Risk Factors for Stroke

The incidence of stroke increases dramatically with advancing age, and increasing age is the most powerful risk factor for stroke. The incidence of stroke doubles each decade past 55 years of age. Half of all strokes occur in people older than 70 to 75 years. Overall, stroke incidence rate is 1.25 times greater in men than women. Men develop ischemic strokes at higher rates than women up to the age of 75 years. With an estimated 20% of the population being older than 65, greater than 10 million octogenarians, and an increasing life expectancy in the United States, it is predicted that in the near future, the incidence of stroke will reach 1 million per year. Compared to whites, African Americans have approximately a twofold increased risk of first-ever stroke. The rate of cerebral infarction is higher in African Americans and Hispanic Americans than in whites; this could be partially explained by the higher prevalence of DM and arterial hypertension experienced by these ethnic minorities. African Americans had been thought to have higher rates of intracranial atherosclerotic occlusive disease compared with whites, but this may actually reflect ascertainment bias (Sacco et al., 1995; Wityk et al., 1996). Furthermore, the stroke incidence and case fatality rates are also markedly different among the major ethnic groups in Auckland, New Zealand. Maori and Pacific Islands people have a higher rate of mortality within 28 days of stroke when compared with Europeans, especially men (Bonita et al., 1997). Chinese, Koreans, and Japanese also may have increased rates of intracranial hemorrhage and intracranial atherosclerotic cerebrovascular disease compared to whites. In comparison with the United States and Western Europe, where hemorrhagic stroke represents 20% or less of all stroke subtypes, 40% of the stroke subtypes are hemorrhagic (intracerebral or subarachnoid hemorrhage) in Japan. Conversely, in India, where ischemic stroke accounts for 80% of all strokes, 10% to 15% of strokes occur in people younger than 40 years and are mostly related to intracranial atherosclerosis.

Heredity and Risk of Stroke

Heredity seems to play a role in the pathogenesis of cerebral infarction. An increased risk is seen with a family history of stroke among first-degree relatives. Genetic factors have been linked with the pathogenesis of ischemic stroke, but specific genetic variants remain largely unknown, and some purported genetic associations have not been replicated (Chinnery et al., 2010). There are a number of genetic causes of stroke. Some inherited diseases, such as the hereditary dyslipoproteinemias, predispose to accelerated atherosclerosis. A number of inherited diseases are associated with nonatherosclerotic vasculopathies, including Ehlers-Danlos (especially type IV) syndrome, Marfan syndrome, Rendu-Osler-Weber disease, and Sturge-Weber syndrome. Familial atrial myxomas, hereditary cardiomyopathies, and hereditary cardiac conduction disorders are examples of inherited cardiac disorders that predispose to stroke. Deficiencies of protein C and S or antithrombin (AT) are examples of inherited hematological abnormalities that can cause stroke. Finally, rare inherited metabolic disorders that can cause stroke include mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and homocystinuria. The presence of the apolipoprotein epsilon-2 allele in elderly individuals and deletion of the gene for the angiotensin-converting enzyme may increase the risk for stroke, but the association with stroke subtype is unclear (Agerholm-Larsen et al., 1997; Slooter et al., 1997; Szolnoki et al., 2001). The most significant findings of the ongoing Siblings With Ischemic Stroke Study (SWISS) to date have been the relationship between age and stroke in probands and sibs, and the lack of a tight association among ischemic stroke subtypes (Adams Jr. et al., 1993) within families (Meschia et al., 2005; Meschia et al., 2006; Wiklund et al., 2007).

Common Modifiable Risk Factors

At least 25% of the adult population has arterial hypertension, defined as systolic blood pressure (SBP) greater than 140 mm Hg or diastolic blood pressure (DBP) greater than 90 mm Hg. Prehypertension is defined as SBP between 120 and 139 mm Hg or DBP between 80 and 90 mm Hg. Optimal blood pressure is defined as SBP less than 120 mm Hg and DBP less than 80 mm Hg (Chobanian et al., 2003). Similar guidelines have been developed by the European Society of Hypertension–European Society of Cardiology Guidelines Committee (2003). The JNC7 Report (Table 51A.2) emphasizes that patients at risk, including those with DM or a history of stroke, should be treated with medications. Unfortunately, arterial hypertension remains poorly treated worldwide, and in the United States many patients are either undertreated or untreated (Hajjar and Kotchen, 2003). Arterial hypertension predisposes to ischemic stroke by aggravating atherosclerosis and accelerating heart disease, increasing the relative risk for stroke an estimated three- to fourfold. The risk is greater for patients with isolated systolic hypertension and elevated pulse pressure. Arterial hypertension is also the most important modifiable risk factor for stroke and the most powerful risk factor for all forms of vascular dementia (vascular cognitive impairment). Lowering blood pressure in stroke survivors helps prevent recurrent stroke and is more important than the specific hypotensive agent used, although there is some suggestion that beta-blockers are less preferred than other agents based on recent meta-analyses (Lindholm et al., 2005). Blood pressure treatment that results in a modest reduction in SBP of 10 to 12 mm Hg and 5 to 6 mm Hg diastolic is associated with a 38% reduction in stroke incidence (MacMahon and Rodgers, 1996). Treatment of isolated systolic hypertension in the elderly is also effective for reducing stroke risk. The Systolic Hypertension in the Elderly Program showed a 36% reduction in nonfatal plus fatal stroke over 5 years in the age 60-and-older group when isolated systolic hypertension was treated. Treating systolic hypertension also slows the progression of carotid artery stenosis. The PROGRESS trial evaluated the effects of perindopril and indapamide on the risk for stroke in patients with histories of stroke or transient ischemic attack (TIA). Regardless of blood pressure at entry, patients clearly benefited from treatment (PROGRESS Collaborative Group, 2001).

About 171 million people worldwide have type 2 DM, including 18 million Americans. It is estimated that these numbers will grow to 366 million people worldwide and 30 million Americans by 2030 (Fonseca et al., 2002). Diabetes mellitus increases the risk of ischemic cerebrovascular disease an estimated two- to fourfold as compared with the risk in people without diabetes. In addition, DM increases morbidity and mortality after stroke. Macrovascular disease is the leading cause of death among patients with DM. The mechanisms of stroke secondary to diabetes may be caused by cerebrovascular atherosclerosis, cardiac embolism, or rheological abnormalities. The excess stroke risk is independent of age or blood pressure status. Diabetes associated with arterial hypertension adds significantly to stroke risk. There is a fourfold increase in the relative risk of cardiovascular events among patients with diabetes and hypertension compared to those without the two conditions. Diabetic persons with retinopathy and autonomic neuropathy appear to be a group at particularly high risk for ischemic stroke. High insulin levels increase the risk for atherosclerosis and may represent a pathogenetic factor in cerebral small-vessel disease. Presently, no evidence exists that tighter diabetic control or normal HbA_1c levels over time decrease the risk for stroke or stroke recurrence. Moreover, optimal target blood glucose levels in stroke patients remain largely unknown (Gray et al., 2004; Van den Berghe et al., 2006). The UK Glucose Insulin in Stroke Trial (GIST-UK) failed to demonstrate any clinical benefit of insulin-induced euglycemia (target glucose 72-126 mg/dL). Furthermore, mortality appeared to be higher among patients with the greatest glucose reduction (Gray et al., 2009). Moreover, in the Spectroscopic Evaluation of Lesion Evolution in Stroke: Trial of Insulin for Acute Lactic Acidosis (SELESTIAL), the infusion of glucose-potassium-insulin did not have a favorable impact on cerebral infarct growth (McCormick et al., 2010).

High total cholesterol and high low-density lipoprotein (LDL) concentration are correlated with atherosclerosis. Dyslipidemia is a recognized risk factor for ischemic stroke. Meta-analyses have suggested that ischemic stroke risk increases with increasing serum cholesterol, and the reduction in stroke risk associated with 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor (statin) therapies is related to reduction in LDL cholesterol (Amarenco et al., 2004; Tirschwell et al., 2004). Lipid-modifying therapy with statins has definitively established that reduction of LDL cholesterol reduces cardiovascular risk. Statins benefit stroke survivors as well. Lipid-lowering agents may slow progression of atherosclerotic plaque growth and may possibly cause a regression in plaque formation.

The Scandinavian Simvastatin Survival Study (4S) (Scandinavian Simvastatin Survival Study Group, 1999) investigated cholesterol lowering in persons with coronary heart disease and hypercholesterolemia and reported a highly significant relative reduction in the total mortality rate, major coronary events, and number of cardiac revascularization procedures. Post hoc analysis also showed a 28% reduction in fatal or nonfatal stroke and TIAs (Pedersen et al., 1998). The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study investigated cholesterol lowering with pravastatin in patients with a previous myocardial infarction (MI) or unstable angina who had cholesterol levels between 155 and 271 mg/dL and reported a remarkable reduction in MI, cardiac revascularizations, and cardiovascular deaths, as well as a 20% reduction in the risk for stroke (Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID] Study Group, 1998). Similar findings were associated with atorvastatin in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial and the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) studies. MIRACL showed a 50% relative risk reduction (RRR) (P = .045) in stroke among high-risk coronary disease patients (Schwartz et al., 2001). The ASCOT-LLA study demonstrated a favorable trend for fatal and nonfatal stroke, with a 27% RRR in patients at low risk for coronary events (hazard ratio, 0.73; 95% confidence interval [CI], 0.56-0.96; P = .0236), though not to the prespecified endpoint of P = .01 (Sever et al., 2003).

Although the Heart Protection Study (HPS) of patients at high risk with DM, coronary artery disease, or other atherosclerotic vascular disease did show an overall reduction in stroke risk, a subgroup analysis of the Heart Protection Study (HPS) did not show a reduction in the risk for stroke among patients with prior cerebrovascular disease (Heart Protection Study Collaborative Group, 2004). This subgroup analysis was limited in that the mean time from event to enrollment was 4.3 years, and the LDL reduction was 38 mg/dL. Subsequently, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study was published (SPARCL Investigators, 2006). This was a study of 4731 patients who had suffered either a stroke or TIA, had no known coronary heart disease, had LDL cholesterol levels of 100 to 190 mg/dL, and who were randomized to placebo or 80 mg of atorvastatin. A 56-mg/dL reduction in LDL treatment was noted in patients on atorvastatin. During a median follow-up of 4.9 years, 11.2% of atorvastatin-treated patients and 13.1% of placebo patients had a fatal or nonfatal stroke for an adjusted hazard ratio of 0.84 (95% CI, 0.71-0.99). A small increase in hemorrhagic stroke was reported in the atorvastatin group. Moreover, recent studies evaluating withdrawal of statins in acute ischemic stroke showed a higher incidence of death or dependency at 90 days (Blanco et al., 2007). Current guidelines of the American Heart Association and proposed modifications of the NCEP-III guidelines would therefore suggest that all patients at risk for stroke or who have had a cerebral infarction should be treated to a goal LDL level of below 70 mg/dL (Grundy et al., 2004; Sacco et al., 2006).

Atrial fibrillation, the most common sustained cardiac arrhythmia in the general population, affects about 1% of adults, is the most common cause for cardioembolic stroke, and is a risk factor for future cardiovascular disease. An estimated 1 to 2 million Americans have chronic nonvalvular atrial fibrillation (NVAF), a condition that is associated with an overall risk for stroke of approximately five- to sixfold, and a mortality rate approximately twice that of age- and sex-matched individuals without atrial fibrillation. The prevalence of atrial fibrillation increases with advancing age and is 0.5% for patients aged 50 to 59 years and 8.8% for those aged 80 to 89 years. Approximately 70% of individuals with atrial fibrillation are between 65 and 85 years of age. NVAF is associated with a substantial risk for stroke. Heart failure, arterial hypertension, DM, prior stroke or TIA, and age older than 75 years increase the risk for embolism in patients with NVAF. High-risk patients have a 5% to 7% yearly risk for thromboembolism. The CHADS2 Score represents a validated quantification of risk, with congestive heart failure, hypertension, age older than 75 years, and a history of DM being assigned 1 point; stroke or TIA are assigned 2 points (Gage et al., 2001). Ischemic stroke rates increase from 1.9 to 18.2 events per 100 patient-years with CHADS 2 scores of 0 and 6, respectively. Warfarin therapy, with the International Normalized Ratio (INR) value adjusted to between 2.0 and 3.0, decreases the relative risk for stroke in patients with NVAF by approximately two-thirds. High-risk patients, regardless of age, sustain particular benefit from warfarin anticoagulation. Left atrial enlargement also increases the risk for stroke in men. Likewise, left ventricular hypertrophy as demonstrated by electrocardiography (ECG) in men with preexisting ischemic heart disease is a major risk factor for stroke.

Cigarette smoking is the leading cause of preventable death in the United States. Cigarette smoking is a major risk factor for coronary artery disease, stroke, and peripheral arterial disease, an independent risk factor for ischemic stroke in men and women of all ages, and a leading risk factor of carotid atherosclerosis in men. The risk for stroke in smokers is two to three times greater than in nonsmokers. The mechanisms of enhanced atherogenesis promoted by cigarette smoking are incompletely understood but include reduced capacity of the blood to deliver oxygen, cardiac arrhythmias, increased blood coagulability, and triggering of arterial thrombosis and arterial spasm. Tobacco also increases carotid artery plaque thickness. More than 5 years may be required before a reduction in stroke risk is observed after cessation of smoking. Switching to pipe or cigar smoking is of no benefit. Counseling, nicotine replacement products, varenicline (a nicotinic receptor partial agonist),and bupropion are efficacious smoking cessation treatments. Selective blockers of the cannabinoid receptor type 1, such as rimonabant, have been proposed for treatment of multiple cardiometabolic risk factors including smoking and abdominal obesity (Gelfand and Cannon, 2006).

There is a J-shaped association between alcohol consumption and ischemic stroke; light to moderate use (up to two drinks a day) evenly distributed throughout the week offers a reduced risk, whereas heavy alcohol consumption is associated with an increased risk for total stroke. Heavy drinking may precipitate cardiogenic brain embolism. Alcohol consumption increases the risk for hemorrhagic stroke; alcohol-induced hypertension predisposes to spontaneous intracranial hemorrhage. Furthermore, active drinkers have a higher frequency of obstructive apneas and more severe hypoxemia. Conversely, moderate alcohol consumption may reduce the risk for ischemic stroke and may elevate HDL concentration. Elimination or reduction of alcohol consumption is recommended for heavy drinkers. Restriction of alcohol consumption to fewer than two drinks daily is recommended for light to moderate drinkers and nonpregnant women.

The prevalence of obesity (body mass index of 30 or higher) has increased nationwide. More than 61% of adult Americans are overweight, and 27% are obese. Obesity, particularly abdominal or truncal, is an important risk factor for cardiovascular disease in men and women of all ages. There is some evidence that physical activity can reduce the risk for stroke. Regular exercise lowers arterial blood pressure, decreases insulin resistance, increases HDL cholesterol, and is associated with lower cardiovascular morbidity and mortality.

Numerous studies have established an association between obstructive sleep apnea (OSA) and stroke; moreover the severity of OSA is much higher in stroke patients than in controls (Dyken, 2000). Habitual snoring increases the risk for stroke and adversely affects the outcome of patients admitted to the hospital with stroke. Mounting evidence also suggests that inflammation, lipoprotein(a) concentration, impaired fibrinolysis, and increased thrombotic potential are important nontraditional cardiovascular risk factors.

Atherosclerotic lesions of the carotid artery bifurcation are a common cause of stroke. Asymptomatic carotid artery disease carries a greater risk for vascular death from coronary artery disease than from stroke. Persons with an asymptomatic carotid bruit have an estimated annual risk for stroke of 1.5% at 1 year and 7.5% at 5 years. Asymptomatic carotid artery stenosis of less than 75% carries a stroke risk of 1.3% annually; with stenosis of greater than 75%, the combined TIA and stroke rate is 10.5% per year, with most events occurring ipsilateral to the stenosed carotid artery. Plaque composition may be an important factor in the pathophysiology of carotid artery disease. Plaque structure rather than degree of carotid artery stenosis may be a critical factor in determining stroke risk. Ultrasonographic carotid artery plaque morphology may identify a subgroup of patients at high risk for stroke. Ulcerated, echolucent, and heterogeneous plaques with a soft core represent unstable plaques at high risk for producing arterioarterial embolism.

Patients who suffer TIAs are at greater risk than normal controls for stroke or death from vascular causes. The risk for stroke is approximately three times higher. Symptomatic carotid artery stenosis of greater than 70% carries an annual risk for stroke of approximately 15%. Approximately 10% to 15% of those experiencing a stroke have TIAs before their stroke. Patients with hemispheric TIAs are at greater risk for ipsilateral stroke than patients with retinal TIAs. Patients with a first stroke are at greater risk for recurrent stroke, especially (but not exclusively) early after the first stroke. Those who suffer a recurrent stroke have a higher mortality than patients with first stroke. If the recurrence is contralateral to the first stroke, prognosis for functional recovery is poor. The risk for stroke recurrence is also increased by the presence of underlying dementia.

The aorta is the most frequent site of atherosclerosis. Protruding atheroma may be the cause of otherwise unexplained TIAs or strokes. Aortic-arch atheromatosis detected by transesophageal echocardiography is an independent risk factor for cerebral ischemia; the association is particularly strong with mobile and thick atherosclerotic plaques more than 4 mm in thickness (French Study of Aortic Plaques in Stroke Group, 1996). The prevalence of ulcerated plaques was 16.9% among patients with cerebrovascular diseases, compared to 5.1% among patients with other neurological diseases. Remarkably, ulcerated plaques were found in 61% of cryptogenic cerebral infarcts, compared to 22% of cerebral infarcts with a known cause.

Other Risk Factors for Stroke

Hemostatic factors may be important in assessing the risk for cerebrovascular disease. Elevated hematocrit, hemoglobin concentration, and increased blood viscosity may be indicators of risk for ischemic stroke. Elevation of plasma fibrinogen is an independent risk factor for the development of cerebral infarction. Epidemiological studies have shown a correlation between elevated plasma fibrinogen levels and both ischemic stroke incidents and mortality. An elevated plasma fibrinogen level may reflect progression of atherogenesis. Plasminogen activator inhibitor-1 excess and factor VII are independent risk factors for coronary heart disease. Compared with white Americans, black Americans have higher mean levels of fibrinogen, factor VIII, von Willebrand factor, and AT, and lower mean levels of protein C. Fibrinogen levels are closely correlated with other stroke risk factors such as cigarette smoking, arterial hypertension, diabetes, obesity, hematocrit levels, and spontaneous echocardiographic contrast. Antiphospholipid (aPL) antibodies are a marker for an increased risk for thrombosis, including TIAs and stroke, particularly in those younger than 50 years. In older patients, the presence of aPL (either lupus anticoagulants [LAs] or anticardiolipin [aCL]) among patients with ischemic stroke does not predict either increased risk for subsequent vascular occlusive events over 2 years or a differential response to aspirin or warfarin therapy. As such, routine screening for aPL in older patients with ischemic stroke does not appear warranted (Levine et al., 2004) The factor V Leiden mutation is associated with deep venous thrombosis in otherwise healthy individuals with additional prothrombotic risk factors. An overall association of the factor V Leiden mutation and arterial thrombosis has not been found. As opposed to homozygous mutations, heterozygous factor V Leiden and prothrombin gene mutations have no clear association with increased stroke risk (Fields and Levine, 2005). Elevated von Willebrand factor is a risk factor for MI and ischemic stroke. Elevated levels of fasting total homocysteine (normal 5-15 mM), a sulfhydryl-containing amino acid, have been associated with an increased risk for stroke and thrombotic events in case-controlled studies. Metabolism of homocysteine requires vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), folate, and betaine. Plasma homocysteine concentrations may be reduced by the administration of folic acid alone or in combination with vitamins B₆ and B₁₂. Conversely, serum folate concentrations of 9.2 nM or less have been associated with elevated plasma levels of homocysteine, and a decreased folate concentration alone may be a risk factor for ischemic stroke, particularly among blacks (Giles et al., 1995). However, folic acid supplementation does not have a major impact on stroke reduction (Lee et al., 2010).

Stroke is uncommon among women of childbearing age, estimated at 4.4/100,000 (Petitti et al., l997). The relative risk for ischemic stroke is increased among users of high-dose estrogen oral contraceptives, particularly with coexistent arterial hypertension, cigarette smoking, and increasing age. Based on an odds ratio of 1.93, the risk is increased to 8.5/100,000, which translates into a number needed to harm of 24,000 women to cause one ischemic stroke (Gillum et al., 2000). Thus, for a healthy young woman without any other stroke risk factors, the risk of stroke associated with oral contraceptives is small and probably outweighed by their benefits. New agents containing lower doses of estrogen and progestin have reduced the frequency of oral contraceptive–related cerebral infarction. Two postmenopausal hormone replacement studies with equine estrogen (Premarin) showed no benefit in reducing the incidence of stroke in a cohort of women with coronary heart disease (Hulley et al., 1998). The Women’s Estrogen for Stroke Treatment study of estradiol replacement in postmenopausal women status post stroke also failed to show a reduction in recurrent stroke (Viscoli et al., 2001). In addition, the Women’s Health Initiative, a prospective randomized trial of estrogen therapy in healthy postmenopausal women, was halted prematurely because the risks outweighed the benefits. Absolute excess risks per 10,000 person-years attributable to estrogen plus progestin were sevenfold for coronary heart disease events, eightfold for strokes, eightfold for pulmonary thromboembolism, and eightfold for invasive cancers, whereas absolute risk reductions per 10,000 person-years were sixfold for colorectal cancers and fivefold for hip fractures (Rossouw et al., 2002). The risk for thrombosis associated with pregnancy is high in the postpartum period. The risk for cerebral infarction is increased in the 6 weeks after delivery but not during pregnancy.

A diurnal and seasonal variation of ischemic events occurs. Circadian changes in physical activity, catecholamine levels, blood pressure, blood viscosity, platelet aggregability, blood coagulability, and fibrinolytic activity may explain the circadian variations in onset of myocardial and cerebral infarction. Although an early-morning peak occurs for all subtypes of stroke, most clinical trials on the use of platelet antiaggregants or other antithrombotic agents do not take these circadian variations into account. Rhythmometric analyses support the notion that stroke is a chrono-risk disease, in which cold temperatures also represent a risk factor. A history of recent infection, particularly of bacterial origin and within 1 week of the event, is also a risk factor for ischemic stroke in patients of all ages. A number of recent reports suggest that Chlamydia pneumoniae, a causative organism of respiratory infections, may have a role in carotid and coronary atherosclerosis. Some studies have also identified an association with chronic infections with Helicobacter pylori and cytomegalovirus (Bittner, 1998; Ross, 1999). These findings have not been confirmed, however (Lindsberg and Grau, 2003).

Transient Ischemic Attacks

An estimated 400,000 individuals experience a TIA each year. A TIA is a prognostic indicator of stroke, with one-third of untreated TIA patients having a stroke within 5 years. About 1 in 10 patients with TIA experience a stroke in the next 3 months. The interval from the last TIA is an important predictor of stroke risk; of all patients who subsequently experience stroke, 21% do so within 1 month and 51% do so within 1 year of the last TIA. In one series, patients with TIA had a 3-month stroke risk of 10.5%, equal to the recurrence rate following a stroke. Furthermore, 50% of those strokes following a TIA occurred within 48 hours of TIA onset (Johnston et al., 2000). Cardiac events are the principal cause of death in patients who have had a TIA. The 5% to 6% annual mortality rate after TIA is mainly caused by MI, similar to the 4% annual cardiac mortality rate in patients with stable angina pectoris.

A TIA is a temporary and “non-marching” neurological deficit of sudden onset; attributed to focal ischemia of the brain, retina, or cochlea; and lasting less than 24 hours. Yet most TIAs last only a few minutes. Episodes that last longer than 1 hour are usually due to small infarctions. With the advent of diffusion-weighted magnetic resonance imaging (DW-MRI) sequences, the time-based definition of TIA is inadequate because infarctions are sometimes evident on DW-MRI in patients whose clinical manifestations resolved completely within a few hours. Thus, a “tissue-based” modification of the TIA definition has been proposed, suggesting that any transient episode, regardless of duration, associated with a clinically appropriate lesion by MRI be defined as a stroke, and that otherwise prolonged events (>1-6 hours in duration) be defined as stroke rather than TIA when otherwise clinically appropriate (Albers et al., 2002). Furthermore, DW-MRI is useful in predicting the risk for early stroke; patients with TIA and DW-MRI lesions are at greater risk for experiencing a subsequent stroke than patients without a lesion (Coutts et al., 2005). Johnston et al. also introduced a new unified score for risk stratification in patients with TIAs, known as the ABCD2 score. The ABCD2 score is based on age, blood pressure (≥140/90 mm Hg), clinical features, TIA duration, and diabetes (Table 51A.3). ABCD2 scores of 4 or greater indicate a moderate to high stroke risk and justify prompt hospital admission (Johnston et al., 2007).

Table 51A.3 ABCD2 Score

The onset of TIA symptoms is sudden, reaching maximum intensity almost immediately. To qualify as a TIA, therefore, an episode should also be followed by complete clinical recovery. TIAs involving the carotid circulation should be distinguished from those involving the vertebrobasilar circulation. Headaches often occur in patients with TIAs. As such, migraine with aura may sometimes be indistinguishable from TIA.

Agreement between physicians to define the likelihood of a TIA, even among fellowship-trained neurologists, remains poor (Castle et al., 2010). The following symptoms are considered typical of TIAs in the carotid circulation: ipsilateral amaurosis fugax, contralateral sensory or motor dysfunction limited to one side of the body, aphasia, contralateral homonymous hemianopia, or any combination thereof. The following symptoms represent typical TIAs in the vertebrobasilar system: bilateral or shifting motor or sensory dysfunction, complete or partial loss of vision in the homonymous fields of both eyes, or any combination of these symptoms. Perioral numbness also occurs. Isolated diplopia, vertigo, dysarthria, and dysphagia should not be considered as being caused by a TIA unless they occur in combination with one another or with any of the other symptoms just listed (Box 51A.1). Older patients with isolated vertebrobasilar symptoms and a significant history of cardiovascular risk factors should, however, be evaluated for possible TIA or stroke, because they are at substantially higher risk for cerebrovascular events (Norrving et al., 1995).

Occlusive disease in the subclavian arteries or the innominate artery can give rise to extracranial steal syndromes. The most well-defined syndrome is subclavian steal syndrome (SSS). In SSS, reversal of flow in the vertebral artery is caused by a high-grade subclavian artery stenosis or occlusion proximal to the origin of the vertebral artery from the aortic arch or innominate artery, with resultant symptoms of brainstem ischemia, usually precipitated by actively exercising the ipsilateral arm. The left side is involved most frequently. With innominate artery occlusion, the origin of the right carotid is also subject to the consequences of reduced pressure. SSS can be suspected by the presence of a reduced or delayed radial pulse and diminished blood pressure in the affected arm relative to the contralateral arm. A subclavian steal may be symptomatic or asymptomatic. Many patients have angiographic evidence of reversed vertebral blood flow without ischemic symptoms. Transcranial Doppler ultrasonography may detect transient retrograde basilar blood flow. Retrograde vertebral artery flow is a benign entity. Brainstem infarction is an uncommon complication of the subclavian steal syndrome.

Transient global amnesia (TGA) is characterized by a reversible antegrade and retrograde memory loss, except for a total amnesia of events that occur during the attacks and inability to learn newly acquired information. During the attacks, patients remain alert without motor or sensory impairments and often ask the same questions repeatedly. Patients are able to retain personal identity and carry on complex activities. TGA most commonly affects patients in their 50s and older. Men are affected more commonly than women. The attacks begin abruptly and without warning. A typical attack lasts several hours (mean, 3-6 hours) but seldom longer than 12 hours. Onset of TGA may follow physical exertion, sudden exposure to cold or heat, or sexual intercourse. Although a large number of conditions have been associated with transient episodes of amnesia, in most instances, TGA is of primary or unknown cause. TGA has been documented in association with epilepsy, migraine, intracranial tumors, overdose of diazepam, cardiac arrhythmias secondary to digitalis intoxication, and as a complication of cerebral and coronary angiography. Many reports have suggested a vascular causal factor for this heterogeneous syndrome. Bilateral hippocampal and parahippocampal complex ischemia, possibly of migrainous origin, in the distribution of the posterior cerebral arteries is a potential mechanism. Acute confusional migraines in children and TGA have a number of similar features. Others have suggested an epileptic causal factor for a minority of patients. Venous hypertension with transient hypoxemia in the context of incompetent internal jugular vein valves has also been suggested as a possible mechanism for TGA (Nedelmann et al., 2005). Transient amnesias have been divided into pure TGA, probable epileptic amnesia, and probable transient ischemic amnesia. In contrast to patients with TIAs, the prognosis of persons with pure TGA is benign, with no apparent increased risk for vascular endpoints. Recurrences are uncommon. Extensive evaluations are not usually required except to distinguish TGA from TIA or seizures. Treatment with platelet antiaggregants is not indicated in most patients unless there is a suspicion for transient ischemic amnesia. The use of prophylactic calcium channel blockers may be justified in patients with a potential migrainous causal factor.

Drop attacks are characterized by the sudden loss of muscle tone and strength. The attacks cause the patients to unexpectedly fall to the ground. Consciousness is preserved. Most attacks occur while standing or walking and often follow head or neck motion. Drop attacks have been considered a symptom of vertebrobasilar ischemia, but many of these patients have other coexistent disorders that could otherwise explain their symptoms. In rare instances, drop attacks may indeed be caused by ischemia of the corticospinal tract or reticular formation. However, isolated drop attacks are seldom a manifestation of vertebrobasilar occlusive disease. In most instances these attacks are secondary to akinetic seizures, high cervical spine or foramen magnum lesions, postural hypotension, Tumarkin otolithic crises (in Ménière disease), or near syncope of cardiac origin.

Transient ischemic attacks may result from atherothromboembolism that originates from ulcerated extracranial arteries, emboli of cardiac origin, occlusion of small penetrating arteries that arise from the large surface arteries of the circle of Willis, altered local blood flow (perfusion failure) due to severe arterial stenosis, nonatherosclerotic vasculopathies, or hypercoagulable states. Preceding TIAs occur in large numbers of patients with brain infarction. In published series of cases of stroke, TIAs occurred before 25% to 50% of atherothrombotic infarcts, in 11% to 30% of cardioembolic infarcts, and in 11% to 14% of lacunar infarcts. Lacunar TIAs in general share the same pathogenetic mechanisms of lacunar infarcts and are associated with a substantially better prognosis than nonlacunar TIAs.

Crescendo episodes of cerebral ischemia that increase in frequency, severity, or duration must be treated as neurological emergencies. One small subset of crescendo TIAs is represented by the capsular warning syndrome, characterized by restricted, stereotyped, repeated episodes of capsular ischemia causing contralateral symptoms involving the face, arm, and leg. When capsular infarction develops, it is usually a lacunar-type stroke and involves a single penetrating vessel. Occasionally, striatocapsular or anterior choroidal artery territory infarction occurs. These may be lacunar in origin but sometimes are associated with carotid artery steno-occlusive disease. Typically these patients are refractory to conventional forms of therapy.

Rational treatment of patients with TIAs depends on a careful history and detailed physical examination. The neurovascular examination may disclose a well-localized bruit in the mid- or upper cervical area. Bruits arise when normal laminar blood flow is disturbed. However, the presence of a cervical bruit does not necessarily indicate underlying carotid artery atherosclerosis. Correlation with angiography or ultrasound studies show only 60% concordance with cervical auscultation in predicting the presence of arterial stenosis. Radiated cardiac murmurs, hyperdynamic states, nonatherosclerotic carotid arterial lesions, and venous hums can produce cervical murmurs. The absence of a bruit has little diagnostic value; the bruit may disappear when the stenosis is advanced. Conversely, a cervical bruit may be heard contralateral to an internal carotid artery occlusion or reflect ipsilateral external carotid artery disease of uncertain clinical significance.

Different types of microemboli (e.g., cholesterol crystals, platelet fibrin, calcium, and other forms of debris) can be seen in the retinal arterioles during or between attacks of transient monocular visual loss. Engorgement of conjunctival and episcleral vessels, corneal edema and rubeosis irides, and anterior-chamber cell flares are indicative of an underlying ischemic oculopathy. Asymmetrical hypertensive retinal changes noted on funduscopy are suggestive of a high-grade carotid artery stenosis or occlusion on the side of the less severely involved retina. Venous stasis retinopathy may occur with high-grade carotid artery stenosis or occlusion and is characterized by diminished or absent venous pulsations, dilated and tortuous retinal veins, peripheral microaneurysms, and blossom-shaped hemorrhages in the midperipheral retina. Retinal microvascular abnormalities correlate with an increased incidence of lacunar strokes (Yatsuya et al., 2010). Corneal arcus senilis may be less obvious or absent on the side of low perfusion.

Many conditions can resemble a TIA. Subdural, intracerebral, or subarachnoid hemorrhage, space-occupying lesions, seizures, hypoglycemia, migraine, syncope, and labyrinthine disorders are among the diverse conditions in the differential diagnosis when TIA is considered. Symptoms of a transient neurological dysfunction that resolve incompletely should lead the physician to question the diagnosis of TIA. Similarly, a migration or “march of symptoms” from one part of the body to another is rare during a TIA and more indicative of a focal seizure or migraine. Fortification phenomena or scintillating bright visual symptoms are suggestive of migraine. In rare instances, involuntary limb-shaking movements can occur, but in general, involuntary movements reflect convulsive activity rather than a TIA.

Carotid Artery System Syndromes

Syndromes of the Anterior Cerebral Artery and Related Blood Vessels

Anterior cerebral artery (ACA) territory infarctions are uncommon (Fig. 51A.1). They occur in patients with vasospasm after subarachnoid hemorrhage caused by ACA or anterior communicating artery aneurysm. Excluding these causes, the percentage of acute cerebral infarcts that are in the ACA territory is less than 3%. The characteristics of ACA infarction vary according to the site of involvement and the extent of collateral blood flow. Contralateral weakness involving primarily the lower extremity and, to a lesser extent, the arm is characteristic of infarction in the territory of the hemispheric branches of the ACA. Other characteristics include abulia, akinetic mutism (with bilateral mesiofrontal damage), impaired memory or emotional disturbances, transcortical motor aphasia (with dominant hemispheric lesions), deviation of the head and eyes toward the lesion, paratonia (gegenhalten), discriminative and proprioceptive sensory loss (primarily in the lower extremity), and sphincter incontinence. An anterior disconnection syndrome with left arm apraxia due to involvement of the anterior corpus callosum can be seen. Pericallosal branch involvement can cause apraxia, agraphia, and tactile anomia of the left hand. Infarction of the basal branches of the ACA can cause memory disorders, anxiety, and agitation. Infarction in the territory of the medial lenticulostriate artery (artery of Heubner) causes more pronounced weakness of the face and arm without sensory loss caused by this artery’s supply of portions of the anterior limb of the internal capsule.

Fig. 51A.1 Nonenhanced axial computed tomographic scan of a 63-year-old man with left-sided weakness and abulia demonstrates a right anterior cerebral artery (ACA) territory infarction. More superior images showed the entire ACA distribution was infarcted.

The anterior choroidal artery syndrome is often characterized by hemiparesis caused by involvement of the posterior limb of the internal capsule, hemisensory loss caused by involvement of the posterolateral nucleus of the thalamus or thalamocortical fibers, and hemianopia secondary to involvement of the lateral geniculate body or the geniculocalcarine tract. The visual field defect with anterior choroidal artery syndrome infarcts is characterized by a homonymous defect in the superior and inferior visual fields that spares the horizontal meridian. In a small number of patients, left spatial hemineglect with right hemispheric infarctions, and a mild language disorder with left hemispheric infarctions, may occur. With bilateral infarctions in the anterior choroidal artery syndrome territory, there can be pseudobulbar mutism and a variety of other features including facial diplegia, hemisensory loss, lethargy, neglect, and affect changes.

Lacunar Syndromes

Ischemic strokes resulting from small-vessel or penetrating artery disease (lacunes) have unique clinical, radiological, and pathological features. Lacunar infarcts are small ischemic infarctions in the deep regions of the brain or brainstem that range in diameter from 0.5 to 15 mm. These infarctions result from occlusion of the penetrating arteries, chiefly the anterior choroidal, middle cerebral, posterior cerebral, and basilar arteries. Lacunar infarcts could also be the result of occlusion of penetrating arteries by atherosclerosis of the parent artery or by microembolism. Lacunes may be single or multiple, symptomatic or asymptomatic. At least 20 lacunar syndromes have been described. Lacunar syndromes are predictive of lacunar infarcts, with a positive predictive value of approximately 84% to 90% (Gan et al., 1997). The five best recognized syndromes are (1) pure motor hemiparesis, (2) pure sensory stroke, (3) sensory-motor stroke, (4) homolateral ataxia and crural paresis (ataxic hemiparesis), and (5) dysarthria–clumsy hand syndrome. Multiple lacunes may be associated with acquired cognitive decline. Headaches are uncommon in patients with lacunar infarcts.

Pure motor hemiparesis is often caused by an internal capsule, basis pontis, or corona radiata lacune and is characterized by a contralateral hemiparesis or hemiplegia involving the face, arm, and, to a lesser extent, the leg, accompanied by mild dysarthria, particularly at onset of stroke. There should be no aphasia, apraxia, or agnosia, and there are no sensory, visual, or other higher cortical disturbances. Pure sensory stroke is the least predictive syndrome of lacunar infarction but may be due to a lacune involving the ventroposterolateral nucleus of the thalamus. However, cortical infarcts of the postcentral gyrus may present with a similar syndrome. Pure sensory stroke is characterized by paresthesias, numbness, and a unilateral hemisensory deficit involving the face, arm, trunk, and leg. Sensory-motor stroke is often caused by a lacuna involving the internal capsule and thalamus or posterior limb of the internal capsule; large striatocapsular infarcts also can cause a similar syndrome. It is characterized by a contralateral unilateral motor deficit with a superimposed hemisensory deficit. Homolateral ataxia and crural paresis are often caused by a lacuna either in the contralateral posterior limb of the internal capsule or the contralateral basis pontis. It is characterized by weakness, predominantly in the lower extremity, and ipsilateral incoordination of the arm and leg. Dysarthria–clumsy hand syndrome is often caused by a lacuna involving the deep areas of the basis pontis and is characterized by supranuclear facial weakness, dysarthria, dysphagia, loss of fine motor control of the hand, and Babinski sign.

Vertebrobasilar System Syndromes

The areas of the cerebellum supplied by the posterior inferior cerebellar artery (PICA) are variable (see Chapter 19). There are several different patterns of PICA territory cerebellar infarctions. If the medial branch territory is affected, involving the vermis and vestibulocerebellum, the clinical findings include prominent vertigo, ataxia, and nystagmus. If the lateral cerebellar hemisphere is involved, patients can have vertigo, gait ataxia, limb dysmetria and ataxia, nausea, vomiting, conjugate or dysconjugate gaze palsies, miosis, and dysarthria. If the infarction is large, altered consciousness or confusion may occur as a result of cerebellar poststroke edema causing brainstem compression. Hydrocephalus or herniation may also develop with compression of the fourth ventricle. Although a PICA occlusion can be the cause of Wallenberg (lateral medullary) syndrome, this syndrome is more often due to an intracranial vertebral artery occlusion.

The anterior inferior cerebellar artery (AICA) syndrome causes a ventral cerebellar infarction. The signs and symptoms include vertigo, nausea, vomiting, and nystagmus caused by involvement of the vestibular nuclei. There may be ipsilateral facial hypalgesia and thermoanesthesia and corneal hypesthesia because of involvement of the trigeminal spinal nucleus and tract. Ipsilateral deafness and facial paralysis occur with involvement of the lateral pontomedullary tegmentum. An ipsilateral Horner syndrome due to compromise of the descending oculosympathetic fibers is present. Contralateral trunk and extremity hypalgesia occurs, and involvement of the lateral spinothalamic tract causes thermoanesthesia. Finally, ipsilateral ataxia and asynergia follow involvement of the cerebellar peduncle and cerebellum.

Infarction in the territory of the superior cerebellar artery (SCA) produces a dorsal cerebellar syndrome (Fig. 51A.2). Vertigo may be present, although it is less common with SCA infarcts than with the other cerebellar syndromes (Fig. 51A.3). Nystagmus is caused by involvement of the medial longitudinal fasciculus and the cerebellar pathways. An ipsilateral Horner syndrome due to involvement of the descending sympathetic tract may be present. Ipsilateral ataxia and asynergia and gait ataxia follow involvement of the superior cerebellar peduncle, brachium pontis, superior cerebellar hemisphere, and dentate nucleus. There is an intention tremor caused by involvement of the dentate nucleus and superior cerebellar peduncle. Choreiform dyskinesias may be present ipsilaterally. Contralaterally, there is hearing loss due to lateral lemniscus disruption and trunk and extremity hypalgesia and thermoanesthesia caused by spinothalamic tract involvement.

Fig. 51A.2 A 15-year-old boy had vomiting, tinnitus, and unsteadiness. A, T1 coronal postgadolinium magnetic resonance imaging shows enhancing lesions in the superior aspect of the left cerebellar hemisphere consistent with superior cerebellar artery infarct. B, Anteroposterior view. Left vertebral artery injection shows a filling defect of the basilar apex also involving the proximal left superior cerebellar artery, consistent with thromboembolus.

Fig. 51A.3 A 74-year-old man had sudden onset of vertigo, vomiting, and gait unsteadiness. T2-weighted axial magnetic resonance imaging of the brain demonstrates an infarct in the posterolateral side of the medulla and a small cerebellar infarct in the distribution of the left posterior inferior cerebellar artery. There is poor flow void seen in the left vertebral artery.

Weber syndrome is caused by infarction in the distribution of the penetrating branches of the posterior cerebral artery (PCA) affecting the cerebral peduncle, especially medially, with damage to the fascicle of cranial nerve III and the pyramidal fibers. The resultant clinical findings are contralateral hemiplegia of the face, arm, and leg secondary to corticospinal and corticobulbar tract involvement, and ipsilateral oculomotor paresis including a dilated pupil. A slight variation of this syndrome is the midbrain syndrome of Foville in which the supranuclear fibers for horizontal gaze are interrupted in the medial peduncle, causing a conjugate gaze palsy to the opposite side. Benedikt syndrome is caused by a lesion affecting the mesencephalic tegmentum in its ventral portion, with involvement of the red nucleus, brachium conjunctivum, and fascicle of cranial nerve III. This syndrome is due to infarction in the distribution of the penetrating branches of the PCA to the midbrain. The clinical manifestations are ipsilateral oculomotor paresis, usually with pupillary dilation and contralateral involuntary movements including intention tremor, hemiathetosis, or hemichorea. Claude syndrome is caused by lesions that are more dorsally placed in the midbrain tegmentum than with Benedikt syndrome. There is injury to the dorsal red nucleus, which results in more prominent cerebellar signs without the involuntary movements. Oculomotor paresis occurs. Nothnagel syndrome is characterized by an ipsilateral oculomotor palsy with contralateral cerebellar ataxia. Infarction in the distribution of the penetrating branches of the PCA to the midbrain is the cause of this syndrome. Parinaud syndrome can result from infarctions in the midbrain territory of PCA penetrating branches. This syndrome is characterized by supranuclear paralysis of eye elevation, defective convergence, convergence-retraction nystagmus, light-near dissociation, lid retraction, and skew deviation (see Chapter 19). Parinaud syndrome occurs more characteristically as a result of mass effect from midline mass lesions such as a pineal gland tumor.

Top of the basilar syndrome (see Chapter 19) is caused by infarction of the midbrain, thalamus, and portions of the temporal and occipital lobes. It is due to occlusive vascular disease, often embolic in nature, of the rostral basilar artery. Associated behavioral abnormalities include somnolence, peduncular hallucinosis, memory disturbances, or agitated delirium. Ocular findings include unilateral or bilateral paralysis of upward or downward gaze, impaired convergence, pseudoabducens palsy, convergence-retraction nystagmus, abnormalities of abduction, Collier sign (which consists of elevation and retraction of the upper eyelids), skew deviation, and oscillatory eye movements. Visual defects that may be present include hemianopia, cortical blindness, and Balint syndrome. Pupillary abnormalities are variable and may be large or small, reactive or fixed. Motor deficits may also occur.

Although there are many named pontine syndromes, the most beneficial categorization is based on neuroanatomical divisions. Locked-in syndrome is the result of bilateral ventral pontine lesions that produce quadriplegia, aphonia, and impairment of horizontal eye movements in some patients. Wakefulness and normal sleep/wake cycles are maintained because the reticular formation is spared. The patient can move his or her eyes vertically and can blink, because the supranuclear ocular motor pathways lie more dorsally. In some patients with symptomatic basilar artery occlusive disease, there may be a herald hemiparesis that suggests a hemispheric lesion. However, within a few hours, there is progression to bilateral hemiplegia and cranial nerve findings associated with the locked-in syndrome. Pure motor hemiparesis and ataxia-hemiparesis caused by pontine lesions are discussed with the lacunar syndromes.

Occlusion of the AICA can lead to the lateral inferior pontine syndrome. Findings associated with this syndrome include ipsilateral facial paralysis, impaired facial sensation, paralysis of conjugate gaze to the side of the lesion, deafness, tinnitus, and ataxia. Contralateral to the lesion, there is hemibody impairment to pain and temperature that in some instances includes the face. There may be horizontal and vertical nystagmus as well as oscillopsia. The medial inferior pontine syndrome is caused by occlusion of a paramedian branch of the basilar artery. With this syndrome, there is ipsilateral paralysis of conjugate gaze to the side of the lesion, abducens palsy, nystagmus, and ataxia. Contralateral to the lesion, there is hemibody impairment of tactile and proprioceptive sensation and paralysis of the face, arm, and leg. An occlusion of the AICA may lead to the total unilateral inferior pontine syndrome, a combination of those symptoms and signs seen with the lateral and medial pontine syndromes.

The lateral pontomedullary syndrome can occur with occlusion of the vertebral artery. The manifestations are a combination of the medial and lateral inferior pontine syndromes.

Occlusion of the paramedian branch of the midbasilar artery can lead to ipsilateral impaired sensory and motor function of the trigeminal nerve with limb ataxia, characteristics of the lateral midpontine syndrome. Ischemia of the medial midpontine region is caused by occlusion of the paramedian branch of the midbasilar artery and can lead to ipsilateral limb ataxia. Contralateral to the lesion, eye deviation and paralysis of the face, arm, and leg occur. Although there are predominant motor symptoms, variable impaired touch and proprioception may also occur. The lateral superior pontine syndrome may occur with occlusion of the SCA and produces a characteristic syndrome of ipsilateral Horner syndrome, horizontal nystagmus, paresis of conjugate gaze, occasional deafness, and severe ataxia of the limbs and gait. Contralateral to the lesion, there is hemibody impairment to pain and temperature, skew deviation, and impaired tactile, vibratory, and proprioceptive sensation in the leg greater than in the arm.

The lateral medullary syndrome (Wallenberg syndrome) is most often due to occlusion of the intracranial segment of the vertebral artery (Fig. 51A.4). Less commonly, it is caused by occlusion of the PICA. This syndrome produces an ipsilateral Horner syndrome; loss of pain and temperature sensation in the face; weakness of the palate, pharynx, and vocal cords; and cerebellar ataxia. Contralateral to the lesion, there is hemibody loss of pain and temperature sensation. The medial medullary (Dejerine) syndrome is less common and may be caused by occlusion of the distal vertebral artery, a branch of the vertebral artery, or the lower basilar artery. Vertebral artery dissection, dolichoectasia of the vertebrobasilar system, and embolism are less common causes of the medial medullary syndrome. The findings with this syndrome include an ipsilateral lower motor neuron paralysis of the tongue and contralateral paralysis of the arm and leg. The face is often spared. In addition, there is contralateral hemibody loss of tactile, vibratory, and position sense. Occlusion of the intracranial vertebral artery can lead to a total unilateral medullary syndrome (of Babinski-Nageotte), a combination of the medial and lateral medullary syndromes.

Fig. 51A.4 A 77-year-old man had alexia without agraphia, right homonymous hemianopia, and antegrade amnesia. Nonenhanced axial cranial computed tomography demonstrates an area of decreased parenchymal attenuation in the left occipitoparietal region.

Posterior Cerebral Artery Syndromes

The manifestations with PCA territory infarctions are variable depending on the site of the occlusion and the availability of collateral blood flow. Occlusion of the precommunal P1 segment causes midbrain, thalamic, and hemispheric infarction. Occlusion of the PCA in the proximal ambient cisternal segment before branching in the thalamogeniculate pedicle causes lateral thalamic and hemispheral symptoms. Occlusions also may affect a single PCA branch, primarily the calcarine artery, or cause a large hemispheric infarction of the PCA territory. Unilateral infarctions in the distribution of the hemispheral branches of the PCA may produce a contralateral homonymous hemianopia caused by infarction of the striate cortex, the optic radiations, or the lateral geniculate body. There is partial or complete macular sparing if the infarction does not reach the occipital pole. The visual field defect may be limited to a quadrantanopia. A superior quadrantanopia is due to infarction of the striate cortex inferior to the calcarine fissure or the inferior optic radiations in the temporo-occipital lobes. An inferior quadrantanopia is the result of an infarction of the striate cortex superior to the calcarine fissure or the superior optic radiations in the parieto-occipital lobes.

More complex visual changes may occur, including formed or unformed visual hallucinations, visual and color agnosias, or prosopagnosia. Finally, some alteration of sensation with PCA hemispheral infarctions occurs, including paresthesias or altered position, pain, and temperature sensations. Infarction in the distribution of the callosal branches of the PCA involving the left occipital region and the splenium of the corpus callosum produces alexia without agraphia (Fig. 51A.5). In this syndrome, patients can write, speak, and spell normally but are unable to read words and sentences. The ability to name letters and numbers may be intact, but there can be inability to name colors, objects, and photographs. Right-hemispheric PCA territory infarctions may cause contralateral visual-field neglect. Amnesia may be present with PCA infarctions that involve the left medial temporal lobe or when there are bilateral mesiotemporal infarctions. In addition, an agitated delirium may occur with unilateral or bilateral penetrating mesiotemporal infarctions. Large infarctions of the left posterior temporal artery territory may produce an anomic or transcortical sensory aphasia.

Fig. 51A.5 Right common carotid angiogram shows 17% right internal carotid artery stenosis (North American Symptomatic Carotid Endarterectomy Trial criteria) just superior to a large carotid ulceration.

(Courtesy Vincent Mathews, MD.)

Infarctions in the distribution of the penetrating branches of the PCA to the thalamus can cause aphasia (if the left pulvinar is involved), akinetic mutism, global amnesia, and Dejerine-Roussy syndrome. In the latter syndrome, the patient has contralateral sensory loss to all modalities, severe dysesthesias on the involved side (thalamic pain), vasomotor disturbances, transient contralateral hemiparesis, and choreoathetoid or ballistic movements. A number of syndromes that can result from infarctions in the distribution of the penetrating branches of the PCA to the midbrain were previously discussed with the midbrain syndromes.

Bilateral infarctions in the distribution of the hemispheric branches of the PCAs may cause bilateral homonymous hemianopias. Bilateral occipital or occipitoparietal infarctions can cause cortical blindness, often with denial or unawareness of blindness (Anton syndrome). Another syndrome, Balint syndrome, seen with bilateral occipital or parieto-occipital infarctions, consists of optic ataxia, psychic paralysis of fixation, with inability to look to the peripheral field and disturbance of visual attention, and simultanagnosia.

Syndromes of Thalamic Infarction

The main thalamic blood supply comes from the posterior communicating arteries and the perimesencephalic segment of the PCA. Thalamic infarctions typically involve one of four major vascular regions: posterolateral, anterior, paramedian, and dorsal. Posterolateral thalamic infarctions result from occlusion of the thalamogeniculate branches arising from the P2 segment of the PCA. Three common clinical syndromes may occur: pure sensory stroke, sensorimotor stroke, and the thalamic syndrome of Dejerine-Roussy. Anterior thalamic infarction results from occlusion of the polar or tuberothalamic artery. The main clinical manifestations consist of neuropsychological disturbances, emotional-facial paresis, occasional hemiparesis, and visual-field deficits. Left-sided infarcts are associated with dysphasia, whereas neglect is seen primarily in patients with right-sided lesions. Paramedian thalamic infarctions result from occlusion of the paramedian, thalamic, and subthalamic arteries. The main clinical manifestations include the classic triad of decreased level of consciousness, memory loss, and vertical-gaze abnormalities. Dorsal thalamic infarctions result from occlusion of the posterior choroidal arteries. These infarctions are characterized by the presence of homonymous quadrantanopia or horizontal sectoranopias. Involvement of the pulvinar may account for thalamic aphasia.

Watershed Ischemic Syndromes

Watershed infarcts occur in the border zone between adjacent arterial perfusion beds. During or after cardiac surgery or after an episode of sustained and severe arterial hypotension that can happen after cardiac arrest, prolonged hypoxemia, or bilateral severe carotid artery disease, ischemia may occur in the watershed areas between the major circulations. Watershed infarctions also may be unilateral when there is only a relative degree of hemodynamic failure in patients with underlying unilateral severe arterial stenosis or occlusion. Watershed infarcts also may be caused by microembolism or hyperviscosity states.

Ischemia in the border zone or junctional territory of the ACA, MCA, and PCA may result in bilateral parieto-occipital infarcts. There can be a variety of visual manifestations, including bilateral lower altitudinal–field defects, optic ataxia, cortical blindness, and difficulty in judging size, distance, and movement. Ischemia between the territories of the ACA and MCA bilaterally may result in bi-brachial cortical sensorimotor impairment (“person in a barrel”) and impaired saccadic eye movements caused by compromise of the frontal eye fields. Ischemia on the border zone regions between the MCA and PCA may cause bilateral parietotemporal infarctions. Initially there is cortical blindness that may improve, but defects such as dyslexia, dyscalculia, dysgraphia, and memory defects for verbal and nonverbal material may persist.

Watershed infarcts are also recognized between the territorial supply of the PICA, AICA, and SCA. Watershed infarctions may also involve the internal watershed region in the centrum semiovale adjacent to and slightly above the body of the lateral ventricles.

Dissections

Cervicocephalic arterial dissections are one of the most frequent nonatherosclerotic vasculopathies causing ischemic stroke in young adults. A dissection is produced by subintimal penetration of blood in a cervicocephalic vessel, with subsequent longitudinal extension of the intramural hematoma between its layers. Most dissections involve the extracranial segment of the internal carotid artery or extracranial vertebral arteries. Intracranial carotid and vertebrobasilar dissections are less common; intracranial dissections are usually subintimal and may follow trivial trauma, closed head trauma, basilar skull fracture, or penetrating injuries. The recurrence rate of extracranial cervicocephalic arterial dissections is approximately 1% per year. The risk for recurrent dissections is increased in younger patients, those with a history of FMD, and in patients with family history of arterial dissections.

Cervicocephalic arterial dissections have been reported after blunt or penetrating trauma and also are associated with FMD, Marfan syndrome, Ehlers-Danlos syndrome type IV, pseudoxanthoma elasticum, coarctation of the aorta, Menkes disease, α₁-antitrypsin deficiency, cystic medial degeneration, reticular fiber deficiency, accumulation of mucopolysaccharides, osteogenesis imperfecta, adult polycystic kidney disease, elevated arterial elastase content, lentiginosis, atherosclerosis, extreme vessel tortuosity, moyamoya syndrome, homocystinuria, the 677TT genotype of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR 677TT), pharyngeal infections, sympathomimetic drug abuse, and luetic arteritis. Most typically, cervicocephalic arterial dissections occur either spontaneously or in relation to minor trauma (Debette and Leys, 2009).

Dissection of the cervicocephalic vessels may cause transient retinal, hemispheric, or posterior fossa ischemia; Horner syndrome; hemicranial pain; cranial nerve palsies; cerebral infarction; or subarachnoid hemorrhage. Ischemic symptoms result from arterial occlusion or secondary embolization. In addition to a postganglionic Horner syndrome, neuro-ophthalmological manifestations of internal carotid artery dissections may also include central retinal artery occlusion, ophthalmic artery occlusion, ischemic optic neuropathy, homonymous hemianopia, and ocular motor nerve palsies (cranial nerve [CN] III, IV, and VI). In addition to a first-order neuron Horner syndrome, other neuro-ophthalmological manifestations of vertebrobasilar dissections include diplopia, nystagmus, oscillopsia, ocular misalignment, skew deviation, ocular motor nerve palsies (CN III, IV, and VI), lateral gaze palsy, internuclear ophthalmoplegia, and homonymous visual-field defects.

Cervicocephalic arterial dissections should be considered in the differential diagnosis of ischemic stroke in any young adult, particularly when traditional risk factors are absent. Diagnosis is based on arteriographic findings, although high-resolution MRI with T1 fat suppression sequences and magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and extracranial and transcranial Doppler ultrasound are rapidly replacing contrast angiography for the diagnosis of cervicocephalic arterial dissections, particularly in cases of carotid artery involvement (Fig. 51A.9).

Fig. 51A.9 Following intravenous administration of iodinated contrast, spiral computed tomography images were obtained using 1.3-mm collimation and 0.5-mm image reconstruction intervals. Pseudoaneurysm of left internal carotid artery is noted, measuring 1.9 × 2.9 cm in greatest axial dimensions. There is calcification in the wall of the aneurysm. There is extensive mural thrombus such that the aneurysm lumen containing contrast measures 12.5 × 10.7 mm (*). Internal carotid artery is severely narrowed just proximal to its entry site into the aneurysm.

Features on arteriography include the presence of a “pearl-and-string” sign; double-lumen sign; short, smooth, tapered occlusion; or pseudoaneurysm formation. MRI demonstrates the intramural hematoma and the false lumen of the dissected artery (Fig. 51A.10). MRA, CTA, or ultrasound studies can be helpful in monitoring the course of dissection.

Fig. 51A.10 A 16-year-old boy collapsed to the ground after experiencing right eye pain and left-sided weakness. A, Axial T2-weighted magnetic resonance imaging of the brain shows ischemic areas in the right basal ganglia and right posterior parietal region, associated with a crescent sign (arrow in B) of high signal consistent with intraluminal blood products on the right internal carotid artery suggestive of a dissection.

Therapeutic interventions have included immediate anticoagulation with heparin, followed by a 3- to 6-month course of warfarin, then platelet antiaggregants instead of or following warfarin. Angioplasty and stenting or surgical correction are reserved for selected individuals with pseudoaneurysms or those who have multiple recurrent events following adequate medical therapy. Although anticoagulants are often empirically recommended, their value in patients with extracranial cervicocephalic arterial dissections has not been firmly established. Anticoagulation should be withheld in patients with intracranial dissections (particularly involving the vertebrobasilar circulation) because of the risk for subarachnoid hemorrhage. The Cervical Artery Dissection in Stroke Study (CADISS) is an ongoing randomized multicenter open-treatment trial comparing anticoagulant and antiplatelet therapies for acute (within 7 days) symptomatic extracranial carotid or vertebral artery dissection (Kasner and Dreier, 2009).

Trauma

Trauma is a leading cause of cerebrovascular mortality in the United States (see Chapter 50B). Blunt or penetrating traumatic cerebrovascular disease may result in cervicocephalic arterial dissection, arterial thrombosis, arterial rupture, pseudoaneurysm formation, or development of an arteriovenous fistula. Internal carotid artery thrombosis also may follow maxillary and mandibular angle fractures. Carotid artery trauma may cause hematoma formation of the lateral neck, retinal or hemispheric ischemia, and Horner syndrome. Neurological deficits may be mild or devastating. Comatose patients with carotid arterial injuries with a Glasgow Coma Scale score of 8 or less do poorly regardless of treatment (see Chapter 5). Missing the diagnosis may lead to devastating results. A thorough evaluation of the airway, oropharynx, and esophagus is needed. Arteriography is indicated in most instances, although CTA has become a preferred screening modality for diagnosis; thereafter, surgical repair or angioplasty may be needed (Nuñez et al., 2004).

Radiation Vasculopathy

Injury to the endothelial cells by high-intensity radiation may cause accelerated atherosclerotic changes, particularly in the presence of hyperlipidemia. These changes may occur months to years after completion of radiation therapy. Radiation vasculopathy correlates with radiation dose and age at time of radiation therapy. Lesions develop in locations that are unusual for atherosclerosis and may involve the extracranial or intracranial vessels. Patients who receive therapeutic radiation therapy for lymphoma, Hodgkin disease, or thyroid carcinoma are at risk for involvement of the extracranial circulation. Follow-up ultrasound carotid and MRI studies are recommended in these patients. Radiation therapy also may cause an occlusive vasculopathy of small and large intracranial arteries following irradiation of craniopharyngiomas, germinomas, pituitary tumors, or other intracranial neoplasms. Intracranial arterial stenosis also may follow stereotactic radiosurgery.

Moyamoya

Moyamoya is a chronic progressive nonatherosclerotic, noninflammatory, nonamyloid occlusive intracranial vasculopathy of unknown cause. Pathologically, there is fibrocellular intimal thickening, smooth muscle cell proliferation, and increased elastin accumulation, resulting in stenosis of the suprasellar intracranial internal carotid arteries. There is also thinning of the media and a tortuous and often multilayered internal elastic lamina. Thrombotic lesions may be seen in major cerebral arteries. There are also numerous perforating and anastomotic branches around the circle of Willis. Intracranial aneurysms may be seen at the circle of Willis or in the peripheral vessels (Yamamoto et al., 1997). Moyamoya disease is sometimes distinguished from moyamoya syndrome associated with a number of different putative causes. Cases have been associated with neonatal anoxia, trauma, basilar meningitis, tuberculous meningitis, leptospirosis, cranial radiation therapy for optic pathway gliomas, neurofibromatosis type 1, tuberous sclerosis, encephalotrigeminal angiomatosis (Sturge-Weber syndrome), phakomatosis pigmentovascularis type IIIb, brain tumors, FMD, polyarteritis nodosa, Marfan syndrome, Turner syndrome, pseudoxanthoma elasticum, hypomelanosis of Ito, Williams syndrome, cerebral dissecting and saccular aneurysms, sickle cell disease, β-thalassemia, Fanconi anemia, hereditary spherocytosis, lupus anticoagulant, Sneddon syndrome, homocystinuria, oral contraceptives, factor XII deficiency, type I glycogenosis, reduced form of nicotinamide adenine dinucleotide phosphate (NADP)–coenzyme Q reductase deficiency, renal artery stenosis, Down syndrome, Apert syndrome, Graves disease, coarctation of the aorta, Alagille syndrome, hyperphosphatasia, Schimke immuno-osseous dysplasia, primary oxalosis, pulmonary sarcoidosis, and Hirschsprung disease.

Moyamoya disease may cause TIAs, including hemodynamic paraparetic TIAs secondary to watershed paracentral lobule ischemia, headaches, seizures, movement disorders (chorea, hemidystonia, hemichoreoathetosis), mental deterioration, cerebral infarction, or intracranial hemorrhage. TIAs are often precipitated by crying, blowing, or hyperventilation.

Moyamoya disease has a bimodal age distribution, with peaks in the first and fourth decades of life. Childhood moyamoya is characterized by ischemic manifestations, whereas adult moyamoya disease presents with hemorrhagic manifestations. Moyamoya affects children, adolescents, and young adults most frequently. Diagnosis is based on a distinct arteriographic appearance as described by Suzuki’s 6 angiographic stages: (1) stenosis of the carotid fork, (2) initial appearance of moyamoya vessels at the base of the brain, (3) intensification of moyamoya vessels, (4) minimization of moyamoya vessels, (5) reduction of moyamoya vessels, and (6) disappearance of moyamoya vessels (collaterals only from external carotid arteries) (Fig. 51A.11). Moyamoya is characterized by progressive bilateral stenosis of the distal internal carotid arteries, extending to the proximal ACA and MCA, often with involvement of the circle of Willis and development of an extensive collateral (parenchymal, leptomeningeal, and transdural) network at the base of the brain like a cloud or puff of smoke (moyamoya). Intracranial aneurysms, particularly located in the posterior circulation, may be present.

Fig. 51A.11 Left carotid angiogram (anteroposterior view) shows occlusion of the supraclinoid internal carotid artery and innumerable moyamoya vessels.

(Courtesy Vincent Mathews, MD.)

The optimal treatment of ischemic moyamoya has not been determined. Platelet antiaggregants, vasodilators, calcium channel blockers, and corticosteroids have been used with variable results. Anticoagulants are not useful. Good results have been reported with superficial temporal artery to MCA anastomosis and other indirect or combined surgical revascularization procedures. No clear superior therapy to prevent rebleeding has been shown in the hemorrhagic type of moyamoya disease.

Fibromuscular Dysplasia

Fibromuscular dysplasia is a segmental, nonatheromatous, dysplastic, noninflammatory angiopathy affecting predominantly young and middle-aged women. Cervicocephalic FMD affects less than 1% of the population, occurs more often in whites than in blacks, and predominantly involves the cervical carotid arteries at the level of the C1 to C2 vertebral bodies. FMD of the intracranial arteries is rare and mainly limited to the intrapetrosal internal carotid artery or carotid artery siphon. The cause of FMD is unknown. Immunological and estrogenic effects on the arterial wall may be causal mechanisms. An association with α₁-antitrypsin deficiency has been reported. Four distinct histological types are recognized: intimal fibroplasia, medial hyperplasia, medial fibroplasia, and perimedial dysplasia. Medial fibroplasia is the most frequent form of FMD, followed by perimedial dysplasia and intimal fibroplasia. The majority of cases of FMD involve the renal arteries, followed by the carotid and iliac arteries. Some cases are familial. Most often, patients with cervicocephalic FMD are asymptomatic or present with headaches, neck pain, carotidynia, tinnitus, vertigo, asymptomatic carotid bruits, transient retinal or cerebral ischemia, cerebral infarction, or subarachnoid hemorrhage. Cervicocephalic FMD may be associated with arterial dissection. Hypertensive patients may have concomitant renal FMD. Cerebral ischemia is usually related to the underlying arterial stenosis or arterial thromboembolism.

The diagnosis of cervicocephalic FMD may be made on the basis of MRA, CTA, or conventional catheter cerebral angiography. Cervicocephalic FMD occurs most often in the extracranial carotid artery and is bilateral in approximately two-thirds of cases. The lesions of medial fibroplasia account for the characteristic “string of beads” angiographic appearance seen in approximately 90% of cases (Fig. 51A.12).

Fig. 51A.12 Lateral left carotid angiogram in a patient with fibromuscular dysplasia. Note “string of pearls” appearance at around the C2 level.

The optimal treatment of symptomatic cervicocephalic FMD has not been determined. In view of the benign natural history of this condition, platelet antiaggregants are recommended. Surgical intervention with angioplasty and stenting, gradual arterial dilatation, resection and reconstruction, or interposition grafting is seldom warranted.

Inflammatory Vasculitides

Inflammatory vasculitides can involve any size of vessel, including the precapillary arterioles and postcapillary venules. Many infectious and multisystem noninfectious inflammatory diseases cause cerebral vasculitis (see Table 51A.6). Cerebral vasculitis is a consideration in young patients with ischemic or hemorrhagic stroke; patients with recurrent stroke; patients with stroke associated with encephalopathic features; and patients with stroke accompanied by fever, multifocal neurological events, mononeuritis multiplex, palpable purpura, or abnormal urinary sediment. Other manifestations of cerebral vasculitis include headaches, seizures, and cognitive deterioration. Laboratory studies typically show anemia of chronic disease, leukocytosis, and an elevated erythrocyte sedimentation rate. The diagnosis of vasculitis usually requires confirmation by arteriography or biopsy. Overall, these disorders have a poor prognosis, but corticosteroids and other immunosuppressive agents have improved the survival rate (Biller and Grau, 2004).

Infections and Stroke

Intracranial vasculitis and stroke can result from meningovascular syphilis; prodromal manifestations are common before stroke. The MCA territory is most commonly affected. Spinal cord infarction may result from meningomyelitis. Other neurological manifestations in patients with secondary syphilis include headaches, meningismus, mental status changes, and cranial nerve abnormalities. The cerebrospinal fluid (CSF) may show a modest lymphocytic pleocytosis, elevated protein content, and a positive Venereal Disease Research Laboratory (VDRL) test result. Concurrent human immunodeficiency virus (HIV-1) infection can lead to rapid progression of early syphilis to neurosyphilis. Luetic aneurysms of the ascending aorta can extend to involve the origin of the great vessels and lead to stroke. Treatment schedules for syphilis are listed in standard textbooks; patients with concurrent HIV-1 infection and meningovascular syphilis may require prolonged antibiotic treatment.

Worldwide, an estimated 1 billion people are infected with Mycobacterium tuberculosis. Neurotuberculosis affects predominantly the basilar meninges. Predisposing conditions include alcoholism, substance abuse, corticosteroid use, and HIV-1 infection. Strokes can result from tuberculous endarteritis. The exudative basilar inflammation entraps the cranial nerves at the base of the brain, most frequently the third, fourth, and sixth cranial nerves. The basilar arteriolitis most commonly involves penetrating branches of the ACA, MCA, and PCA (medial and lateral lenticulostriate, anterior choroidal, thalamoperforators, and thalamogeniculate arteries). There is usually a modest lymphocytic and mononuclear pleocytosis. The CSF protein is usually elevated, and the glucose level is depressed. In the early stages, a predominantly neutrophilic response may be noted. Smears of CSF demonstrate M. tuberculosis in 10% to 20% of cases. Repeated CSF examinations increase the yield considerably.

Fungal arteritis may result in aneurysms, pseudoaneurysms, thrombus formation, and cerebral infarction. Complications of acute purulent meningitis include intracranial arteritis and thrombophlebitis of the major venous sinuses and cortical veins. Intracranial arterial stenoses have been associated with a complicated clinical course. Varicella-zoster may cause a virus-induced necrotizing arteritis similar to granulomatous angiitis. Cerebral infarction is a complication of acquired immunodeficiency syndrome (AIDS) and may result from vasculitis, meningovascular syphilis, varicella-zoster virus vasculitis, opportunistic infections, infective endocarditis, aneurysmal dilation of major cerebral arteries, nonbacterial thrombotic endocarditis, aPL antibodies, or other hypercoagulable states, or from hyperlipidemia resulting from protease inhibitors and other factors such as HIV-1-related malignancy, cancer chemotherapy, and thrombotic thrombocytopenic purpura (TTP). Large-artery cerebrovascular occlusions have been found in association with meningoencephalitis caused by free living amebae. Other infectious agents known to produce cerebral infarcts include Mycoplasma pneumoniae, coxsackie 9 virus, California encephalitis virus, mumps paramyxovirus, hepatitis C virus, Borrelia burgdorferi, Rickettsia typhi group, cat-scratch disease, Trichinella infection, and the larval stage (cysticercus) of Taenia solium. Cerebrovascular involvement in neurocysticercosis is usually ischemic and is caused by chronic meningitis, arteritis, or endarteritis of small vessels. Unilateral or bilateral carotid artery occlusion can complicate necrotizing fasciitis of the parapharyngeal space. Infection with Chlamydia pneumoniae accelerates the process of atherosclerosis in animal studies; treatment with azithromycin has been shown to reduce the degree of atherosclerotic lesions in a rabbit model (Moazed et al., 1999; Muhlestein et al., 1998).

Drug Abuse and Stroke

Ischemic stroke is a complication of illicit drug use and use of over-the-counter sympathomimetic drugs. Stroke mechanisms associated with the use of illicit drugs are multifactorial, including foreign-body embolization, vasculitis, vasospasm, acute onset of arterial hypertension or arterial hypotension, endothelial damage, accelerated atherosclerosis, hyper- or hypocoagulability, cardiac arrhythmias, embolism from an MI, or AIDS. The substances implicated most commonly are the amphetamines, cocaine (freebase or “crack”), phenylpropanolamine, pentazocine (Talwin) in combination with Pyribenzamine (“T’s and blues”), phencyclidine, heroin, anabolic steroids, and glue sniffing. Ischemic or hemorrhagic strokes may follow within hours of cocaine use, whether the drug is smoked, snorted, or injected (Fig. 51A.13) (see Chapters 51E and 58). The risk for intracerebral hemorrhage, especially among young women, has led to removal from the American market of phenylpropanolamine (Kernan et al., 2000). Ephedra, also called ma-huang, widely used in weight-loss products, has been associated with high blood pressure, heart attacks, and strokes. Stroke in young athletes may also be the result of anabolic-androgen steroid abuse and recombinant erythropoietin (“blood doping”) administration.

Fig. 51A.13 A 41-year-old woman with a history of cocaine abuse had acute onset of left-sided hemiplegia, left hemibody sensory deficit, and a left homonymous visual field deficit. Axial fluid-attenuated inversion recovery images of the brain demonstrates an area of infarction in the posterior limb of the right internal capsule in the distribution of the anterior choroidal artery territory. There is associated periventricular ischemia.

Stroke and Systemic Vasculitides

Ischemic stroke is also a complication of a variety of multisystem vasculitides. Stroke in patients with systemic lupus erythematosus may be attributable to cardiogenic embolism (nonbacterial verrucous or Libman-Sacks endocarditis, which occurs in the ventricular surface of the mitral valve), aPL antibodies, or underlying vasculopathy, or nephrotic syndrome associated with lupus nephritis, or less often to an immune-mediated vasculitis (Fig. 51A.14) (see Chapter 49A).

Fig. 51A.14 Lateral carotid angiogram demonstrates irregular beading appearance (arrowheads) of large and medium branches of the anterior, middle, and posterior cerebral arteries in a patient with systemic lupus erythematosus.

(Courtesy Vincent Mathews, MD.)

Behçet syndrome may involve vessels of any size. Venous thrombosis is more frequent than occlusive arterial compromise. Affected patients are mainly of Mediterranean or East Asian origin and may have a history of iritis, uveitis, and oral, genital, and mucocutaneous ulcerations. Cerebrovascular complications include strokes, carotid aneurysm formation, and cerebral venous thrombosis. Cogan syndrome is a rare condition characterized by nonsyphilitic interstitial keratitis, vestibular dysfunction, and deafness. Complications include aortic insufficiency and mesenteric ischemia. The angiitic form of sarcoidosis primarily affects the eyes, meninges, and cerebral arteries and veins. Kohlmeier-Degos disease or malignant atrophic papulosis is a multisystem occlusive vasculopathy characterized by cutaneous, gastrointestinal, and neurological manifestations; it may be complicated by ischemic or hemorrhagic strokes. Cerebral vasculitis may also complicate the course of children with acute poststreptococcal glomerulonephritis. The multisystem vasculitides are described in more detail in Chapter 49A.

Takayasu arteritis is a chronic inflammatory arteriopathy of the aorta and its major branches, as well as the pulmonary artery. The cause is unknown, but an immune mechanism is suspected. The disease, prevalent in young women of Asian, Mexican, or Native American ancestry, develops insidiously, causing stenosis, occlusion, aneurysmal dilatation, or coarctation of the involved vessels. The disease has two phases. In the acute or “prepulseless” phase, nonspecific systemic manifestations are present. Patients have rashes, erythema nodosum, fever, myalgias, arthritis, pleuritis, carotidynia, and elevated erythrocyte sedimentation rate. Months or years later, the second or occlusive phase develops and is characterized by multiple arterial occlusions. Patients may have cervical bruits, absent carotid or radial pulses, asymmetrical blood pressure recordings, and arterial hypertension. Neurological symptoms result from CNS or retinal ischemia associated with stenosis or occlusion of the aortic arch and arch vessels, or arterial hypertension caused by aortic coarctation or renal artery stenosis. Visual disturbances are most often bilateral. The diagnosis can be confirmed by MRA or CTA, but the most accurate assessment still requires aortography (Fig. 51A.15).

Fig. 51A.15 A, Aortogram demonstrates a nonocclusive stenosis of the brachiocephalic artery. There is complete occlusion of the left subclavian artery. The left vertebra is absent or occluded. B, The right common carotid artery shows a long segment of critical stenosis extending from C3 to C5. C, There is also a very long stenosis of the left common carotid artery. D, A larger cervical right vertebral artery provides vigorous filling of the intracranial right internal carotid circulation.

Patients with active disease are treated with oral glucocorticoids; cyclophosphamide, azathioprine, or methotrexate may be needed in special circumstances. Surgical treatment (angioplasty or bypass) of severely stenotic vessels may be required (Kerr et al., 1999).

Cranial (giant cell or temporal) arteritis is a polysymptomatic systemic large-vessel arteritis with a predilection to involve carotid artery branches (see Chapter 69). Thromboangiitis obliterans, also known as Buerger disease, is a rare segmental, inflammatory, obliterative angiopathy of unknown cause. The condition involves small and medium arteries and veins. It is suspected in young men who smoke and have a history of superficial migratory thrombophlebitis presenting with distal limb ischemia accompanied by digital gangrene. The disorder is characterized by remissions and exacerbations. Cerebral involvement is uncommon. Strokes can result from isolated angiitis of the CNS. Symptoms of large-vessel involvement include stroke-like presentations. Small-vessel involvement may be manifested as a mass lesion in the brain or multifocal encephalopathy (Fig. 51A.16). The erythrocyte sedimentation rate is usually normal or minimally elevated (see Chapter 51E).

Fig. 51A.16 Cerebellum. A, Within an area of recent hemorrhage, there is a small blood vessel showing focal infiltration with lymphocytes and a couple of multinucleated giant cells (arrows). Vessel lumen is marked with an arrowhead (hematoxylin and eosin, ×680). B, Same vessel as in A. Immunostain with CD3 demonstrates intense perivascular infiltration with T lymphocytes (×680).

Migraine and Stroke

Migraine (see Chapters 18 and 69) affects women more often than men and may start during childhood or adolescence. Epidemiological studies suggest a nonrandom association of both headache and migraine with stroke, particularly among young women. This rare association was limited to women younger than age 35 in a large Italian case-controlled study (Carolei et al., 1996). The possible association between migraine headache and stroke was also evaluated by the Physician’s Health Study; physicians reporting migraine had increased risks of subsequent total stroke and ischemic stroke compared with those not reporting migraines (Buring et al., 1995). In the Women’s Health Study, migraine with aura raised the risk of stroke by 108% (95% CI, 30%-231%). Migraine without aura raised the stroke risk by approximately 25%. The risk of MI was also increased (Kurth et al., 2005; Woodward, 2009). The risk of white-matter abnormalities on MRI is also increased, particularly among subjects with migraine with aura (Kruit et al., 2004). The risk of intracerebral hemorrhage is not increased in persons who have migraines.

The International Headache Society Classification and Diagnostic Criteria require that to establish a diagnosis of migrainous infarction, one or more migrainous aura symptoms must be present and not fully reversed within 7 days from onset, and must be associated with neuroimaging confirmation of ischemic infarction (see Chapter 73). This definition implies that a firm diagnosis of migraine with aura has been made in the past. Also, the clinical manifestations judged to be the result of a migrainous infarction must be those typical of previous attacks for that individual, and finally, other causes of infarction, including those related to migraine therapy, need to be excluded by appropriate investigations.

Headache accompanies a number of embolic or thrombotic causes of stroke, including cervicocephalic arterial dissections. Migraines also can be a prominent symptom in the aPL antibody syndrome (APAS). Symptomatic migraine attacks are more frequent than migraine-induced ischemic insults. The presence of headache with a stroke is therefore not sufficient to make the diagnosis of migraine as the cause of the patient’s symptoms. Furthermore, patchy subcortical abnormalities on MRI in patients with migraine with aura should be interpreted with caution. In other words, migrainous infarction remains a diagnosis of exclusion.

The pathogenesis of migrainous infarction is controversial. Cerebral infarcts complicating migraine are mostly cortical and involve the distribution of the PCA. The usual scenario of migrainous infarction is one of recurrent episodes of gradual buildup of unilateral throbbing headaches, associated with stereotyped visual phenomena occurring in both visual fields simultaneously, in one of which the vision loss becomes permanent. Migrainous infarctions have been subdivided as definite when all the International Headache Society criteria are fulfilled, and possible when some but not all criteria are fulfilled. Patients with migrainous infarction are at increased risk for recurrent stroke.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial nonarteriosclerotic, nonamyloid microangiopathy characterized by migraine with aura, recurrent subcortical ischemic strokes starting in mid-adulthood, leading to pseudobulbar palsy, cognitive decline, subcortical dementia, and early white matter hyperintensities on MRI. CADASIL is caused by simple missense mutations or small deletions in the Notch 3 gene on chromosome 19q12 encoding a transmembrane receptor Notch 3. The Notch 3 mutation has been thought to be one of the most common human mutations. Pathologically, there is a characteristic granular osmiophilic material in arterial walls, including dermal arteries (Kalimo et al., 2002). A subtype of migraine known as familial hemiplegic migraine and characterized by transient weakness or frank paralysis during the aura has also been mapped close to the CADASIL locus (Hutchinson et al., 1995). The newer acronym, CADASILM (cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and migraine), refers to a subvariety of CADASIL characterized by the high frequency of migraine (Verin et al., 1995). A clinical trial of donepezil in CADASIL patients with subcortical vascular cognitive impairment showed no improvement in general cognition, but improvement in some executive functions such as processing speed and attention (Schneider, 2008).