTS

• The nucleoside analogues zalcitabine (dideoxycytidine or ddC), didanosine (dideoxyinosine or ddI),
stavudine (d4T), lamivudine (3TC), and antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) are
used to treat HIV infection.
• One of the major dose-limiting side effects of these medications is a predominantly sensory, length-
dependent, symmetrically painful neuropathy. Hexacarbons (N-Hexane, Methyl N-Butyl Ketone)/Glue
Sniffer's Neuropathy

VIII. HEXACARBONS / GLUE SNIFFER’S NEUROPATHY

• Exposure through inhalation, accidentally or intentionally (glue sniffing), or through skin absorption can lead
to a profound subacute sensory and motor polyneuropathy.

IX. LEAD
 • Lead neuropathy is uncommon but it can be seen in children who accidentally ingest lead-based paints in
older buildings and in industrial workers exposed to lead-containing products.
• The MOST common presentation of lead poisoning is an ENCEPHALOPATHY

X. MERCURY
• Mercury toxicity may occur as a result of exposure to either organic or inorganic mercurials.

XI.THALLIUM
• Can exist in a monovalent or trivalent form and is primarily used as a rodenticide. The toxic neuropathy
usually manifests as burning paresthesias of the feet, abdominal pain, and vomiting.
• Increased thirst, sleep disturbances, and psychotic behavior may be noted. increasing tissue availability from
the serum.

XII. ARESNIC
• Arsenic is another heavy metal that can cause a toxic sensorimotor polyneuropathy.
• The neuropathy manifests 5–10 days after ingestion of arsenic and progresses for several weeks, sometimes
mimicking GBS

NUTRITIONAL NEUROPATHIES

I. COBALAMIN (VITAMIN B12)

• Pernicious anemia is the most common cause of cobalamin deficiency. Other causes include dietary
avoidance (vegetarians), gastrectomy, gastric bypass surgery, inflammatory bowel disease, pancreatic
insufficiency, bacterial overgrowth, and possibly histamine-2 blockers and proton-pump inhibitors.
• Deficiency neuropathy and subacute combined degeneration.

II. THIAMINE DEFICIENCY

• Thiamine (vitamin B1) deficiency is an uncommon cause of peripheral neuropathy in developed countries.
• It is now most often seen as a consequence of chronic alcohol abuse, recurrent vomiting, total parenteral
nutrition, and bariatric surgery. Thiamine deficiency polyneuropathy can occur in normal, healthy young
• Dry beriberi refers to neuropathic symptoms
• Wet beriberi is used when cardiac manifestations predominate (in reference to edema).
• Beriberi was relatively uncommon until the late 1800s when it became widespread among people for whom
rice was a dietary mainstay. This epidemic was due to a new technique of processing rice that removed
the germ from the rice shaft, rendering the so- called polished rice deficient in thiamine and other essential
nutrients.

III. VITAMIN E DEFICIENCY

• Clinical features may not appear until many years after the onset of deficiency.
• Main clinical features are spinocerebellar ataxia and polyneuropathy, thus resembling, Friedreich’s ataxia
or other spinocerebellar ataxias.
• Patient manifest progressive ataxia and signs of posterior column dysfunction, such as impaired joint
position and vibratory sensation.

IV. VITAMIN B6 DEFICIENCY

• Can produce neuropathic manifestations from both deficiency and toxicity manifesting as generalized
axonal sensorimotor polyneuropathy.
• Vitamin B supplementation with 50-100 mg/d is suggested for patients being treated with isoniazid or
hydralazine.

V. PELLAGRA (NIACIN DEFICIENCY)

• Neurologic manifestations are variable; abnormalities can develop in the brain and spinal cord as well as
peripheral nerves.
• When peripheral nerves are involved, the neuropathy is usually mild and resembles beri beri.
• Treatment is with niacin 40-250 mg/d

VI. COPPER DEFICIENCY

• Most patients present with lower limb paresthesias, weakness, spasticity, and gait difficulties.
• Replacement consists of oral copper sulfate or gluconate 2mg one to three times a day.

VII. NEUROPATHY ASSOCIATED WITH GASTRIC SURGERY

• The clinical picture is one of acute or subacute sensory loss and weakness.
• Neuropathy following weight loss surgery usually occurs in the first several months after surgery.
 • Management consist of parenteral vitamin supplementation, especially including thiamine.

GUILLAIN-BARRÉ SYNDROME

GUILLAIN-BARRÉ SYNDROME (GBS)

• Acute, frequently severe, and fulminant polyradiculoneuropathy that is autoimmune in nature.

• Males are at slightly higher risk for GBS than females

I. CLINICAL MANIFESTATIONS
• GBS manifests as a rapidly evolving AREFLEXIC MOTOR PARALYSIS with or without sensory disturbance.
• The usual pattern is an ASCENDING paralysis that may be first noticed as rubbery legs.
• Weakness typically evolves over hours to a few days and is frequently accompanied by tingling dysesthesias
in the extremities.
• The legs are usually more affected than the arms, and facial diparesis is present in 50% of affected
individuals.
• The lower cranial nerves are also frequently involved, causing bulbar weakness with difficulty handling
secretions and maintaining an airway; the diagnosis in these patients may initially be mistaken for
brainstem ischemia.
• Pain in the neck, shoulder, back, or diffusely over the spine is also common in the early stages of GBS,
occurring in 50% of patients.
• Most patients require hospitalization, and in different series up to 30% require ventilatory assistance at some
time during the illness.
• Once clinical worsening stops and patient reaches a plateau (almost always within 4 weeks of onset),
further progression is unlikely.
• Autonomic involvement is common and may occur even in patients whose GBS is otherwise mild: usual
manifestations are:
o Loss of vasomotor control with wide fluctuation in blood pressure
o Postural hypotension
o Cardiac dysrhythmias
o These features require close monitoring and management and can be fatal.

II. ANTECEDENT EVENTS

• Approximately 70% of cases of GBS occur 1–3 weeks after an acute infectious process, usually
respiratory or gastrointestinal.
• Culture and seroepidemiologic techniques show that 20–30% of all cases occurring in North America,
Europe, and Australia are preceded by infection or reinfection with Campylobacter jejuni.
• A similar proportion is preceded by a human herpes virus infection, often CMV or Epstein-Barr virus.
III.
• In the demyelinating forms of GBS, the basis for flaccid paralysis and sensory disturbance is conduction
block.
• This finding, demonstrable electrophysiologically, implies that the axonal connections remain intact.
• Hence, recovery can take place rapidly as remyelination occurs.

IV. LABORATORY FEATURES

 • CSF findings are DISTINCTIVE, consisting of:
o Elevated CSF protein level [1–10 g/L (100–1000 mg/dL)] WITHOUT accompanying pleocytosis
o Often NORMAL when symptoms have been present for < 48 hours
o By the end of the first week, level of protein is usually ELEVATED

V. DIAGNOSIS
• The diagnosis of AIDP is made by recognizing the pattern of rapidly evolving paralysis with areflexia,
absence of fever or other systemic symptoms, and characteristic antecedent events.

VI. TREATMENT: GUILLAIN-BARRÉ SYNDROME

• Treatment should be initiated as soon as after diagnosis if possible
• 2 weeks after the motor symptom, it is not known whether immunotherapy is still effective.
• If the patient has already reached the plateau stage, then treatment probably is no longer indicated, unless
the patient has severe motor weakness and one cannot exclude the possibility that an immunologic attack
is still ongoing.
• High-dose intravenous immune globulin (IVIg) or plasmapheresis can be initiated, as they are equally
effective for typical GBS
• A combination of the two therapies is not significantly better than either alone.
• IVIg is often the INITIAL therapy chosen because of its ease of administration and good safety record
• IVIg is administered as five daily infusions for a total dose of 2 g/kg body weight.
• A course of plasmapheresis usually consists of 40–50 mL/kg plasma exchange (PE) four to five times over
a week.
• Glucocorticoids have not been found to be effective in GBS.

MYASTHENIA GRAVIS

MYASTHENIA GRAVIS

• Myasthenia gravis (MG) is a neuromuscular disorder characterized by weakness and fatigability of skeletal
muscles.
• Underlying defect is a DECREASE in the number of available acetylcholine receptors (AChRs) at
neuromuscular junctions due to an antibody-mediated autoimmune attack.

I. PATHOPHYSIOLOGY
• At the neuromuscular junction, acetylcholine (ACh) is synthesized in the motor nerve terminal and stored in
vesicles (quanta).
• Fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle
membrane

II. CLINICAL FEATURES

• MG is not rare, having a prevalence of 2–7 in 10,000.
• Affects individuals in all age groups: peaks of incidence occur in women in their twenties & thirties and in
men in fifties & sixties.
• Overall, women are affected more frequently than men, in a ratio of 3:2.
• CARDINAL features = WEAKNESS and FATIGABILITY of muscles.
• The weakness INCREASES during repeated use (fatigue) or late in the day, and may IMPROVE following
rest or sleep
• Exacerbations and remissions may occur, particularly during the first few years after the onset of the disease.
• Remissions are rarely complete or permanent. Unrelated infections or systemic disorders can lead to
increased myasthenic weakness and may precipitate "crisis”.

III. DIAGNOSIS AND EVALUATION

• Diagnosis is suspected on the basis of weakness and fatigability in the typical distribution described above,
without loss of reflexes or impairment of sensation or other neurologic function
TREATMENT OF MYASTHENIA GRAVIS
 I. ANTI-CHOLINESTERASE MEDICATIONS
• PYRIDOSTIGMINE = MOST widely used
anticholinesterase drug.
• Overlap with anticholinesterase medication: may
cause increased weakness and other side effects
o Muscarinic effects = diarrhea, abdominal cramps,
salivation, nausea
o Atropine / diphenoxylate or loperamide is useful for
the treatment of gastrointestinal symptoms

II. THYMECTOMY
• Two separate issues should be distinguished:
o 1) Surgical removal of thymoma
o 2) Thymectomy as a treatment for MG.
• Surgical removal of a thymoma is necessary because
of the possibility of local tumor spread, although most
thymomas are histologically benign.
• In the absence of a tumor, the available evidence
suggests that up to 85% of patients experience
improvement after thymectomy; of these, 35% achieve
drug-free remission.

III. IMMUNOSUPPRESSION
• Using glucocorticoids, azathioprine, and other drugs is
effective in nearly all patients with MG.
• The choice of drugs or other immunomodulatory
treatments should be guided by the relative benefits and
risks for the individual patient and the urgency of
treatment.

• Glucocorticoid Therapy
o Produce improvement in myasthenic weakness in the great majority of patients.
o To minimize adverse effects, prednisone should be given in a single dose rather than in divided
doses throughout the day.

SEIZURES AND EPILEPSY

• Seizure- transient occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal
activity in the brain.
• Manifestations range from dramatic convulsive activity to experiential phenomena not readily discernible by
an observer.
• ~5–10% of the population will have at least one seizure; highest incidence occurring in early childhood and
late adulthood
• Epilepsy- a person has a risk of recurrent seizures due to a chronic, underlying process.
• Epilepsy refers to a clinical phenomenon rather than a single disease entity,
• There are various epilepsy syndromes in which the clinical and pathologic characteristics are distinctive and
suggest a specific underlying etiology.
• Epilepsy definition- two or more unprovoked seizures
• Incidence of epilepsy is ~0.3–0.5% in
• Prevalence of epilepsy has been estimated at 5–30 persons per 1000.
• International League Against Epilepsy (ILAE) Commission on Classification and Terminology is based on the
clinical features of seizures and associated electroencephalographic findings.
 • Other potentially distinctive features such as etiology or cellular substrate are not considered in this
classification system
• Focal seizures originate within networks limited to one brain region (note that the term partial seizures is no
longer used
o Usually associated with structural abnormalities of the brain
• Generalized seizures arise within and rapidly engage networks distributed across both cerebral hemispheres
o may result from cellular, biochemical, or structural abnormalities that have a more widespread
distribution

Focal Onset Seizures

• arise from a neuronal network either discretely localized within one brain region or more broadly distributed
but still within a cerebral hemisphere.
• classification emphasizes the effect on awareness (intact or impaired) and nature of the onset (motor or
nonmotor)
• Can also evolve into generalized seizures.
• Routine interictal EEG in patients with focal seizures is often normal or may show brief discharges termed
epileptiform spikes, or sharp wave
• can arise from the medial temporal lobe or inferior frontal lobe
• EEG recorded during the seizure may be nonlocalizing

Focal seizure with intact awareness

• can have motor manifestations (such as tonic, clonic, or myoclonic movements) or nonmotor manifestations
(such as sensory, autonomic, or emotional symptoms) without impairment of awareness.
• Jacksonian march abnormal motor movements may begin in a very restricted region such as the fingers and
gradually progress (over seconds to minutes) to include a larger portion of the extremity.
o spread of seizure activity over a progressively larger region of motor cortex
• patients may experience a localized paresis (Todd’s paralysis) for minutes to many hours in the involved
region following the seizure.
• Epilepsia partialis continua- seizure may continue for hours or days.
o often refractory to medical therapy.
• May also manifest as changes in somatic sensation (e.g., paresthesias), vision (flashing lights or formed
hallucinations), equilibrium (sensation of falling or vertigo), or autonomic function; also causes alterations in
hearing, olfaction, or emotional state.
• Auras- odd, internal feelings such as fear, a sense of impending change, detachment, depersonalization, déjá
vu, or illusions that objects are growing smaller (micropsia) or larger (macropsia). These subjective, “internal”
events that are not directly observable by someone else.

Focal Seizure with Impaired Awareness

• Focal seizures that are accompanied by a transient impairment of the patient’s ability to maintain normal
contact with the environment.
• unable to respond appropriately to visual or verbal commands during the seizure and has impaired recollection
or awareness of the ictal phase.
• frequently begin with an aura
• Start of the ictal phase is often a motionless stare (mark of impaired awareness)
• Usually accompanied by automatisms--- involuntary, automatic behaviors that have a wide range of
manifestations.
o chewing, lip smacking, swallowing, or “picking” movements of the hands, or more elaborate
behaviors such as a display of emotion or running.
• Examination immediately following the seizure may show an anterograde amnesia or transient neurological
deficits (such as aphasia, hemi-neglect, or visual loss)
Evolution of Focal to Generalized Seizures
 • Focal seizures can spread to involve both cerebral hemispheres and produce a generalized seizure, usually
of the tonic-clonic variety.
• Usually following focal seizures arising from a region in the frontal lobe
• Focal onset of the seizure becomes apparent only when a careful history identifies a preceding aura
• Focal onset is often not clinically evident

Generalized Onset Seizures

Typical Absence Seizure

• characterized by sudden, brief lapses of consciousness without loss of postural control, usually lasting for only
seconds, consciousness returns as suddenly as it was lost, and there is no postictal confusion.
• usually accompanied by subtle, bilateral motor signs
o rapid blinking of the eyelids, chewing movements, or small-amplitude, clonic movements of the
hands.
• Associated with a group of genetically determined epilepsies with onset usually in childhood (ages 4–10 years)
or early adolescence and are the main seizure type in 15–20% of children with epilepsy.
• the first clue to absence epilepsy is often unexplained “daydreaming” and a decline in school performance
recognized by a teacher.
• Electrophysiologic hallmark is a generalized, symmetric, 3-Hz spike-and-slow-wave discharges that begins
and ends suddenly, superimposed on a normal EEG background.
• Hyperventilation tends to provoke these electrographic discharges and even the seizures themselves

Atypical Absence Seizures

• Have features that deviate both clinically and electrophysiologically from typical absence seizures.
• Lapse of consciousness is usually of longer duration and less abrupt in onset and cessation
• seizure is accompanied by more obvious motor signs that may include focal or lateralizing features.
• EEG- generalized, slow spike-and-slow-wave pattern with a frequency of ≤2.5 per second.
• usually associated with diffuse or multifocal structural abnormalities of the brain
• may accompany other signs of neurologic dysfunction( ie. mental retardation).
• Less responsive to anticonvulsants compared to typical absence seizures.

Generalized, Tonic- Clonic Seizures

• The main seizure type in ~10% of all persons with epilepsy

• The most common seizure type resulting from metabolic derangements
• Usually begins abruptly without warning
• Initial phase of the seizure is usually tonic contraction of muscles throughout the body
• Tonic contraction of the muscles of expiration and the larynx at the onset----produces a loud moan or “ictal
cry.”
o Respirations are impaired, secretions pool in the oropharynx, and cyanosis develops.
• Contraction of the jaw muscles----tongue biting.
• Increased sympathetic tone leads to increases in heart rate, blood pressure, and pupillary size.
• After 10–20s------evolves into the clonic phase (superimposition of periods of muscle relaxation on the tonic
muscle contraction).
• The periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more
than 1 min.
• Postictal phase---- unresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorous
breathing and partial airway obstruction.
o Bladder or bowel incontinence may also occur
• Gradually regain consciousness over minutes to hours, with a period of postictal confusion.
• Duration of impaired consciousness in the postictal phase can be extremely long in patients with prolonged
seizures or underlying central nervous system (CNS) diseases
 • EEG during the tonic phase--- progressive increase in generalized low-voltage fast activity, followed by gener-
alized high-amplitude, polyspike discharges; clonic phase----high-amplitude activity is typically interrupted by
slow waves to create a spike-and-slow-wave pattern.
• Postictal EEG shows diffuse suppression of all cerebral activity, -----gradual recovery

Atonic Seizures

• Characterized by sudden loss of postural muscle tone lasting 1–2 s.

• Consciousness is briefly impaired, but with no postictal confusion.
• EEG shows brief, generalized spike-and-wave discharges followed immediately by diffuse slow waves that
correlate with the loss of muscle tone.
• usually seen in association with known epilepsy syndromes.

Myoclonic Seizures

• Sudden and brief muscle contraction that may involve one part of the body or the entire body.
• Pathologic myoclonus- most commonly seen in association with metabolic disorders, degenerative CNS
diseases, or anoxic brain injury.
• Myoclonic seizures are considered to be true epileptic events because they are caused by cortical dysfunction.
• EEG shows bilaterally synchronous spike-and-slow-wave discharges immediately prior to the movement and
muscle artifact associated with the myoclonus.
• Usually coexist with other forms of generalized seizures but are the predominant feature of juvenile myoclonic
epilepsy (JME)

Epileptic Spasms

• Characterized by a briefly sustained flexion or extension of predominantly proximal muscles, including truncal
muscles.
• EEG usually shows hypsarrhythmia-- diffuse, giant slow waves with a chaotic background of irregular,
multifocal spikes and sharp waves.
• Clinical spasm-----marked suppression of the EEG background (“electrodecremental response”)
• EMG---- characteristic rhomboid pattern
• Occur predominantly in infants likely due to differences in neuronal function and connectivity in the immature
versus mature CNS.

Epilepsy Syndromes

Juvenile Myoclonic Epilepsy

• Generalized seizure disorder of unknown cause that appears in early adolescence and is usually
characterized by bilateral myoclonic jerks that may be single or repetitive.
• Most frequent in the morning after awakening and can be provoked by sleep deprivation.
• Consciousness is preserved unless the myoclonus is especially severe.
• Many patients also experience generalized tonic-clonic seizures; 1/3 have absence seizures.
• Seizures usually respond well to appropriate anticonvulsant medication, however complete remission is
uncommon.
• Often a family history of epilepsy, and genetic linkage studies suggest a polygenic cause.

Lennox-Gastaut Syndrome

• Occurs in children and is defined by the following triad:

1. multiple seizure types (usually including generalized tonic-clonic, atonic, and atypical absence
seizures)
2. an EEG showing slow (<3 Hz) spike-and-wave discharges and a variety of other abnormalities
 3. impaired cognitive function in most but not all cases.
• Associated with CNS disease or dysfunction from a variety of causes,
• de novo mutations, developmental abnormalities, perinatal hypoxia/ischemia, trauma, infection, and other
acquired lesions.
• A nonspecific response of the brain to diffuse neuronal dysfunction.
• many patients have a poor prognosis
due to the underlying CNS disease
and the physical and psychosocial
consequences of severe, poorly
controlled epilepsy.

Mesial Temporal Lobe Epilepsy Syndrome

• Most common syndrome associated

with focal seizures with impairment of
consciousness
• High-resolution magnetic resonance
imaging (MRI) can detect the
characteristic hippocampal sclerosis --
--essential in the pathophysiology of
MTLE for many patients
• Tends to be refractory to treatment
with anticonvulsants but responds well
to surgical intervention.

The Causes of Seizure and Epilepsy

3 clinical Observations:
• The normal brain is capable of having
a seizure under the appropriate
circumstances, and there are
differences between individuals in the
susceptibility or threshold for seizures.
o With various underlying
endogenous factors that influence the threshold for having a seizure (genetic, normal development)

• There are a variety of conditions that have an extremely high likelihood of resulting in a chronic seizure disorder
o Ex: Penetrating head trauma--- 45% risk of subsequent epilepsy

• Seizures are episodic

o there are important provocative or precipitating factors that induce seizures in patients with epilepsy.
Causes According to Age

• Age is one of the most important factors

determining both the incidence and the likely
causes of seizures or epilepsy.
• Neonatal period and early infancy---- causes
include hypoxic-ischemic encephalopathy,
trauma, CNS infection, congenital CNS
abnormalities, and metabolic disorders
o Hypoglycemia and hypocalcemia
are also causes of seizures early
after delivery.
o Seizures due to inborn errors of
metabolism usually present once
regular feeding begins, typically 2–
3 days after birth.
o Pyridoxine (vitamin B6) deficiency--
effectively treated with pyridoxine
replacement

• Late infancy and early childhood---most

commonly febrile seizures (fevers with no
evidence of CNS infection or other defined
causes).
o The overall prevalence is 3–5%.
o Patients often have a family history
of febrile seizures or epilepsy.
o Usually occur between 3 months
and 5 years of age (peak incidence
between 18 and 24 months).
o Likely to occur during the rising
phase of the temperature curve
o Simple febrile seizure- single,
isolated event, brief, and symmetric
in appearance.
▪ Not associated with
increased risk of
developing epilepsy
o Complex febrile seizures--
characterized by repeated seizure
activity, duration >15 minutes, or by focal features.
▪ One-third of patients with febrile seizures will have a recurrence(mostly if seizure occurs in
the 1st year of life), but <10% have three or more episodes
▪ Have a risk of 2–5% of developing epilepsy;

• Childhood--- many well-defined epilepsy syndromes present.

o Temporal lobe epilepsy usually presents in childhood (may be related to mesial temporal lobe
sclerosis).
• Adolescence and early adulthood---idiopathic or genetically based epilepsy syndromes (JME and juvenile
absence epilepsy) become less common; epilepsies secondary to acquired CNS lesions begin to predomi-
nate.
o Seizures may be associated with head trauma, parasitic CNS infections (ie cysticercosis), brain
tumors, congenital CNS abnormalities, illicit drug use, or alcohol withdrawal.
o Autoantibodies directed against CNS antigens such as potassium channels or glutamate receptors
are a newly recognized cause of epilepsy that also begins to appear in this age group
o Head trauma- common cause of epilepsy in adolescents and adults; likelihood of developing epilepsy
is strongly correlated with the severity of the injury.
▪ Penetrating head wound, depressed skull fracture, intracranial hemorrhage, or prolonged
posttraumatic coma or amnesia has a 30–50% risk of developing epilepsy
▪ Closed head injury and cerebral contusion has a 5–25% risk.
 ▪ Older adults ----cerebrovascular disease, trauma (including subdural hematoma), CNS tumors, and degenera-
tive diseases.
▪ Cerebrovascular disease may account for ~50% of new cases of epilepsy in patients >65 years.
▪ Acute seizures are seen more often with embolic rather than hemorrhagic or thrombotic stroke.
▪ Chronic seizures typically appear months to years after the initial event and are associated with all forms of
stroke.
▪ Metabolic disturbances such as electrolyte imbalance, hypo- or hyperglycemia, renal failure, and hepatic
failure may cause seizures at any age.

Basic Mechanisms

Mechanisms of Seizure Initiation and Propagation

▪ Focal seizure activity can begin in a very discrete region of cortex and then slowly invade the surrounding
regions.
▪ Hallmark of an established seizure--- electrographic “spike” due to intense near-simultaneous firing of a large
number of local excitatory neurons,
▪ Bursting activity in individual neurons (the “paroxysmal depolarization shift”) is caused by a relatively long-
lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+)-----opening of
voltage-dependent sodium (Na+) channels, influx of Na+, and generation of repetitive action potentials.
▪ Next is a hyperpolarizing afterpotential mediated by γ-aminobutyric acid (GABA) receptors or potassium (K+)
channels, depending on the cell type.
▪ Synchronized bursts from a sufficient number of neurons ---- spike discharge on the EEG.
▪ Spreading seizure wavefront is thought to slow and ultimately halt by intact hyperpolarization and a “surround”
inhibition created by feedforward activation of inhibitory neurons.
▪ Recruitment of surrounding neurons via a number of synaptic and nonsynaptic mechanisms, including:
1. an increase in extracellular K+, which blunts hyperpolarization and depolarizes neighboring neurons;
(2) accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release
2. depolarization-induced activation of the N-methyl-d-aspartate (NMDA) subtype of the excitatory
amino acid receptor, which causes additional Ca2+ influx and neuronal activation
3. ephaptic interactions related to changes in tissue osmolarity and cell swelling.

• Mechanisms intrinsic to the neuron include changes in the conductance of ion channels, response
characteristics of membrane receptors, cytoplasmic buffering, second-messenger systems, and protein
expression as determined by gene transcription, translation, and posttranslational modification.
• Mechanisms extrinsic to the neuron include changes in the amount or type of neurotransmitters present at the
synapse, modulation of receptors by extracellular ions and other molecules, and temporal and spatial
properties of synaptic and nonsynaptic input.
• Nonneural cells, such as astrocytes and oligodendrocytes, have an important role in many of these
mechanisms as well.
• Basic mechanisms of other precipitating factors of seizures, such as sleep deprivation, fever, alcohol
withdrawal, hypoxia, and infection, are not as well understood
• Knowledge of the mechanisms responsible for initiation and propagation of most generalized seizures remains
rudimentary and reflects the limited understanding of the connectivity of the brain at a systems level.

Mechanisms of Epileptogenesis

• Epileptogenesis---transformation of a normal neuronal network into one that is chronically hyperexcitable.

• Delay of months to years between an initial CNS injury and the first clinically evident seizure.
• The injury gradually lowers the seizure threshold in the affected region until a spontaneous seizure occurs.
• Some forms of epileptogenesis are related to structural changes in neuronal networks.
• In response to the loss of neurons-- reorganization of surviving neurons in a way that affects the excitability of
the network.
• Similar models have provided strong evidence for long-term alterations in intrinsic, biochemical properties of
cells within the network such as chronic changes in glutamate or GABA receptor function. Induction of
inflammatory cascades may be a critical factor in these processes as well.

Genetic causes of Epilepsy

 • Many of the inherited epilepsies are due to mutations affecting ion channel function.
• part of the larger group of channelopathies causing paroxysmal disorders such as cardiac arrhythmias,
episodic ataxia, periodic weakness, and familial hemiplegic migraine
• De novo mutations may explain a significant proportion of these syndromes, especially those with onset in
early childhood

Mechanisms of Action of Antiepileptic Drugs

• Antiepileptic drugs appear to act primarily by blocking the initiation or spread of seizures.
• Through a variety of mechanisms that modify the activity of ion channels or neurotransmitters
o Inhibition of Na+-dependent action potentials in a frequency-dependent manner (e.g., phenytoin,
carbamazepine, lamotrigine, topiramate, zonisamide, lacosamide, rufinamide)
o Inhibition of voltage-gated Ca2+ channels (phenytoin, gabapentin, pregabalin)
o Facilitating the opening of potassium channels (ezogabine)
o Attenuation of glutamate activity (lamotrigine, topiramate, felbamate), potentiation of GABA receptor
function (benzodiazepines and barbiturates)
o Increase in the availability of GABA (valproic acid, gabapentin, tiagabine)
o Modulation of release of synaptic vesicles (levetiracetam, brivaracetam)
• Ethosuximide and valproic acid probably act by inhibiting T-type Ca2+ channels in thalamic neurons.
• Currently no drugs known to prevent the formation of a seizure focus following CNS injury.

Approach to a patient with Seizure

• First priorities are attention to vital signs, respiratory and cardiovascular support, and treatment of seizures
if they resume.
• Life-threatening conditions such as CNS infection, metabolic derangement, or drug toxicity must be
recognized and managed appropriately.
• If not acutely ill----evaluation will initially focus on whether there is a history of earlier seizures.
• If the first seizure, emphasis will be to:
1. establish whether the reported episode was a seizure rather than another paroxysmal event
2. determine the cause of the seizure by identifying risk factors and precipitating events
3. decide whether anticonvulsant therapy is required in addition to treatment for any underlying illness.
• With prior seizures or a known history of epilepsy, evaluation is directed toward:
1. identification of the underlying cause and precipitating factors
2. determination of the adequacy of the patient’s current therapy.

History and Examination

• First goal is to determine whether the event was truly a seizure.

• in many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and laboratory
studies are often normal.
• Questions should focus on the symptoms before, during, and after the seizure.
• History should also focus on risk factors and predisposing events.
• In children, a careful assessment of developmental milestones may provide evidence for underlying CNS
disease.
• Precipitating factors such as sleep deprivation, systemic diseases, electrolyte or metabolic derangements,
acute infection, drugs that lower the seizure threshold, or alcohol or illicit drug use should also be identified.
• Physical examination includes a search for signs of infection or systemic illness.
• All patients require a complete neurologic examination, with particular emphasis on eliciting signs of cerebral
hemispheric disease.
o Careful assessment of mental status (including memory, language function, and abstract thinking)--
- lesions in the anterior frontal, parietal, or temporal lobes.
o Visual fields---- optic pathways and occipital lobes.
o Screening tests of motor function such as pronator drift, deep tendon reflexes, gait, and coordination
may suggest lesions in motor (frontal) cortex, and cortical sensory testing (e.g., double simultaneous
stimulation) may detect lesions in the parietal cortex.

Laboratory Studies

• Routine blood studies are indicated to identify the more common metabolic causes of seizures
• Screen for toxins in blood and urine should also be obtained
 • A lumbar puncture is indicated if there is any suspicion of meningitis or encephalitis (mandatory in patients
with HIV, even without signs and symptoms)
• Testing for autoantibodies in the serum and cerebrospinal fluid (CSF) should be considered in patients
presenting with a seemingly aggressive form of epilepsy associated with other abnormalities such as
psychiatric symptoms or cognitive disturbances.

Electrophysiologic Studies

• Potential difference between pairs of electrodes on the scalp (bipolar derivation) or between individual scalp
electrodes and a relatively inactive common reference point (referential derivation) is amplified and displayed
on a computer monitor, oscilloscope, or paper.
• The characteristics of the normal EEG depend on the patient’s age and level of arousal.
• The rhythmic activity normally recorded represents the postsynaptic potentials of vertically oriented pyramidal
cells of the cerebral cortex and is characterized by its frequency.
• Normal awake adults with the eyes closed---- 8- to 13-Hz alpha rhythm is seen posteriorly in the EEG,
intermixed with a variable amount of generalized faster (beta) activity (>13 Hz)
o the alpha rhythm is attenuated when the eyes are opened.
• During drowsiness, the alpha rhythm is also attenuated; with light sleep, slower activity in the theta (4–7 Hz)
and delta (<4 Hz) ranges becomes more conspicuous.
• All patients who have a possible seizure disorder should be evaluated with an EEG as soon as possible.
• Presence of electrographic seizure activity during the clinically evident event clearly establishes the diagnosis.
• The absence of electrographic seizure activity does not exclude a seizure disorder
o EEG is always abnormal during generalized tonic-clonic seizures.
• Activating procedures to provoke abnormalities--- commonly include hyperventilation (for 3 or 4 min), photic
stimulation, sleep, and sleep deprivation on the night prior to the recording.

• Video-EEG telemetry---routine approach for the accurate diagnosis of epilepsy in patients with poorly
characterized events or seizures that are difficult to control.

• EEG may also be helpful in the interictal period by showing certain abnormalities that are highly supportive of
the diagnosis of epilepsy.
o Epileptiform activity consists of bursts of abnormal discharges containing spikes or sharp waves.
• EEG cannot establish the diagnosis of epilepsy in many cases.
• EEG is also used for classifying seizure disorders and aiding in the selection of anticonvulsant medications
• Routine scalp-recorded EEG may also be used to assess the prognosis of seizure disorders
o normal EEG implies a better prognosis; abnormal background or profuse epileptiform activity---
worse outcome.
• EEG has not proved to be useful in predicting which patients with predisposing conditions such as head injury
or brain tumor will go on to develop epilepsy
• Magnetoencephalography (MEG)- another way of looking noninvasively at cortical activity.
o measures the small magnetic fields that are generated by electrical activity

Brain Imaging

• Almost all patients with new-onset seizures should have a brain imaging
• Exception are children who have an unambiguous history and examination suggestive of a benign,
generalized seizure disorder (ie absence epilepsy)
• MRI is superior to CT Scan for the detection of cerebral lesions associated with epilepsy
• CT scanning should be performed emergently when MRI is not immediately available
• Positron Emission Tomography (PET) and single-photon emission computed tomography (SPECT) are also
used to evaluate certain patients with medically refractory seizures

Genetic Testing

• Genetic testing is beginning to emerge as part of the diagnostic evaluation of patients with epilepsy.
 • May offer a guide for therapeutic options
• Being done mainly in infants and children with epilepsy
syndromes thought to have a genetic cause. Should
also be considered in older patients with a history
suggesting an undiagnosed genetic epilepsy syndrome
that began early in life.

Differential Diagnosis of Seizures

Syncope

• Syncopal episode is more likely if the event was

provoked by acute pain or emotional stress or occurred
immediately after arising from the lying or sitting
position.
• Patients describe a stereotyped transition from
consciousness to unconsciousness that includes
tiredness, sweating, nausea, and tunneling of vision,
and they experience a relatively brief loss of con-
sciousness.
• Headache or incontinence usually suggests a seizure
but may on occasion also occur with syncope.
• A brief period (i.e., 1–10 s) of convulsive motor activity is frequently seen immediately at the onset of a
syncopal episode, especially if the patient remains in an upright posture after fainting (e.g., in a dentist’s chair)
and therefore has a sustained decrease in cerebral perfusion.
• Rarely, a syncopal episode can induce a full tonic-clonic seizure.
• Must evaluate for both seizure and syncopal episode

Psychogenic Seizure

• Nonepileptic behaviors that resemble seizures.

• Often part of a conversion reaction precipitated by
underlying psychological distress.
• Behaviors like side-to-side turning of the head,
asymmetric and large-amplitude shaking movements of
the limbs, twitching of all four extremities without loss of
consciousness, and pelvic thrusting are more commonly
associated with psychogenic seizures.
• Often last longer than epileptic seizures and may wax
and wane over minutes to hours.
• Video-EEG monitoring is very useful when historic
features are nondiagnostic.
• Measurement of serum prolactin levels may also help to
distinguish between epileptic and psychogenic seizures
• Most generalized seizures and some focal seizures are
accompanied by rises in serum prolactin
• Diagnosis of psychogenic seizures does not exclude a
concurrent diagnosis of epilepsy

Treatment of Seizures and Epilepsy

• Almost always multimodal and includes:
o Treatment of underlying conditions that cause
or contribute to the seizures
o Avoidance of precipitating factors
o Suppression of recurrent seizures by
prophylactic therapy with antiepileptic
medications or surgery
o Addressing a variety of psychological and
social issues.
• Treatment plans must be individualized
Treatment of Underlying Conditions
• If with a metabolic disturbance, then treatment is aimed at reversing the metabolic problem and preventing
its recurrence.
• Therapy with antiepileptic drugs is usually unnecessary unless the metabolic disorder cannot be corrected
promptly and the patient is at risk of having further seizures.
• Avoidance of the drug is done if a medication is the cause of the seizure
o there is usually no need for antiepileptic medications unless subsequent seizures occur in the
absence of these precipitants.
• Seizures caused by a structural CNS lesion such as a brain tumor, vascular malformation, or brain abscess
may not recur after appropriate treatment of the underlying lesion.
o risk that the seizure focus will remain in the surrounding tissue or develop de novo as a result of
gliosis and other processes induced by surgery, radiation, or other therapies.
o Most patients maintained on an antiepileptic medication for at least 1 year, and an attempt is made
to withdraw medications only if the patient has been completely seizure free.
o If refractory to medication----- surgical removal of the epileptic brain region
Avoidance of Precipitating Factors
• Almost universal precipitating factor for seizures is sleep deprivation
• Alcohol related----encouraged to modify their drinking habits accordingly.
• Relatively rare cases of patients with seizures that are induced by highly specific stimuli like a video game
monitor, music, or an individual’s voice (“reflex epilepsy”).
• Often an association between stress and seizures---- stress reduction techniques such as physical exercise,
meditation, or counseling may be helpful.
Antiepileptic Drug Therapy

• Mainstay of treatment for most patients with epilepsy.

• Overall goal is to completely prevent seizures without causing any untoward side effects
• preferably with a single medication and a dosing schedule that is easy for the patient to follow.
• Seizure classification is an important element in designing the treatment plan
When to initiate Antiepileptic Drug Therapy

• Should be started in any patient with recurrent seizures of unknown etiology or a known cause that cannot be
reversed
• Patients with a single seizure due to an identified lesion such as a CNS tumor, infection, or trauma, in which
there is strong evidence that the lesion is epileptogenic, should be treated.
• The risk of seizure recurrence in a patient with an apparently unprovoked or idiopathic seizure is uncertain,
with estimates ranging from 31 to 71% in the first 12 months after the initial seizure.
• Generally accepted risk factors associated with recurrent seizures include:
▪ an abnormal neurologic examination
▪ seizures presenting as status epilepticus
▪ postictal Todd’s paralysis
▪ a strong family history of seizures
▪ an abnormal EEG

Selection of Antieplieptic Drugs

• Worldwide, older medications such as phenytoin, valproic acid, carbamazepine, phenobarbital, and
ethosuximide are generally used as first-line therapy for most seizure disorders
• Most of the new drugs that have become available in the past decade are used as add-on or alternative
therapy

• Factors influencing the choice of an initial medication include the convenience of dosing and potential side
effects.
o newer drugs have reduced drug–drug interactions and easier dosing.
• Almost all cause similar, dose-related side effects such as sedation, ataxia, and diplopia.
• Most of the older drugs and some of the newer ones can also cause idiosyncratic toxicity such as rash, bone
marrow suppression, or hepatotoxicity.
• Patients with mutations in SCN1A should generally avoid taking phenytoin or lamotrigine
• Patients with mutations in the SCN2A or SCN8A respond favorably to high-dose phenytoin. Genetic testing
may also help predict antiepileptic drug toxicity.
Antiepileptic Drugs for Focal Seizures
 • Carbamazepine, oxcarbazepine, lamotrigine, phenytoin, and levetiracetam---drugs of choice for initial
treatment of focal seizures
• Overall they have very similar efficacy, but differences in pharmacokinetics and toxicity are the main
determinants for use in a given patient
• Carbamazepine can cause leukopenia, aplastic anemia, or hepatotoxicity
• Oxcarbazepine has the advantage of being metabolized in a way that avoids an intermediate metabolite
associated with some of the side effects of carbamazepine; also with fewer drug interactions.
• Lamotrigine tends to be well tolerated in terms of side effects.
o Can be at risk for extremely severe skin disease and lead to Stevens-Johnson syndrome if
unrecognized and if the medication is not discontinued immediately.
o risk reduced by the use of low initial doses and slow titration
o Must be started at lower initial doses when used as add-on therapy with valproic acid,
• Phenytoin has a relatively long half-life and offers the advantage of once or twice daily dosing
o Shows properties of nonlinear kinetics (small increases can precipitate marked side effects)
o Long-term use of phenytoin is associated with untoward cosmetic effects (e.g., hirsutism, coarsening
of facial features, gingival hypertrophy) and effects on bone metabolism.
• Levetiracetam----no known drug–drug interactions
o some complain of irritability, anxiety, and other psychiatric symptoms.
• Topiramate can be used for both focal and generalized seizures.
o can cause significant psychomotor slowing and other cognitive problems.
o should not be used in patients at risk for the development of glaucoma or renal stones.
• Valproic acid-- effective alternative for focal seizures, especially when the seizures generalize.
o Gastrointestinal side effects are fewer when using the delayed-release formulation (Depakote)
o can rarely cause reversible bone marrow suppression and hepatotoxicity
o has relatively high risks of unacceptable adverse effects for women of childbearing age,
(hyperandrogenism and teratogenesis)
o Irreversible, fatal hepatic failure appearing as an idiosyncratic is a relatively rare complication; risk
is highest in children <2 years old, especially those taking other antiepileptic drugs or with inborn
errors of metabolism.
• Zonisamide, brivaracetam, tiagabine, gabapentin, and lacosamide are additional drugs currently used for the
treatment of focal seizures with or without evolution into generalized seizures.
• Phenobarbital and other barbiturate compounds were commonly used in the past as first-line therapy for many
forms of epilepsy.
o frequently cause sedation in adults, hyperactivity in children, and other more subtle cognitive
changes
Antiepileptic Drug for Generalized Seizures
• Lamotrigine, valproic acid and levetiracetam--considered the best initial choice for the treatment of primary
generalized, tonic-clonic seizures.
• Topiramate, zonisamide, phenytoin, carbamazepine, and oxcarbazepine are suitable alternatives
• Valproic acid--effective in absence, myoclonic, and atonic seizures.
• Levetiracetam is increasingly considered the initial drug of choice for women with epilepsies having mixed
seizure types
• Lamotrigine is also an alternative to valproate, especially for absence epilepsies.
• Ethosuximide is a particularly effective drug for the treatment of uncomplicated absence seizures
o Periodic monitoring of blood cell counts is required since ethosuximide rarely causes bone marrow
suppression.
Initiation and Monitoring of Therapy
• Goal is to prevent seizures and minimize the side effects of treatment
• Most antiepileptic drugs need to be introduced relatively slow to minimize side effects.
• Minor side effects (mild sedation, slight changes in cognition, or imbalance) typically resolves within a few
days.
• Subsequent increases should be made only after achieving a steady state with the previous dose (i.e., after
an interval of five or more half-lives).
• Monitoring of serum antiepileptic drug levels can be very useful for establishing the initial dosing schedule.
• Key determinants of optimum dosing are the clinical measures of seizure frequency and presence of side
effects.
• Conventional assays of serum drug levels measure the total drug (i.e., both free and protein bound).
o Concentration of free drug that reflects extracellular levels in the brain and correlates best with
efficacy.
 • Dose should be changed only if seizures remain uncontrolled, not just to achieve a “therapeutic” level.
Monitoring of antiepileptic drug levels is most useful for documenting adherence or assessing clinical
suspicion of toxicity.
• If seizures continue despite gradual increases to the maximum tolerated dose and documented compliance--
---- switch to another antiepileptic drug.
o Maintaining the patient on the first drug while a second drug is added.
o The dose of the second drug should be adjusted to decrease seizure frequency without causing
toxicity.
o First drug can then be gradually withdrawn (usually over weeks unless there is significant toxicity).
o Dose of the second drug is then further optimized based on seizure response and side effects.
• Monotherapy should be the goal whenever possible.

When to discontinue therapy

• Overall, about 50–60% of patients who have their seizures completely controlled with antiepileptic drugs can
eventually discontinue therapy.
• Profile which yields the greatest chance of remaining seizure free after drug withdrawal:
▪ complete medical control of seizures for 1–5 years
▪ single seizure type, with generalized seizures having a better prognosis than focal seizures
▪ normal neurologic examination, including intelligence
▪ no family history of epilepsy
▪ normal EEG
• Reasonable to attempt withdrawal of therapy after 2 years in a patient who meets all of the above criteria, is
motivated to discontinue the medication, and clearly understands the potential risks and benefits.
• Preferable to reduce the dose of the drug gradually over 2–3 months.
• Most recurrences occur in the first 3 months after discontinuing therapy,
o avoid potentially dangerous situations (driving or swimming)

Treatment of Refractory Epilepsy

• Approximately one-third of patients with epilepsy do not respond to treatment with a single antiepileptic drug
• Patients who have focal epilepsy related to an underlying structural lesion or those with multiple seizure types
and developmental delay are particularly likely to require multiple drugs.
• There are currently no clear guidelines for rational polypharmacy,
• In most cases, the initial combination therapy combines first-line drugs (i.e., carbamazepine, oxcarbazepine,
lamotrigine, valproic acid, levetiracetam, and phenytoin).
• If unsuccessful, add other drugs such as zonisamide, brivaracetam, topiramate, lacosamide, or tiagabine is
indicated.
• Patients with myoclonic seizures resistant to valproic acid may benefit from the addition of clonazepam or
clobazam,
• Those with absence seizures may respond to a combination of valproic acid and ethosuximide.
• If there is no improvement, a third drug can be added while the first two are maintained.
• If with response, the less effective/well tolerated of the first two drugs should be gradually withdrawn.
Surgical Treatment of Refractory Epilepsy
• Approximately 20–30% of patients with epilepsy continue to have seizures despite efforts
• Surgery can be extremely effective in substantially reducing seizure frequency and even providing complete
seizure control.
• Patient should have an efficient but relatively brief attempt at medical therapy and then be referred for
surgical evaluation.
• Most common surgical procedure for patients with temporal lobe epilepsy involves resection of the
anteromedial temporal lobe (temporal lobectomy) or a more limited removal of the underlying hippocampus
and amygdala (amygdalohippocampectomy).
• Focal seizures arising from extratemporal regions may be abolished by a focal neocortical resection with
precise removal of an identified lesion (lesionectomy).
• Localized neocortical resection without a clear lesion identified on MRI is also possible when other tests
(e.g., MEG, PET, SPECT) implicate a focal cortical region as a seizure onset zone.
• Cortical region cannot be removed---multiple subpial transection, which disrupts intracortical connections---
--used to prevent seizure spread.
• Hemispherectomy or multilobar resection is useful for some patients with severe seizures due to hemispheric
abnormalities (eg hemimegalencephaly)
 • Corpus callosotomy has been shown to be effective for disabling tonic or atonic seizures, usually when they
are part of a mixed-seizure syndrome (e.g., Lennox-Gastaut syndrome).
• Presurgical evaluation is designed to identify the functional and structural basis of the patient’s seizure
disorder.
• Inpatient video-EEG monitoring is used to define the anatomic location of the seizure focus and to correlate
the abnormal electrophysiologic activity with behavioral manifestations of the seizure.
• Routine scalp or scalp-sphenoidal recordings and a high-resolution MRI scan are usually sufficient for
localization of the epileptogenic focus
• Functional imaging studies such as SPECT, PET, and MEG are adjunctive tests that may help to reveal or
verify the localization of an apparent epileptogenic region.
• Once the presumed location of the seizure onset is identified, additional studies, including neuropsychological
testing, the intracarotid amobarbital test (Wada test), and functional MRI may be used to assess language
and memory localization and to determine the possible functional consequences of surgical removal of the
epileptogenic region.
• Standard noninvasive evaluation is not sufficient to localize the seizure onset zone,
• Exact extent of the resection to be undertaken can also be determined by performing cortical mapping at the
time of the surgical procedure
o Involves electrocorticographic recordings made with electrodes on the surface of the brain to identify
the extent of epileptiform disturbances.
• Clinically significant complications of surgery are <5%, and the use of functional mapping procedures has
markedly reduced the neurologic sequelae due to removal or sectioning of brain tissue.
• Marked improvement is also usually seen in patients treated with hemispherectomy for catastrophic seizure
disorders due to large hemispheric abnormalities.
• Postoperatively, patients generally need to remain on antiepileptic drug therapy, but the marked reduction
of seizures following resective surgery can have a very beneficial effect on quality of life.
• Not all medically refractory patients are suitable candidates for resective surgery.
• Vagus nerve stimulation (VNS) has been used in some of these cases, although the results are limited
• Implantable device that can detect the onset of a seizure (in some instances before the seizure becomes
clinically apparent) and deliver an electrical stimulation to abort the seizure (Responsive NeuroStimulation)
has proved to be of benefit in selected patients.

Status Epilepticus

• Refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal
period.
• has numerous subtypes, including generalized convulsive status epilepticus (GCSE) (e.g., persistent,
generalized electrographic seizures, coma, and tonic-clonic movements) and nonconvulsive status epilepticus
(e.g., persistent absence seizures or focal seizures with confusion or partially impaired consciousness, and
minimal motor abnormalities)
• Duration of seizure activity sufficient to meet the definition of status epilepticus has traditionally been specified
as 15–30 min.
• More practical definition is to consider status epilepticus as a situation in which the duration of seizures
prompts the acute use of anticonvulsant therapy.
• GCSE typically when seizures last beyond 5 min.
• GCSE is an emergency and must be treated immediately-- cardiorespiratory dysfunction, hyperthermia, and
metabolic derangements can develop------irreversible neuronal injury.
• CNS injury can occur even when the patient is paralyzed with neuromuscular blockade but continues to have
electrographic seizures.
• Most common causes of GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances,
drug toxicity, CNS infection, CNS tumors, refractory epilepsy, and head trauma.
• GSCE, after 30–45 min of uninterrupted seizures-----increasingly subtle signs.
o may have mild clonic movements of only the fingers or fine, rapid movements of the eyes.
o may be paroxysmal episodes of tachycardia, hypertension, and pupillary dilation
o EEG establishes the diagnosis.
• If still comatose, an EEG should be performed to rule out ongoing status epilepticus.
• First steps in the management of a patient in GCSE
o attend to any acute cardiorespiratory problems or hyperthermia
o perform a brief medical and neurologic examination
o establish venous access
o send samples for laboratory studies to identify metabolic abnormalities.
• Anticonvulsant therapy should then begin without delay
 • Treatment of nonconvulsive status epilepticus----less urgent than GCSE
o not accompanied by the severe metabolic disturbances
o associated with cellular injury in the region of the seizure focus
o should be treated as promptly as possible

Beyond Seizures: Other Management Issues

Epilepsy Comorbidities
• Many epilepsy patients are completely normal between seizures and live highly successful and productive
lives.
• Significant proportion of patients suffer from varying degrees of cognitive dysfunction, including psychiatric
disease
• Frequent interictal EEG abnormalities are associated with subtle dysfunction of memory and attention
• Patients with many seizures (especially from the temporal lobe) often note an impairment of short-term
memory that may progress over time.
• Psychiatric problems---depression, anxiety, and psychosis
• Risk varies considerably depending on many factors (etiology, frequency, and severity of seizures, age and
family history)
• Depression occurs in ~20% of patients; should be treated through counseling or medication.
o SSRIs typically have minimal effect on seizures, whereas TCAs may lower the seizure threshold.
• Anxiety can be a seizure symptom, and anxious or psychotic behavior can occur during a postictal delirium.
• Postictal psychosis---rare phenomenon that typically occurs after a period of increased seizure frequency.
usually a brief lucid interval lasting up to a week, followed by days to weeks of agitated, psychotic behavior.
o Psychosis usually resolves spontaneously but frequently will require short-term treatment with
antipsychotic or anxiolytic medications.
Mortality of Epilepsy
• Have a risk of death that is roughly two to three times greater than expected
• Most of the increased mortality is due to the underlying etiology of epilepsy
• significant number of patients die from accidents, status epilepticus, and a syndrome known as sudden
unexpected death in epilepsy (SUDEP), which usually affects young people with convulsive seizures and
tends to occur at night
o Cause of SUDEP is unknown; may result from brainstem-mediated effects of seizures on pulmonary,
cardiac, and arousal functions.
o recent studies suggest that a genetic mutation may be the cause of both epilepsy and a cardiac
conduction defect that gives rise to sudden death.
Psychosocial Issues
• There continues to be a cultural stigma about epilepsy
• Many with epilepsy harbor fears such as the fear of becoming mentally retarded or dying during a seizure.
• These issues need to be carefully addressed

Employment, Driving and Other Activities

• Many patients with epilepsy face difficulty in obtaining or maintaining employment
• Loss of driving privileges is one of the most disruptive social consequences of epilepsy.
• Physician’s responsibility to warn patients of the danger imposed on themselves and others while driving if
their seizures are uncontrolled (unless the seizures are not associated with impairment of consciousness or
motor control)
• Patients with incompletely controlled seizures must also contend with the risk of being in other situations where
an impairment of consciousness or loss of motor control could lead to major injury or death.
• Many patients need to be instructed to avoid working at heights or with machinery or to have someone close
by for activities such as bathing and swimming.

Special Issues Related to Women and Epilepsy

Catamenial Epilepsy
• Marked increase in seizure frequency around the time of menses.
• mediated by either the effects of estrogen and progesterone on neuronal excitability or changes in antiepileptic
drug levels due to altered protein binding or metabolism.
• Some may benefit from increases in antiepileptic drug dosages during menses.
• Natural progestins or intramuscular medroxyprogesterone may be of benefit
Pregnancy
 • Most women with epilepsy who become pregnant will have an uncomplicated gestation and deliver a normal
baby
• Seizure frequency during pregnancy will remain unchanged in ~50% of women, increase in ~30%, and
decrease in ~20%.
o attributed to endocrine effects on the CNS, variations in antiepileptic drug and changes in medication
compliance.
• Measurement of the unbound drug concentrations may be useful if there is an increase in seizure frequency
or worsening of side effects of antiepileptic drugs.
• Overall incidence of fetal abnormalities in children born to mothers with epilepsy is 5–6%
o due to teratogenic effects of antiepileptic drugs
o risk increases with the number of medications used (e.g., 10–20% risk of malformations with three
drugs).
o most common malformations were defects in the cardiovascular and musculoskeletal system (1.4–
1.8%).
• Valproic acid is strongly associated with an increased risk of adverse fetal outcomes (7–20%).
o newer antiepileptic drugs are far safer than valproic acid.
• Currently recommended that pregnant women be maintained on effective drug therapy.
o prudent to have the patient on monotherapy at the lowest effective dose, especially during the first
trimester
• Patients should also take folate (1–4 mg/d)---antifolate effects of anticonvulsants are thought to play a role in
the development of neural tube defects
o Benefits of this treatment remain unproved
• Enzyme-inducing drugs such as phenytoin, carbamazepine, oxcarbazepine, topiramate, phenobarbital, and
primidone cause a transient and reversible deficiency of vitamin K–dependent clotting factors in ~50% of
newborn infants.
• Neonatal hemorrhage is uncommon----mother should be still be treated with oral vitamin K (20 mg/d,
phylloquinone) in the last 2 weeks of pregnancy
o infant should receive intramuscular vitamin K (1 mg) at birth.

Contraception
• Special care should be taken when prescribing antiepileptic medications for women who are taking oral
contraceptive agents
• Drugs such as carbamazepine, phenytoin, phenobarbital, and topiramate can significantly decrease the
efficacy of oral contraceptives (via enzyme induction)
• Advised to consider alternative forms of contraception, or their contraceptive medications should be modified

Breast feeding
• Antiepileptic medications are excreted into breast milk to a variable degree.
• Ratio of drug concentration in breast milk relative to serum ranges from ~5% (valproic acid) to 300%
(levetiracetam).
• Given the overall benefits of breast-feeding and the lack of evidence for long-term harm to the infant by being
exposed to antiepileptic drugs, mothers with epilepsy can be encouraged to breast-feed.
• Reconsideredif there is any evidence of drug effects on the infant such as lethargy or poor feeding.

Migraine and Other Primary Headache Disorders

Migraine
• Second most common cause of headache
• most common headache-related and neurologic cause of disability in the world
• afflicts ~15% of women and 6% of men over a 1-year period.
 • Usually an episodic headache associated with certain features such as sensitivity to light, sound, or
movement; nausea and vomiting often accompany the headache.
• recurring syndrome of headache associated with other symptoms of neurologic dysfunction in varying
admixtures
• Migraine attack has three phases: premonitory (prodrome), headache phase, and postdrome; each has
distinct and sometimes disabling symptoms.
• About 20–25% of migraine patients have a fourth, aura, phase.
• Often be recognized by its activators, referred to as triggers.
• Migraineurs are particularly sensitive to environmental and sensory stimuli; migraine-prone patients do not
habituate easily to sensory stimuli.
• amplified in females during the menstrual cycle
• Headache can be initiated or amplified by various triggers, including glare, bright lights, sounds, or other types
of afferent stimulation; hunger; let-down from stress; physical exertion; stormy weather or barometric pressure
changes; hormonal fluctuations during menses; lack of or excess sleep; and alcohol or other chemical
stimulation, such as with nitrates.
• Knowledge of a patient’s susceptibility to specific triggers can be useful in management strategies
Pathogenesis
• Sensory sensitivity probably due to dysfunction of monoaminergic sensory control systems located in the
brainstem and hypothalamus
• Activation of cells in the trigeminal nucleus results in the release of vasoactive neuropeptides, particularly
calcitonin gene–related peptide (CGRP), at vascular terminals of the trigeminal nerve and within the trigeminal
nucleus.
• Six CGRP receptor antagonists, gepants---effective in the acute treatment of migraine, and four monoclonal
antibodies to CGRP or its receptor have been shown to be effective in migraine prevention.
• There are projections to the periaqueductal gray and hypothalamus, from which reciprocal descending
systems have established antinociceptive effects. Other brainstem regions involved in descending modulation
of trigeminal pain include the nucleus locus coeruleus in the pons and the rostroventromedial medulla.
• Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT;
also known as serotonin) in migraine
• Methysergide was found to antagonize certain peripheral actions of 5-HT
o first drug capable of preventing migraine attacks
• triptans were designed to stimulate selectively subpopulations of 5-HT receptors;
o potent agonists of 5-HT1B and 5-HT1D receptors, and some are active at the 5-HT1F receptor
(exclusive agonists are called ditans)
• Triptans arrest nerve signaling in the nociceptive pathways of the trigeminovascular system, at least in the
trigeminal nucleus caudalis and trigeminal sensory thalamus, in addition to promoting cranial vasoconstriction
• Ditans act only at neural and not vascular targets.
• Most migraine symptoms can be induced by dopaminergic stimulation.
• There is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning,
nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses
that do not affect nonmigraineurs.
• Dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given
parenterally or concurrently with other antimigraine agents.
• Hypothalamic activation, anterior to that seen in cluster headache, has been shown in the premonitory (prodro-
mal) phase of migraine using functional imaging, may hold a key to dopamine’s role in headache
• Migraine genes ----involvement of ion channels; alterations in membrane excitability can predispose to
migraine.
• Mutations involving the Cav2.1 (P/Q)–type voltage-gated calcium channel CACNA1A gene are now known to
cause FHM 1; responsible for about 50% of FHM cases.
• Mutations in the Na+-K+ATPase ATP1A2 gene (FHM 2) are responsible for about 20% of FHMs.
• Mutations in the neuronal voltage-gated sodium channel SCN1A cause FHM 3.

Diagnosis and Clinical Features

• A high index of suspicion is required to diagnose migraine: the migraine aura, consisting of visual disturbances
with flashing lights or zigzag lines moving across the visual field or of other neurologic symptoms, is reported
in only 20–25% of patients.
• Should be distinguished from the pan-field television static-like disturbance (visual snow syndrome)
• The first phase of a migraine attack for most patients is the premonitory (prodromal) phase consisting of some
or all of the following: yawning, tiredness, cognitive dysfunction, mood change, neck discomfort, polyuria, and
food cravings; this can last from a few hours to days.
 • Typically, the headache phase follows with its associated features, such as nausea, photophobia, and
phonophobia as well as allodynia.
• headache lessens, then many patients enter a postdrome, most commonly feeling tired/weary, having
problems concentrating, and experiencing mild neck discomfort that can last for hours and sometimes up to a
day
• Headache diary can often be helpful in making the diagnosis; this is also helpful in assessing disability and
the frequency of treatment for acute attacks.
• Patients with episodes of migraine on eight or more days per month and with at least 15 total days of headache
per month are considered to have chronic
• Migraine must be differentiated from TTH which is reported to be the most common primary headache
syndrome. Migraine has several forms: migraine with and without aura and chronic migraine are the most
important.
• Migraine at its most basic level is headache with associated features, and tension-type headache is headache
that is featureless.
• Most patients with disabling headache probably have migraine.
• Patients with acephalgic migraine experience recurrent neurologic symptoms, often with nausea or vomiting,
but with little or no headache.
o Vertigo can be prominent
• Migraine aura can have prominent brainstem symptoms,
o Terms basilar artery and basilar-type migraine have now been replaced by migraine with brainstem
aura

Treatment of Migraine Headache

• Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-to-use tool

• Patient education---important aspect of migraine management.
• Migraine---inherited tendency to headache; can be modified and controlled by lifestyle adjustments and
medications, but it cannot be eradicated;
• Migraine is not associated with serious or life-threatening illnesses (except in some cases with women on
contraceptives)

Non-pharmacologic management

Avoidance of triggers can be useful

• A regulated lifestyle is helpful (healthy diet, regular exercise, regular sleep patterns, avoidance of excess
caffeine and alcohol, and avoidance of acute changes in stress levels)
• Lessening one’s response to stress by various techniques is helpful for many patients.
o include yoga, transcendental meditation, hypnosis, and conditioning techniques such as biofeedback
o an adjunct to pharmacotherapy.
• Nonpharmacologic measures are unlikely to prevent all migraine attacks.

Acute Attack Therapies for Migraine

• Mainstay is the judicious use of one or more of the many medicines that are effective in migraine
• Severity of the attack- most important factor for drug selection.
• Mild migraine attacks can usually be managed by oral agents (efficacy rate is 50–70%.)
• Severe migraine attacks-- parenteral therapy.
• Three major pharmacologic classes: nonsteroidal anti-inflammatory drugs, 5-HT1B/1D receptor agonists,
and dopamine receptor antagonists.
• Two new classes of therapeutic agents, CGRP receptor antagonists, such as rimegepant and ubrogepant,
and 5-HT1F receptor agonists, such as lasmiditan, should soon be available.
• Adequate dose should be used as soon as possible after the onset of an attack.
• If additional medication is required within 60 min because symptoms return or have not abated, the initial dose
should be increased for subsequent attacks or a different class of drug tried as first-line treatment.
• Migraine therapy must be individualized
• Therapeutic regimen may need to be constantly refined until one is identified that provides the patient with
rapid, complete, and consistent relief with minimal side effects

NSAIDs
 • Both the severity and duration of a migraine attack can be reduced significantly by NSAIDs
• NSAIDs are most effective when taken early in the migraine attack.
• Effectiveness of these agents in migraine is usually less than optimal in moderate or severe migraine attacks.
The combination of acetaminophen (paracetamol), aspirin, and caffeine has been approved for use for the
treatment of mild to moderate migraine.
• The combination of aspirin and metoclopramide comparable to a single dose of oral sumatriptan.
• Side effects of NSAIDs include dyspepsia and gastrointestinal irritation.

5HT receptor Agonists

• Stimulation of 5-HT1B/1D receptors can stop an acute migraine attack.
• Ergotamine and dihydroergotamine are nonselective receptor agonists; triptans are selective 5-HT1B/1D
receptor agonists.
• A variety of triptans—sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and
zolmitriptan—are available for the treatment of migraine.
• varies slightly in terms of clinical efficacy.
• Rizatriptan and eletriptan----the most efficacious of the triptans
• Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, with an advantage of
having multiple formulations
• Almotriptan has a similar rate of efficacy to sumatriptan and is better tolerated
• Frovatriptan and naratriptan are somewhat slower in onset and are also well tolerated.
• Faster-acting analgesics are more effective than slower-acting agents.
• Monotherapy with a selective oral 5-HT1B/1D receptor agonist does not result in rapid, consistent, and
complete relief of migraine in all patients.
• Triptans are generally not effective in migraine with aura unless given after the aura is completed and the
headache initiated.
• Side effects are common (often mild and transient)
• Contraindicated in individuals with a history of cardiovascular and cerebrovascular disease.
• Recurrence of headache, within usual time course of an attack----limitation of triptan use
• Ergotamine preparations offer a nonselective means of stimulating 5-HT1 receptors.
• A non-nauseating dose of ergotamine should be sought
• Oral (excluding sublingual) formulations of ergotamine also contain 100 mg caffeine (to enhance ergotamine
absorption and possibly to add additional analgesic activity)
• Average oral ergotamine dose for a migraine attack is 2 mg.
• With use of ergotamine there appears to be a much higher incidence of nausea than with triptans but less
headache recurrence.
• Nasal formulations of dihydroergotamine, zolmitriptan, or sumatriptan can be useful in patients requiring a
nonoral route of administration
• Result in substantial blood levels within 30–60 min.
• Reported efficacy is only ~50–60%.
• Administration of drugs by injection (dihydroergotamine and sumatriptan) for the rapid relief of a migraine
attack
• Peak plasma levels of dihydroergotamine are achieved 3 min after IV dosing, 30 min after IM dosing, and 45
min after SC dosing.
• Sumatriptan, 4–6 mg SC, is effective in ~50–80% of patients

Dopamine Receptor Antagonists

• Oral dopamine receptor antagonists can be considered as adjunctive therapy in migraine.

• Drug absorption is impaired during migraine because of reduced gastrointestinal motility.
• Delayed absorption occurs even in the absence of nausea ---- related to the severity of the attack and not its
duration
• Addition of a dopamine receptor antagonist (metoclopramide 10 mg or domperidone 10 mg) should be
considered to enhance gastric absorption
• Dopamine receptor antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) by injection can
also provide significant acute relief of migraine; can be used in combination with parenteral 5-HT1B/1D
receptor agonists.

Other Options for Acute Migraine

 • Combination of acetaminophen, dichloralphenazone, and isometheptene, one to two capsules---“possibly”
effective in the treatment of migraine.
• Opioids are modestly effective in the acute treatment of migraine.
• “works” in the sense that the pain of migraine is eliminated.
• Prochlorperazine is superior to hydromorphone in the emergency room setting.
• Opioids are suboptimal for patients with recurrent headache.
• Opioids do not treat the underlying headache mechanism; they act to alter the pain sensation
• Opioid use may decrease the likelihood of a response to triptans in the future.
• Habituation or addiction can greatly confuse the treatment of migraine
• Opioid craving and/or withdrawal can aggravate and accentuate migraine.
• Recommended that opioid use in migraine be limited to patients with severe, but infrequent, headaches that
are unresponsive to other pharmacologic approaches/contraindications to other therapies.
• Single pulse transcranial magnetic stimulation (sTMS) is FDA-approved for the acute treatment of migraine.
o Two pulses can be applied at the onset of an attack (can be repeated)
o Safe where there is no cranial metal implant
• Noninvasive vagus nerve stimulator (nVNS) is FDA-approved for the treatment of migraine attacks in adults
o One to two 120-second doses may be applied for attack treatment.

Medications Overuse Headache

• Acute attack medications, particularly opioid or barbiturate-containing compound analgesics, have a
propensity to aggravate headache frequency and induce a state of refractory daily or near-daily headache
• Reaction of the migraine patient’s biology to a particular medicine.

Preventive Treatment for Migraine

• Patients with an increasing frequency of migraine attacks or with attacks that are either unresponsive or
poorly responsive to abortive treatments-----candidates for preventive agents.
• Preventive medication should be considered in patients with four or more attacks a month
• Mechanism of action of these drugs is unclear; it seems likely that the brain sensitivity that underlies migraine
is modified.
• Patients are usually started on a low dose of a chosen treatment; the dose is then gradually increased, up
to a reasonable maximum, to achieve clinical benefit.
• Most treatments must be taken daily
• Usually a lag of between 2 and 12 weeks before an effect is seen.
• Includes propranolol, timolol, sodium valproate, and topiramate.
• Other drugs includes amitriptyline, nortriptyline, flunarizine, phenelzine, and cyproheptadine.
• sTMS approved for the preventive treatment of migraine
o well-tolerated, effective option for patients.
• Phenelzine----monoamine oxidase inhibitor (MAOI); tyramine-containing foods, decongestants, and
meperidine are contraindicated,
o reserved for only very recalcitrant cases.
• Methysergide---of historical interest only
• Melatonin--reported to be useful
• The probability of success with any one of the antimigraine drugs is 50%.
• Many patients are managed adequately with well-tolerated doses of candesartan, propranolol, amitriptyline,
topiramate, or valproate.
• Once effective stabilization is achieved---- drug is continued for ~6 months and then slowly tapered to assess
the continued need.
• Many patients are able to discontinue medication and experience fewer and milder attacks for long periods---
-may alter the natural history of migraine

Tension type Headache

• Chronic head-pain syndrome characterized by bilateral tight, band-like discomfort.
• Pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for many days
• May be episodic or chronic (present >15 days per month)
• Main differential diagnosis is Migraine Headache
• International Headache Society’s main definition of TTH allows an admixture of nausea, photophobia, or
phonophobia in various combinations, although the appendix definition does not
• TTH may be infrequent (episodic) or occur on 15 days or more a month (chronic)
Pathophysiology

• TTH is due to a primary disorder of central nervous system pain modulation alone, unlike migraine, which
involves a more generalized disturbance of sensory modulation.
• Tension-type headache implies that pain is a product of nervous tension, but there is no clear evidence for
tension as an etiology.
• Muscle contraction has been considered to be a feature that distinguishes TTH from migraine (however with
no difference in contraction)

Treatment of Tension Type Headache

• Pain of TTH can generally be managed with simple analgesics such as acetaminophen, aspirin, or NSAIDs.
• Behavioral approaches including relaxation can also be effective
• Triptans in pure TTH are not helpful; effective in TTH when the patient also has migraine
• For chronic TTH, amitriptyline is the only proven treatment
• No evidence for the efficacy of acupuncture.
• Placebo-controlled trials of onabotulinum toxin type A in chronic TTH were negative.

Trigeminal Autonomic Cephalgias, including Cluster Headache

• TACs describe a grouping of primary headaches including cluster headache, paroxysmal hemicrania (PH),
SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing)/SUNA
(short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms), and hemicrania
continua
• Characterized by relatively short-lasting attacks of head pain associated with cranial autonomic symptoms,
such as lacrimation, conjunctival injection, aural fullness, or nasal congestion
• Pain is usually severe and may occur more than once a day
• often misdiagnosed with “sinus headache” and treated with decongestants, which are ineffective
• Should undergo pituitary imaging and pituitary function tests---excess of TAC presentations in patients with
pituitary tumor–related headache, particularly prolactin and growth hormone secreting tumors

Cluster headache
 • Relatively rare form of primary headache, although nonetheless a common condition, with a population
frequency of ~0.1%.
• Pain is deep, usually retroorbital, often excruciating in intensity, nonfluctuating, and explosive in quality.
• Core feature of cluster headache is periodicity
• At least one of the daily attacks of pain recurs at about the same hour each day for the duration of a cluster
bout
• Typical cluster headache patient has daily bouts of one to two attacks of relatively short-duration unilateral
pain for 8–10 weeks a year---- followed by a pain-free interval that averages a little less than 1 year.
• Characterized as chronic when there is <3 months of sustained remission without treatment.
• Patients are generally perfectly well between episodes.
• Onset of attacks is nocturnal in about 50% of patients
• Men are affected three times more often than women.
• Tend to move about during attacks, pacing, rocking, or rubbing their head for relief; some may even become
aggressive during attacks.
o sharp contrast to patients with migraine (remain motionless during attacks)
• Associated with ipsilateral symptoms of cranial parasympathetic autonomic activation: conjunctival injection
or lacrimation, aural fullness, rhinorrhea or nasal congestion, or cranial sympathetic dysfunction (i.e. ptosis)
• Photophobia and phonophobia are more likely to be unilateral and on the same side of the pain
o characteristic of TACs
o Migraine- bilateral
• Likely to be a disorder involving central pacemaker neurons and neurons in the posterior hypothalamic region

Treatment of Cluster Headache

Acute Attack Treatment

• Treatment with rapid onset is required.
• Respond very well to oxygen inhalation--- given as 100% oxygen at 10–12 L/min for 15–20 min.
o high flow and high oxygen content are important.
• Sumatriptan 6 mg SC -- rapid in onset; shorten an attack to 10–15 min; there is no evidence of tachyphylaxis.
• Sumatriptan (20 mg) and zolmitriptan (5 mg) nasal sprays are both effective in acute cluster headache,
• Noninvasive vagus nerve stimulation (nVNS) is FDA approved for the acute treatment of attacks in episodic
cluster headache using three 2-min stimulation cycles applied consecutively at the onset of headache on the
side of pain; this may be repeated after nine minutes.
• Oral sumatriptan is not effective for prevention or for acute treatment of cluster headache.

Preventive Treatment
• With long bouts or those with
chronic cluster headache
require medicines that are
safe when taken for long
periods.
• With relatively short bouts,
limited courses of oral
glucocorticoids can be very
useful.
• A 10-day course of
prednisone, beginning at 60
mg daily for 7 days and
followed by a rapid taper,
may interrupt the pain bout
for many patients.
• Greater occipital nerve
injection with lidocaine and glucocorticoids has been shown to be effective in randomized controlled trials,
with a benefit that lasts up to 6–8 weeks.
• Most experts favor verapamil as the first-line preventive treatment for patients with chronic cluster headache
or with prolonged bouts.
o initial dose range is 40–80 mg twice daily; effective doses may be as high as 960 mg/d.
o Side effects such as constipation, leg swelling, or gingival hyperplasia can be problematic.
o Paramount concern is the cardiovascular safety of verapamil, particularly at high doses.
o Verapamil can cause heart block by slowing conduction in the atrioventricular node
 o Approximately 20% of patients treated with verapamil develop ECG abnormalities----can be observed
with doses as low as 240 mg/d
o A baseline ECG is recommended for all patients.
o ECG is repeated 10 days after a dose change in patients whose dose is being increased above 240
mg daily.
o Dose increases are usually made in 80-mg increments.
• Long-term verapamil-----ECG monitoring every 6 months is advised.

Neuromodulation Therapy
• Sphenopalatine ganglion (SPG) stimulation with an implanted battery-free stimulator --- effective in aborting
attacks and reducing their frequency over time
• nVNS compares favorably to standard-of-care
• Occipital nerve stimulation has been used open label and appears to be beneficial.
• Deep-brain stimulation of the region of the posterior hypothalamic gray matter is successful in about 50% of
patients treated,
o risk-benefit ratio makes it inappropriate before all other less invasive options have been explored

Paroxysmal Hemicrania
• Characterized by frequent unilateral, severe, short-lasting episodes of headache.
• Pain tends to be retroorbital but may be experienced all over the head
• Associated with autonomic phenomena such as lacrimation and nasal congestion
• Patients with remissions are said to have episodic PH, whereas those with the nonremitting form are said to
have chronic PH.
• Essential features of PH are unilateral; very severe pain; short-lasting attacks (2–45 min); very frequent attacks
(usually >5 a day); marked autonomic features ipsilateral to the pain; rapid course (<72 h); and excellent
response to indomethacin.
• Male-to-female ratio in PH is close to 1:1.
• Indomethacin (25–75 mg tid)-----treatment of choice.
o May be complicated by indomethacin-induced gastrointestinal side effects
• Topiramate helpful in some cases.
• Piroxicam--- not as effective as indomethacin.
• Verapamil does not appear to be useful for PH.
• nVNS can be useful in these patients and can be very effective.
• PH can coexist with TN (PH-tic syndrome); may require separate treatment.
• Secondary PH has been reported with lesions in the region of the sella turcica---including arteriovenous
malformation, cavernous sinus meningioma, pituitary pathology, and epidermoid tumors.
o more likely if the patient requires high doses (>200 mg/d) of indomethacin.
• Apparent bilateral PH----raised cerebrospinal fluid (CSF) pressure should be suspected.
o indomethacin reduces CSF pressure
• Magnetic resonance imaging (MRI) is indicated to exclude a pituitary lesion

SUNCT/SUNA

• SUNCT --- rare primary headache syndrome characterized by severe, unilateral orbital or temporal pain that
is stabbing or throbbing in quality.
• Diagnosis requires at least 20 attacks, lasting for 5–240 s; ipsilateral conjunctival injection and lacrimation
should be present.
• conjunctival injection or lacrimation is missing----diagnosis of SUNA can be made
• Pain is unilateral and may be located anywhere in the head.
• Three basic patterns can be seen: single stabs, which are usually short-lived; groups of stabs; or a longer
attack comprising many stabs between which the pain does not completely resolve, (“saw-tooth” phenomenon
with attacks lasting many minutes)
• Characteristics that lead to a suspected diagnosis of SUNCT are:
o cutaneous (or other) triggers of attacks
o a lack of refractory period to triggering between attacks
o lack of a response to indomethacin
• Apart from trigeminal sensory disturbance, the neurologic examination is normal in primary SUNCT/SUNA.
• The diagnosis of SUNCT/SUNA is often confused with TN particularly in first-division TN
• Minimal or no cranial autonomic symptoms and a clear refractory period to triggering indicate a diagnosis of
TN.
 • SUNCT can be seen with posterior fossa or pituitary lesions (secondary SUNCT)
o All patients with SUNCT/SUNA should be evaluated with pituitary function tests and a brain MRI with
pituitary views.

Treatment of SUNCT/SUNA
Abortive Therapy
• Not a useful concept in SUNCT/SUNA---- attacks are of such short duration
• IV lidocaine--- arrests the symptoms; can be used in hospitalized patients
PREVENTIVE THERAPY
• Long-term prevention to minimize disability and hospitalization--- goal of treatment.
• Most effective treatment for prevention is lamotrigine, 200–400 mg/d
• Topiramate and gabapentin may also be effective.
• Carbamazepine, 400–500 mg/d, has been reported by patients to offer modest benefit.
• Microvascular decompression or destructive trigeminal procedures are seldom useful and often produce long-
term complications.
• Greater occipital nerve injection has produced limited benefit in some patients.
• Occipital nerve stimulation is probably helpful
• Intractable cases----short-term prevention with IV lidocaine can be effective

Hemicrania Continua

• Essential features are:

o moderate and continuous unilateral pain associated with fluctuations of severe pain
o complete resolution of pain with indomethacin
o exacerbations that may be associated with autonomic features, including conjunctival injection,
lacrimation, and photophobia on the affected side.
• Age of onset ranges from 10 to 70 years
• women are affected twice as often as men
• cause is unknown

Treatment of Hemicrania Continua

• Treatment consists of indomethacin
o other NSAIDs appear to be of little or no benefit
o IM injection of 100 mg of indomethacin---proposed as a diagnostic tool,
o Alternatively, a trial of oral indomethacin, starting with 25 mg tid, then 50 mg tid, and then 75 mg tid,
can be given.
o Up to 2 weeks at the maximal dose may be necessary to assess whether a dose has a useful effect.
• Topiramate can be helpful in some patients.
• nVNS can be useful
• Occipital nerve stimulation probably has a role in patients who are unable to tolerate indomethacin

Other Primary Headaches

Primary Cough Headache

• Generalized headache that begins suddenly, lasts for seconds or several minutes, sometimes up to a few
hours, and is precipitated by coughing
o preventable by avoiding coughing or other precipitating events (sneezing, stooping)
• Serious etiologies must be excluded before a diagnosis of “benign” primary cough headache can be
established.
• Chiari malformation or any lesion causing obstruction of CSF pathways or displacing cerebral structures can
be the cause of the head pain.
• Other conditions include cerebral aneurysm, carotid stenosis, and vertebrobasilar disease.
• Benign cough headache can resemble benign exertional headache, however are typically older

Treatment of Primary Cough Headache

 • Indomethacin 25–50 mg two to three times daily is the treatment of choice.
• Some obtain complete cessation of their attacks with lumbar puncture;
o effective in about one-third of patients.
o Mechanism of this response is unclear.

Primary Exercise Headache

• Primary exercise headache has features resembling both cough headache and migraine
• May be precipitated by any form of exercise; it often has the pulsatile quality of migraine
• Pain lasts <48 h, is bilateral and often throbbing at onset
• migrainous features may develop in patients susceptible to migraine
• Duration tends to be shorter in adolescents than in older adults
• Can be prevented by avoiding excessive exertion, particularly in hot weather or at high altitude.
• Mechanism is unclear
• Acute venous distension likely explains one syndrome—the acute onset of headache with straining and breath
holding, as in weightlifter’s headache
• Pain from angina may be referred to the head, probably by central connections of vagal afferents, and may
present as exercise headache (cardiac cephalgia)
• Link to exercise is the main clinical clue that headache is of cardiac origin
• Pheochromocytoma may occasionally cause exercise headache
• Intracranial lesions and stenosis of the carotid arteries---other possible etiologies

Treatment of Primary Exercise Headache

• Exercise regimens should begin modestly---progress gradually to higher levels of intensity
• Indomethacin at daily doses from 25 to 150 mg is generally effective in benign exertional headache.
• Indomethacin (50 mg), ergotamine (1 mg orally), and dihydroergotamine (2 mg by nasal spray) are useful
prophylactic measures.

Primary Headache Associated with Sexual Activity

• Three types are reported:
o a dull bilateral ache in the head and neck that intensifies as sexual excitement increases
o a sudden, severe, explosive headache occurring at orgasm
o postural headache developing after coitus----arises from vigorous sexual activity and is a form of low
CSF pressure headache (not a primary headache disorder)
• Headaches developing at the time of orgasm are not always benign
• 5–12% of cases of subarachnoid hemorrhage are precipitated by sexual intercourse
• Reported by men more often than women; may occur at any time during the years of sexual activity
• In patients who stop sexual activity, the pain may subside within a period of 5 min to 2 h.
• In about half of patients, sex headache will subside within 6 months.
• Most patients with sex headache do not have exercise or cough---marker of primary sex headache. Migraine
is probably more common in patients with sex headache

Treatment of Primary Sex Headache

• Benign sex headaches recur irregularly and infrequently
• Management can often be limited to reassurance and advice about ceasing sexual activity if a mild, warning
headache develops
• Propranolol can be used to prevent headache that recurs regularly or frequently (dosage required varies from
40 to 200 mg/d)
• Alternative ---- Diltiazem, 60 mg tid
• Indomethacin (25–50 mg) or frovatriptan (2.5 mg) taken 30–45 min prior to sexual activity can also be helpful

Primary Thunderclap Headache

• Sudden onset of severe headache may occur in the absence of any known provocation.
• Differential diagnosis includes the sentinel bleed of an intracranial aneurysm, cervicocephalic arterial
dissection, and cerebral venous thrombosis
• May also be caused by the ingestion of sympathomimetic drugs/ tyramine-containing foods in a patient who
is taking MAOIs, or they may be a symptom of pheochromocytoma
• Patients with thunderclap headache usually do very well over the long term (if subarachnoid hemorrhage is
excluded)
• First presentation of any sudden-onset severe headache should be diligently investigated with neuroimaging
and CSF examination
 • Reversible segmental cerebral vasoconstriction may be seen in primary thunderclap headache without an
intracranial aneurysm-----may be an under-diagnosed condition
• If with posterior leukoencephalopathy----differential diagnosis includes cerebral angiitis, drug toxicity
(cyclosporine, intrathecal methotrexate/ cytarabine, pseudoephedrine, or cocaine), posttransfusion effects,
and postpartum angiopathy
• Treatment with nimodipine may be helpful----vasoconstriction of primary thunderclap headache resolves
spontaneously.

Cold Stimulus Headache

• Refers to head pain triggered by application or ingestion/inhalation of something cold.
• Brought on quickly and typically resolves within 10–30 min of the stimulus being removed.
• Best recognized as “brain-freeze” headache or ice-cream headache when due to ingestion.
• Transient receptor potential cation subfamily M member 8 (TRPM8) channel, a known cold temperature
sensor, may be a mediator of this syndrome.

External Pressure Headache

• External pressure from compression or traction on the head--- pain largely focused around the site of the
pressure
• Typically resolves within an hour of the stimulus being removed
• Treatment is to recognize the problem and remove the stimulus

Primary Stabbing Headache

• Essential features of primary stabbing headache are:
• stabbing pain confined to the head or, rarely, the face, lasting from 1 to many seconds and occurring as a
single stab or a series of stabs
• absence of associated cranial autonomic features
• absence of cutaneous triggering of attacks
• pattern of recurrence at irregular intervals (hours to days)
• Described as “ice-pick pains” or “jabs and jolts
• More common in patients with other primary headaches

Treatment of Primary Stabbing Headache

• Indomethacin (25–50 mg two to three times daily)
• Symptoms wax and wane
• After a period of control on indomethacin---- appropriate to withdraw treatment and observe the outcome

Nummular Headache
• Felt as a round or elliptical discomfort that is fixed in place, ranges in size from 1 to 6 cm, and may be
continuous or intermittent.
o May be multifocal
o May be episodic but more often continuous during exacerbations
o There may be a local sensory disturbance, such as allodynia or hypesthesia.
• Local dermatologic or bony lesions need to be excluded by examination and investigation.
• Can be difficult to treat when present in isolation
o tricyclics, such as amitriptyline, or anticonvulsants, such as topiramate or valproate, are most often
tried. Can be seen in combination with migraine and the TACs

Hypnic Headache
• Typically begins a few hours after sleep onset
• Last from 15 to 30 min
• Typically moderately severe and generalized
o may be unilateral and can be throbbing
• Daytime naps can also precipitate head pain
• Most patients are female
• Onset is usually after age 60 years
• Headaches are bilateral in most
o may be unilateral
• Photophobia, phonophobia, and nausea are usually absent
 • Major secondary consideration in this headache type is poorly controlled hypertension
o 24-h blood pressure monitoring is recommended

Treatment of Hypnic Headache

• Generally respond to a bedtime dose of lithium carbonate (200–600 mg)
• Intolerant of lithium----verapamil (160 mg) is an alternative
• One to two cups of coffee or caffeine, 60 mg orally, at bedtime may be effective in approximately one-third of
patients.
• Flunarizine, 5 mg nightly, or indomethacin, 25–75 mg nightly, can be effective.

New Daily Persistent Headache

• Occurs in both males and females
• It can be of the migrainous type or it can be featureless, appearing as new-onset TTH.
• Those with migrainous features are the most common form,
• Nausea, photophobia, and/or phonophobia occur in about half of patients
• Some patients have a previous history of migraine
• NDPH may be more common in adolesents
• Treatment of migrainous-type primary NDPH consists of using the preventive therapies effective in migraine
• Featureless NDPH is one of the most refractory to treatment.
• Standard preventive therapies can be offered but are often ineffective.

Encephalitis

Definition
• An inflammation of the brain caused either by infection, usually with a virus, or from a primary autoimmune
process
• Brain parenchyma is also involved
• Many have evidence of associated meningitis (meningoencephalitis) and, in some cases, involvement of the
spinal cord or nerve roots (encephalomyelitis, encephalomyeloradiculitis)

Clinical Manifestations

• Commonly has an altered level of consciousness (confusion, behavioral abnormalities), or a depressed level
of consciousness ranging from mild lethargy to coma
• With evidence of either focal or diffuse neurologic signs and symptoms.
• May have hallucinations, agitation, personality change, behavioral disorders, and a frankly psychotic state.
• Focal or generalized seizures occur in many patients with encephalitis.
• Most commonly encountered focal findings are aphasia, ataxia, upper or lower motor neuron patterns of
weakness, involuntary movements (e.g., myoclonic jerks, tremor), and cranial nerve deficits
• Involvement of the HPA axis---temperature dysregulation, diabetes insipidus, or the development of SIADH

Etiology
• Majority of cases of acute encephalitis of suspected viral etiology remain of unknown cause
• Hundreds of viruses are capable of causing encephalitis, although only a limited subset is responsible for most
cases in which a specific cause is identified
• Most commonly identified viruses causing sporadic cases of acute encephalitis in immunocompetent adults
are herpesviruses (herpes simplex virus [HSV], varicella-zoster virus [VZV], Epstein-Barr virus [EBV])
• Epidemics of encephalitis are caused by arboviruses, including Alphaviruses (e.g., eastern equine encephalitis
[EEE] virus), Flaviviruses (e.g., West Nile virus [WNV], St. Louis encephalitis virus, Japanese encephalitis
virus, Powassan virus), and Bunyaviruses (e.g., California encephalitis virus serogroup, La Crosse virus).
• Since 2002, WNV has been responsible for the majority of arbovirus meningitis and encephalitis cases in the
United States.
• WNV epidemics are unpredictable and that cases have occurred in every state in the continental United
States.

Laboratory Diagnosis
 • Cerebrospinal fluid (CSF) examination should be performed in all patients with suspected viral encephalitis
unless contraindicated by the presence of severely increased intracranial pressure (ICP)
• Ideally at least 20 mL should be collected with 5–10 mL stored frozen for future studies.
• Characteristic CSF profile is indistinguishable from that of viral meningitis; typically consists of a lymphocytic
pleocytosis, a mildly elevated protein concentration, and a normal glucose concentration.
• A CSF pleocytosis (>5 cells/μL) occurs in >95% of immunocompetent patients with documented viral
encephalitis.
o may be absent on the initial lumbar puncture (LP) but present on subsequent LPs.
• Patients who are severely immunocompromised by HIV infection, glucocorticoid or other immunosuppressant
drugs, chemotherapy, or lymphoreticular malignancies may fail to mount a CSF inflammatory response.
• CSF cell counts exceed 500/μL in only about 10% of patients with encephalitis.
• Atypical lymphocytes in the CSF may be seen in EBV infection and less commonly with other viruses, including
cytomegalovirus (CMV), HSV, and enteroviruses.
• Increased numbers of plasmacytoid or Mollaret-like large mononuclear cells have been reported in WNV
encephalitis.
• Polymorphonuclear pleocytosis occurs in ~45% of patients with WNV encephalitis; also a common feature in
CMV myeloradiculitis in immunocompromised patients.
• Persisting CSF neutrophilia should prompt consideration of bacterial infection, leptospirosis, amebic infection,
and noninfectious processes such as acute hemorrhagic leukoencephalitis.
• About 20% of patients with encephalitis will have a significant number of red blood cells (>500/μL) in the CSF
in a nontraumatic tap
o may be a hemorrhagic encephalitis of the type seen with HSV
• CSF red blood cells occur with similar frequency and in similar numbers in patients with nonherpetic focal
encephalitides.
• A decreased CSF glucose concentration is distinctly unusual in viral encephalitis and should suggest the
possibility of bacterial, fungal, tuberculous, parasitic, leptospiral, syphilitic, sarcoid, or neoplastic meningitis.
• Rare patients with mumps, LCMV, or advanced HSV encephalitis and many patients with CMV myeloradiculitis
have low CSF glucose concentrations

CSF Polymerase Reaction

• CSF PCR has become the primary diagnostic test for CNS infections caused by CMV, EBV, HHV-6, and
enteroviruses
• VZV CNS infection---CSF PCR and detection of virus-specific IgM or intrathecal antibody synthesis both
provide important aids to diagnosis
• Sensitivity and specificity of CSF PCRs vary with the virus.
• Sensitivity (~96%) and specificity (~99%) of HSV CSF PCR are equivalent to or exceed those of brain biopsy.
• A negative HSV CSF PCR test performed by a qualified laboratory at the appropriate time during illness in a
patient with a high likelihood of HSV encephalitis based on clinical and laboratory abnormalities significantly
reduces the likelihood of HSV encephalitis but does not exclude it
• Frequency of positive HSV CSF PCRs in patients with herpes encephalitis also decreases as a function of the
duration of illness, with only ~20% of cases remaining positive after ≥14 days
• PCR results are generally not affected by ≤1 week of antiviral therapy
• Sensitivity and specificity of CSF PCR tests for viruses other than HSV have not been definitively
characterized.
• Enteroviral (EV) CSF PCR appears to have a sensitivity and specificity of >95%.
• EV PCR sensitivity for EV71 may be considerably lower (~30% in some reports)
• Parechoviruses are also not detected by standard EV RT-PCRs
 • Positive EBV CSF PCRs associated with
positive tests for other pathogens have
been reported and may reflect reactivation
of EBV latent in lymphocytes
• CNS infection due to VZV----CSF antibody
and PCR studies should be considered
complementary
• WNV infection---CSF PCR appears to be
less sensitive than detection of WNV-
specific CSF IgM

CSF Culture

• Generally of limited utility in the diagnosis of

acute viral encephalitis
• Culture may be insensitive (e.g., >95% of
patients with HSV encephalitis have
negative CSF cultures as do virtually all
patients with EBV-associated CNS
disease)
• Takes too long to significantly effect
immediate therapy.

Serologic Studies and Antigen Detection

• Serum antibody determination is less useful
for viruses with high seroprevalence rates
in the general population such as HSV,
VZV, CMV, and EBV
• Viruses with low seroprevalence rates,
diagnosis of acute viral infection can be
made by documenting seroconversion
between acute-phase and convalescent
sera (typically obtained after 2–4 weeks) or
by demonstrating the presence of virus-
specific IgM antibodies
• For viruses with high seroprevalence,
demonstration of synthesis of virus-specific antibodies in CSF may be useful and can provide presumptive
evidence of CNS infection
• Serologic data are useful mainly for the retrospective establishment of a specific diagnosis rather than in aiding
acute diagnosis or management.
• HSV encephalitis--- antibodies to HSV-1 glycoproteins and HSV glycoprotein antigens have been detected in
the CSF
• Optimal detection of both HSV antibodies and antigen typically occurs after the first week of illness
• HSV CSF antibody testing is of value in patients whose illness is >1 week in duration and who are CSF PCR–
negative for HSV.
• VZV infection------CSF antibody tests may be positive when PCR fails to detect viral DNA, (both tests should
be complementary)
• Demonstration of WNV IgM antibodies is diagnostic of WNV encephalitis
• Timing of antibody collection may be important because the rate of CSF WNV IgM seropositivity increases by
~10% per day during the first week after illness onset, reaching 80% or higher on day 7 after symptom onset.
• WNV serum IgM has been shown to persist in some patients for >1 year following acute infection

MRI, CT and EEG

• Patients with suspected encephalitis almost invariably undergo neuroimaging studies and often
electroencephalogram (EEG).
• Help identify or exclude alternative diagnoses and assist in the differentiation between a focal, as opposed to
diffuse, encephalitic process.
• Focal findings in a patient with encephalitis should always raise the possibility of HSV encephalitis
• Examples of focal findings include:
 ▪ areas of increased signal intensity in the frontotemporal, cingulate, or insular regions of the
brain on T2-weighted, fluid-attenuated inversion recovery (FLAIR), or diffusion-weighted
MRI
▪ focal areas of low absorption, mass effect, and contrast enhancement on CT
▪ periodic focal temporal lobe spikes on a background of slow or low-amplitude (“flattened”)
activity on EEG
• Approximately 10% of patients with PCR-documented HSV encephalitis will have a normal MRI; nearly 80%
will have abnormalities in the temporal lobe, and an additional 10% in extratemporal regions.
o Lesions are typically hyperintense on T2-weighted images
• Children with HSV encephalitis may have atypical patterns of MRI lesions and often show involvement of brain
regions outside the frontotemporal areas
• CT is less sensitive than MRI and is normal in up to 20–35% of patients
• EEG abnormalities occur in >75% of PCR-documented cases of HSV encephalitis; they typically involve the
temporal lobes but are often nonspecific
• Some patients with HSV encephalitis have a distinctive EEG pattern consisting of periodic, stereotyped, sharp-
and-slow complexes originating in one or both temporal lobes and repeating at regular intervals of 2–3 s
• The periodic complexes are typically noted between days 2 and 15 of the illness and are present in two-thirds
of pathologically proven cases of HSV encephalitis.
• Significant MRI abnormalities are found in only approximately two-thirds of patients with WNV encephalitis
o often involve deep brain structures (thalamus, basal ganglia, and brainstem)
• EEGs in patients with WNV encephalitis typically show generalized slowing that may be more anteriorly
prominent rather than the temporally predominant pattern of sharp or periodic discharges more characteristic
of HSV encephalitis.
• Patients with VZV encephalitis may show multifocal areas of hemorrhagic and ischemic infarction
o tendency to produce a CNS vasculopathy rather than a true encephalitis
• Immunocompromised adult patients with CMV often have enlarged ventricles with areas of increased T2 signal
on MRI outlining the ventricles and subependymal enhancement on T1-weighted postcontrast images.

Brain Biopsy
• Reserved for patients in:
o whom CSF PCR studies fail to lead to a specific diagnosis
o who have focal abnormalities on MRI
o no serologic evidence of autoimmune disease
o who continue to show progressive clinical deterioration despite treatment with acyclovir and
supportive therapy.

Differential Diagnosis
• Infection by a variety of other organisms can mimic viral encephalitis.
• Common infectious mimics of focal viral encephalitis included mycobacteria, fungi, rickettsiae, Listeria,
Mycoplasma, and other bacteria (including Bartonella sp.).
• Antibodies that cause autoimmune encephalitis----- associated with antibodies against N-methyl-d-aspartate
(NMDA) receptor, voltage-gated potassium channels/leucine-rich glioma inactivated protein-1 (VGKC/ LGI-I),
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid (GABA) receptors, and
glutamic acid decarboxylase (GAD 65)
• Diagnosis is made by detection of the specific autoantibodies in serum and/or CSF
• NMDA receptor antibodies have been reported in some patients with HSE encephalitis
• Development of NMDAR antibodies in patients with HSE may contribute to delayed recovery or clinical relapse
• Autoimmune encephalitis may also be associated with specific cancers (paraneoplastic) and onconeuronal
antibodies (e.g., anti-Hu, Yo, Ma2, amphiphysin, CRMP5, CV2)
• Subacute or chronic forms of encephalitis may occur in association with autoantibodies against thyroglobulin
and thyroperoxidase (Hashimoto’s encephalopathy) and with prion diseases
• Naegleria fowleri--- can also cause acute meningoencephalitis (primary amebic meningoencephalitis)
o thrive in warm, iron-rich pools of water, including those found in drains, canals, and both natural and
human-made outdoor pools
o with a history of swimming in potentially infected water
o CSF often resembles that of bacterial meningitis with a neutrophilic pleocytosis and hypo-
glycorrhachia.
o Motile trophozoites can be seen in a wet mount of warm, fresh CSF.
• Acanthamoeba and Balamuthia----subacute or chronic granulomatous amebic meningoencephalitis
• Increasing number of cases of Balamuthia mandrillaris amebic encephalitis mimicking acute viral encephalitis
in children and immunocompetent adults.
 o also been associated with encephalitis in recipients of transplanted organs from a donor with
unrecognized infection
o No effective treatment has been identified
o mortality approaches 100%.
• Raccoon pinworm Baylisascaris procyonis---history of raccoon exposure, especially of playing in or eating dirt
potentially contaminated with raccoon feces.
o Most patients are children
o many have an associated eosinophilia.
• Major diagnostic challenge is to distinguish HSV from other viruses that cause encephalitis.
o particularly important because in virtually every other instance the therapy is supportive, whereas
specific and effective antiviral therapy is available for HSV
• HSV encephalitis should be considered when clinical features suggest involvement of the inferomedial
frontotemporal regions of the brain--- prominent olfactory or gustatory hallucinations, anosmia, unusual or
bizarre behavior or personality alterations, or memory disturbance
o should always be suspected in patients with signs and symptoms consistent with acute encephalitis
with focal findings on clinical examination, neuroimaging studies, or EEG
• CSF PCR analysis--- diagnostic procedure of choice
• A positive CSF PCR establishes the diagnosis; negative test dramatically reduces the likelihood of HSV
encephalitis
• Patients with rapidly progressive encephalitis and prominent brainstem signs, symptoms, or neuroimaging
abnormalities may be infected by flaviviruses (WNV, St. Louis encephalitis virus, Japanese encephalitis virus),
HSV, enterovirus 71 (EV71), rabies, or Listeria monocytogenes.
• Significant involvement of deep gray matter structures (basal ganglia and thalamus) should also suggest
possible flavivirus infection.
o May present clinically with prominent movement disorders (tremor, myoclonus) or parkinsonian
features.
• WNV infection---can present with a poliomyelitis-like acute flaccid paralysis
• Acute flaccid paralysis is characterized by the acute onset of a lower motor neuron type of weakness with
flaccid tone, reduced or absent reflexes, and relatively preserved sensation.
• Complete eradication of polio remains an ongoing challenge
• Epidemiologic factors----season of the year; the geographic location and travel history; and possible exposure
to animal bites or scratches, rodents, and ticks.
• Classic clinical presentation of encephalitic (furious) rabies is fever, fluctuating consciousness, and autonomic
hyperactivity
• Phobic spasms of the larynx, pharynx, neck muscles, and diaphragm can be triggered by attempts to swallow
water (hydrophobia) or by inspiration (aerophobia).
• May also present with paralytic (dumb) rabies characterized by acute ascending paralysis.
• Rabies due to the bite of a bat has a different clinical presentation than classic rabies due to a dog or wolf
bite.
o focal neurologic deficits, myoclonus, seizures, and hallucinations; phobic spasms are not a typical
feature. Have a CSF lymphocytic pleocytosis and may show areas of increased T2 signal abnormality
in the brainstem, hippocampus, and hypothalamus.
• Diagnosis can be made by finding rabies virus antigen in brain tissue or in the neural innervation of hair follicles
at the nape of the neck.
• PCR amplification of viral nucleic acid from CSF and saliva or tears may also enable diagnosis.
• Serology is frequently negative in both serum and CSF in the first week after onset of infection
• No specific therapy is available

Treatment of Viral Encephalitis

• Specific antiviral therapy should be initiated when appropriate
• Vital functions should be monitored continuously and supported as required
• In the initial stages many patients will require care in an ICU
• Basic management and supportive therapy should include careful monitoring of ICP, fluid restriction,
avoidance of hypotonic intravenous solutions, and suppression of fever.
• Seizures should be treated with standard anticonvulsant regimens
o prophylactic therapy should be considered in view of the high frequency of seizures in severe
• At risk for aspiration pneumonia, stasis ulcers and decubiti, contractures, deep-venous thrombosis and its
complications, and infections of indwelling lines and catheters
• Acyclovir is of benefit in the treatment of HSV; should be started empirically in patients with suspected viral
encephalitis especially if focal features are present
o Discontinued in patients found not to have HSV encephalitis, with the possible exception of patients
with severe encephalitis due to VZV or EBV.
o Adults should receive a dose of 10 mg/kg of acyclovir intravenously every 8 h (30 mg/kg per day total
dose) for 21 days
• Neonatal HSV CNS infection is less responsive to acyclovir therapy; it is recommended that neonates with
HSV encephalitis receive 20 mg/kg of acyclovir every 8 h (60 mg/kg per day total dose) for a minimum of 21
days
• Acyclovir should be diluted to a concentration ≤7 mg/mL; infused slowly over 1 h, rather than by rapid or
bolus infusion, to minimize the risk of renal dysfunction.
o can cause local inflammation and phlebitis (9%)
o Dose adjustment is required in patients with impaired renal glomerular filtration
o Penetration into CSF is excellent, with average drug levels ~50% of serum levels.
o Complications include elevations in blood urea nitrogen and creatinine levels (5%),
thrombocytopenia (6%), gastrointestinal toxicity (nausea, vomiting, diarrhea) (7%), and
neurotoxicity (lethargy or obtundation, disorientation, confusion, agitation, hallucinations, tremors,
seizures) (1%).
• Oral antiviral drugs with efficacy against HSV, VZV, and EBV, including acyclovir, famciclovir, and
valacyclovir, have not been evaluated in the treatment of encephalitis either as primary therapy or as
supplemental therapy following completion of a course of parenteral acyclovir
• Role of adjunctive intravenous glucocorticoids in treatment of HSV and VZV infection remains unclear.
• Ganciclovir and foscarnet, either alone or in combination, are often used in the treatment of CMV-related
CNS infections---efficacy remains unproven
• Cidofovir may provide an alternative in patients who fail to respond to ganciclovir and foscarnet
• Ganciclovir--synthetic nucleoside analogue of 2′-deoxyguanosine
o preferentially phosphorylated by virus-induced cellular kinases
o Ganciclovir triphosphate--- competitive inhibitor of the CMV DNA polymerase---incorporation into
nascent viral DNA----premature chain termination.
o Usual dose for treatment of severe neurologic illnesses is 5 mg/kg every 12 h given intravenously at
a constant rate over 1 h.
o Maintenance therapy of 5 mg/kg every day for an indefinite period
o Induction therapy should be continued until patients show a decline in CSF pleocytosis and a
reduction in CSF CMV DNA copy number on quantitative PCR testing
o Doses should be adjusted in patients with renal insufficiency
o Treatment is often limited by the development of granulocytopenia and thrombocytopenia (20–25%),
which may require reduction in or discontinuation of therapy.
o Gastrointestinal side effects (nausea, vomiting, diarrhea, and abdominal pain) occur in ~20% of
patients. Valganciclovir is an orally bioavailable prodrug that can generate high serum levels of
ganciclovir
• Foscarnet---pyrophosphate analogue that inhibits viral DNA polymerases by binding to the pyrophosphate-
binding site
o CSF concentrations range from 15 to 100% of coincident plasma levels
o Usual dose for serious CMV-related neurologic illness is 60 mg/kg every 8 h administered by
constant infusion over 1 h
o Induction therapy for 14–21 days is followed by maintenance therapy (60–120 mg/kg per day)
o Induction therapy--- extended in patients who fail to show a decline in CSF pleocytosis and a
reduction in CSF CMV DNA copy number on quantitative PCR tests
o Many patients experience fatigue and nausea
o Reductions in serum calcium, magnesium, and potassium occur in ~15% of patients and may be
associated with tetany, cardiac rhythm disturbances, or seizures.
• Cidofovir ---nucleotide analogue that is effective in treating CMV retinitis
o Usual dose is 5 mg/kg intravenously once weekly for 2 weeks, then biweekly for two or more
additional doses, depending on clinical response
o Patients must be prehydrated with normal saline (e.g., 1 L over 1–2 h) prior to each dose and
treated with probenecid (e.g., 1 g 3 h before cidofovir and 1 g 2 and 8 h after cidofovir)
o Nephrotoxicity is common; the dose should be reduced if renal function deteriorates.
o Intravenous ribavirin (15–25 mg/kg per day in divided doses given every 8 h) reported to be of
benefit in isolated cases of severe encephalitis due to California encephalitis (La Crosse) virus
▪ Might be of benefit for the rare patients (infants or young children) with severe adenovirus
or rotavirus encephalitis and in patients with encephalitis due to LCMV or other arenavi-
ruses.
 ▪ Hemolysis with resulting anemia has been the major side effect limiting therapy
o No specific antiviral therapy of proven efficacy is currently available for treatment of WNV
encephalitis. Both chimeric and killed inactivated WNV vaccines have been found to be safe and
effective in preventing equine WNV infection
Sequelae
o Variation in the incidence and severity of sequelae in patients surviving viral encephalitis
o EEE virus infection----nearly 80% of survivors have severe neurologic sequelae
o Many patients with WNV infection have sequelae, including cognitive impairment; weakness; and hyper- or
hypokinetic movement disorders, including tremor, myoclonus, and parkinsonism

Chronic Encephalitis

Progressive Multifocal Leukoencephalopathy (PML)

o characterized pathologically by multifocal areas of demyelination of varying size distributed throughout the
brain but sparing the spinal cord and optic nerves.
o There are characteristic cytologic alterations in both astrocytes and oligodendrocytes
o Astrocytes are enlarged and contain hyperchromatic, deformed, and bizarre nuclei and frequent mitotic figures
o Oligodendrocytes have enlarged, densely staining nuclei that contain viral inclusions formed by crystalline
arrays of JC virus (JCV) particles.
o Often present with visual deficits (45%), typically a homonymous hemianopia; mental impairment (38%)
(dementia, confusion, personality change); weakness, including hemi- or monoparesis; and ataxia.
o Seizures occur in ~20% of patients, predominantly in those with lesions abutting the cortex.
o Almost all patients have an underlying immunosuppressive disorder or are receiving immunomodulatory
therapy
o most common associated conditions were AIDS (80%), hematologic malignancies (13%), transplant recipients
(5%), and chronic inflammatory diseases (2%)
o up to 5% of AIDS patients will develop PML
o Patients who lack detectable JCV antibody have a risk of developing PML of <0.1 case/1000 patients
o JCV seropositive and have been exposed to prior immunosuppressive therapy and have received >24 months
of natalizumab therapy have a risk of >1.3 case/100 treated patients
o Also been reported in patients receiving other humanized monoclonal antibodies with immunomodulatory
activity like efalizumab and rituximab
o Basic clinical and diagnostic features appear to be similar in HIV-associated PML and PML associated with
immunomodulatory drugs; exception is an increased likelihood of MRI enhancement of PML lesions in
immunomodulatory cases
o Natalizumab-associated PML--- almost invariably develop clinical and radiographic worsening of lesions with
discontinuation of therapy----development of immune reconstitution inflammatory syndrome (IRIS)
o Diagnosis of PML--suggested by MRI, revealing multifocal asymmetric, coalescing white matter lesions
located periventricularly, in the centrum semiovale, in the parietal-occipital region, and in the cerebellum
o Increased signal on T2 and FLAIR images; decreased signal on T1-weighted images
o HIV-PML lesions--classically nonenhancing (90%); patients with immunomodulatory drug-associated PML
may have peripheral ring enhancement.
o Not typically associated with edema or mass effect
o CT scans often show hypodense nonenhancing white matter lesions.
o CSF is typically normal
o although mild elevation in protein and/or IgG may be found
o Pleocytosis occurs in <25% of cases (predominantly mononuclear); rarely exceeds 25 cells/μL.
o PCR amplification of JCV DNA from CSF has become an important diagnostic tool
o Positive CSF PCR for JCV DNA in association with typical MRI lesions----diagnostic of PML---relatively high
specificity (92–100%); however, sensitivity is variable
o negative CSF PCR does not exclude the diagnosis
o HIV-negative patients and HIV-positive patients not receiving highly active antiviral therapy (HAART),
sensitivity is likely 70–90%
o HAART-treated patients--- sensitivity may be closer to 60%----lower JCV CSF viral load in
o Patients with low JCV loads (<100 copies/μL) have a generally better prognosis than those with higher viral
loads
o Negative CSF PCR studies--- may require brain biopsy for definitive diagnosis
o Serologic studies are of no utility in diagnosis due to high basal seroprevalence level--- may contribute to risk
stratification in patients contemplating therapy with immunomodulatory drugs such as natalizumab

Treatment of PML
o No effective therapy for PML is available
 o Case reports of potential beneficial effects of the 5-HT2a receptor antagonist mirtazapine, which may inhibit
binding of JCV to its receptor on oligodendrocytes.
o Possible beneficial effect of treatment with interferon-α
o Because PML almost invariably occurs in immunocompromised individuals, any therapeutic interventions
designed to enhance or restore immunocompetence should be considered.
o HIV-positive PML patients treated with HAART, 1-year survival is ~50%, although up to 80% of survivors may
have significant neurologic sequelae.
o HIV-positive PML patients with higher CD4 counts (>300/μL) and low or nondetectable HIV viral loads have a
better prognosis than those with lower CD4 counts and higher viral loads
o Associated immune reconstitution in patients with an underlying opportunistic infection such as PML may also
result in a severe CNS inflammatory syndrome (IRIS) associated with clinical worsening, CSF pleocytosis,
and the appearance of new enhancing MRI lesions
o Receiving natalizumab or other immunomodulatory antibodies who are suspected of having PML---therapy
immediately stopped.
o Removal of drugs with long pharmacokinetic or biological half-lives with plasma exchange or
immunoadsorption is frequently utilized
o Should be closely monitored for development of IRIS---treated with intravenous glucocorticoids

Subacute Sclerosing Panencephalitis (SSPE)

o Rare, chronic, progressive demyelinating disease of the CNS associated with a chronic nonpermissive
infection of brain tissue with measles virus
o Frequency has been estimated at 1 in 100,000–500,000 measles cases.
o Most patients give a history of primary measles infection at an early age (2 years)---- followed after a latent
interval of 6–8 years by the development of a progressive neurologic disorder
o 85% of patients are between 5 and 15 years old at diagnosis
o Initial manifestations include poor school performance and mood and personality changes
o Typical signs of a CNS viral infection, including fever and headache, do not occur
o Patients develop progressive intellectual deterioration, focal and/or generalized seizures, myoclonus, ataxia,
and visual disturbances
o Late stage of the illness---- patients are unresponsive, quadriparetic, and spastic, with hyperactive tendon
reflexes and extensor plantar responses
o MRI is often normal early
o Areas of increased T2 signal develop in the white matter of the brain and brainstem as disease progresses
o EEG may initially show only nonspecific slowing---progression--- characteristic periodic pattern with bursts of
high-voltage, sharp, slow waves every 3–8 s, followed by periods of attenuated (“flat”) background
o CSF is acellular with a normal or mildly elevated protein concentration and a markedly elevated gamma
globulin level (>20% of total CSF protein)
o CSF antimeasles antibody levels are invariably elevated
o Oligoclonal antimeasles antibodies are often present
o Measles virus can be cultured from brain tissue
o Viral antigen can be identified immunocytochemically

Treatment of SSPE
o No definitive therapy for SSPE is available
o Treatment with isoprinosine (Inosiplex, 100 mg/kg per day), alone or in combination with intrathecal or
intraventricular interferon-α----reported to prolong survival and produce clinical improvement in some patients.

Progressive Rubella Panencephalitis

o Extremely rare disorder that primarily affects males with congenital rubella syndrome
o Latent period of 8–19 years-----progressive neurologic deterioration
o Manifestations are similar to those seen in SSPE
o CSF--mild lymphocytic pleocytosis, slightly elevated protein concentration, markedly increased gamma
globulin, and rubella virus–specific oligoclonal bands
o No therapy is available
o Universal prevention of both congenital and childhood rubella through the use of the available live attenuated
rubella vaccine--- expected to eliminate the disease.