STROKE

Table 9–1. Territories of the principal cerebral arteries.

Approach to diagnosis

Acute onset

Duration of deficits

Focal involvement

Vascular origin
Focal cerebral ischemia

Etiology

Pathology

Clinicoanatomic correlation

Clinical findings

Investigative studies

Differential diagnosis

Treatment

Prognosis
Intracerebral hemorrhage

Hypertensive hemorrhage

Other causes of intracerebral hemorrhage
Global cerebral ischemia

Etiology

Pathology

Clinical findings

Treatment
Chapter References

KEY CONCEPTS

Stroke is a syndrome characterized by the acute onset of a neurologic deficit that persists for at least 24 hours, reflects focal involvement of the central nervous system, and is the result of a disturbance of the cerebral circulation.

Stroke results from either of two types of cerebral vascular disturbance: ischemia or hemorrhage.

Ischemia, the most common cause of stroke, can be caused by either local thrombosis or embolization from a distant site, such as the heart.

Transient ischemic attack and acute stroke are medical emergencies that require prompt diagnosis, because they may be treatable with antiplatelet drugs, anticoagulants, thrombolytic agents, or surgery.

Stroke is the third most common cause of death in the United States and the most common disabling neurologic disorder. About 750,000 new strokes occur and about 150,000 people die from stroke in the United states each year. The incidence increases with age, with about two-thirds of all strokes occurring in those over age 65 years, and is somewhat higher in men than in women and in African-Americans than in whites. Risk factors for stroke include systolic or diastolic hypertension, hypercholesterolemia, cigarette smoking, heavy alcohol consumption, and oral contraceptive use. The incidence of stroke has decreased in recent decades, largely because of improved treatment of hypertension.
APPROACH TO DIAGNOSIS

Stroke is a syndrome characterized by the acute onset of a neurologic deficit that persists for at least 24 hours, reflects focal involvement of the central nervous system, and is the result of a disturbance of the cerebral circulation. The acute onset and subsequent duration of symptoms are documented by the history. The site of central nervous system involvement is suggested by the nature of the symptoms. It is delineated more precisely by the neurologic examination and confirmed by imaging studies [computed tomography (CT) scans or magnetic resonance imaging (MRI)]. A vascular etiology may be inferred from the acute onset of symptoms and often from the patient’s age, the presence of risk factors for stroke, and the occurrence of symptoms and signs referable to the territory of a particular cerebral blood vessel. When this is confirmed by imaging studies, further investigations can be undertaken to identify a specific cause.

Acute Onset
Strokes begin abruptly. Neurologic deficits may be maximal at onset, as is common in embolic stroke, or may progress over seconds to hours (or occasionally days), which is characteristic of progressive arterial thrombosis or recurrent emboli. A stroke that is actively progressing as a direct consequence of the underlying vascular disorder (but not because of associated cerebral edema) or has done so in recent minutes is termed stroke in evolution or progressing stroke (Figure 9–1). Focal cerebral deficits that develop slowly (over weeks to months) are unlikely to be due to stroke and are more suggestive of tumor or inflammatory or degenerative disease.

Figure 9–1. Time course of cerebral ischemic events. A transient ischemic attack (TIA) produces neurologic deficits that resolve completely within 24 hours and usually within 30 minutes. Stroke-in-evolution, or progressing stroke, causes deficits that continue to worsen even as the patient is seen. Completed stroke is defined by the presence of residual deficits (which may be stable or improving) at 24 hours; it does not necessarily imply that the entire territory of the involved vessel is affected or that no improvement has occurred since the onset.

Duration of Deficits
By definition, stroke produces neurologic deficits that persist for at least 24 hours. When symptoms and signs resolve completely after briefer periods (usually within 30 minutes), the term transient ischemic attack (TIA) is used (see Figure 9–1). Recurrent TIAs with identical clinical features are usually caused by thrombosis or embolism arising within the cerebral circulation. TIAs that differ in character from event to event suggest recurrent emboli from a cardiac source. Although TIAs do not themselves produce lasting neurologic dysfunction, they are important to recognize because about one-third of patients with TIAs will go on to have a stroke within 5 years—and because this risk may be reduced with treatment.
In some cases, deficits last for longer than 24 hours but resolve completely or almost completely within a few days; the term reversible ischemic neurological deficit (RIND) or minor stroke is sometimes used to describe these events.
As their names imply, TIAs and RINDs are uniquely associated with cerebral ischemia, as opposed to hemorrhage.
Focal Involvement
Stroke produces focal symptoms and signs that correlate with the area of the brain supplied by the affected blood vessel. In ischemic stroke, occlusion of a blood vessel interrupts the flow of blood to a specific region of the brain, interfering with neurologic functions dependent on that region and producing a more or less stereotyped pattern of deficits. Hemorrhage produces a less predictable pattern of focal involvement because complications such as increased intracranial pressure, cerebral edema, compression of brain tissue and blood vessels, or dispersion of blood through the subarachnoid space or cerebral ventricles can impair brain function at sites remote from the hemorrhage.
Cerebrovascular disorders can also affect the brain in more diffuse fashion and produce global cerebral dysfunction, but the term stroke should not be applied in these cases. These disorders include global cerebral ischemia (usually from cardiac arrest) and subarachnoid hemorrhage (discussed in Chapter 2). In most cases of stroke, the history and neurologic examination provide enough information to localize the lesion to one side of the brain (eg, to the side opposite a hemiparesis or hemisensory deficit or to the left side if aphasia is present) and to the anterior or posterior cerebral circulation.
A. ANTERIOR CIRCULATION

The anterior cerebral circulation, which supplies most of the cerebral cortex and subcortical white matter, basal ganglia, and internal capsule, consists of the internal carotid artery and its branches: the anterior choroidal, anterior cerebral, and middle cerebral arteries. The middle cerebral artery in turn gives rise to deep, penetrating lenticulostriate branches (Figure 9–2). The specific territory of each of these vessels is shown in Table 9–1. Anterior circulation strokes are commonly associated with symptoms and signs that indicate hemispheric dysfunction (Table 9–2), such as aphasia, apraxia, or agnosia. They also produce hemiparesis, hemisensory disturbances, and visual field defects, which can also occur with posterior circulation strokes.

Figure 9–2. Arteries of the anterior (white) and posterior (blue) cerebral circulation in relation to the circle of Willis.

Table 9–2. Symptoms and signs of anterior and posterior circulation ischemia.1

B. POSTERIOR CIRCULATION

The posterior cerebral circulation supplies the brainstem, cerebellum, and thalamus and portions of the occipital and temporal lobes. It consists of the paired vertebral arteries, the basilar artery, and their branches: the posterior inferior cerebellar, anterior inferior cerebellar, superior cerebellar, and posterior cerebral arteries (see Figure 9–2). The posterior cerebral artery also gives off thalamoperforate and thalamogeniculate branches. Areas supplied by these arteries are listed in Table 9–1. Posterior circulation strokes produce symptoms and signs of brainstem dysfunction (see Table 9–2), including coma, drop attacks (sudden collapse without loss of consciousness), vertigo, nausea and vomiting, cranial nerve palsies, ataxia, and crossed sensorimotor deficits that affect the face on one side of the body and the limbs on the other. Hemiparesis, hemisensory disturbances, and visual field deficits also occur, but are not specific to posterior circulation strokes.
Vascular Origin
Although hypoglycemia, other metabolic disturbances, trauma, and seizures can produce focal central neurologic deficits that begin abruptly and last for at least 24 hours, the term stroke is used only when such events are caused by cerebrovascular disease.

The underlying pathologic process in stroke can be either ischemia or hemorrhage, usually from an arterial lesion. In recent series, ischemia accounted for about two-thirds and hemorrhage for about one-third of strokes. It may not be possible to distinguish between ischemia and hemorrhage from the history and neurologic examination, but CT scan or MRI permits a definitive diagnosis.

A. ISCHEMIA

Interruption of blood flow to the brain deprives neurons and other cells of substrate glucose and oxygen and, unless blood flow is promptly restored, leads ultimately to cell death. The pattern of cell death depends on the severity of ischemia. With mild ischemia, as may occur in cardiac arrest with reperfusion, selective vulnerability of certain neuronal populations results in their preferential loss. More severe ischemia produces selective neuronal necrosis, in which all neurons die but glia and endothelial cells are preserved. Complete, permanent ischemia causes pannecrosis, affecting all cell types, and results in the chronic cavitary brain lesions seen after clinical stroke.
Ischemic neuronal injury is an active biochemical process that evolves over time (Figure 9–3). Lack of glucose and oxygen depletes the cellular energy stores required to maintain membrane potentials and transmembrane ion gradients. Potassium leaks out of cells, causing depolarization-induced calcium entry, and also stimulates the release of glutamate through glial glutamate transporters. Synaptic glutamate activates excitatory amino acid receptors coupled to calcium- and sodium-preferring ion channels. The resulting influx of sodium into postsynaptic neuronal cell bodies and dendrites causes depolarization and acute swelling. Calcium influx that exceeds the ability of the cell to extrude, sequester, or buffer calcium activates calcium-dependent enzymes (proteases, lipases, and nucleases). These enzymes and their metabolic products, such as eicosanoids and oxygen free radicals, cause the breakdown of plasma membranes and cytoskeletal elements, leading to cell death. This sequence of events has been termed excitotoxicity because of the pivotal role of excitatory amino acids such as glutamate.

Figure 9–3. Pathogenesis of ischemic neuronal death. Ischemia deprives the brain of metabolic substrates, especially oxygen and glucose, making it impossible for cells to carry out energy-dependent functions such as the maintenance of trans-membrane ion gradients. Loss of these gradients depolarizes cell membranes, leading to the influx of calcium through voltage-gated calcium channels and triggering the release of neurotransmitters such as glutamate from presynaptic nerve terminals. Glutamate binds to receptors on the postsynaptic neuronal membrane to activate the influx of sodium and calcium. This sets in motion a cascade of biochemical events that causes cellular swelling, injures mitochondria, generates toxic free radicals, and activates proteases, nucleases, and other enzymes. Depending on the severity and duration of ischemia, neurons may die rapidly, from necrosis, or more gradually, from programmed cell death or apoptosis. Necrotic cell death is characterized by shrinkage of the nucleus (pyknosis), early loss of membrane integrity, structural changes in mitochondria, and eventually cellular lysis. Apoptosis, which depends on the synthesis of new proteins, is associated with margination of nuclear chromatin, relative preservation of cell membrane and mitochondrial integrity, and the formation of membrane-bound extracellular blebs (apoptotic bodies). Necrosis and apoptosis can coexist in different regions of an ischemic lesion.

Where ischemia is incomplete and therefore permits more prolonged cell survival—as in the border zone or penumbra surrounding the core of an ischemic brain region—other biochemical processes that regulate cell death may be set into motion. These include the expression of proteins involved in programmed cell death, such as Bcl (B-cell lymphoma)-2-family proteins and caspases (proenzymes for cysteine proteases that cleave at aspartate residues). The action of these proteins may lead to apoptosis, a form of programmed cell death that is distinct from necrosis and is characterized by margination of nuclear chromatin, cleavage of DNA into fragments of defined length (nucleosomes), relative preservation of cell membrane integrity, blebbing of the plasma membrane to form apoptotic bodies, and phagocytosis without inflammation.
If the blood flow to ischemic brain tissue is restored before neurons are irreversibly injured, the clinical symptoms and signs are transient. Prolonged interruption of blood flow, however, leads to irreversible ischemic injury (infarction) and persistent neurologic deficits.

Two pathogenetic mechanisms can produce ischemic stroke—thrombosis and embolism. While about two-thirds of ischemic strokes are attributed to thrombosis and about one-third to embolism, the distinction is often difficult or impossible to make on clinical grounds.

1. Thrombosis produces stroke by occluding large cerebral arteries (especially the internal carotid, middle cerebral, or basilar), small penetrating arteries (as in lacunar stroke), cerebral veins, or venous sinuses. Symptoms typically evolve over minutes to hours. Thrombotic strokes are often preceded by TIAs, which tend to produce similar symptoms because they affect the same territory recurrently.
2. Embolism produces stroke when cerebral arteries are occluded by the distal passage of thrombus from the heart, aortic arch, or large cerebral arteries. Emboli in the anterior cerebral circulation most often occlude the middle cerebral artery or its branches, since about 85% of the hemispheric blood flow is carried by this vessel. Emboli in the posterior cerebral circulation usually lodge at the apex of the basilar artery or in the posterior cerebral arteries. Embolic strokes characteristically produce neurologic deficits that are maximal at onset. When TIAs precede embolic strokes, especially those arising from a cardiac source, symptoms typically vary between attacks since different vascular territories are affected.
B. HEMORRHAGE

Hemorrhage may interfere with cerebral function through a variety of mechanisms, including destruction or compression of brain tissue and compression of vascular structures, leading to secondary ischemia and edema. Intracranial hemorrhage is classified by its location as intracerebral, subarachnoid, subdural, or epidural, all of which—except subdural hemorrhage—are usually caused by arterial bleeding.
1. Intracerebral hemorrhage causes symptoms by compressing adjacent tissue (which can then produce local ischemia) and, to a lesser extent, by destroying tissue. Unlike ischemic stroke, intracerebral hemorrhage tends to cause more severe headache and depression of consciousness as well as neurologic deficits that do not correspond to the distribution of any single blood vessel.
2. Subarachnoid hemorrhage leads to cerebral dysfunction by elevating intracranial pressure as well as by exerting still poorly understood toxic effects of subarachnoid blood on brain tissue. In addition, subarachnoid hemorrhage may be complicated by vasospasm (leading to ischemia), rebleeding, extension of blood into brain tissue (producing an intracerebral hematoma), or hydrocephalus. Subarachnoid hemorrhage typically presents with headache rather than focal neurologic deficits; it is discussed in Chapter 2.
3. Subdural or epidural hemorrhage produces a mass lesion that can compress the underlying brain. These hemorrhages are often traumatic in origin, and usually present with headache or altered consciousness. Because their recognition is most critical in the setting of coma, subdural and epidural hemorrhage are discussed in Chapter 10.

FOCAL CEREBRAL ISCHEMIA
Etiology
A variety of disorders of the blood, blood vessels, and heart can lead to focal cerebral ischemia (Table 9–3).

Table 9–3. Conditions associated with focal cerebral ischemia.

A. VASCULAR DISORDERS

1. Atherosclerosis—Atherosclerosis of the large extracranial arteries in the neck and at the base of the brain is the underlying cause of focal cerebral ischemia in the great majority of cases. Atherosclerosis affects large and medium-sized elastic and muscular arteries. Within the cerebral circulation, the sites of predilection (Figure 9–4) are the origin of the common carotid artery, the internal carotid artery just above the common carotid bifurcation and within the cavernous sinus, the origin of the middle cerebral artery, the vertebral artery at its origin and just above where it enters the skull, and the basilar artery.

Figure 9–4. Sites of predilection (blue areas) for atherosclerosis in the intracranial arterial circulation.

The pathogenesis of atherosclerosis is incompletely understood, but injury to and resulting dysfunction of vascular endothelial cells is thought to be an early step. Endothelial cells may be injured by low-density lipoproteins, free radicals, hypertension, diabetes, homocysteine, or infectious agents. Blood monocytes and T lymphocytes adhere to the sites of endothelial injury and subsequently migrate subendothelially, where monocytes and monocyte-derived macrophages are transformed into lipid-laden foam cells. The resulting lesion is called a fatty streak. The release of growth and chemotactic factors from endothelial cells and macrophages stimulates the proliferation and migration of intimal smooth muscle cells, and leads to formation of a fibrous plaque. Platelets adhere to sites of endothelial injury and release growth and chemotactic factors. The resulting atheromatous lesion (Figure 9–5) may enlarge or rupture to occlude the vessel lumen, or it may provide a source of atheromatous or platelet emboli. Ulcerated atheromas may be especially likely sources of emboli.

Figure 9–5. Arterial lesion in atherosclerosis. Endothelial injury permits circulating mononuclear cells to adhere to the vessel wall and then migrate beneath the endothelial layer, where they form a fatty streak. The subsequent attachment of platelets and proliferation of smooth muscle cells within this lesion produce a fibrous plaque arising from the intimal surface. This encroaches on the arterial lumen and may occlude the vessel or provide a source of emboli.

The most important risk factor for atherosclerosis leading to stroke is systolic or diastolic hypertension. In one study of more than 5000 symptom-free men and women aged from 30 to 60 years followed prospectively for 18 years, the likelihood of hypertensive subjects developing stroke was seven times that of the nonhypertensive subjects. Furthermore, the incidence of all the major cardiac and cerebrovascular sequelae of hypertension increased in direct proportion to the blood pressure even in the nonhypertensive range, without any identifiable critical or safe value. A blood pressure of 160 mm Hg systolic or 95 mm Hg diastolic observed during any clinic visit tripled the risk of stroke, suggesting that such patients should receive antihypertensive treatment.
Atherosclerosis can also occur in the absence of hypertension. In such cases, other factors such as diabetes, elevated serum cholesterol and triglycerides, hyperhomocysteinemia, cigarette smoking, hereditary predisposition, and the use of oral contraceptives may be implicated. Genetic disorders associated with accelerated atherosclerosis include homocystinuria and dyslipoproteinemias.
2. Other inflammatory disorders
a. Giant cell arteritis (see Chapter 2), also called temporal arteritis, produces inflammatory changes that affect branches of the external carotid, cervical internal carotid, posterior ciliary, extracranial vertebral, and intracranial arteries. Inflammatory changes in the arterial wall may stimulate platelet adhesion and aggregation on damaged surfaces, leading to thrombosis or distal embolism. Physical examination may show tender, nodular, or pulseless temporal arteries. Laboratory findings include an increased erythrocyte sedimentation rate and evidence of vascular stenosis or occlusion on angiography or color duplex ultrasonography. Definitive diagnosis is by temporal artery biopsy. Although it is an uncommon cause of cerebral ischemic symptoms, giant cell arteritis should be considered in patients with transient monocular blindness or transient cerebral ischemic attacks—especially elderly patients—because the disorder is responsive to corticosteroid therapy and its complications (especially permanent blindness) may thus be avoided.
b. Systemic lupus erythematosus is associated with a vasculopathy that involves small cerebral vessels and leads to multiple microinfarctions. Inflammatory changes characteristic of true vasculitis are absent. Libman-Sacks endocarditis may also be a source of cardiogenic emboli.
c. Polyarteritis nodosa is a segmental vasculitis of small and medium-sized arteries that affects multiple organs. Transient symptoms of cerebral ischemia, including typical spells of transient monocular blindness, can occur.
d. Granulomatous angiitis (also called primary angiitis of the central nervous system) is an idiopathic inflammatory disease that affects small arteries and veins in the central nervous system and can cause transient or progressive multifocal lesions. Clinical features include headache, hemiparesis and other focal neurologic abnormalities, and cognitive disturbances. The cerebrospinal fluid (CSF) usually shows pleocytosis and elevated protein, but because the systemic vasculature is spared, the erythrocyte sedimentation rate is typically normal. The diagnosis should be suspected in any patient with multifocal central nervous system dysfunction and CSF pleocytosis. Angiography demonstrates focal and segmental narrowing of small arteries and veins, and a meningeal biopsy is diagnostic. Treatment with corticosteroids, alone or in combination with cyclophosphamide, may be beneficial.
e. Syphilitic arteritis occurs within 5 years after a primary syphilitic infection and reflects the underlying meningeal inflammatory process. It is important to recognize and treat the disorder at this early stage to prevent the development of tertiary parenchymal neurosyphilis (general paresis or tabes dorsalis). Medium-sized penetrating vessels are typically involved (Figure 9–6), producing punctate areas of infarction in the deep white matter of the cerebral hemisphere, that can be seen on CT scan or MRI.

Figure 9–6. Left carotid angiogram (AP projection) in syphilitic arteritis showing marked narrowing of the proximal middle cerebral artery (arrows at right) and anterior cerebral artery (arrow at left). (Reproduced, with permission, from Lowenstein DH, Mills C, Simon RP: Acute syphilitic transverse myelitis: unusual presentation of meningovascular syphilis. Genitourin Med 1987;63:333–338.)

f. AIDS is associated with an increased incidence of TIAs and ischemic stroke. In some cases, ischemic neurologic complications of AIDS are associated with endocarditis or with opportunistic infections of the central nervous system, such as toxoplasmosis or cryptococcal meningitis.
3. Fibromuscular dysplasia—This affects large arteries of children and young adults, producing segmental thinning of the media and fragmentation of the elastic lamina, alternating with rings of fibrous and muscular hyperplasia within the media. Extracranial vessels are involved more often than intracranial ones, and the cervical portion of the internal carotid artery is involved more than the vertebral artery. Lesions are often bilateral. Fibromuscular dysphasia may be inherited as an autosomal dominant disorder and is more common in women than in men. Symptoms may be due to the embolization of vascular thrombi. There is a characteristic “string-of-beads” appearance on angiography. Antiplatelet drugs or intraluminal dilation of affected extracranial vessels may be beneficial in symptomatic cases.
4. Carotid or vertebral artery dissection—Dissection of the carotid or vertebral artery is associated with hemorrhage into the vessel wall, which can occlude the vessel or predispose to thrombus formation and embolization. Posttraumatic carotid dissections present little difficulty in diagnosis. Certain patients, however—usually young men—suffer cerebral infarction after apparently spontaneous carotid artery dissection. Internal carotid artery dissections usually originate near the carotid bifurcation and can extend to the base of the skull. The underlying pathologic process is usually cystic medial necrosis. Prodromal transient hemispheric ischemia or monocular blindness sometimes precedes a devastating stroke. Carotid dissection may be accompanied by pain in the jaw or neck, visual abnormalities akin to those that occur in migraine, or Horner’s syndrome.
Dissection of the vertebral or basilar artery is less common. The clinical features of this disorder include headache, posterior neck pain, and the sudden onset of signs of brainstem dysfunction.
The treatment of carotid or vertebral artery dissection is controversial. Approaches include no treatment, removal of the intramural hematoma, and measures to prevent embolization from the site of dissection (aspirin, anticoagulants, or occlusion of the vessel distal to the dissection). Recurrent dissection is uncommon and usually occurs within 1 month of the initial event.
5. Lacunar infarction—Lacunar infarction of the brain results from the occlusion of small penetrating branches of the major cerebral arteries, especially those that supply the basal ganglia, thalamus, internal capsule, and pons. Lacunar infarcts are believed to be caused by either atherosclerosis or degenerative changes in arterial walls (including lipohyalinosis and fibrinoid necrosis) that are related to long-standing hypertension. Both hypertension and diabetes appear to predispose to this type of stroke.
6. Drug abuse—Use of cocaine hydrochloride, alkaloidal (crack) cocaine, amphetamines, or heroin is a risk factor for stroke in patients younger than 35 years old. Patients who take these agents intravenously may develop infective endocarditis (see below) leading to embolic stroke. Stroke also occurs in drug users without endocarditis, however, including those who take drugs only intranasally or by smoke or vapor inhalation, and often has its onset within hours of drug use. Mechanisms that have been proposed to explain these events include drug-induced vasospasm, vasculitis, and the rupture of preexisting aneurysms or vascular malformations. Cocaine hydrochloride is most often associated with intracerebral hemorrhage but can also cause subarachnoid hemorrhage or ischemic stroke. Stroke from crack cocaine is most commonly ischemic in origin, but intracerebral or subarachnoid hemorrhage also occurs. Amphetamines can produce vasculitis, with necrosis of the vessel wall leading to intracerebral hemorrhage; ischemic stroke and subarachnoid hemorrhage are less frequent. Other sympathomimetic amines, including phenylpropanolamine and ephedrine, are also associated with an increased risk of stroke. Heroin is associated primarily with embolic stroke resulting from endocarditis.
7. Multiple progressive intracranial arterial occlusions (moyamoya)—This syndrome has two essential features: bilateral narrowing or occlusion of the distal internal carotid arteries and the adjacent anterior and middle cerebral artery trunks; and the presence of a fine network of collateral channels at the base of the brain. The term moyamoya derives from a Japanese word meaning smoke or haze, which characterizes the angiographic appearance of these fine collaterals (Figure 9–7). Moyamoya is most common in Japanese girls and is sometimes inherited as an autosomal recessive disorder that maps to chromosome 3p26–p24.2, but occurs in all ethnic groups and in patients with atherosclerosis, sickle cell anemia, or a history of basilar meningitis. The term therefore denotes an angiographic pattern of collateral vessels rather than a clinical or pathologic syndrome. Children tend to present with ischemic strokes; adults present with intracerebral, subdural, or subarachnoid hemorrhage. Transient episodes of cerebral ischemia are infrequent.

Figure 9–7. Right carotid angiogram in moyamoya. The middle cerebral artery and its branches are replaced by a diffuse capillary pattern that has the appearance of a puff of smoke. A: AP view. B: lateral view.

8. Migraine—Migraine with aura has been proposed as a cause of stroke, but in many cases, other stroke risk factors (eg, oral contraceptive use) may coexist. Stroke in migraineurs may occur during an attack of classic migraine and in the same vascular territory affected by previous migraine attacks. The anterior (especially the middle cerebral artery) and posterior (especially the posterior cerebral artery) cerebral circulations are affected about equally often. Investigative studies show no other cause of stroke (eg, occlusion of large cerebral arteries).
9. Venous or sinus thrombosis—This uncommon cause of stroke is typically associated with a predisposing condition such as otitis or sinusitis, a postpartum state, dehydration, or coagulopathy. Clinical features include headache, papilledema, impaired consciousness, seizures, and focal neurologic deficits. CSF pressure is typically increased, and in cases of septic thrombosis, pleocytosis may occur. A CT scan may demonstrate hemorrhage associated with venous infarction, and in superior sagittal sinus thrombosis a CT scan with contrast sometimes shows a filling defect corresponding to the clot (delta sign). However, MRI with contrast is the diagnostic procedure of choice in most cases. The diagnosis may be confirmed by MR angiography, but conventional intraarterial x-ray angiography is now rarely indicated. In patients presenting with headache and papilledema, venous or sinus thrombosis must be differentiated from intracranial mass lesions and idiopathic pseudotumor cerebri. The radiologic studies mentioned above are useful in this regard. Septic thromboses are treated with antibiotics. Anticoagulation has been used for aseptic thrombosis, but its efficacy has not been proved, and it may precipitate intracranial hemorrhage.
B. CARDIAC DISORDERS

1. Mural thrombus—Mural thrombus complicating myocardial infarction or cardiomyopathy is a recognized source of cerebral embolism. The risk of stroke in the first weeks after myocardial infarction is related to the size of the cardiac lesion. More extensive myocardial damage may increase the tendency for mural thrombi to form; it may exacerbate the generalized hypercoagulable state that accompanies the infarct—or it may do both. Accordingly, patients with large transmural myocardial infarcts require anticoagulation therapy to substantially reduce the incidence of early thromboembolic events, including stroke.
2. Rheumatic heart disease—The incidence of focal cerebral ischemia is increased in patients with rheumatic heart disease—particularly those with mitral stenosis and atrial fibrillation—presumably as a result of embolization. In other cases, symptoms are temporally related to exertion, suggesting hypoperfusion as the cause.
3. Arrhythmias—Atrial fibrillation (especially when associated with rheumatic heart disease) and the bradycardia-tachycardia (sick sinus) syndrome are well-recognized causes of embolic stroke. Other cardiac arrhythmias are more likely to produce pancerebral hypoperfusion with diffuse rather than focal symptoms (eg, syncope, dimming of vision, nonspecific lightheadedness, generalized seizures) unless severe carotid artery stenosis is also present.
4. Endocarditis
a. Infective (bacterial or fungal) endocarditis is a cause of transient cerebral ischemia and embolic cerebral infarction during the active phase of infection and during the first few months following antibiotic cure. At autopsy, cerebral emboli are identified in 30% and systemic emboli in 60% of such patients. The middle cerebral artery is the most common site of cerebral embolization. Intracerebral or subarachnoid hemorrhage can also occur as a result of bleeding into an infarct or rupture of a mycotic aneurysm. Infective endocarditis is seen most often in intravenous drug users and patients with valvular heart disease or prosthetic valves. Streptococci and staphylococci are the most common causes, but gram-negative bacilli (eg, Pseudomonas) and fungi (especially Candida and Aspergillus) are also frequent pathogens in intravenous drug users and prosthetic valve recipients.
Signs of infective endocarditis include heart murmurs, petechiae, subungual splinter hemorrhages, retinal Roth’s spots (red spots with white centers), Osler’s nodes (painful red or purple digital nodules), Janeway’s lesions (red macules on the palms or soles), and clubbing of the fingers or toes. The diagnosis is usually made by culturing the responsible organism from the blood. Treatment is with antibiotics; valve replacement is sometimes required. Anticoagulation should be avoided because of the risk of intracranial hemorrhage.
b. Nonbacterial (marantic) endocarditis is most frequent in patients with cancer and is responsible for the vast majority of ischemic strokes in this population. The tumors most often associated with this type of stroke are adenocarcinomas of the lung or gastrointestinal tract. Vegetations are present on the mitral or aortic valves; associated murmurs are rare. Identification of valvular vegetations by two-dimensional echocardiography may be diagnostic, but failure to demonstrate vegetations does not exclude the diagnosis. Anticoagulation with heparin may be useful in patients with treatable tumors or with other treatable causes of marantic endocarditis, such as sepsis.
5. Mitral valve prolapse—Buckling of the mitral valve due to stretching of the mitral annulus (mitral valve prolapse) is common, occurring in 4–8% of young adults, and usually produces no symptoms. In some cases there appears to be an association with cerebral ischemia, but the degree to which the disorder increases the risk of stroke is apparently small, and massive strokes related to mitral valve prolapse are rare.
6. Paradoxic embolus—Congenital cardiac anomalies associated with a pathologic communication between the right and left sides of the heart, such as atrial septal defect or patent foramen ovale, permit the passage of embolic material from the systemic venous circulation to the brain. Under these circumstances, venous thrombi can give rise to embolic stroke.
7. Atrial myxoma—This rare disorder can lead to either embolization (producing stroke) or cardiac outflow obstruction (producing syncope). Embolic events occur in one-fourth to one-half of patients with nonhereditary left atrial myxoma; some cases, however, are familial. Hemorrhagic strokes may occur. Diagnosis is by echocardiography.
8. Prosthetic heart valves—Patients with prosthetic heart valves are at particular risk for cerebral emboli and are generally treated with anticoagulants on a long-term basis.
C. HEMATOLOGICAL DISORDERS

1. Thrombocytosis—Thrombocytosis occurs in myeloproliferative disorders, other neoplastic or infections diseases, and following splenectomy. Thrombocytosis may predispose to focal cerebral ischemia when the platelet count exceeds 1,000,000/µL.
2. Polycythemia—Patients with polycythemia may have focal neurologic symptoms that respond to venesection. Hematocrits above 46% are associated with reduced cerebral blood flow, and the risk of stroke. This risk increases with hematocrits of more than 50%, and rises dramatically above 60%.
3. Sickle cell disease—Sickle cell (hemoglobin S) disease is due to a single amino acid substitution (Glu-6-Val) in the hemoglobin beta locus on chromosome 11 (11p15.5) that results in an abnormal beta hemoglobin chain. Persons of African, especially West African, descent are most frequently affected. The mutation causes the sickle-shaped deformation of erythrocytes when the partial pressure of oxygen in blood is reduced, and produces hemolytic anemia and vascular occlusions, which may be extremely painful (sickle cell crises). Homozygotes are more severely affected than heterozygotes. The most frequent neurologic complication is stroke, which characteristically affects the intracranial internal carotid or proximal middle or anterior cerebral artery. Detection of increased cerebral blood flow velocity by transcranial Doppler studies may help to identify individuals at increased risk for stroke. Therapies in clinical or experimental use include hydration and analgesia for painful crises, blood transfusion, hydroxyurea (which increases levels of fetal hemoglobin), and bone marrow or hematopoietic stem cell transplantation. In patients with sickle cell disease who must undergo angiography, the level of hemoglobin S should be reduced by exchange transfusion to less than 20%, since radiologic contrast media may induce sickling.
4. Leukocytosis—Transient cerebral ischemia has been reported in association with leukocytosis, usually in patients with leukemia and white blood cell counts in excess of 150,000/µL.
5. Hypercoagulable states—Hyperviscosity of the serum from paraproteinemia (especially macroglobulinemia) is an infrequent cause of focal cerebral ischemia. Estrogen therapy, oral contraceptive use, postpartum and postoperative states, and cancer may be accompanied by coagulopathies that lead to cerebral thrombosis or embolism.
Antiphospholipid antibodies, including lupus anticoagulants and anticardiolipin antibodies, may be associated with an increased incidence of ischemic stroke. Stroke has also been reported in patients with hereditary coagulopathies, including heparin cofactor II deficiency, protein C deficiency, defective release of plasminogen activator, and factor XII deficiency.
Pathology
A. INFARCTION IN MAJOR-CEREBRAL-ARTERY DISTRIBUTION

On gross inspection at autopsy, a recent infarct is a swollen, softened area of brain that usually affects both gray and white matter. Microscopy shows acute ischemic changes in neurons (shrinkage, microvacuolization, dark staining), destruction of glial cells, necrosis of small blood vessels, disruption of nerve axons and myelin, and accumulation of interstitial fluid from vasogenic edema. In some cases, perivascular hemorrhages are observed in the infarcted area.
Cerebral infarcts are typically associated with cerebral edema, which is maximal during the first 4 or 5 days after onset. Most deaths that occur within 1 week after massive cerebral infarction are attributable to cerebral edema, with swelling of the affected hemisphere causing herniation of the ipsilateral cingulate gyrus across the midline beneath the free edge of the dural falx, followed by downward displacement of the brain through the tentorial incisure.
B. LACUNAR INFARCTION

In contrast to infarcts associated with major cerebral blood vessels, smaller lacunar infarcts result from lipohyalinosis of small resistance vessels, usually in patients with chronic hypertension. Lacunar infarcts—often multiple—are found in about 10% of brains at autopsy. The pathologic appearance is of small cavities ranging in size from 0.5 to 15 mm in diameter.
Clinicoanatomic Correlation
A rational clinical approach to cerebral ischemia depends on the ability to identify the neuroanatomic basis of clinical deficits.
A. ANTERIOR CEREBRAL ARTERY

1. Anatomy—The anterior cerebral artery supplies the parasagittal cerebral cortex (Figure 9–8 and Figure 9–9), which includes portions of motor and sensory cortex related to the contralateral leg and the so-called bladder inhibitory or micturition center.

Figure 9–8. Arterial supply of the primary motor and sensory cortex (lateral view).

Figure 9–9. Arterial supply of the primary motor and sensory cortex (coronal view).

2. Clinical syndrome of anterior cerebral artery occlusion—Anterior cerebral artery strokes are uncommon, perhaps because emboli from the extracranial vessels or the heart are more apt to enter the larger-caliber middle cerebral artery, which receives the bulk of cerebral blood flow. There is a contralateral paralysis and sensory loss affecting the leg. Voluntary control of micturition may be impaired because of failure to inhibit reflex bladder contractions, resulting in precipitate micturition.
B. MIDDLE CEREBRAL ARTERY

1. Anatomy—The middle cerebral artery supplies most of the remainder of the cerebral hemisphere and deep subcortical structures (see Figure 9–8 and Figure 9–9). The cortical branches of the middle cerebral artery include the superior division, which supplies the entire motor and sensory cortical representation of the face, hand, and arm; and the expressive language (Broca’s) area of the dominant hemisphere (Figure 9–10). The inferior division supplies the visual radiations, the region of visual cortex related to macular vision, and the receptive language (Wernicke’s) area of the dominant hemisphere. Lenticulostriate branches of the most proximal portion (stem) of the middle cerebral artery supply the basal ganglia as well as motor fibers related to the face, hand, arm, and leg as they descend in the genu and the posterior limb of the internal capsule.

Figure 9–10. Anatomic basis of middle cerebral artery syndromes.

2. Clinical syndrome of middle cerebral artery occlusion—The middle cerebral artery is the vessel most commonly involved in ischemic stroke. Depending on the site of involvement, several clinical syndromes can occur (see Figure 9–10).
a. Superior division stroke results in contralateral hemiparesis that affects the face, hand, and arm but spares the leg; contralateral hemisensory deficit in the same distribution; but no homonymous hemianopia. If the dominant hemisphere is involved, these features are combined with Broca’s (expressive) aphasia, which is characterized by impairment of language expression with intact comprehension.
b. Inferior division stroke is less common in isolation and results in contralateral homonymous hemianopia that may be denser inferiorly; marked impairment of cortical sensory functions, such as graphesthesia and stereognosis on the contralateral side of the body; and disorders of spatial thought, including a lack of awareness that a deficit exists (anosognosia), neglect of and failure to recognize the contralateral limbs, neglect of the contralateral side of external space, dressing apraxia, and constructional apraxia. If the dominant hemisphere is involved, Wernicke’s (receptive) aphasia occurs and is manifested by impaired comprehension and fluent but often nonsensical speech. With involvement of the nondominant hemisphere, an acute confusional state may occur.
c. Occlusion at the bifurcation or trifurcation of the middle cerebral artery involves a lesion situated at the point where the artery splits into two (superior and inferior) or three (superior, middle, and inferior) major divisions. This severe stroke syndrome combines the features of superior and inferior division stroke. Its clinical features include contralateral hemiparesis and hemisensory deficit involving the face and arm far more than the leg; homonymous hemianopia; and, if the dominant hemisphere is affected, global (combined expressive and receptive) aphasia.
d. Occlusion of the stem of the middle cerebral artery occurs proximal to the origin of the lenticulostriate branches. Because the entire territory of the artery is affected, this is the most devastating of middle cerebral artery strokes. The resulting clinical syndrome is similar to that seen following occlusion at the trifurcation except that, in addition, infarction of motor fibers in the internal capsule causes paralysis of the contralateral leg. The result is a contralateral hemiplegia and sensory loss affecting the face, hand, arm, and leg.
C. INTERNAL CAROTID ARTERY

1. Anatomy—The internal carotid artery arises where the common carotid artery divides into internal and external carotid branches in the neck. In addition to its anterior cerebral and middle cerebral branches discussed above, the internal carotid artery also gives rise to the ophthalmic artery, which supplies the retina. The severity of internal carotid artery strokes is highly variable, depending on the adequacy of collateral circulation, which tends to develop in compensation for a slowly evolving occlusion.
2. Clinical syndrome of internal carotid artery occlusion—Intra- or extracranial internal carotid artery occlusion is responsible for about one-fifth of ischemic strokes. In approximately 15% of cases, progressive atherosclerotic occlusion of the internal carotid artery is preceded by premonitory TIAs or by transient monocular blindness caused by ipsilateral retinal artery ischemia.
Carotid artery occlusion may be asymptomatic. Symptomatic occlusion results in a syndrome similar to that of middle cerebral artery stroke (contralateral hemiplegia, hemisensory deficit, and homonymous hemianopia; aphasia is also present with dominant hemisphere involvement).
D. POSTERIOR CEREBRAL ARTERY

1. Anatomy—The paired posterior cerebral arteries arise from the tip of the basilar artery (Figure 9–11) and supply the occipital cerebral cortex, medial temporal lobes, thalamus, and rostral midbrain. Emboli carried up the basilar artery tend to lodge at its apex, where they can occlude one or both posterior cerebral arteries. These emboli can subsequently break up and produce signs of asymmetric or patchy posterior cerebral artery infarction.

Figure 9–11. Sites of thrombotic and embolic occlusions in the vertebrobasilar circulation. A: Thrombotic occlusion of the basilar artery. B: Thrombotic occlusion of both vertebral arteries. C: Embolic occlusion at the apex of the basilar artery. D: Embolic occlusion of both posterior cerebral arteries.

2. Clinical syndrome of posterior cerebral artery occlusion—Occlusion of a posterior cerebral artery produces homonymous hemianopia affecting the contralateral visual field. Macular vision may be spared, however, because of the dual (middle and posterior cerebral artery) blood supply to the portion of the visual cortex representing the macula (see Chapter 4). In contrast to visual field defects from infarction in the middle cerebral artery territory, those caused by posterior cerebral artery occlusion may be denser superiorly. With occlusions near the origin of the posterior cerebral artery at the level of the midbrain, ocular abnormalities can include vertical gaze palsy, oculomotor (III) nerve palsy, internuclear ophthalmoplegia, and vertical skew deviation of the eyes. When posterior cerebral artery occlusion affects the occipital lobe of the dominant (usually left) hemisphere, patients may exhibit anomic aphasia (difficulty in naming objects), alexia without agraphia (inability to read, with no impairment of writing), or visual agnosia. The last is a failure to identify objects presented in the left side of the visual field, caused by a lesion of the corpus callosum that disconnects the right visual cortex from language areas of the left hemisphere. Bilateral posterior cerebral artery infarction may result in cortical blindness, memory impairment (from temporal lobe involvement), or the inability to recognize familiar faces (prosopagnosia), as well as a variety of exotic visual and behavioral syndromes.
E. BASILAR ARTERY

1. Anatomy—The basilar artery usually arises from the junction of the paired vertebral arteries (Figure 9–11), though in some cases only a single vertebral artery is present. The basilar artery courses over the ventral surface of the brainstem to terminate at the level of the midbrain, where it bifurcates to form the posterior cerebral arteries (see above). Branches of the basilar artery supply the occipital and medial temporal lobes, the medial thalamus, the posterior limb of the internal capsule, and the entire brainstem and cerebellum.
2. Clinical syndromes of basilar artery occlusion—
a. Thrombosis—Thrombotic occlusion of the basilar artery (Figure 9–11A)—a serious event that is often incompatible with survival—produces bilateral neurologic signs referable to involvement of multiple branch arteries (Figure 9–12). Occlusion of both vertebral arteries (Figure 9–11B) or of a lone unpaired vertebral artery produces a similar syndrome. Temporary occlusion of one or both vertebral arteries can also occur in relation to rotation of the head in patients with cervical spondylosis, leading to transient symptoms and signs of brainstem dysfunction.

Figure 9–12. Arterial supply of the brainstem. A: Midbrain. The basilar artery gives off paramedian branches that supply the oculomotor (III) nerve nucleus and the red nucleus (RN). A larger branch, the posterior cerebral artery, courses laterally around the midbrain, giving off a basal branch that supplies the cerebral peduncle (CP) and a dorsolateral branch supplying the spinothalamic tract (ST) and medial lemniscus (ML). The posterior cerebral artery continues (upper arrows) to supply the thalamus, occipital lobe, and medial temporal lobe. B: Pons. Paramedian branches of the basilar artery supply the abducens (VI) nucleus and the medial lemniscus (ML). The anterior inferior cerebellar artery gives off a basal branch to the descending motor pathways in the basis pontis (BP) and a dorsolateral branch to the trigeminal (V) nucleus, the vestibular (VIII) nucleus, and the spinothalamic tract (ST), before passing to the cerebellum (upper arrows). C: Medulla. Paramedian branches of the vertebral arteries supply descending motor pathways in the pyramid (P), the medial lemniscus (ML), and the hypoglossal (XII) nucleus. Another vertebral branch, the posterior inferior cerebellar artery, gives off a basal branch to the olivary nuclei (ON) and a dorsolateral branch that supplies the trigeminal (V) nucleus, the vestibular (VIII) nucleus, and the spinothalamic tract (ST), on its way to the cerebellum (upper arrows).

Major stenosis or occlusion of the subclavian artery before it has given rise to the vertebral artery can lead to the subclavian steal syndrome, in which blood passes from the vertebral artery into the distal subclavian artery with physical activity of the ipsilateral arm. The syndrome is a manifestation of generalized atherosclerosis and is not predictive of stroke in the vertebrobasilar system. Patients are usually asymptomatic, and stroke, when it occurs, is typically due to coexisting carotid lesions.
Basilar thrombosis usually affects the proximal portion of the basilar artery (Figure 9–11A), which supplies the pons. Involvement of the dorsal portion (tegmentum) of the pons produces unilateral or bilateral abducens (VI) nerve palsy; horizontal eye movements are impaired, but vertical nystagmus and ocular bobbing may be present. The pupils are constricted as a result of the involvement of descending sympathetic pupillodilator fibers in the pons, but they may remain reactive. Hemiplegia or quadriplegia is usually present, and coma is common. Although the syndrome of basilar occlusion in unconscious patients may be confused with pontine hemorrhage, a CT or MRI brain scan will differentiate the two.
In some patients with basilar occlusion, the ventral portion of the pons (basis pontis) is infarcted and the tegmentum is spared. Such patients remain conscious but quadriplegic. The term locked-in syndrome has been applied to this state. Locked-in patients may be able to signify that they are conscious by opening their eyes or moving their eyes vertically on command. In other cases, a conventional electroencephalogram (EEG) with stimulation may be needed to distinguish the locked-in state (in which the EEG is normal) from coma (see Chapter 10).
b. Embolism—Emboli small enough to pass through the vertebral arteries into the larger basilar artery are usually arrested at the top of the basilar artery, where it bifurcates into the posterior cerebral arteries (Figure 9–11C). The resulting reduction in blood flow to the ascending reticular formation of the midbrain and thalamus produces immediate loss or impairment of consciousness. Unilateral or bilateral oculomotor (III) nerve palsies are characteristic. Hemiplegia or quadriplegia with decerebrate or decorticate posturing occurs because of the involvement of the cerebral peduncles in the midbrain. Thus, the top of the basilar syndrome may be confused with midbrain failure caused by transtentorial uncal herniation. Less commonly, an embolus may lodge more proximally in an atheromatous narrowed portion of the basilar artery, producing a syndrome indistinguishable from basilar thrombosis.
Smaller emboli may occlude the rostral basilar artery transiently before fragmenting and passing into one or both posterior cerebral arteries (Figure 9–11D). In such cases, portions of the midbrain, thalamus, and temporal and occipital lobes can be infarcted. If conscious, these patients display a variety of visual (homonymous hemianopia, cortical blindness), visuomotor (impaired convergence, paralysis of upward or downward gaze, diplopia), and behavioral (especially confusion) abnormalities without prominent motor dysfunction. Sluggish pupillary responses are a helpful sign of midbrain involvement.
F. LONG CIRCUMFERENTIAL VERTEBROBASILAR BRANCHES

1. Anatomy—The long circumferential branches arising from the vertebral and basilar arteries are the posterior inferior cerebellar, the anterior inferior cerebellar, and the superior cerebellar arteries (Figure 9–12). These vessels supply the dorsolateral brainstem, including dorsolaterally situated cranial nerve nuclei (V, VII, VIII) and pathways entering and leaving the cerebellum in the cerebellar peduncles.
2. Clinical syndrome of long circumferential artery occlusion—Occlusion of one of the circumferential branches produces infarction in the dorsolateral area of the medulla or pons.
a. Posterior inferior cerebellar artery occlusion results in the lateral medullary (Wallenberg’s) syndrome (see Chapter 3). This syndrome varies in its presentation with the extent of infarction, but it can include ipsilateral cerebellar ataxia, Horner’s syndrome, and facial sensory deficit; contralateral impaired pain and temperature sensation; and nystagmus, vertigo, nausea, vomiting, dysphagia, dysarthria, and hiccup. The motor system is characteristically spared because of its ventral location in the brainstem.
b. Anterior inferior cerebellar artery occlusion leads to infarction of the lateral portion of the caudal pons and produces a syndrome with many of the same features. Horner’s syndrome, dysphagia, dysarthria, and hiccup do not occur, however, but ipsilateral facial weakness, gaze palsy, deafness, and tinnitus are common findings.
c. The syndrome of lateral rostral pontine infarction from superior cerebellar artery occlusion resembles that associated with anterior inferior cerebellar artery lesions, but impaired optokinetic nystagmus or skew deviation of the eyes may occur. Auditory function is unaffected, and the contralateral sensory disturbance may involve touch, vibration, and position sense as well as pain and temperature sense.
G. LONG PENETRATING PARAMEDIAN VERTEBROBASILAR BRANCHES

1. Anatomy—Long penetrating paramedian arteries supply the medial brainstem from its ventral surface to the floor of the fourth ventricle. Structures located in this region include the medial portion of the cerebral peduncle, sensory pathways, the red nucleus, the reticular formation, and the midline cranial nerve nuclei (III, IV, VI, XII).
2. Clinical syndrome of long penetrating paramedian artery occlusion—Occlusion of a long penetrating artery causes paramedian infarction of the brainstem and results in contralateral hemiparesis if the cerebral peduncle is affected. Associated cranial nerve involvement depends on the level of the brainstem at which occlusion occurs. Occlusion in the midbrain results in ipsilateral third nerve palsy, which may be associated with contralateral tremor or ataxia from involvement of pathways connecting the red nucleus and cerebellum. Ipsilateral 6th and 7th nerve palsies are seen in the pons, and 12th nerve involvement can occur in the medulla.
If the lesion appears patchy or involves both sides of the brainstem (as manifested by coma or quadriparesis), the differential diagnosis includes occlusion of a main trunk vessel (both vertebral arteries or the basilar artery); intramedullary lesions such as hemorrhage, pontine glioma, or multiple sclerosis; and compression of the brainstem by a cerebellar mass (hemorrhage, infarct, or tumor).
H. SHORT BASAL VERTEBROBASILAR BRANCHES

1. Anatomy—Short branches arising from the long circumferential arteries (discussed above) penetrate the ventral brainstem to supply the brainstem motor pathways.
2. Clinical syndrome of basal brainstem infarction—The most striking finding is contralateral hemiparesis caused by corticospinal tract involvement in the cerebral peduncle or basis pontis. Cranial nerves (eg, III, VI, VII) that emerge from the ventral surface of the brainstem may be affected as well, giving rise to ipsilateral cranial nerve palsies.
I. LACUNAR INFARCTION

Small penetrating arteries located deep in the brain may become occluded as a result of changes in the vessel wall induced by chronic hypertension. The resulting lacunar infarcts are most common in deep nuclei of the brain (putamen, 37%; thalamus, 14%; caudate nucleus, 10%), the pons (16%), and the posterior limb of the internal capsule (10%) (Figure 9–13). They occur in lesser numbers in the deep cerebral white matter, the anterior limb of the internal capsule, and the cerebellum. Because of their small size and their frequent location in relatively silent areas of the brain, many lacunar infarctions are not recognized clinically. In as many as three-fourths of autopsy-proved cases, there is no history of stroke or clear evidence of neurologic deficit on antemortem examinations.

Figure 9–13. Arterial supply of deep cerebral structures frequently involved in lacunar infarction. Descending motor fibers to the face (F), arm (A), and leg (L) and ascending sensory fibers from face (f), arm (a), and leg (l) are shown in the posterior limb of the internal capsule.

In many cases, the isolated nature of the neurologic deficit makes the clinical picture of lacunar infarction distinctive. The onset of lacunar stroke may be gradual, developing over several hours or days. Headache is absent or minor, and the level of consciousness is unchanged.
Recognition of lacunar stroke syndromes is important because the prognosis for complete or nearly complete recovery is good. In addition, the likelihood of future lacunar strokes can be reduced by treating the hypertension that is usually associated with and causally related to them. Because the arteries involved are small, angiography is normal (for that reason, it is not required). The CSF is also normal, and it is possible that a CT brain scan or MRI will not disclose the lesion. CT scanning or MRI should be performed to exclude other causes of stroke, however. Anticoagulation is not indicated since there is no evidence that it confers any benefit in this context. Aspirin is also of uncertain benefit, but it is often given because of the low risk of serious complications. Although a wide variety of deficits can be produced, there are four classic and distinctive lacunar syndromes.
1. Pure motor hemiparesis—This consists of hemiparesis affecting the face, arm, and leg to a roughly equal extent, without an associated disturbance of sensation, vision, or language. When lacunar in origin, it is usually due to a lesion in the contralateral internal capsule or pons. Pure motor hemiparesis may also be caused by internal carotid or middle cerebral artery occlusion, subdural hematoma, or intracerebral mass lesions.
2. Pure sensory stroke—This is characterized by hemisensory loss, which may be associated with paresthesia, and results from lacunar infarction in the contralateral thalamus. It may be mimicked by occlusion of the posterior cerebral artery or by a small hemorrhage in the thalamus or midbrain.
3. Ataxic hemiparesis—In this syndrome, sometimes called ipsilateral ataxia and crural (leg) paresis, pure motor hemiparesis is combined with ataxia of the hemiparetic side and usually predominantly affects the leg. Symptoms result from a lesion in the contralateral pons, internal capsule, or subcortical white matter.
4. Dysarthria-clumsy hand syndrome—This consists of dysarthria, facial weakness, dysphagia, and mild weakness and clumsiness of the hand on the side of facial involvement. When the syndrome is caused by a lacunar infarct, the lesion is in the contralateral pons or internal capsule. Infarcts or small intracerebral hemorrhages at a variety of locations can produce a similar syndrome, however. In contrast to the lacunar syndromes described above, premonitory TIAs are unusual.
Clinical Findings
A. HISTORY

1. Predisposing factors—In patients with cerebrovascular disorders, possible risk factors such as TIAs, hypertension, and diabetes should be sought. In women, the use of oral contraceptives has been associated with cerebral arterial and venous occlusive disease, especially in the presence of hypertension and cigarette smoking. The presence of such medical conditions as ischemic or valvular heart disease or cardiac arrhythmias must also be ascertained. A variety of systemic disorders involving the blood or blood vessels (see Table 9–3) also increase the risk of stroke. Antihypertensive drugs can precipitate cerebrovascular symptoms if the blood pressure is lowered excessively in patients with nearly total cerebrovascular occlusion and poor collateral circulation.
2. Onset and course—The history must address whether the clinical picture is that of TIA, stroke in evolution, or completed stroke. In some cases, it may also be possible to evaluate whether a stroke is likely to be thrombotic or embolic in origin from the clinical history.
a. Features suggesting thrombotic stroke—Patients with thrombotic vascular occlusion often present with stepwise incremental neurologic deficits; the occlusion may be preceded by a series of TIAs. TIAs, for example, precede infarction in 25–50% of patients with occlusive atherosclerotic disease of the extracranial internal carotid arteries. In approximately one-third of such patients, however, the onset of infarction is abrupt, suggesting that embolization from the distal extracranial artery to the intracranial artery may be the cause of stroke.
b. Features suggesting embolic stroke—Cerebral embolism typically causes neurologic deficits that occur abruptly with no warning and are maximal at onset. In many patients, a cardiac origin of emboli is suggested by signs of multifocal cerebral infarction, cardiac valvular disease, cardiomegaly, arrhythmias, or endocarditis.
3. Associated symptoms
a. Seizures accompany the onset of stroke in a small number of cases; in other instances, they follow the stroke by weeks to years. The presence of seizures does not definitively distinguish embolic from thrombotic strokes, but seizure at the onset of stroke may be more common with embolus. If patients with vertebrobasilar stroke or an additional condition predisposing to seizures are not considered, the incidence of epilepsy after stroke is about 10%. The risk of epilepsy increases to about 25% with cortical strokes and to 50% when cortical strokes are associated with a persistent motor deficit.
b. Headache occurs in about 25% of patients with ischemic stroke, possibly because of the acute dilation of collateral vessels.
B. PHYSICAL EXAMINATION

1. General physical examination—The general physical examination of a patient with a cerebrovascular disorder should focus on searching for an underlying systemic cause, especially a treatable one.
a. The blood pressure should be measured to ascertain whether hypertension—a known risk factor for stroke—is present.
b. Comparison of blood pressure and pulse on the two sides can reveal differences related to atherosclerotic disease of the aortic arch or coarctation of the aorta.
c. Ophthalmoscopic examination of the retina can provide evidence of embolization in the anterior circulation in the form of visible embolic material in retinal blood vessels.
d. Examination of the neck may reveal the absence of carotid pulses or the presence of carotid bruits. Reduced carotid artery pulsation in the neck is a poor indicator of internal carotid artery disease, however. Although carotid bruits have been associated with cerebrovascular disease, significant carotid stenosis can occur without an audible bruit; conversely, a loud bruit can occur without stenosis.
e. A careful cardiac examination is essential in order to detect arrhythmias or murmurs related to valvular disease, either of which may predispose to embolization from heart to brain.
f. Palpation of the temporal arteries is useful in the diagnosis of giant cell arteritis, in which these vessels may be tender, nodular, or pulseless.
2. Neurologic examination—Patients with cerebrovascular disorders may or may not have abnormal neurologic findings on examination. A normal examination is expected, for example, after a TIA has resolved. Where deficits are found, the goal of the neurologic examination is to define the anatomic site of the lesion, which may suggest the cause or optimal management of the stroke. Thus, clear evidence that the anterior circulation is involved may lead to angiographic evaluation in contemplation of possible surgical correction of an internal carotid lesion. Establishing that the symptoms are referable to the vertebrobasilar circulation or to a lacunar infarction is likely to dictate a different course of action.
a. Cognitive deficits that indicate cortical lesions in the anterior circulation should be sought. For example, if aphasia is present, the underlying disorder cannot be in the posterior circulation and is unlikely to represent lacunar infarction. The same is true for nondominant hemisphere lesions producing parietal lobe syndromes such as unilateral neglect or constructional apraxia (see discussion of inferior division middle cerebral artery stroke, above).
b. The presence of visual field abnormalities similarly excludes lacunar infarction. Hemianopia may occur, however, with involvement of either the anterior or posterior cerebral arteries. Isolated hemianopia suggests posterior cerebral artery infarction.
c. Ocular palsies, nystagmus, or internuclear ophthalmoplegia assign the underlying lesion to the brainstem and thus to the posterior circulation.
d. Hemiparesis can be due to lesions in cerebral cortical regions supplied by the anterior circulation, descending motor pathways in the brainstem supplied by the vertebrobasilar system, or lacunae at subcortical (corona radiata, internal capsule) or brainstem sites. However, hemiparesis affecting the face, hand, and arm more than the leg is characteristic of lesions within the distribution of the middle cerebral artery. Hemiparesis that is nonselective with respect to the face, arm, and leg is consistent with occlusion of the internal carotid artery or the stem of the middle cerebral artery, lacunar infarction in the internal capsule or basal ganglia, or brainstem disease. A crossed hemiparesis—ie, one that involves the face on one side and the rest of the body on the other—means that the abnormality must lie between the level of the facial nerve nucleus in the pons and the decussation of the pyramids in the medulla.
e. Cortical sensory deficits such as astereognosis and agraphesthesia with preserved primary sensory modalities imply a cerebral cortical deficit within the territory of the middle cerebral artery. Isolated hemisensory deficits without associated motor involvement are usually lacunar in origin. Crossed sensory deficits result from brainstem lesions in the medulla, as seen in the lateral medullary syndrome (Wallenberg’s syndrome).
f. Hemiataxia usually points to a lesion in the ipsilateral brainstem or cerebellum but can also be produced by lacunae in the internal capsule.
Investigative Studies
A. BLOOD TESTS

These should be obtained routinely to detect treatable causes of stroke and to exclude conditions that can mimic stroke. The recommended studies are listed below.
1. Complete blood count to investigate such possible causes of stroke as thrombocytosis, thrombocytopenia, polycythemia, anemia (including sickle cell disease), and leukocytosis (eg, leukemia).
2. Erythrocyte sedimentation rate to detect elevations indicative of giant cell arteritis or other vasculitides.
3. Serologic assay for syphilis—treponemal assay in blood, such as the FTA-ABS or MHA-TP, or the CSF VDRL test.
4. Serum glucose to document hypoglycemia or hyperosmolar nonketotic hyperglycemia, which can present with focal neurologic signs and thereby masquerade as stroke.
5. Serum cholesterol and lipids to detect elevations that can represent risk factors for stroke.
B. ELECTROCARDIOGRAM (ECG)

An ECG should be obtained routinely to detect unrecognized myocardial infarction or cardiac arrythmias, such as atrial fibrillation, which predispose to embolic stroke.
C. CT SCAN OR MRI

A CT scan or MRI (Figure 9–14) should be obtained routinely to distinguish between infarction and hemorrhage as the cause of stroke, to exclude other lesions (eg, tumor, abscess) that can mimic stroke, and to localize the lesion. CT is usually preferred for initial diagnosis because it is widely available and rapid and can readily make the critical distinction between ischemia and hemorrhage. MRI may be superior to CT scan for demonstrating early ischemic infarcts, showing ischemic strokes in the brainstem or cerebellum, and detecting thrombotic occlusion of venous sinuses.

Figure 9–14. Imaging studies in ischemic stroke in the right middle cerebral artery territory. A: CT scan showing low density and effacement of cortical sulci (between arrowheads) and compression of the anterior horn of the lateral ventricle (arrow). B: T1-weighted MRI scan showing loss of sulcal markings (between arrowheads) and compression of the anterior horn of the lateral ventricle (arrow). C: T2-weighted MRI scan showing increased signal intensity (between arrowheads) and ventricular compression (arrow).

D. LUMBAR PUNCTURE

This should be performed in selected cases to exclude subarachnoid hemorrhage (manifested by xanthochromia and red blood cells) or to document meningovascular syphilis (reactive VDRL) as the cause of stroke.
E. CEREBRAL ANGIOGRAPHY

Intaarterial angiography is used to identify operable extracranial carotid lesions in patients with anterior circulation TIAs who are good surgical candidates. It is also useful in the diagnosis of certain vascular disorders associated with stroke, including vasculitis, fibromuscular dysplasia, and carotid or vertebral artery dissection. Transfemoral arch aortography with selective catheterization of the carotid (and, if indicated, vertebral) arteries is the procedure of choice. Magnetic resonance angiography may detect stenosis of large cerebral arteries, aneurysms, and other vascular lesions, but its sensitivity is generally inferior to that of conventional angiography.
F. ULTRASONOGRAPHY

Doppler ultrasonography can detect stenosis or occlusion of the internal carotid artery, but it lacks the sensitivity of angiography. In cases in which the likelihood of finding operable symptomatic carotid stenosis is insufficient to justify the risk of angiography or in which the risk is especially high because of coexisting illness or the lack of angiographic expertise, the finding of normal carotid blood flow or complete occlusion by Doppler studies can obviate the need for angiography. Transcranial doppler ultrasonography is sometimes used in the evaluation of suspected stenosis of the intracranial internal carotid artery, middle cerebral artery, or basilar artery and for detecting and following the course of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
G. ECHOCARDIOGRAPHY

Echocardiography may be useful for demonstrating the cardiac lesions responsible for embolic stroke in patients with clinically evident cardiac disease, such as atrial fibrillation.
H. ELECTROENCEPHALOGRAM (EEG)

The EEG is rarely useful in evaluating stroke. It may, however, help differentiate between a seizure disorder and TIAs or between lacunar and cortical infarcts in the occasional patient in whom these possibilities cannot otherwise be distinguished.
Differential Diagnosis
In patients presenting with focal central nervous system dysfunction of sudden onset, ischemic stroke must be distinguished from structural and metabolic processes that can mimic it. An underlying process other than focal cerebral ischemia should be suspected when the resulting neurologic deficit does not conform to the distribution of any single cerebral artery. In addition, strokes do not typically impair consciousness in the absence of profound focal deficits, whereas other cerebral disorders may do so.
Vascular disorders mistaken for ischemic stroke include intracerebral hemorrhage, subdural or epidural hematoma, and subarachnoid hemorrhage from rupture of an aneurysm or vascular malformation. These conditions can often be distinguished by a history of trauma or of excruciating headache at onset, by a more marked depression of consciousness, or by the presence of neck stiffness on examination. They can be excluded by CT scan or MRI.
Other structural brain lesions such as tumor or abscess can also produce focal cerebral symptoms of acute onset. Brain abscess is suggested by concurrent fever, and both abscess and tumor can usually be diagnosed by CT scan or MRI. Metabolic disturbances, particularly hypoglycemia and hyperosmolar nonketotic hyperglycemia, may present in strokelike fashion. The serum glucose level should therefore be determined in all patients with apparent stroke.
Treatment
The treatment options commonly available for cerebrovascular disease are summarized in Table 9–4.

Table 9–4. Recommended treatment of cerebrovascular disease.1

A. ASYMPTOMATIC CAROTID BRUIT OR STENOSIS

Carotid bruits are commonly detected during routine examinations of asymptomatic patients, with a frequency that reaches 7% above age 65. Carotid artery stenosis is also common, and can be demonstrated by ultrasonography in as many as 30% of men over age 75. Because the natural history of carotid artery stenosis is variable, the relationship of asymptomatic bruit or stenosis to an individual’s risk for stroke is difficult to assess. In large studies, severe stenosis is associated with increased stroke risk (2.5% per year for ipsilateral stroke with 75% stenosis), but the risk of contralateral stroke is increased as well, and the risk of myocardial ischemia in these patients is even higher. Moreover, carotid endarterectomy—which has been advocated in this setting—carries significant perioperative risk of stroke or death, and this risk varies widely across institutions. Although asymptomatic patients with high-grade carotid stenosis have appeared to benefit from endarterectomy in some studies, this effect was dependent on an extremely low surgical morbidity and mortality rate. For these reasons, antiplatelet therapy with aspirin (see below) is probably the approach of choice for asymptomatic carotid bruit or stenosis at present.
B. TRANSIENT ISCHEMIC ATTACK

Because TIAs can indicate an impending stroke and because it may be possible to prevent such an event by appropriate treatment, TIAs must be accurately and promptly diagnosed and treatment instituted (Table 9–4).

1. Antiplatelet therapy—Of the various medical treatments proposed for stroke prophylaxis in patients with noncardiogenic TIAs, antiplatelet agents appear to have the best benefit-to-risk ratio. The rationale for this approach is that embolism from platelet-fibrin thrombi on arterial surfaces may be responsible for many cases of TIA and stroke. Antiplatelet agents interfere with platelet function by irreversibly inhibiting the enzyme cyclooxygenase-1, which catalyzes the synthesis of thromboxane A2, an eicosanoid with procoagulant and platelet-aggregating properties.
Aspirin, when administered to patients with TIAs or minor stroke (defined as little or no neurologic deficit after 1 week), has been shown to reduce the incidence of subsequent TIAs, stroke, or death in several studies. Although most studies have focused on noncardiogenic TIA or stroke, aspirin is also beneficial for preventing recurrent cerebral ischemia caused by cardiac emboli. In some cases (eg, patients with artificial heart valves), the combination of aspirin and anticoagulation may be more effective than anticoagulation alone. Doses of aspirin between 80 and 1300 mg orally daily (one baby aspirin to four adult aspirin tablets) appear to be effective, and daily oral administration of 325 mg of aspirin is probably used most often in North America. A sex-related difference in benefit favoring men has been observed, but only inconsistently. Administration of low-dose aspirin (325 mg orally every other day) to men age 40 and older without a history of TIA or stroke does not reduce the risk of stroke, although it decreases the incidence of myocardial infarction. Adverse effects of aspirin include dyspepsia, nausea, abdominal pain, diarrhea, skin rash, peptic ulcer, gastritis, and gastrointestinal bleeding.
Ticlopidine (250 mg orally twice daily), another antiplatelet agent, may be somewhat more effective than aspirin in preventing stroke and reducing mortality in patients with TIAs or mild stroke. However, ticlopidine is more expensive than aspirin and appears to be associated with such side effects as diarrhea, skin rash, and occasional cases of severe but reversible neutropenia.
Clopidogrel (75 mg orally daily), which inhibits platelet aggregation by binding irreversibly to adenosine diphosphate (ADP) receptors on the platelet surface, has also been shown to reduce the incidence of ischemic stroke, myocardial infarction, or death from other vascular causes in patients with recent ischemic stroke, myocardial infarction, or symptomatic peripheral arterial disease. Diarrhea and skin rash were more common than with aspirin, but neutropenia and thrombocytopenia occurred at the same rate. Thrombotic thrombocytopenic purpura (see Chapter 1) has complicated clopidogrel treatment in some patients.
Other antiplatelet drugs such as sulfinpyrazone and dipyridamole are commonly used to treat thrombotic vascular disease. Some experts recommend the use of a combination of aspirin (25 mg) and extended-release dipyridamole (200 mg), taken twice daily to prevent stroke in patients with prior TIA or stroke. Glycoprotein IIb/IIIa antagonists are also under investigation as platelet aggregation inhibitors.
2. Anticoagulation—Anticoagulation is indicated for patients with TIAs caused by cardiac embolus and is typically continued indefinitely or for as long as the cause of embolization (eg, atrial fibrillation or prosthetic heart valve) persists. The value of anticoagulation for TIAs from arterial thrombosis is uncertain.
Heparin is the drug of choice for acute anticoagulation, whereas warfarin is used for long-term therapy. Heparin is usually administered by continuous intravenous infusion at 1000–2000 units/h. The activated partial thromboplastin time (aPTT) is measured at least daily, and the dose of heparin is adjusted to maintain the aPTT at about 1.5 to 2.5 times the pretreatment value.
Warfarin (the usual maintenance dose is 5–15 mg/d orally) can be started simultaneously with heparin therapy. About 2 days after the prothrombin time (PT) reaches roughly one and one-half times the pretreatment value (typically about 5 days), heparin can be discontinued. The PT or international normalized ratio (INR) should be measured at least every 2 weeks and the dose of warfarin adjusted to maintain PT = 1.5 times control or INR = 3.0–4.0.
Enthusiasm for the use of anticoagulant therapy should be tempered by an appreciation of its potential hazards. The risk of intracranial hemorrhage is greatest in hypertensive patients and those over 65 years of age.
3. Carotid endarterectomy—Carotid endarterectomy involves the surgical removal of thrombus from a stenotic common or internal carotid artery in the neck. In patients with anterior-circulation TIAs and moderate (50–70%) or high-grade (70–99%) carotid stenosis on the side appropriate to account for the symptoms, the combination of endarterectomy and aspirin is superior to aspirin alone in preventing stroke. Endarterectomy has no place in the treatment of vertebrobasilar TIAs or those related to intracranial arterial disease or complete carotid occlusion. The value of carotid endarterectomy for minimally stenotic but ulcerated carotid lesions is uncertain. The operative mortality rate for carotid endarterectomy has ranged from 1 to 5% or more.
4. Angioplasty and intralumenal stents—Transluminal angioplasty of the carotid and vertebral arteries and surgical placement of tubular metal stents to maintain lumen patency in stenotic cerebral arteries are under investigation. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), in which patients with carotid stenosis were randomized to receive carotid endarterectomy or percutaneous transluminal angioplasty, provided preliminary evidence for the greater safety of angioplasty, but also a higher rate of restenosis. A second phase of the study, the International Carotid Stenting Study (ICSS), is underway to evaluate the efficacy of stenting for symptomatic carotid stenosis.
5. Extracranial-intracranial bypass—Many patients with TIAs referable to the carotid circulation have stenoses in intracranial portions of the artery not accessible through the neck, or they exhibit tandem lesions in both the extracranial and intracranial cerebral circulations. Because carotid endarterectomy does not correct these problems, an alternative approach has been explored involving anastomosis of the extracranial (temporal artery) and intracranial (middle cerebral artery) circulations distal to the stenosis. The bulk of current evidence suggests that this bypass procedure is ineffective.
6. Conclusions—In experienced hands, carotid endarterectomy can be a safe procedure that reduces the risk of subsequent TIAs or stroke in patients with carotid TIAs. Angiography should be used with these patients to define surgically accessible moderate to high-grade (50– 99%) stenotic lesions.
Medical treatment with aspirin should be instituted with both nonsurgical and postoperative patients. For patients who continue to have TIAs despite aspirin treatment, increasing the dose of aspirin, substituting ticlopidine or clopidogrel, or adding sulfinpyrazone or dipyridamole should be considered. Alternatively, a 3-month course of warfarin should be substituted unless there are contraindications such as active peptic ulcer disease or severe hypertension. The prothrombin time should be maintained at one and one-half times the control value (INR = 3.0–4.0). In addition to the above measures, such contributory risk factors as hypertension and cardiac disease should be treated and cigarette smoking discontinued.
C. STROKE IN EVOLUTION

The optimal treatment for stroke in evolution is uncertain. The onset of aspirin’s antiplatelet effect is delayed after oral administration, and endarterectomy also involves considerable delay in treatment.
The most widely used treatment is anticoagulation with heparin and subsequent administration of warfarin at the doses described above, although the efficacy of this approach has not been proved.
Thrombolytic agents such as tissue plasminogen activator might also be of value for stroke in evolution, but require further study in this context.
D. COMPLETED STROKE

1. Intravenous thrombolytic therapy—Tissue plasminogen activator (t-PA) is a serine protease that maps to chromosome 8 (8p12) in humans and catalyzes the conversion of plasminogen to plasmin. This accounts for its ability to lyse fibrin-containing clots such as those found in cerebrovascular thrombotic lesions. Some but not all controlled clinical data suggest that the intravenous administration of recombinant t-PA (rt-PA) within 3 hours of the onset of symptoms reduces disability and mortality from ischemic stroke (technically, from TIA, since stroke is defined by a deficit that persists for at least 24 hours). The drug is administered at a dose of 0.9 mg/kg, up to a maximum total dose of 90 mg; 10% of the dose is given as an intravenous bolus and the remainder as a continuous intravenous infusion over 60 minutes. The efficacy of rt-PA given more than 3 hours after symptoms begin, of other thrombolytic agents such as urokinase, or of intraarterial administration of these agents has not been demonstrated in stroke.
The major complication of rt-PA treatment is hemorrhage, which may affect the brain or other tissues. The lack of proven benefit when rt-PA is given after 3 hours, the risk of bleeding complications, and the importance of a correct diagnosis when treatment is potentially dangerous dictate that rt-PA not be given in certain settings. It is important that the time of onset of symptoms can be established with confidence. The CT scan should not already show evidence of a large ischemic stroke or of hemorrhage. Patients whose coagulation function has been compromised by the administration of warfarin or heparin or by thrombocytopenia (platelet count <100,000/mm3) should not receive rt-PA, nor should those who are at increased risk of hemorrhage because of seizures at the onset of symptoms, prior intracranial hemorrhage, another intracranial disorder (including stroke or trauma) within 3 months, a major surgical procedure within 14 days, bleeding from the gastrointestinal or urinary tract within 21 days, or marked hypertension (systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg). To avoid treating TIAs that are already resolving or other conditions unlikely to respond to rt-PA, or for which the risk exceeds likely benefit, patients whose deficits are improving rapidly and spontaneously, patients with mild and isolated deficits, and those with blood glucose concentrations consistent with a hypo- or hypergycemic origin of symptoms (<50 mg/dl or >400 mg/dl) should be excluded.
Patients receiving rt-PA for stroke should be managed in facilities in which the capacity exists to diagnose stroke with a high degree of certainty and to manage bleeding complications. Within the first 24 hours after administration of rt-PA, anticoagulants and antiplatelet agents should not be given, blood pressure should be carefully monitored, and arterial puncture and placement of central venous lines, bladder catheters, and nasogastric tubes should be avoided.
2. Intraarterial thrombolytic therapy—Intraarterial administration of urokinase, prourokinase, or rt-TPA has also been investigated for the acute treatment of stroke. Early results with this approach suggest that prourokinase, and perhaps the other thrombolytic agents, given together with low-dose intravenous heparin, may be beneficial for patients with middle cerebral artery distribution stroke who can be treated within 3–6 hours of the onset of symptoms. Less is known about the benefit of intraarterial thrombolytic therapy for vertebrobasilar stroke, and about the comparative efficacy of intravenous and intrarterial thrombolysis.
3. Antiplatelet agents—As noted above in discussing the treatment of TIAs, some but not all studies have shown a decrease in the incidence of subsequent stroke when aspirin is administered chronically following a stroke. The regimen is as described in the section on treatment of TIA.
4. Anticoagulation—Anticoagulation has not been shown to be useful in most cases of completed stroke. An exception is where a persistent source of cardiac embolus is present; anticoagulation is then indicated to prevent subsequent embolic strokes, although it does not affect the course of the stroke that has already occurred. Recent evidence indicates that although immediate anticoagulation of such patients may result in hemorrhage into the infarct, this rarely affects the ultimate outcome adversely unless the infarct is massive. The risk of hemorrhage is more than offset by the particularly high risk of recurrent embolization soon after an embolic stroke, and anticoagulation should not be delayed in this setting. Heparin and warfarin are administered as described in the section on treatment of TIA.
5. Surgery—The indications for surgical treatment of completed stroke are extremely limited. When patients deteriorate as a consequence of brainstem compression following cerebellar infarction, however, posterior fossa decompression with evacuation of infarcted cerebellar tissue can be lifesaving.
6. Antihypertensive agents—Although hypertension contributes to the pathogenesis of stroke and many patients with acute stroke have elevated blood pressures, attempts to reduce the blood pressure in stroke patients can have disastrous results, since the blood supply to ischemic but as yet uninfarcted brain tissue may be further compromised. Therefore, such attempts should not be made. In the usual course of events, the blood pressure declines spontaneously over a period of hours to a few days.
7. Antiedema agents—Antiedema agents such as mannitol and corticosteroids have not been shown to be of benefit for cytotoxic edema (cellular swelling) associated with cerebral infarction.
8. Neuroprotective agents—A variety of drugs with diverse pharmacologic actions have been proposed as neuroprotective agents that might reduce ischemic brain injury by decreasing cerebral metabolism or interfering with the cytotoxic mechanisms triggered by ischemia. These include barbiturates, the opioid antagonist naloxone, voltage-gated calcium channel antagonists, and excitatory amino acid receptor antagonists. Thus far, however clinical trials with these agents have yielded disappointing results.
Prognosis
Outcome following stroke is influenced by a number of factors, the most important being the nature and severity of the resulting neurologic deficit. The patient’s age, the cause of stroke, and coexisting medical disorders also affect prognosis. Overall, somewhat less than 80% of patients with stroke survive for at least 1 month, and 10-year survival rates in the neighborhood of 35% have been cited. The latter figure is not surprising, considering the advanced age at which stroke commonly occurs. Of patients who survive the acute period, about one-half to two-thirds regain independent function, while approximately 15% require institutional care.
INTRACEREBRAL HEMORRHAGE
Hypertensive Hemorrhage
Hypertension is the most common underlying cause of nontraumatic intracerebral hemorrhage.
A. PATHOPHYSIOLOGY

1. Cerebral autoregulation—Autoregulation of cerebral blood flow (Figure 9–15), which is achieved by changes in the caliber of small resistance cerebral arteries, maintains constant cerebral blood flow as systemic blood pressure rises and falls. The range of autoregulated blood pressures is variable.

Figure 9–15. Cerebrovascular autoregulation. A: Cerebral blood flow is maintained in the normal range over a wide range of blood pressures. At very low pressures, cerebral hypoperfusion occurs, producing syncope. Pressures that rise beyond the autoregulatory range can cause hypertensive encephalopathy. B: Structural changes in cerebral arteries shift the autoregulatory range to higher blood pressures. Hypoperfusion and syncope can occur at normal pressures, and pressures associated with hypertensive encephalopathy are increased.

In normotensive individuals, the lowest mean blood pressure at which autoregulation is effective is approximately 60 mm Hg. Below this level, changes in the caliber of cerebral arteries cannot compensate for decreased perfusion pressure; cerebral blood flow therefore declines, producing symptoms of hypoxia, such as lightheadedness, confusion, and dimming of vision. These symptoms are followed by somnolence and loss of consciousness if the mean blood pressure falls below 35–40 mm Hg. In contrast, at blood pressures above the upper limit of the range of autoregulation (150–200 mm Hg), cerebral blood flow is increased, which can produce hypertensive encephalopathy.
In chronically hypertensive individuals, the lower limit of the autoregulatory range is higher (Figure 9–15), which may be due to damage to small arterial walls. As a result, cerebral blood flow declines when the mean arterial blood pressure falls below about 120 mm Hg. The clinical relevance of this observation is that blood pressure should be reduced rarely, if ever—and never to hypotensive levels—in patients with stroke.
2. Chronic hypertension—Chronic hypertension appears to promote structural changes in the walls of penetrating arteries, predisposing them to intracerebral hemorrhage. In 1888, Charcot and Bouchard found minute aneurysms on the small intraparenchymal arteries of hypertensive patients and postulated that aneurysmal rupture led to intracerebral hemorrhage. Subsequently, Ross Russell showed microaneurysms of small resistance arteries in cerebral sites at which hypertensive hemorrhages occur most commonly. Some aneurysms were surrounded by small areas of hemorrhage, and the aneurysmal walls often showed changes of lipohyalinosis or fibrinoid necrosis. These processes are characterized by destruction of the vessel wall with deposition of fibrinoid material, focal aneurysmal expansion of the involved vessel, thrombotic occlusion, and extravasation of red cells. There is now general agreement that massive cerebral hemorrhage often follows the rupture of either a microaneurysmal or lipohyalinotic segment of a small resistance artery and that the underlying lesion is caused by chronic hypertension.
3. Acute hypertension—In addition to structural changes in the cerebral arterial wall produced by chronic hypertension, acute elevation of blood pressure appears to play a role in the pathogenesis of intracerebral hemorrhage. Although most patients with intracerebral hemorrhage are hypertensive following the event, many have no history of hypertension and lack such signs of hypertensive end-organ disease as left ventricular hypertrophy, retinopathy, or nephropathy. It has therefore been suggested that a sudden increase in blood pressure may itself be sufficient to cause intracerebral hemorrhage, as with amphetamine or cocaine abuse. Acute elevation of blood pressure may also be the immediate precipitating cause of intracerebral hemorrhage in chronically hypertensive patients with Charcot-Bouchard aneurysms.
B. PATHOLOGY

Most hypertensive hemorrhages originate in certain areas of predilection, corresponding to long, narrow, penetrating arterial branches along which Charcot-Bouchard aneurysms are found at autopsy (Figure 9–16). These include the caudate and putaminal branches of the middle cerebral arteries (42%); branches of the basilar artery supplying the pons (16%); thalamic branches of the posterior cerebral arteries (15%); branches of the superior cerebellar arteries supplying the dentate nuclei and the deep white matter of the cerebellum (12%); and some white matter branches of the cerebral arteries (10%), especially in the parietooccipital and temporal lobes.

Figure 9–16. Distribution of Charcot-Bouchard aneurysms (stippling) underlying hypertensive intracerebral hemorrhage.

C. CLINICAL FINDINGS

Hypertensive hemorrhage occurs without warning, most commonly while the patient is awake. Headache is present in 50% of patients and may be severe; vomiting is common. Blood pressure is elevated after the hemorrhage has occurred. Thus, normal or low blood pressure in a patient with stroke makes the diagnosis of hypertensive hemorrhage unlikely, as does onset before 50 years of age.
Following the hemorrhage, edema surrounding the area of hemorrhage produces clinical worsening over a period of minutes to days. The duration of active bleeding, however, is brief. Once the deficit stabilizes, improvement occurs slowly. Because the deficit is caused principally by hemorrhage and edema, which compress rather than destroy brain tissue, considerable return of neurologic function can occur.
Massive hypertensive hemorrhages may rupture through brain tissue into the ventricles, producing bloody CSF; direct rupture through the cortical mantle is unusual. A fatal outcome is most often due to herniation caused by the combined mass effect of the hematoma and the surrounding edema.
Clinical features vary with the site of hemorrhage (Table 9–5).

Table 9–5. Clinical features of hypertensive intracerebral hemorrhage.

1. Deep cerebral hemorrhage—The two most common sites of hypertensive hemorrhage are the putamen and the thalamus, which are separated by the posterior limb of the internal capsule. This segment of the internal capsule is traversed by descending motor fibers and ascending sensory fibers, including the optic radiations (Figure 9–17). Pressure on these fibers from an expanding lateral (putaminal) or medial (thalamic) hematoma produces a contralateral sensorimotor deficit. In general, putaminal hemorrhage leads to a more severe motor deficit and thalamic hemorrhage to a more marked sensory disturbance. Homonymous hemianopia may occur as a transient phenomenon after thalamic hemorrhage and is often a persistent finding in putaminal hemorrhage. In large thalamic hemorrhages, the eyes may deviate downward, as in staring at the tip of the nose, because of impingement on the midbrain center for upward gaze. Aphasia may occur if hemorrhage at either site exerts pressure on the cortical language areas. A separate aphasic syndrome has been described with localized hemorrhage into the thalamus; it carries an excellent prognosis for full recovery.

Figure 9–17. Anatomic relationships in deep cerebral hemorrhage. Top: Plane of section. Bottom: Putaminal (1) and thalamic (2) hemorrhages can compress or transect the adjacent posterior limb of the internal capsule. Thalamic hemorrhages can also extend into the ventricles or compress the hypothalamus or midbrain upgaze center (3).

2. Lobar hemorrhage—Hypertensive hemorrhages also occur in subcortical white matter underlying the frontal, parietal, temporal, and occipital lobes. Symptoms and signs vary according to the location; they can include headache, vomiting, hemiparesis, hemisensory deficits, aphasia, and visual field abnormalities. Seizures are more frequent than with hemorrhages in other locations, while coma is less so.
3. Pontine hemorrhage—With bleeding into the pons, coma occurs within seconds to minutes and usually leads to death within 48 hours. Ocular findings typically include pinpoint pupils. Horizontal eye movements are absent or impaired, but vertical eye movements may be preserved. In some patients, there may be ocular bobbing, a bilateral downbeating excursion of the eyes at about 5-second intervals. Patients are commonly quadriparetic and exhibit decerebrate posturing. Hyperthermia is sometimes present. The hemorrhage usually ruptures into the fourth ventricle, and rostral extension of the hemorrhage into the midbrain with resultant midposition fixed pupils is common. In contrast to the classic presentation of pontine hemorrhage described above, small hemorrhages that spare the reticular activating system—and that are associated with less severe deficits and excellent recovery—also occur.
4. Cerebellar hemorrhage—The distinctive symptoms of cerebellar hemorrhage (headache, dizziness, vomiting, and the inability to stand or walk) begin suddenly, within minutes after onset of bleeding. Although patients may initially be alert or only mildly confused, large hemorrhages lead to coma within 12 hours in 75% of patients and within 24 hours in 90%. When coma is present at the onset, the clinical picture is indistinguishable from that of pontine hemorrhage.
Common ocular findings include impairment of gaze to the side of the lesion or forced deviation away from the lesion caused by pressure on the pontine lateral gaze center. Skew deviation may also occur, in which case the eye ipsilateral to the lesion is depressed. The pupils are small and reactive. Ipsilateral facial weakness of lower motor neuron type occurs in about 50% of cases, but strength in the limbs is normal. Limb ataxia is usually slight or absent. Plantar responses are flexor early in the course but become extensor as the brainstem becomes compromised and the patient deteriorates. Impairment of voluntary or reflex upward gaze indicates upward transtentorial herniation of the cerebellar vermis and midbrain, leading to compression of the pretectum. It implies a poor prognosis.
D. DIFFERENTIAL DIAGNOSIS

Putaminal, thalamic, and lobar hypertensive hemorrhages may be difficult to distinguish from cerebral infarctions. To some extent, the presence of severe headache, nausea and vomiting, and impairment of consciousness are useful clues that a hemorrhage may have occurred; the CT scan (Figure 9–18) identifies the underlying disorder definitively.

Figure 9–18. CT scan in hypertensive intracerebral hemorrhage. Blood is seen as a high-density signal at the site of hemorrhage in the thalamus (left arrow) and extends into the third ventricle (top arrow) and the occipital horns of the ipsilateral (bottom arrow) and contralateral (right arrow) lateral ventricles.

Brainstem stroke or cerebellar infarction can mimic cerebellar hemorrhage. When cerebellar hemorrhage is a possibility, CT scan or MRI is the most useful diagnostic procedure, since hematomas can be quickly and accurately localized. If neither CT nor MRI is available, vertebral angiography should be performed. The angiogram shows a cerebellar mass effect in about 85% of cases, but the procedure is time consuming. Bloody CSF will confirm the diagnosis of hemorrhage, but a clear tap does not exclude the possibility of an intracerebellar hematoma—and lumbar puncture may hasten the process of herniation. Lumbar puncture is therefore not advocated if a cerebellar hemorrhage is suspected.
Like cerebellar hemorrhage, acute peripheral vestibulopathy also produces nausea, vomiting, and gait ataxia. Severe headache, impaired consciousness, elevated blood pressure, or later age at onset, however, strongly favors cerebellar hemorrhage.
E. TREATMENT

1. Surgical measures
a. Cerebellar decompression—The most important therapeutic intervention in hypertensive hemorrhage is surgical decompression for cerebellar hematomas. Unless this step is taken promptly, there may be a fatal outcome or unexpected deterioration. Note that this procedure may also reverse the neurologic deficit. Because surgical results are much better for responsive than unresponsive patients, surgery should be performed early in the course when the patient is still conscious.
b. Cerebral decompression—Surgery can be useful when a superficial hemorrhage in the cerebral white matter is large enough to cause a mass effect with shift of midline structures and incipient herniation. The prognosis is directly related to the level of consciousness before the operation, and surgery is usually fruitless in an already comatose patient.
c. Contraindications to surgery—Surgery is not indicated for pontine or deep cerebral hypertensive hemorrhages, because in most cases spontaneous decompression occurs with rupture into the ventricles—and the areas in question are accessible only at the expense of normal overlying brain.
2. Medical measures—The use of antihypertensive agents in acute intracerebral hemorrhage is controversial. Attempts to lower systemic blood pressure may compromise cerebral blood flow and lead to infarction, but continued hypertension may exacerbate cerebral edema. On this basis, it seems reasonable to lower blood pressure to diastolic levels of approximately 100 mm Hg following intracerebral hemorrhage, but this must be done with great care because the cerebral vasculature may be unusually sensitive to antihypertensive agents. The use of nitroglycerin paste (½–1 in. topically) has an advantage—if the blood pressure declines excessively, the drug can be wiped off the skin and its effect rapidly terminated. If volume overload is considered to contribute to the hypertension, the judicious use of a diuretic such as furosemide (from 10 mg intravenously in patients unused to the drug to 40 mg intravenously in patients accustomed to receiving it) can be helpful.
There is no other effective medical treatment for intracerebral hemorrhage. Rebleeding at the site of a hypertensive intracerebral hemorrhage is uncommon, and antifibrinolytic agents are not indicated. Corticosteroids are commonly prescribed to reduce vasogenic edema in patients with intracerebral hemorrhage, but the evidence of their benefit is poor. Antiedema agents provide only temporary benefit.
Other Causes of Intracerebral Hemorrhage
A. TRAUMA

Intracerebral hemorrhage is a frequent consequence of closed-head trauma. Such hemorrhages may occur under the skull at the site of impact or directly opposite the site of impact (contrecoup injury). The most common locations are the frontal and temporal poles. The appearance of traumatic hemorrhages on CT scans may be delayed for as much as 24 hours after injury; MRI permits earlier detection.
B. VASCULAR MALFORMATIONS

Bleeding from cerebral angiomas and aneurysms can lead to both intracerebral and subarachnoid hemorrhage. Angiomas may come to medical attention because of seizures, in which case anticonvulsants are the treatment of choice, or because of bleeding. In the latter instance, surgical removal is indicated to prevent rebleeding—provided the malformation is surgically accessible. Aneurysms usually present with intracranial hemorrhage but occasionally with compressive focal deficits such as third-nerve palsy. Their treatment is considered in Chapter 2.
C. HEMORRHAGE INTO CEREBRAL INFARCTS

Some cases of cerebral infarction, especially when embolic in origin, are accompanied by hemorrhage into the infarct.
D. AMPHETAMINE OR COCAINE ABUSE

Intravenous, intranasal, and oral amphetamine or cocaine use can result in intracerebral hemorrhage, which typically occurs within minutes to hours after the drug is administered. Most such hemorrhages are located in subcortical white matter and may be related to either acute elevation of blood pressure, leading to spontaneous hemorrhage or rupture of a vascular anomaly, or drug-induced arteritis.
E. CEREBRAL AMYLOID ANGIOPATHY

Cerebral amyloid (congophilic) angiopathy is a rare cause of intracerebral hemorrhage. Amyloid deposits are present in the walls of small cortical blood vessels and in the meninges. The disorder is most common in elderly patients (a mean age of 70 years) and typically produces lobar hemorrhages at multiple sites. Some cases are familial.
F. ACUTE HEMORRHAGIC LEUKOENCEPHALITIS

This is a demyelinating and hemorrhagic disorder that characteristically follows a respiratory infection and has a fulminant course resulting in death within several days. Multiple small hemorrhages are found in the brain, and red blood cells may be present in the CSF.
G. HEMORRHAGE INTO TUMORS

Bleeding into primary or metastatic brain tumors is an occasional cause of intracerebral hemorrhage. Tumors associated with hemorrhage include glioblastoma multiforme, melanoma, choriocarcinoma, renal cell carcinoma, and bronchogenic carcinoma. Bleeding into a tumor should be considered when a patient with known cancer experiences acute neurologic deterioration; it may also be the presenting manifestation of cancer.
H. COAGULOPATHIES

Intracerebral hemorrhage is a complication of disorders of both clotting factors and platelets, such as hemophilia (factor VIII deficiency) and idiopathic thrombocytopenic purpura. Acute myelogenous leukemia with white blood cell counts greater than 150,000/µL may also predispose to intracerebral hemorrhage.
I. ANTICOAGULATION

Patients receiving heparin or warfarin are at increased risk for developing spontaneous or traumatic intracerebral hemorrhage.
GLOBAL CEREBRAL ISCHEMIA
Etiology
Global cerebral ischemia occurs when the blood flow is inadequate to meet the metabolic requirements of the brain, as in cardiac arrest. The result is a spectrum of neurologic disorders. The greater severity of neurologic involvement in ischemia than in pure anoxia may be due to the fact that in the former condition, the delivery of glucose and removal of potentially toxic metabolites are also impaired.
Pathology
Neuropathologic changes depend on the degree and duration of cerebral ischemia.
A. DISTRIBUTION

Complete interruption of cerebral blood flow followed by reperfusion, such as occurs in cardiac arrest with resuscitation, produces damage that selectively affects metabolically vulnerable neurons of the cerebral cortex, basal ganglia, and cerebellum.
With less profound hypotension for prolonged periods, the damage is concentrated in the anatomically vulnerable border zones between the territories supplied by the major arteries of cerebral cortex, cerebellum, basal ganglia, and spinal cord. It is most severe in the watershed region between the territories supplied by the anterior, middle, and posterior cerebral arteries (Figure 9–19).

Figure 9–19. Distribution of watershed cerebral infarctions (blue areas).

B. MODIFYING FACTORS

Reducing cerebral energy requirements, such as with deep anesthesia or hypothermia, can minimize or prevent brain damage from ischemic insults. Hyperglycemia or hypermetabolic states such as status epilepticus, on the other hand, can increase ischemic damage. Superimposed occlusive atherosclerotic disease of the craniocervical arteries may lead to asymmetries in the distribution of cerebral damage from panhypoperfusion.
Clinical Findings
A. BRIEF ISCHEMIC EPISODES

Reversible encephalopathies are common following brief episodes of systemic circulatory arrest. In such cases, coma persists for less than 12 hours. Transient confusion or amnesia may occur on awakening, but recovery is rapid and complete. Some patients show a severe anterograde and variable retrograde amnesia and a bland, unconcerned affect with or without confabulation. Recovery often occurs within 7–10 days but may be delayed by 1 month or longer. This syndrome may reflect reversible bilateral damage to the thalamus or hippocampus.
B. PROLONGED ISCHEMIC EPISODES

1. Focal cerebral dysfunction—Patients are usually comatose for at least 12 hours and may have lasting focal or multifocal motor, sensory, and cognitive deficits if they awaken. Full recovery may not occur or may require weeks to months. Some patients are eventually capable of leading an independent existence, whereas those who are more severely disabled may require institutional care.
Focal neurologic signs after cardiac arrest include partial or complete cortical blindness, weakness of both arms (bibrachial paresis), and quadriparesis. Cortical blindness is usually transient but can rarely be permanent. It probably results from disproportionate ischemia of the occipital poles because of their location in the border zone between the middle and posterior cerebral arteries (see Figure 9–19). Bibrachial paresis (man-in-a-barrel syndrome) results from bilateral infarction of the motor cortex in the border zone between the anterior and middle cerebral arteries (see Figure 9–19).
2. Persistent vegetative state—Some patients who are initially comatose following cardiac arrest survive and awaken but remain functionally decorticate and unaware of their surroundings. They typically regain spontaneous eye-opening, sleep-wake cycles, and roving eye movements and brainstem and spinal cord reflexes. The persistent vegetative state is thus distinct from coma and appears to be associated with destruction of the neocortex. A persistent vegetative state associated with an isoelectric (flat) EEG is termed neocortical death. Persistent vegetative states must be distinguished from brain death (see Chapter 10), in which both cerebral and brainstem function are absent.
3. Spinal cord syndromes—The spinal cord seems to be more resistant to transient ischemia than the brain, so that cord damage from hypoperfusion is usually accompanied by profound cerebral involvement. Hypoperfusion does occasionally lead to isolated spinal cord infarction, however. In such cases, the anterior and central structures of the spinal cord are more involved because of their location in the critical border zones between territories supplied by the anterior and posterior spinal arteries (see Chapter 5). These watersheds, especially in the upper and lower levels of the thoracic cord, are vulnerable to profound drops in perfusion pressure. In the acute period, spinal stroke from hypotension produces a flaccid paraplegia and urinary retention. The sensory level in the thoracic region is characterized more by marked impairment of pain and temperature sensation than of light touch. With time, flaccid paralysis is replaced by spastic paraplegia with brisk tendon reflexes in the legs and extensor plantar responses.
Treatment
A. ESTABLISHED MEASURES

The clinical management of patients in coma caused by global cerebral ischemia involves immediate restoration of adequate cerebral circulation, elimination of cardiac dysrhythmias, maintenance of effective systemic blood pressure, and correction of acid-base or electrolyte abnormalities. Ventilatory assistance may be necessary if either medullary depression or injury to the chest wall prevents adequate ventilation, and supplemental oxygen can also be administered.
Beyond these measures, there are no other uniformly satisfactory methods of treatment. Attempts to prevent cerebral edema in this setting have not been successful, and treatment with corticosteroids, dehydrating agents, calcium channel antagonists, hypothermia, and hyperventilation have not improved the prognosis.
B. EXPERIMENTAL MEASURES

Although barbiturates have a protective effect in some experimental models of global cerebral ischemia, a similar benefit does not appear to occur in patients.
Excitatory amino acid receptor antagonists may find application in the treatment of cerebral anoxic ischemia but are at present experimental. The rationale for considering the use of these drugs lies in existing evidence that ischemia or hypoxia may trigger the release of excitatory amino acid neurotransmitters, which may in turn interact with vulnerable neurons to promote cell death.
CHAPTER REFERENCES
General
Barnett HJM et al: Stroke: Pathophysiology, Diagnosis and Management, 3rd ed. WB Saunders, 1998.
Epidemiology
Berger K et al: Light-to-moderate alcohol consumption and the risk of stroke among US male physicians. N Engl J Med 1999; 341:1557–1564.
Bousser MG, Kittner SJ: Oral contraceptives and stroke. Cephalalgia 2000;20:183–189.
Elkind MS, Sacco RL: Stroke risk factors and stroke prevention. Semin Neurol 1998;18:429–440.
Gillum RF: Stroke mortality in blacks: disturbing trends. Stroke 1999;30:1711–1715.
Kittner SJ et al: Pregnancy and the risk of stroke. N Engl J Med 1996;335:768–774.
Sagie A, Larson MG, Levy D: The natural history of borderline isolated systolic hypertension. N Engl J Med 1993;329:1912– 1917.
White HD et al: Pravastatin therapy and the risk of stroke. N Engl J Med 2000;343:317–326.
Focal Cerebral Ischemia
Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999;22:391– 397.
Graham SH, Chen J: Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab 2001;21:99–109.
Sharp FR et al: Multiple molecular penumbras after focal cerebral ischemia. J Cereb Blood Flow Metab 2000;20:1011–1032.
Tatu L et al: Arterial territories of human brain: brainstem and cerebellum. Neurology 1996;47:1125–1135.
Atherosclerosis
Lusis AJ: Atherosclerosis. Nature 2000;407:233–241.
Russell, R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–126.
Other Vascular Causes
Ferro JM: Vasculitis of the central nervous system. J Neurol 1998; 245:766–776.
Haller CA, Benowitz NL: Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833– 1838.
Ikeda H et al: Mapping of a familial moyamoya disease gene to chromosome 3p24.2–p26. Am J Hum Genet 1999;64:533– 537.
Kernan WN et al: Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826–1832.
Neiman J, Haapaniemi HM, Hillbom M: Neurological complications of drug abuse: pathophysiological mechanisms. Eur J Neurol 2000;7:595–606.
Pantoni L, Garcia JH: Pathogenesis of leukoaraiosis: a review. Stroke 1997;28:652–659.
Schievink WI: Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;344:898–906.
Tzourio C et al: Migraine and stroke in young women. Cephalalgia. 2000;20:190–199.
Welch GN, Loscalzo J: Homocysteine and atherothrombosis. N Engl J Med 1998;338:1042–1050.
Cardiac Causes
Babikian VL, Caplan LR: Brain embolism is a dynamic process with variable characteristics. Neurology 2000;54:797–801.
Falk R H: Atrial fibrillation. N Engl J Med 2001;344:1067–1078.
Gilon D et al: Lack of evidence of an association between mitral-valve prolapse and stroke in young patients. N Engl J Med 1999;341:8–13.
Maggioni AP et al: The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. N Engl J Med 1992;327:1–6.
Hematologic Causes
Adams RJ et al: Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial doppler ultrasonography. N Engl J Med 1998;339: 5–11.
Medical Treatment
Albers GW et al: Antithrombotic and thrombolytic therapy for ishemic stroke. Chest 2001;119:300S–320S.
Bath PMW, Iddenden R, Bath FJ: Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials. Stroke 2000;31:1770–1778.
Bednar MM, Gross CE: Antiplatelet therapy in acute cerebral ischemia. Stroke 1999;30:887–893.
Brott T, Bogousslavsky J: Treatment of acute ischemic stroke. N Engl J Med 2000;343:710–722.
CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339.
International Stroke Trial Collaborative Group: The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997;349:1569–1581.
Kwiatkowski TG et al: Effects of tissue plasminogen activator for acute ischemic stroke at one year. N Engl J Med 1999; 340:1781–1787.
Lyden PD et al: Intravenous thrombolysis for acute stroke. Neurology 1997;49:14–20.
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–1587.
Powers WJ: Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology 1993;43:461–467.
Report of the Quality Standards Subcommittee of the American Academy of Neurology: Practice advisory: Thrombolytic therapy for acute ischemic stroke—summary statement. Neurology 1996;47:835 –839.
Ridker PM et al: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979.
Surgical Treatment
Barnett HJM et al: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998;339:1415–1425.
European Carotid Surgery Trialists’ Collaborative Group: Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379–1387.
Wong JH et al: Regional performance of carotid endarterectomy: Appropriateness, outcomes, and risk factors for complications. Stroke 1997;28:891–898.
Prognosis
Sacco RL: Risk factors and outcomes for ischemic stroke. Neurology 1995;45:S10–14.
Intracerebral Hemorrhage
Brilstra EH et al: Treatment of intracranial aneurysms by embolization with coils: a systematic review. Stroke 1999;30:470– 476.
Fernandes HM et al: Surgery in intracerebral hemorrhage: the uncertainty continues. Stroke 2000;31:2511–2516.
Qureshi AI et al: Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344:1450–1460.
Global Cerebral Ischemia
Hossmann KA: Reperfusion of the brain after global ischemia: hemodynamic disturbances. Shock 1997;8:95–101.
White BC et al: Global brain ischemia and reperfusion. Ann Emerg Med 1996;27:588–594.