Stroke as a Complication of Medical Disease (printer-friendly) 05/09/2009 09:28

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From Seminars in Neurology

Stroke as a Complication of Medical Disease

Michael Chen, M.D.
Published: 07/28/2009
Abstract and Introduction

Abstract

This article focuses on the medical diseases that not only lead to cerebrovascular complications, but at times initially
manifest as cerebral infarction. Specifically, I examine the relationships between stroke and various medical diseases
(inflammatory disease, migraine and other vasoconstrictive disorders, congenital heart disease, connective tissue
disorders, infectious disease, malignancy, and polycystic kidney disease). Many of these conditions may cause
cerebrovascular ischemia via nonatherosclerotic mechanisms. Understanding these relationships between stroke and
medical disease will allow the reader to better recognize etiologic relationships, and thereby reach more accurate
diagnoses.

Introduction

Many medical diseases not only lead to cerebrovascular complications, but also, at times, initially manifest as cerebral
infarction. The prognosis, course, and management of stroke secondary to medical disease may be influenced by
factors not limited to managing atherosclerosis. Many of the topics chosen for this article are not just the medical
diseases associated with cerebrovascular complications, such as malignancy, infection, and connective tissue disease,
but also those rarer conditions that are becoming increasingly recognized, such as systemic inflammatory conditions.
Understanding the relationships between stroke and medical disease allows for more effective patient care, helping the
neurologist communicate better and work in collaboration with internal medicine colleagues.

Stroke as a Complication of Inflammatory Diseases

Giant-cell Arteritis

Giant-cell arteritis, also known as temporal arteritis, affects medium-to-large arteries and is characterized pathologically
by infiltration of mononuclear cells (lymphocytes and plasma cells) along with granulomas composed of multinucleated
or foreign-body giant cells into the arterial wall. Incidence increases with age, with a peak incidence of 44.6 per
100,000 population for those older than 80 years. [1] The characteristic symptom is a tender headache over the scalp
that interferes with sleep and is associated with jaw claudication. [2] Polymyalgia rheumatica may precede the
symptoms of headache and jaw claudication, but it is visual loss that is the most feared complication. The posterior
ciliary arteries are most commonly involved and can cause an anterior ischemic optic neuropathy. During the active
phase of the disease, stroke, particularly in the posterior circulation, is a potentially lethal complication.

Three of the following five criteria are required to meet the American College of Rheumatology classification for giant-
cell arteritis: age older than 50 years, new-onset localized headache, temporal artery tenderness, erythrocyte
sedimentation rate > 50 mm/h, and typical histological findings on temporal artery biopsy. These criteria have a
reported sensitivity of 93.5% and a reported specificity of 91.2% for the classification of giant-cell arteritis compared
with other vasculitides.[3] Because the disease is segmental, biopsy may be normal. Angiographically, the superficial
temporal artery may show areas of dilation and constriction along the length of the artery.

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Once clinically suspected, steroids should be prescribed and arrangements made for a temporal artery biopsy as soon
as possible. Steroids should be started at 40 to 60 mg/d for the first month or until symptoms are controlled.

Takayasu's Arteritis

Like giant-cell arteritis, Takayasu's arteritis is pathologically characterized by granulomatous changes, but preferentially
affects large vessels including the aorta. Takayasu's arteritis has been detected most frequently in young women (less
than 50 years of age) from Asia. Characteristic clinical findings include asymmetrical or absent pulses, which can be
associated with constitutional symptoms and sometimes retinal or cerebral ischemia. The mechanism for stroke in
Takayasu's arteritis is via stenosis or occlusion of extracranial carotid or vertebral arteries, including the subclavian
steal syndrome.

The mainstay of treatment is steroids and cytotoxic agents. Attempts at surgical reconstructive or bypass procedures
are generally reserved for cases refractory to anti-inflammatory agents. Unusual collateral pathways have been reported
to develop without surgery.[4]

Systemic Lupus Erythematosus

One of the 13 cardinal manifestations recognized by the American College of Rheumatology for the diagnosis of
systemic lupus erythematosus (SLE) is neuropsychiatric disease. [5] Johnson and Richardson's necropsy series showed
widespread microinfarction in the cortex and brainstem.[6] Although vasculitis is frequently mentioned as an important
cause of stroke in SLE patients, it has never been convincingly documented on postmortem studies. Better accepted is
cardiogenic brain embolism (with or without associated nonbacterial thrombotic endocarditis) as a mechanism of stroke
in patients with SLE. If cardiogenic embolism is found, anticoagulation may be instituted. Thrombotic thrombocytopenic
purpura, which may develop in the late stages of SLE, is yet another mechanism for stroke. [7] Antiphospholipid
antibodies, including anticardiolipin antibodies and the lupus anticoagulant, have been detected in 38 to 43% of patients
with SLE. [5] Again, if found, anticoagulation may be considered for future stroke risk reduction. However, Levine et al
found no differential response to aspirin or warfarin therapy in patients with antiphospholipid antibodies in their
subsequent risk of vascular occlusive events.[8]

Herpes Zoster

A syndrome of hemiparesis contralateral to herpes zoster ophthalmicus is a rare but well-described syndrome.
Hemiparesis may occur weeks or months after the initial vesicular eruption and has been pathologically correlated with
a necrotizing arteritis with or without thrombosis. There are no granulomatous changes, but instead herpes-like virions,
leading to Cowdry A inclusion bodies in the media of cerebral vessels. The vasculopathy becomes multifocal, however,
in immunocompromised individuals, affecting branches of large cerebral arteries and small cerebral arteries. Detection
of anti-varicella zoster virus (VZV) immunoglobulin (Ig) G antibody in cerebrospinal fluid (CSF) is a sensitive indicator of
infection and an indication for intravenous acyclovir therapy.[9]

Isolated Angiitis of the Central Nervous System

Isolated angiitis of the central nervous system (CNS), or granulomatous angiitis of the CNS, is arterial inflammation
restricted to the CNS. Unlike giant-cell arteritis, patients of any age can be affected, small arteries and veins are
preferentially involved, and the response to steroids is poor. Laboratory testing is of little benefit. Angiography may be
normal or show a pattern of alternating dilation and constriction that is nonspecific. Brain biopsy is the typical definitive
test and is usually done to distinguish vasculitis from tumor and infection. Progression of the disease and death
frequently occur despite steroid treatment. [10]

Stroke as a Complication of Migraine and Other Vasoconstrictive Conditions

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Migraine

A migraine is a severe, pulsating, unilateral episodic headache worsened by physical activity. Migraine is often
associated with nausea or vomiting, photophobia, and phonophobia. A migraine-induced stroke, a diagnosis of
exclusion, is thought of as a migraine with a neurological deficit that mimics the aura symptoms of previous attacks,
and the stroke must occur during the course of a typical migraine attack. [11]

Although current proposed mechanisms of migraine emphasize a cortical spreading depression, there is associated
vasoconstriction that likely occurs as a result. Rascol et al [12] reported a series of patients with a mean age of 33 years
with not only computed tomography (CT)-confirmed cerebral infarctions during the course of the migraine attack, but
also angiographic evidence of vasoconstriction or occlusion in the involved vascular territory. Caplan reported his series
of patients with migraine and posterior circulation ischemia and found significant rates of either basilar artery narrowing
or occlusion on angiography. [13] Furthermore, there is a transient propensity for clot formation as the endothelium is
disturbed during the vasoconstriction, and excessive vomiting may contribute to dehydration. An associated fibrotic
change to the vessel wall may occur, similar to that seen during cerebral vasospasm from subarachnoid hemorrhage,
which may further contribute to vascular narrowing and cerebral ischemia.

Reversible Cerebral Vasoconstriction Syndrome

Reversible cerebral vasoconstriction syndrome (Call-Fleming syndrome), originally described by Call in 1988, is used to
describe a group of disorders sharing the cardinal clinical and angiographic features of reversible segmental multifocal
cerebral vasoconstriction with severe headaches, focal ischemia, and/or seizures. Ducros et al described the largest
series of 67 consecutive patients with vascular imaging, documenting both initial vasoconstriction and its disappearance
in less than 3 months. [14] Stroke occurred in 9% of their patients. This syndrome is particularly common during
puerperium or postpartum, especially in those taking serotonin reuptake inhibitors for postpartum depression, and is
referred to as postpartum angiopathy. The use of selective serotonin reuptake inhibitors (venlafaxine and paroxetine),
hypercalcemia, pheochromocytoma, and pre-eclampsia have all been associated with this pattern of cerebral
vasoconstriction. The temporal pattern of recurrent headache and small convexity subarachnoid hemorrhage followed
by secondary ischemia suggests a sequential disturbance in cerebral arterial tone. First, small distal arteries appear
affected and are responsible for cortical hemorrhages. Subsequently, medium-to-large arteries are involved, leading to
ischemic events. Severe headache is a distinguishing feature of this syndrome. The pattern of cerebral ischemia is
multifocal and mild. Transcranial Doppler invariably shows diffuse increased velocities.

Awareness of this syndrome is of particular importance when the diagnosis of cerebral vasculitis is also being
considered, and this is often the diagnosis made by radiologists after reviewing the vascular imaging. Accurate
recognition of this syndrome can prevent a patient from unnecessary laboratory testing, brain biopsy, and inadvertent
long-term immunosuppressant therapy. The role of calcium channel antagonists, particularly verapamil, is controversial,
but generally found to be beneficial. Vasoactive agents such as pseudoephedrine should be avoided.

Reversible Posterior Leukoencephalopathy Syndrome

Similar to the Call-Fleming syndrome, reversible posterior leukoencephalopathy syndrome is characterized by reversible
cerebral vasoconstriction causing cerebral ischemia. Reversible posterior leukoencephalopathy syndrome is often
associated with an abrupt rise in arterial blood pressure and is seen with eclampsia, renal disease, hypertensive
encephalopathy, and in association with cytotoxic or immunosuppressive drugs. [15] Typical symptoms include a severe
headache, decreased level of consciousness, cognitive changes, and seizures, all developing over hours. The
distinctive symptom is due to the associated cortical visual changes, including cortical blindness (Balint's syndrome).
One proposed mechanism is a sudden elevation in systemic blood pressure exceeding the autoregulatory capability of
cerebral vessels. With disruption of the blood-brain barrier, there is focal transudation of fluid and petechial

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cerebral vessels. With disruption of the blood-brain barrier, there is focal transudation of fluid and petechial
hemorrhage.[16] Radiographic findings include bilateral parieto-occipital white matter edema with characteristic sparing
of the calcarine and paramedian occipital lobes, distinguishing this from bilateral infarction of the posterior cerebral
arteries. Although the cause of this syndrome is multifactorial, it should be promptly recognized because it is not only
reversible, but also treatable with blood pressure control and/or lowering the dose of immunosuppressive agents.

Bartleson's Syndrome

Bartleson and colleagues described a benign syndrome characterized by episodic migraine-like headaches, focal
neurological deficits indicative of cerebral ischemia, and CSF abnormalities. They described seven patients with
episodic, severe headaches associated with sensory, motor, speech, and visual disturbances. The neurological deficits
recurred and were usually short, stereotyped, and sequentially involved different sensory modalities in a certain pattern.
Cerebrospinal fluid showed a predominantly lymphocytic pleocytosis, increased protein concentration, and elevated
opening pressure. All seven patients in this series recovered completely. The migrainous episodes were thought to be
symptomatic of an underlying inflammatory disorder of the CNS. [17]

Stroke as a Complication of Congenital Heart Disease

Paradoxical embolism is the unique mechanism of stroke in congenital heart disease. A blood clot, air, or fat is allowed
passage from the venous compartment -- through an abnormal venous-to-arterial communication -- to the arterial
circulation. Under normal circumstances, a blood clot dislodged from a venous site would be trapped in the lungs and
dissolved by endogenous thrombolytics. A self-perpetuating cycle, cyanotic heart disease leads to increased systemic
venous pressure, peripheral edema, and a lower functional capacity, resulting in a sedentary lifestyle, all promoting
venous thrombosis. Patients at risk for paradoxical emboli are also at high risk for air emboli from inadvertent air in an
intravenous line. Pulmonary arteriovenous fistula, another mechanism for paradoxical embolism, is a prominent part of
the Osler-Weber-Rendu syndrome. Finding echo-contrast bubbles in the left atrium after several cardiac cycles after
passage through the right atrium suggests that a mechanism for paradoxical embolism exists.

Coarctation of the aorta is a congenital narrowing located at the aortic isthmus, just distal to the origin of the left
subclavian artery. As a consequence of this, there is functional hypertension proximal to the narrowing, with subsequent
intracerebral hemorrhage or accelerated atherosclerosis and ischemic stroke.

Although previously regarded to be an independent risk factor for stroke since described by Barnett et al in 1976, [18]
more recent echocardiogram-based studies have shown no association between mitral valve prolapse and stroke in
young people.[19] Patent foramen ovale (PFO), which may occur in 27% of the population,[20] is an anomaly formed
after birth when fibrous adhesions fail to seal the atrial septum. It is considered a possible risk factor for stroke,
particularly with cryptogenic stroke in the young where no other cause is found, particularly when there is no history of
atherosclerosis. An atrial septal aneurysm (ASA) is congenital, redundant tissue at the fossa ovalis that bulges into
either atrium during respiration and is associated with an increased risk for stroke. [21] Conflicting data attribute an
increased risk of stroke with PFO alone and with PFO and ASA together. Several randomized studies comparing
medical therapy with endovascular closure of PFOs are underway.

Stroke as a Complication of Connective Tissue Disorders

Gene mutations that encode extracellular matrix components such as collagen and proteoglycans can cause a
vasculopathy, resulting in aneurysm formation, occlusive arterial diseases, dissection, and arteriovenous fistulae.

Arterial dissections are particularly common and arise from an intimal tear that leads to an intramural hematoma that
can be classified as either subintimal or subadventitial. The presentation of neck, head, or face pain accompanied by
focal ischemic symptoms should raise suspicion for an arterial dissection. Head, face, or neck pain is the most common
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focal ischemic symptoms should raise suspicion for an arterial dissection. Head, face, or neck pain is the most common
overall symptom, present in nearly 80% of cases. [22] In about a third of cases, partial Horner's syndrome (ptosis and
miosis with intact facial sweating) is present,[23] which is related to mechanical distortion of the sympathetic fibers of the
internal carotid plexus. Focal neurological symptoms and subarachnoid hemorrhage can occur if the dissection is
intracranial, which tends to occur in the supraclinoid segment or the middle cerebral artery. Vertebral artery dissections
usually also manifest as ipsilateral neck and occipital pain associated with ischemic symptoms.

When suspected, the diagnostic evaluation should be performed expeditiously. Magnetic resonance imaging (MRI) and
magnetic resonance angiography (MRA) are the most direct, noninvasive modalities for the confirmation of arterial
dissection. [24] The characteristic imaging finding on MRI is an attenuation or absence of flow signal and a crescent
sign. The crescent sign is due to the intramural dissection appearing in a semilunar fashion as a spiraling periarterial
rim of intramural hematoma best visualized on T1-weighted and fluid attenuated inversion recovery (FLAIR) axial views.
As expected, the sensitivity of MRI and MRA for vertebral dissection is limited, and conventional catheter angiography is
usually warranted.

Conventional catheter angiography more accurately defines the dissection morphology, particularly with regards to the
details of a dissecting aneurysm, intimal flap, double lumen, vessel stenosis with string sign, and intraluminal clot.
Dissecting aneurysms are usually found at nonbifurcation locations.

Treatment for extracranial arterial dissections is focused on preventing secondary thrombotic events, especially artery-
to-artery embolism. [23] Common practice is to immediately institute anticoagulation and reassess at 3 months with
noninvasive imaging. Dissections located intracranially are treated more for their predisposition for subarachnoid
hemorrhage rather than for artery-to-artery embolism. [24]

If the short-term risk of stroke is sufficiently high, such as a situation with a flow-limiting defect, therapeutic
neuroendovascular options exist. In such dire situations, arterial stenting with or without gentle balloon angioplasty
obliterates the false lumen and restores normal arterial blood flow in the true lumen, reducing the risk of artery-to-artery
embolism. The risk of subarachnoid hemorrhage due to subadventitial dissection is usually reduced with parent vessel
occlusion because the dysplastic arterial framework is too fragile to support conventional coil embolization.

The overall natural history of extracranial arterial dissections depends on the severity of the initial dissection, but is, in
general, favorable. More than 75% of patients have an excellent clinical recovery. [25] The prognosis with intracranial
dissections is not as good, with 50% of survivors suffering major residual deficits. [26] Angiographic improvement occurs
within the first 2 to 3 months in ~80 to 90% of cases. [24]

Four inherited connective tissue disorders are regarded as significantly associated with cerebrovascular disease:
Ehlers-Danlos syndrome, Marfan's syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. Early
recognition of these syndromes may help in the investigation of asymptomatic carriers, allowing for appropriate genetic
counseling.

Ehlers-Danlos Syndrome

Ten Ehlers-Danlos syndrome phenotypes have been identified, with type IV being the most malignant form with an
abnormality in collagen type III. Common clinical manifestations include joint hypermobility, hyperextensible skin,
bruising, and abnormal scarring.[27] Spontaneous direct carotid-cavernous fistula is the most common neurovascular
manifestation of Ehlers-Danlos syndrome. Such fistulas consist of high-flow direct communication between the
cavernous segment of the internal carotid artery and the cavernous sinus, and result from intracavernous carotid
aneurysm rupture or dissection. Other times, dural carotid-cavernous fistulas result from low-flow communication
between dural branches of the internal carotid artery and the cavernous sinus thought to be secondary to cavernous
sinus thrombosis.
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sinus thrombosis.

Given the vascular fragility, extracranial and intracranial dissections are common, some even occurring spontaneously.
Diagnosis is usually made by skin biopsy, with fibroblast culture and biochemical studies showing abnormal type III
procollagen molecules. Management is generally conservative. Due to blood vessel wall fragility, there may be a
predisposition to further arterial dissections, even with routine catheterization during cerebral angiography. [28]

Marfan's Syndrome

Marfan's syndrome, with its well-recognized phenotype, is an autosomal-dominant connective tissue disorder with
neurovascular manifestations consisting of arterial dissections and cerebral aneurysms. Characteristic systemic
manifestations include tall stature, pectus excavatum, scoliosis, prognathism, high-arched palate and joint hypermobility,
striae atrophicae, hernias, myopia ectopia lentis, aortic aneurysms and dissections, and mitral valve prolapse. [28]

The most common and life-threatening neurovascular complication is extension of aortic dissection into the common
carotid arteries leading to either a fulminant severe hemispheric stroke syndrome or an ischemic myelopathy from
involvement of the spinal arteries.[29]

The genetic mutation can be found as a defect on chromosome 15q21.1 encoding fibrillin-1. This protein is an important
component of the extracellular matrix found in elastic tissue throughout the body including the skin, aorta, and all three
layers of the arterial wall.

Osteogenesis Imperfecta

Genetic mutations encoding for type I collagen lead to osteogenesis imperfecta, a heterogeneous group of connective
tissue disorders known for affected patients having brittle bones. Cerebrovascular complications are rare, but cerebral
aneurysms associated with fenestrated vertebral arteries, vertebral dissections, and carotid-cavernous fistulas have
been reported. [30]

Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum has been mapped to a defect in chromosome 16p13.1, which causes deficiency in the
elastic fiber in skin, the eyes, and cardiovascular system. The primary neurovascular manifestation is via premature
occlusive disease of the carotid or vertebral arteries, leading to multiple small cerebral infarcts. Associated ruptured
cerebral aneurysms have been reported and are frequent causes of death in these patients. [28]

Stroke as a Complication of Infectious Disease

Evidence suggests that acute infection (e.g., respiratory tract and urinary tract) is indeed a generic trigger for acute
stroke. [31] Increased levels of C-reactive protein (CRP), proinflammatory cytokines, and other acute-phase reactants in
acute systemic infections and/or surgery may contribute to a procoagulant state by elevating levels of fibrinogen; factors
VII, VIII, and XII; and activating platelets. C-reactive protein promotes localized coagulation and thrombosis by
stimulating monocytes to produce tissue factor, a membrane-bound glycoprotein that initiates the extrinsic pathway of
coagulation. [32] Increased platelet reactivity has been seen in volunteers with presumed upper respiratory tract
infection. [33] Bacterial and viral infection increases the risk for cardioembolic stroke, often associated with atrial
fibrillation. [34] Infections in this circumstance may transform an underlying prothrombotic state to that of an embolus or
thrombus formation. A significant association has been found between recent infection and cervical artery dissection. [35]
Similarly, an infection may further exacerbate the instability of preexisting abnormalities of the extracellular matrix
proteins. The occlusions, including dural sinus occlusions, may be either arterial or venous.

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Therefore, prevention of infection in patients at high risk for stroke is important. Influenza vaccination in patients with a
history of cerebrovascular disease or who are at high risk for stroke may confer protection against not only influenza
but also stroke. Published guidelines advocate influenza vaccination as part of a comprehensive secondary stroke
prevention strategy in patients with coronary or other atherosclerotic vascular disease. [36]

Bacterial Infections

Acute Bacterial Meningitis. If allowed to progress, the subarachnoid inflammatory reaction from Haemophilus
influenzae, Streptococcus pneumoniae, or Neisseria meningitides may cause ischemic strokes via several different
mechanisms. Both small and large arteries can be occluded as well as thrombosis of the cortical veins and dural
sinuses.[37] Extension of the infection through the adventitia can also lead to formation of brain aneurysms. If infarctions
are found when antimicrobial therapy is being instituted, corticosteroids are important to attenuate the cerebrovascular
complications.

Infective Endocarditis. Stroke is the most common neurological complication of infective endocarditis, although
encephalopathy, retinal emboli, mycotic aneurysm, abscess, meningitis, and seizures are also seen.[38] Ischemic
strokes are found in 10 to 45% of patients with infective endocarditis.[39] Clinically, stroke most often occurs during the
uncontrolled infection. The clinical spectrum of stroke as a complication for infective endocarditis has changed. Today
many patients are older and less likely to have underlying rheumatic valvular disease associated with Streptococcus
viridans infection as the treatments for this condition have improved. Over the last decade, Staphylococcus aureus
endocarditis has been reported with an increased incidence due to intravenous drug use. As such, cerebral infarctions
caused by S. aureus endocarditis tend to occur early, to be multiple, and to carry a poor prognosis. Emboli from S.
aureus endocarditis may also cause intracranial hemorrhage due to pyogenic arteritis during uncontrolled infection.
Cerebral emboli from Streptococcus species infection usually occur late, are usually single, and also involve the
systemic circulation. Streptococcus species is the infection usually associated with dilated mycotic aneurysms, which
are a rare finding that may heal with antimicrobial therapy. If anticoagulation is planned for valve replacement, the
infectious intracranial aneurysms may be embolized to prevent future hemorrhage.

With appropriate antimicrobial treatment, the risk of recurrent embolism is low, around 0.3% per day. There are no data
to support the use of anticoagulation for primary or secondary prevention of stroke complicating endocarditis.[40]

Tuberculosis. When Mycobacterium tuberculosis tubercles near the surface of the brain rupture into the subarachnoid
space causing meningoencephalitis, the inflammatory changes can cause arterial narrowing and cerebral infarction. [41]
Patients with tuberculous meningitis develop stroke in up to 40% of cases, usually involving the small, terminal
lenticulostriate branches. Characteristic CSF findings include a lymphocytic pleocytosis, increased protein, and low
glucose concentration. Imaging may show hydrocephalus, leptomeningeal enhancement, and strokes. If suspected,
antituberculous drugs need to be started before the diagnosis is confirmed. Again, steroids may reduce the risk of
stroke from cerebrovascular inflammation.

Neurosyphilis. With the availability of penicillin, the typical presentation of neurosyphilis has shifted from chronic forms,
such as tabes dorsalis, to more acute forms, which include meningovascular syphilis. The stigmata of syphilis include
previous chancre, regional lymphadenopathy, alopecia, uveitis, retinitis, and rash. In a patient with a history of chancre
and/or stigmata of syphilis, prominent headache associated with ischemic stroke suggests meningovascular syphilis.
Heubner's arteritis is a crescentic endarteritis obliterans affecting large- and medium-size arteries. Histopathologically,
fibrous and inflammatory changes in the adventitia are associated with thinning of the media and fibroblastic
proliferation of the intima. This process leads to vascular stenosis or occlusion, causing cerebral infarction. [42]

Neurocysticercosis

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The most common parasitic infection of the CNS, cysticercus, causes an inflammatory response in the brain
parenchyma, subarachnoid space, ventricles, and spinal cord. Leptomeningeal thickening leads to inflammatory
occlusions of small perforator vessels, causing lacunar syndromes. Cerebrospinal fluid shows lymphocytic pleocytosis,
elevated protein, and normal glucose concentrations. Albendazole in conjunction with dexamethasone is the
recommended therapy. A ventriculoperitoneal shunt may be needed for refractory hydrocephalus. [43]

Fungal Infections

Nearly all CNS fungal infections have the propensity to occlude small subarachnoid blood vessels in the course of
meningitis. Fungi may also cause mycotic aneurysms. The development of cerebral infarctions usually indicates
advanced fungal infection, and antifungal agents are effective in only a proportion of patients. Aspergillus is associated
with a specific stroke syndrome via hyphae invasion of small- and medium-size cerebral vessels, causing either a
coagulative necrosis, which induces arterial thrombosis, or formation of mycotic aneurysms that may induce fatal
hemorrhage.[44] Aspergillosis needs to be considered in immunocompromised patients who develop
meningoencephalitis and hemorrhagic strokes associated with pulmonary or craniofacial sinus lesions. Cryptococcal
meningitis also causes inflammatory changes to cerebral vessels, most prominently in the distribution of small
leptomeningeal vessels.[45] Mucormycosis is usually suspected in patients with diabetic ketoacidosis. The rhinocerebral
form may easily spread from the paranasal sinuses and orbit to the CNS via the cavernous sinus causing thrombosis
and occlusion of the cavernous carotid artery. Prompt evaluation is crucial because therapy with amphotericin B has
been described to be effective. [46]

Viral Infections

HIV. An intracranial vasculopathy in HIV-infected patients is characterized by medium-size vessel occlusive disease
sometimes associated with fusiform aneurysms, stenosis, or vessel caliber variation. Intracranially, the focus of
pathology is in the intima. [47] Autopsy studies have shown widespread intracranial vascular degenerative ectasia with
superimposed thrombosis. More specifically, the following were found: hyaline small-vessel wall thickening, perivascular
space dilatation, rarefaction, and pigment deposition with vessel wall mineralization and occasional perivascular
inflammatory cell infiltrates. The pathogenesis behind extracranial vasculopathy in HIV patients centers on the vaso
vasorum.

Stroke as a Complication of Malignancy

Neurological complications in patients with cancer and, in particular, stroke are common reasons for hospitalization.
Cancer has been proposed to cause ischemic stroke by several mechanisms, including direct compression or invasion
of the cerebral vasculature, tumor-induced coagulation disorders, treatment-related side effects, and nonbacterial
thrombotic endocarditis.[48] Conventional, atherosclerotic risk factors still account for the majority of stroke events even
among patients with cancer.

Neoplasms such as meningioma and gliosarcoma have been reported to cause stroke by compression of the
intracranial vessels.[49] Cerebral venous thrombosis from compression or invasion from solid tumors or metastases
tends to be acute in onset. A coagulopathy has been associated with solid tumors as well as serial cancer treatments,
whereby a low-grade, activated coagulation results in systemic and cerebral arterial or venous thrombosis. [50] Radiation
therapy, particularly that administered to head and neck epithelial cancers or lymphoma, can induce severe carotid
atherosclerosis. The most common cause of stroke in cancer patients, however, is nonbacterial thrombotic endocarditis.
The mechanism is via sterile fibrin vegetation that, depending on the size and number, can manifest either as focal
neurological deficits or as a more diffuse presentation such as encephalopathy. [51]

Hematologic malignancies cause hemorrhagic stroke. Disseminated intravascular coagulation is an important etiology
and is thought to be aggravated by chemotherapy-induced tumor cell lysis. Intracerebral hemorrhage may also occur
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and is thought to be aggravated by chemotherapy-induced tumor cell lysis. Intracerebral hemorrhage may also occur
secondary to venous sinus thrombosis. As expected, liver metastases and concomitant liver failure can lead to
intracerebral hemorrhage from a decrease in clotting factor production. Metastases to bone marrow can result in
intracerebral hemorrhage due to thrombocytopenia.

The clinical signs of cerebral ischemia in a patient with cancer are often more diffuse than focal, particularly when
venous occlusion leads to increased intracranial pressure. [48] Multiple embolic strokes, new onset cardiac murmur, and
negative blood cultures should raise a suspicion of nonbacterial thrombotic endocarditis. A transesophageal
echocardiogram will then show valvular vegetations. Leptomeningeal metastases may be diagnosed via CSF
examination. A stroke may very well be the first clinical event preceding the identification of a systemic malignancy,
particularly for cardiac myxoma.[52]

Although not clearly established, anticoagulation is generally considered for the thrombotic coagulopathy associated
with cancer. The overall prognosis of stroke in cancer patients is poor. Median survival is on the order of months.

Stroke as a Complication of Polycystic Kidney Disease

Neurovascular complications are found in the autosomal-dominant form of polycystic kidney disease (PKD), which is
characterized by bilateral multiple renal cysts. Unruptured intracranial aneurysms in polycystic kidney disease are four
times as frequent as in the general population.[53] Patients usually have small aneurysms involving the middle cerebral
artery and have a positive family history of intracranial aneurysms. Hypertensive intracerebral hemorrhage located in
the deep white matter is also common. The gene mutation is located on chromosome 16 (ADPKD1). Although
screening for unruptured cerebral aneurysms is commonly pursued using noninvasive imaging, such as MRA or CT
angiography, the natural history is unknown. Therefore, the benefit of screening must be weighed against the cost and
associated anxiety of either knowing an aneurysm exists or the unknown. If an aneurysm is identified, however, risk
factors such as blood pressure control and cessation of alcohol and cigarette use should be addressed.

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Authors and Disclosures

Michael Chen, Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois

Reprint Address
Michael Chen, M.D., Assistant Professor in Neurology, Neurosurgery, and Radiology, Department of Neurological Sciences, Rush University
Medical Center, 1725 West Harrison Street, Suite 1118, Chicago, IL 60612; E-mail: Michael_Chen@rush.edu.
Semin Neurol. 2009;29(2):154-162. © 2009 Thieme Medical Publishers

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