Chapter 13: Stroke

Stroke is the fifth leading cause of death in the United States (after heart disease, cancer, chronic lung disease, and injuries and accidents) and the most common disabling neurologic disorder. Approximately 800,000 new strokes occur and approximately 130,000 people die from stroke in the United States each year.

The incidence of stroke increases with age; approximately two-thirds of all strokes occur in those older than 65 years. Modifiable risk factors for stroke include systolic or diastolic hypertension, atrial fibrillation, diabetes, dyslipidemia, physical inactivity, and obstructive sleep apnea (Table 13-1). Genetic, usually polygenic, factors also contribute to stroke risk. The incidence of stroke has decreased in recent decades, largely because of improved treatment of hypertension, dyslipidemia, and diabetes and reduction in smoking.

Stroke is a syndrome with four key features:

1. Sudden onset—The sudden onset of symptoms is documented by the history.

2. Focal involvement of the central nervous system—The site of involvement is suggested by symptoms and signs, pinpointed more precisely by neurologic examination, and confirmed by imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]).

3. Lack of rapid resolution—The duration of neurologic deficits is documented by the history. The classic definition of stroke requires that deficits persist for at least 24 hours (to distinguish stroke from transient ischemic attack, discussed later). However, any such time point is arbitrary, and transient ischemic attacks usually resolve within 1 hour.

4. Vascular cause—A vascular cause 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. Investigative studies can often identify a more specific etiology, such as arterial thrombosis, cardiogenic embolus, or clotting disorder.

ACUTE ONSET

Strokes begin abruptly. Neurologic deficits may be maximal at onset or may progress over seconds to hours (or occasionally days).

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 13-1).

Focal cerebral deficits that develop slowly (over weeks to months) suggest a cause other than stroke, such as tumor or inflammatory or degenerative disease.

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.

Global cerebral ischemia (usually from cardiac arrest) and subarachnoid hemorrhage (discussed in Chapter 6, Headache & Facial Pain) affect the brain in more diffuse fashion and produce global cerebral dysfunction; the term stroke is not usually applied in these cases.

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.

ANTERIOR (CAROTID) CIRCULATION

The anterior cerebral circulation supplies most of the cerebral cortex and subcortical white matter, basal ganglia, and internal capsule. It 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 13-2). The specific territory of each of these vessels is listed in Table 13-2.

Anterior circulation strokes are commonly associated with symptoms and signs of hemispheric dysfunction (Table 13-3), such as aphasia, apraxia, or agnosia (described in Chapter 1, Neurologic History & Examination). They also often produce hemiparesis, hemisensory disturbances, and visual field defects, but these can occur with posterior circulation strokes as well.

POSTERIOR (VERTEBROBASILAR) CIRCULATION

The posterior cerebral circulation supplies the brainstem, cerebellum, 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 13-2). The posterior cerebral artery also gives off thalamoperforate and thalamogeniculate branches. Areas supplied by these arteries are listed in Table 13-2.

Posterior circulation strokes produce symptoms and signs of brainstem or cerebellar dysfunction or both (see Table 13-3), 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.

DURATION OF DEFICITS

Stroke produces neurologic deficits that persist. When symptoms and signs resolve completely after brief periods (usually within 1 hour) without evidence of cerebral infarction, the term transient ischemic attack (TIA) is used (see Figure 13-1). About 15% of strokes are preceded by TIAs. Recurrent TIAs with identical clinical features (stereotypic TIAs) are usually caused by thrombosis or embolism arising from the same site within the cerebral circulation. TIAs that differ in character from event to event suggest recurrent emboli from distant (eg, cardiac) or multiple sites. Although TIAs do not themselves produce lasting neurologic dysfunction, they are important to recognize because 3-10% of patients with TIAs will have a stroke within 2 days and 9-17% will have a stroke within 90 days—and because this risk may be reduced with treatment.

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 vascular disease.

The underlying pathologic process in stroke can be either ischemia or hemorrhage, usually arising from an arterial lesion. Ischemia and hemorrhage account for approximately 90% and 10% of strokes, respectively. It may not be possible to distinguish the two by history and neurologic examination, but CT scan or MRI permits definitive diagnosis. Among ischemic strokes, about 35% are attributed to large artery occlusion, 25% to small artery occlusion, 20% to cardiac embolism, 15% to unknown causes (cryptogenic), and 5% to other processes.

ISCHEMIA

Interruption of blood flow to the brain deprives neurons, glia, and vascular cells of glucose and oxygen. Unless blood flow is promptly restored, this leads to death of brain tissue (infarction) within the ischemic core, where flow is typically less than 20% of normal. The pattern of cell death depends on the severity of ischemia. With mild ischemia, as in cardiac arrest with rapid reperfusion, selective vulnerability of certain neuronal populations may be observed. More severe ischemia produces selective neuronal necrosis, in which most or all neurons die but glia and vascular cells are preserved. Complete, permanent ischemia, such as occurs in stroke without reperfusion, causes pannecrosis, affecting all cell types and resulting in chronic cavitary lesions.

Where ischemia is incomplete (20-40% of normal blood flow)—as in the ischemic border zone or penumbra—cell damage is potentially reversible and cell survival may be prolonged. However, unless blood flow is restored, by recanalization of the occluded vessel or collateral circulation from other vessels, reversibly damaged cells begin to die as well, and the infarct expands. Death of penumbral tissue is associated with a worse clinical outcome.

Brain edema is another determinant of stroke outcome. Ischemia leads to vasogenic edema as fluid leaks from the intravascular compartment into brain parenchyma. Edema is usually maximal approximately 2 to 3 days after stroke and may be sufficiently severe that it produces a mass effect that causes herniation (displacement of brain tissue between intracranial compartments) and death.

Two pathogenetic mechanisms can produce ischemic stroke—thrombosis and embolism. However, the distinction is often difficult or impossible to make on clinical grounds.

Thrombosis

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.

Embolism

Embolism produces stroke when cerebral arteries are occluded by the distal passage of clot 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, because most hemispheric blood flow is through 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 often 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 because different vascular territories are affected.

HEMORRHAGE

Hemorrhage may interfere with cerebral function through a variety of mechanisms, including destruction or compression of brain tissue, compression of vascular structures, 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.

Intracerebral Hemorrhage

Intracerebral hemorrhage causes symptoms by destroying or compressing brain tissue. Unlike ischemic stroke, intracerebral hemorrhage tends to cause more severe headache and depression of consciousness, as well as neurologic deficits that do not necessarily correspond to the distribution of any single blood vessel.

Subarachnoid Hemorrhage

Subarachnoid hemorrhage leads to cerebral dysfunction due to increased intracranial pressure, resulting hypoperfusion, direct destruction of tissue, and toxic constituents of subarachnoid blood. 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 usually presents with headache rather than focal neurologic deficits, and is therefore discussed in Chapter 6, Headache & Facial Pain.

Subdural or Epidural Hemorrhage

Subdural or epidural hemorrhage produces a mass lesion that can compress the underlying brain. These hemorrhages are typically traumatic in origin and usually present with headache or altered consciousness. Because of their importance as causes of coma, subdural and epidural hemorrhages are discussed in Chapter 3, Coma.

PATHOPHYSIOLOGY

The pathophysiology of focal cerebral ischemia is complex, as it evolves over time, affects the brain nonuniformly, and targets multiple cell types. Nevertheless, several potentially important underlying mechanisms have been identified, some of which are likely to operate early and others later in the course of stroke. Moreover, some mechanisms contribute to ischemic injury, whereas others promote tissue survival or repair.

INJURY MECHANISMS

Energy Failure

Neurons rely on oxidative metabolism to generate adenosine triphosphate (ATP) for their high energy demands. Reduction of blood flow interferes with the delivery of two key substrates for this process—oxygen and glucose—causing ATP levels to fall. Cells can compensate to a limited extent by generating ATP via glycolysis but, without prompt reperfusion, they cease to function and eventually die. Like other ischemic injury mechanisms, energy failure is most pronounced in the ischemic core and less so in the surrounding penumbra.

Ion Gradients

A major use of cellular energy is the maintenance of transmembrane ion gradients. With energy failure, these are dissipated. Na⁺/K⁺-ATPase, which accounts for the majority of neuronal energy expenditure and is responsible for maintaining high intracellular K⁺ concentrations, fails to do so. K⁺ leaks from cells and depolarizes adjacent cells, activating voltage-gated ion channels and neurotransmitter release. Extracellular K⁺ and neurotransmitter glutamate trigger cortical spreading depression, leading to further neuron and astrocyte depolarization. This consumes additional energy and may extend the infarct.

Calcium Dysregulation

Intracellular Ca²⁺ is normally maintained at low levels, but ischemic elevation of extracellular K⁺ causes membrane depolarization and triggers influx of extracellular Ca²⁺ into neurons. Catabolic enzymes are activated, mitochondrial function is compromised, and cell death pathways are mobilized.

Excitotoxicity

Excitotoxicity refers to the neurotoxic effects of excitatory neurotransmitters, especially glutamate. Ischemia promotes excitotoxicity by stimulating neuronal glutamate release, reversing astrocytic glutamate uptake, and activating glutamate receptor-coupled ion channels. Influx of Ca²⁺ through these channels contributes to Ca²⁺ dysregulation and activates neuronal nitric oxide synthase, generating potentially neurotoxic nitric oxide.

Oxidative & Nitrosative Injury

Some toxic effects of ischemia are mediated by highly reactive oxidative and nitrosative compounds, including superoxide and nitric oxide, which act primarily during the reperfusion phase that follows ischemia. Their effects include inhibiting mitochondrial enzymes and function, damaging DNA, activating ion channels, causing covalent modification of proteins, and triggering cell death pathways.

Cell Death Cascades

Ischemic cell death occurs most rapidly in the infarct core and more slowly in the penumbra and during reperfusion. Rapid cell death involves necrosis, in which cells and organelles swell, membranes rupture, and cellular contents spill into the extracellular space, whereas more delayed (programmed) cell death (eg, apoptosis) predominates in the penumbra and during reperfusion.

Inflammation

Cerebral ischemia triggers an inflammatory response that involves both resident and blood-borne cells of the innate immune system. The former include astrocytes and microglia, and the latter neutrophils, lymphocytes, and monocytes. Adaptive immune responses emerge later in the course. Molecular mediators of ischemia-induced inflammation include adhesion molecules, cytokines, chemokines, and proteases. Although the early inflammatory response to ischemia exacerbates injury, subsequent inflammatory events may be neuroprotective or contribute to repair.

SURVIVAL & REPAIR MECHANISMS

Collateral Circulation

The first line of defense against ischemia is collateral circulation, which, if adequate, can bypass an arterial occlusion. The cerebral circulation contains numerous collateral pathways, accounting for the observation that patients with total occlusion of a major vessel are sometimes asymptomatic. However, this is not always the case, especially when occlusion is abrupt. Collateral routes for cerebral blood flow during arterial occlusion include the following:

1. Bilateral vertebral artery occlusion—anterior spinal artery

2. Common carotid artery occlusion—contralateral common carotid artery via ipsilateral external carotid artery or vertebral artery via ipsilateral occipital artery

3. Internal carotid artery occlusion—ipsilateral external carotid artery via ophthalmic artery or circle of Willis

4. Middle cerebral artery occlusion—ipsilateral anterior or posterior cerebral artery via leptomeningeal anastomoses

Inhibitory Neurotransmitters

Enhanced tonic inhibition mediated through extrasynaptic GABA_A receptors may mitigate excitotoxic injury early in the course of stroke. However, persistent inhibition may impair recovery.

Transcriptional Hypoxia Response

Hypoxia activates transcription of proteins that promote cell survival and tissue recovery, including glycolytic enzymes, erythropoietin, and vascular endothelial growth factor. Other cytoprotective proteins induced after ischemia include antiapoptotic proteins, growth factors, and heat-shock proteins.

Neurogenesis

Cerebral ischemia stimulates neurogenesis and some new neurons migrate to ischemic brain regions. Here they may promote survival and repair by releasing growth factors, suppressing inflammation, or other effects.

Angiogenesis

Ischemia also stimulates capillary sprouting to enhance local blood supply. The impact of this process (angiogenesis) in the acute phase of stroke is uncertain, but it may help to protect against subsequent ischemic episodes.

Ischemic Tolerance

Ischemia may provide paradoxical protection against subsequent ischemia through ischemic tolerance, in which mild ischemia preconditions brain tissue and confers relative ischemia resistance. Ischemic tolerance involves extensive changes in gene expression and numerous molecular mediators.

Repair Mechanisms

Most patients recover to some extent after stroke, reflecting a capacity for spontaneous postischemic repair and the brain’s innate plasticity. Plastic changes occur in the peri-infarct region and at remote sites, such as the contralateral cerebral hemisphere, and include changes in gene expression, increased neuronal excitability, axonal sprouting, synaptogenesis, somatotopic reorganization, and formation of new neuronal circuits.

PATHOLOGY

LARGE ARTERY OCCLUSION

On gross inspection, a recent infarct from large artery occlusion is a swollen, softened area of brain that usually involves both gray and white matter (Figure 13-3). 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. Perivascular hemorrhages may be observed. Depending on the interval between infarction and death, cerebral edema may also be present. Edema is maximal during the first 4-5 days after stroke and can cause herniation of the cingulate gyrus across the midline or of the temporal lobe below the tentorium (see Chapter 3, Coma). In the chronic phase, the infarct site appears as a cavitary lesion.

SMALL ARTERY OCCLUSION

Infarcts from small artery occlusion rarely cause death, so only chronic lesions are usually found at autopsy. These include lacunes, or small cavities up to ~15 mm in diameter, usually located in subcortical white (eg, internal capsule) or deep gray (eg, basal ganglia or thalamus) matter (Figure 13-4); white matter (including periventricular) lesions showing punctate or confluent myelin rarefaction, gliosis, and axonal loss; and microbleeds. Small vessel occlusion may be associated with atherosclerosis, lipohyalinosis (collagenous thickening and inflammation of the vessel wall), or fibrinoid necrosis (vessel-wall destruction with perivascular inflammation).

CLINICAL-ANATOMIC CORRELATION

Infarction in the distribution of different cerebral arteries produces distinctive clinical syndromes, which can facilitate anatomic and etiologic diagnosis and help guide treatment.

ANTERIOR CEREBRAL ARTERY

Anatomy

The anterior cerebral artery supplies the parasagittal cerebral cortex (Figures 13-5 and 13-6), which includes portions of motor and sensory cortex related to the contralateral leg, the so-called bladder inhibitory or micturition center, and the anterior corpus callosum.

Clinical Syndrome

Anterior cerebral artery strokes produce contralateral paralysis and sensory loss exclusively or primarily affecting the leg. There may also be abulia (apathy), disconnection syndromes such as the alien hand (involuntary performance of complex motor activity), transcortical expressive aphasia (see Chapter 1, Neurologic History & Examination), and urinary incontinence.

MIDDLE CEREBRAL ARTERY

Anatomy

The middle cerebral artery supplies most of the remainder of the cerebral hemisphere and deep subcortical structures (see Figures 13-5 and 13-6). Cortical branches include the superior division, which supplies motor and sensory representation of the face, hand, and arm, and the expressive language (Broca) area of the dominant hemisphere (Figure 13-7). The inferior division supplies the visual radiations, visual cortex related to macular vision, and the receptive language (Wernicke) area of the dominant hemisphere. Lenticulostriate branches of the most proximal portion (stem) of the middle cerebral artery supply the basal ganglia and motor fibers to the face, hand, arm, and leg as they descend in the genu and posterior limb of the internal capsule.

Clinical Syndrome

Depending on the site of involvement, several clinical syndromes can occur.

1. Superior division stroke results in contralateral hemiparesis that affects the face, hand, and arm but spares the leg, and contralateral hemisensory deficit in the same distribution, but no homonymous hemianopia. If the dominant hemisphere is involved, there is Broca (expressive) aphasia, which is characterized by impaired language expression with intact comprehension.

2. Inferior division stroke results in contralateral homonymous hemianopia that may be denser inferiorly, impaired cortical sensory functions (eg, graphesthesia and stereognosis) on the contralateral side of the body, and disorders of spatial thought (eg, anosognosia [unawareness of deficit], neglect of the contralateral limbs and contralateral side of external space, dressing apraxia, and constructional apraxia). If the dominant hemisphere is involved, Wernicke (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.

3. Occlusion at the bifurcation or trifurcation of the middle cerebral artery combines the features of superior and inferior division stroke, including contralateral hemiparesis and hemisensory deficit involving the face and arm more than leg, homonymous hemianopia, and—if the dominant hemisphere is affected—global (combined expressive and receptive) aphasia.

4. Occlusion of the stem of the middle cerebral artery occurs proximal to the origin of the lenticulostriate branches, resulting in a clinical syndrome similar to that seen after occlusion at the trifurcation. In addition, however, involvement of the internal capsule causes paralysis of the contralateral leg, so hemiplegia and sensory loss affect the face, hand, arm, and leg.

INTERNAL CAROTID ARTERY

Anatomy

The internal carotid artery arises at the bifurcation of the common carotid artery in the neck. In addition to the anterior and middle cerebral arteries, it also gives rise to the ophthalmic artery, which supplies the retina.

Clinical Syndrome

Internal carotid artery occlusion may be asymptomatic, or cause strokes of highly variable severity, depending on the adequacy of collateral circulation. Symptomatic occlusion results in a syndrome similar to that of middle cerebral artery stroke (contralateral hemiplegia, hemisensory deficit, and homonymous hemianopia, together with aphasia if the dominant hemisphere is involved). Monocular blindness is also common.

POSTERIOR CEREBRAL ARTERY

Anatomy

The paired posterior cerebral arteries arise from the tip of the basilar artery (Figure 13-8) and supply the occipital cerebral cortex, medial temporal lobes, posterior corpus callosum, thalamus, and rostral midbrain. Emboli in the basilar artery tend to lodge at its apex and occlude one or both posterior cerebral arteries; subsequent fragmentation can produce asymmetric or patchy posterior cerebral artery infarction.

Clinical Syndrome

Posterior cerebral artery occlusion produces homonymous hemianopia affecting the contralateral visual field, except that macular vision may be spared. 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 occlusion near the origin of the posterior cerebral artery at the level of the midbrain, ocular abnormalities may occur, including vertical gaze palsy, oculomotor (III) nerve palsy, internuclear ophthalmoplegia, and vertical skew deviation of the eyes. Involvement of the occipital lobe of the dominant hemisphere may cause anomic aphasia (difficulty in naming objects), alexia without agraphia (inability to read without impairment of writing), or visual agnosia. The last is 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 inability to recognize familiar faces (prosopagnosia), as well as a variety of exotic visual and behavioral syndromes.

BASILAR ARTERY

Anatomy

The basilar artery arises from the junction of the paired vertebral arteries (see Figure 13-8) and 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. Branches of the basilar artery supply the occipital and medial temporal lobes, medial thalamus, posterior limb of the internal capsule, brainstem, and cerebellum.

Clinical Syndromes

1. Thrombosis—Thrombotic occlusion of the basilar artery or both vertebral arteries (see Figure 13-8) is often incompatible with survival. It causes bilateral symptoms and signs of brainstem and cerebellar dysfunction from involvement of multiple branch arteries (Figure 13-9). Temporary occlusion of one or both vertebral arteries, leading to transient brainstem dysfunction, can also result from rotating the head in patients with cervical spondylosis.

   Basilar thrombosis usually affects the proximal basilar artery (see Figure 13-8), which supplies the pons. Involvement of the dorsal pons (tegmentum) 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 due to involvement of descending sympathetic pupillodilator fibers, but may be reactive. Hemiplegia or quadriplegia is usually present, and coma is common. A CT or MRI brain scan will differentiate between basilar occlusion and pontine hemorrhage.

   In some patients, the ventral pons (basis pontis) is infarcted and the tegmentum is spared. Such patients remain conscious but quadriplegic (locked-in syndrome). Locked-in patients may be able to open or move their eyes vertically on command. A normal conventional electroencephalogram (EEG) further distinguishes the locked-in state from coma (see Chapter 3, Coma).

   Stenosis or occlusion of the subclavian artery proximal to the origin of the vertebral artery can lead to the subclavian steal syndrome, in which blood is diverted from the vertebral artery into the distal subclavian artery with physical activity of the ipsilateral arm. The resulting brainstem ischemia can mimic basilar thrombosis, but is not predictive of stroke.

2. Embolism—Emboli in the basilar artery usually lodge at its apex (see Figure 13-8). Interruption of blood flow to the ascending reticular formation in 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 results from involvement of the cerebral peduncles in the midbrain. Thus, the top of the basilar syndrome may be confused with midbrain damage caused by transtentorial uncal herniation. Less commonly, an embolus may lodge more proximally, 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 (see Figure 13-8). In such cases, portions of the midbrain, thalamus, and temporal and occipital lobes can be infarcted. Patients may display 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.

LONG CIRCUMFERENTIAL VERTEBROBASILAR BRANCHES

Anatomy

The long circumferential branches of the vertebral and basilar arteries are the posterior inferior cerebellar, anterior inferior cerebellar, and superior cerebellar arteries (see Figure 13-2). They supply the dorsolateral brainstem, including dorsolateral cranial nerve nuclei (V, VII, and VIII) and pathways entering and leaving the cerebellum in the cerebellar peduncles.

Clinical Syndromes

Occlusion of a circumferential branch produces infarction in the dorsolateral medulla or pons.

1. Posterior inferior cerebellar artery occlusion results in the lateral medullary (Wallenberg) syndrome (see Chapter 8, Disorders of Equilibrium). The presentation varies, but can include ipsilateral cerebellar ataxia, Horner 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.

2. Anterior inferior cerebellar artery occlusion leads to infarction of the lateral portion of the caudal pons and produces many of the same features. Horner syndrome, dysphagia, dysarthria, and hiccup do not occur, but ipsilateral facial weakness, gaze palsy, deafness, and tinnitus are common.

3. Superior cerebellar artery occlusion causes lateral rostral pontine infarction and resembles anterior inferior cerebellar artery lesions, but impaired optokinetic nystagmus (nystagmus evoked by tracking a moving object) or skew deviation (vertical dysconjugacy) of the eyes may occur, hearing is unaffected, and contralateral sensory loss may involve touch, vibration, and position as well as pain and temperature sense.

LONG PENETRATING PARAMEDIAN VERTEBROBASILAR BRANCHES

Anatomy

Long penetrating paramedian arteries supply the medial brainstem, including the medial portion of the cerebral peduncle, sensory pathways, red nucleus, reticular formation, and midline cranial nerve nuclei (III, IV, VI, XII).

Clinical Syndrome

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 oculomotor (III) nerve palsy, which may be associated with contralateral tremor or ataxia from involvement of pathways connecting the red nucleus and cerebellum. Ipsilateral abducens (VI) and facial (VII) nerve palsies are seen with lesions in the pons, and hypoglossal (XII) nerve involvement may occur with lesions in the medulla.

SHORT BASAL VERTEBROBASILAR BRANCHES

Anatomy

Short branches arising from the long circumferential arteries (discussed previously) penetrate the ventral brainstem to supply the brainstem motor pathways.

Clinical Syndrome

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.

LACUNAR INFARCTION

Anatomy

Small vessel occlusion affecting penetrating arteries deep in the brain may cause infarcts in the putamen or, less commonly, the thalamus, caudate nucleus, pons, posterior limb of the internal capsule, or other sites (Figure 13-10). These are referred to as lacunar infarcts or lacunes.

Clinical Syndromes

Many lacunar infarcts are not recognized clinically and are detected only as incidental findings on imaging studies or at autopsy. In other cases, however, they produce distinctive clinical syndromes. Lacunar strokes develop over hours to days. Headache is absent or minor, and the level of consciousness is unchanged. Hypertension and diabetes are thought to predispose to lacunar stroke, but these and other cardiovascular risk factors may be absent. The prognosis for recovery from a lacunar stroke is good, but recurrent stroke is common. Although a variety of deficits can be produced, there are four classic and distinctive lacunar syndromes.

1. Pure motor hemiparesis consists of hemiparesis affecting the face, arm, and leg to a roughly equal extent, without associated disturbance of sensation, vision, or language. Lacunes that produce this syndrome are usually located in the contralateral internal capsule or pons. Pure motor hemiparesis also may be caused by internal carotid or middle cerebral artery occlusion, subdural hematoma, or intracerebral mass lesions.

2. Pure sensory stroke 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, sometimes called ipsilateral ataxia and crural (leg) paresis, comprises pure motor hemiparesis combined with ataxia of the hemiparetic side and usually affects the leg predominantly. Symptoms result from a lesion in the contralateral pons, internal capsule, or subcortical white matter.

4. Dysarthria-clumsy hand syndrome consists of dysarthria, facial weakness, dysphagia, and mild weakness and clumsiness of the hand on the side of facial involvement. Lacunes causing this syndrome are located 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 earlier, premonitory TIAs are unusual.

ETIOLOGY

Focal cerebral ischemia can result from underlying disorders that primarily affect the blood, blood vessels, or heart (Table 13-4).

VASCULAR DISORDERS

Atherosclerosis

Atherosclerosis of the large extracranial arteries in the neck and at the base of the brain and of smaller intracranial arteries is the most common cause of focal cerebral ischemia. Within the cerebral circulation, the sites of predilection (Figure 13-11) 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.

The pathogenesis of atherosclerosis is incompletely understood, but endothelial cell dysfunction is thought to be an early step (Figure 13-12). This tends to occur at sites of low or disturbed blood flow, such as curvatures and branch points of large and medium-sized arteries. Endothelial dysfunction allows adhesion and subendothelial migration of circulating monocytes and intramural accumulation of lipids. Inflammation ensues, and engulfment of lipids by monocyte-derived macrophages produces lipid-laden foam cells, which contribute to an early atheromatous lesion, the fatty streak.

At this stage, growth and chemotactic factors released by endothelial cells and macrophages stimulate proliferation of intimal smooth muscle cells and migration of additional smooth muscle cells to the intima from the tunica media. These cells secrete extracellular matrix constituents, leading to the formation of a fibrous cap over the atherosclerotic plaque, in which a necrotic core develops (Figure 13-13). In some cases, fractures in the cap lead to plaque rupture, a serious complication associated with the release of procoagulant factors and subsequent thrombosis. Possible outcomes include thrombotic occlusion of the vessel lumen or embolization.

Major risk factors for atherosclerosis leading to stroke include systolic or diastolic hypertension, elevated serum LDL cholesterol, and diabetes mellitus. Treatment of atherosclerotic cerebrovascular disease is discussed under Prevention & Treatment later in this chapter.

Hypertension

Hypertension, commonly (but not universally) defined as systemic blood pressure >140 mm Hg systolic or >90 mm Hg diastolic, is a major risk factor for stroke. Screening and treatment for hypertension have had key roles in reducing stroke incidence in recent decades. Blood pressure should be measured with the patient seated and relaxed for 5 minutes before three readings are taken at 1-minute intervals, and calculated as the average of the last two readings. Values obtained in the clinic may be confounded by sampling error or patient anxiety, however, leading to spuriously low (masked hypertension) or high (white coat hypertension) readings. Consequently, 24-hour ambulatory or automated unattended blood pressure measurement is sometimes used to improve diagnostic accuracy.

Chronic hypertension causes degenerative changes in the walls of small arteries and arterioles; such changes include lipohyalinosis (collagenous thickening and inflammation) and fibrinoid necrosis (degeneration with perivascular inflammation). In the cerebral circulation, these effects are most pronounced in penetrating small arteries and arterioles of the subcortical white matter, basal ganglia, thalamus, pons, and cerebellum. Hypertensive vascular disease predisposes to both ischemic stroke (see Lacunar Infarction earlier in this chapter) and intracerebral hemorrhage (see Hypertensive Hemorrhage later in this chapter).

Diabetes

Type 1 and type 2 diabetes mellitus is associated with an increased risk of both ischemic stroke and intracerebral hemorrhage. Diabetes affects large and medium-sized arteries, which exacerbates atherosclerosis, as well as small arteries and arterioles, such as those involved in lacunar infarction (discussed earlier in this chapter). It has been difficult to demonstrate a beneficial effect of glycemic control on stroke incidence in diabetics, but treatment of diabetes is indicated to prevent other adverse effects. Antihypertensive drugs and statins can reduce stroke risk in diabetic as in non-diabetic patients.

Vasculitis

Vasculitis is an uncommon cause of stroke but is important to recognize because it is treatable. Stroke can result from either primary central nervous system vasculitis or systemic vasculitis, and may be the earliest manifestation of the disease.

1. Primary central nervous system vasculitis is an idiopathic inflammatory disease that affects small arteries and veins in the brain and spinal cord and can cause transient or progressive multifocal ischemia. Clinical features include headache, hemiparesis and other focal neurologic abnormalities, and cognitive disturbances. The cerebrospinal fluid (CSF) may show elevated protein and lymphocytic pleocytosis, but the erythrocyte sedimentation rate is typically normal. Diagnosis is by angiography, which shows focal and segmental narrowing of small arteries and veins, or brain biopsy. Differential diagnosis includes reversible cerebral vasoconstriction syndrome (discussed later in this chapter). Treatment is discussed in Chapter 4, Confusional States.

2. Giant cell (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 stimulate platelet adhesion and aggregation, 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. Giant cell arteritis should be considered in patients with transient monocular blindness or transient cerebral ischemic attacks—especially the elderly—because corticosteroid therapy can prevent its complications, notably permanent blindness. Treatment is discussed in Chapter 6, Headache & Facial Pain.

3. Systemic lupus erythematosus is associated with a vasculopathy that involves small cerebral vessels and leads to multiple microinfarcts, but true vasculitis is absent. Libman-Sacks endocarditis accompanying systemic lupus may also be a source of cardiogenic emboli.

4. 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.

5. Syphilitic arteritis occurs within 5 years after primary syphilitic infection and may cause stroke. Medium-sized penetrating vessels are typically involved (Figure 13-14), producing punctate infarcts in the deep cerebral white matter that can be seen on CT scan or MRI. Treatment (discussed in Chapter 4) is important to prevent tertiary neurosyphilis (general paresis or tabes dorsalis).

6. AIDS is associated with an increased incidence of TIAs and ischemic stroke. In some cases, cerebrovascular complications of AIDS are related to endocarditis or opportunistic infections, such as toxoplasmosis or cryptococcal meningitis.

Other Vasculopathies

1. Fibromuscular dysplasia produces segmental medial fibroplasia of large (especially renal, carotid, and vertebral) arteries and is associated with arterial dissection (see below) and aneurysms. Familial cases suggest autosomal dominant inheritance with incomplete penetrance. Stroke is most common in children and young and middle-aged adults, especially females. A characteristic “string-of-beads” appearance on angiography is diagnostically helpful. Symptomatic carotid artery disease is usually treated with antiplatelet drugs and intraluminal dilation of the affected vessel.

2. Carotid or vertebral artery dissection may occur spontaneously or in response to minor trauma, and is most common in middle age. It results from medial degeneration followed by hemorrhage into the vessel wall, and causes stroke by occluding the vessel or predisposing to thromboembolism. Carotid dissection may be accompanied by prodromal transient hemispheric ischemia or monocular blindness, jaw or neck pain, visual abnormalities that mimic those seen in migraine, or Horner syndrome. Vertebral dissection may produce headache, neck pain, and signs of brainstem dysfunction. Treatment is with antiplatelet drugs, sometimes combined with endovascular repair.

3. Multiple progressive intracranial arterial occlusions (moyamoya) produce bilateral narrowing or occlusion of the distal internal carotid arteries and adjacent anterior and middle cerebral artery trunks. Reactive arteriogenesis leads to a fine network of collateral channels at the base of the brain, which can be seen by angiography (Figure 13-15). Moyamoya may be idiopathic (moyamoya disease) or due to atherosclerosis, sickle cell disease, or other arteriopathies. It is most common in children and middle-aged adults, and more common in females than males, but occurs in all ethnic groups, and may be sporadic or inherited. Children tend to present with ischemic strokes and adults with intracerebral, subdural, or subarachnoid hemorrhage. Treatment includes antiplatelet drugs and surgical revascularization procedures.

4. Drug abuse, especially involving cocaine, amphetamines, other stimulants (eg, phenylpropanolamine, ephedrine, or ecstasy), or heroin, is a risk factor for stroke. Intravenous drug users may develop infective endocarditis leading to embolic stroke, but stroke also occurs in drug users without endocarditis, including those who take drugs only orally, intranasally, or by inhalation. In these cases, stroke typically has its onset within hours of drug use. Cocaine hydrochloride and amphetamines are most often associated with intracerebral hemorrhage, whereas stroke from alkaloidal (crack) cocaine use is usually ischemic; proposed mechanisms include drug-induced endothelial dysfunction leading to a prothrombotic state, vasospasm, rupture of preexisting aneurysms or vascular malformations, and vasculitis. Stroke has also been reported after use of synthetic cannabinoids.

5. Migraine with (but not without) aura is a rare cause of ischemic stroke, most common in women, patients less than 65 years old, smokers, and oral contraceptive users. Both thrombotic and cardioembolic mechanisms have been proposed. Migraineurs exhibit a higher incidence of subclinical white matter lesions in the posterior circulation, patent foramen ovale, and cervical artery dissection, but their relationship to clinical stroke is uncertain. Sporadic or familial (autosomal dominant) hemiplegic migraine is associated with focal cerebral edema during attacks and with cerebellar atrophy, but not with stroke.

6. Reversible cerebral vasoconstriction syndrome is characterized by recurrent thunderclap headache (excruciating pain that reaches peak severity within 1 minute of onset), multifocal construction of cerebral arteries and, in most cases, spontaneous resolution within 3 months. Women are affected more often than men, and recent use of vasoconstrictor drugs, especially serotonergic antidepressants, is common. Focal neurologic symptoms and signs, including hemiparesis, aphasia, visual disturbances and seizures are present in about one-half of cases. CT or MRI may show multiple lesions, including hemispheric borderzone infarctions, subarachnoid hemorrhage, intracerebral hemorrhage and vasogenic edema. Angiography is abnormal bilaterally, with concentric smooth tapering and segmental dilatation the most frequent findings. Cerebrospinal fluid is usually normal. Treatment is with nimodipine (eg, 60 mg orally every 4-8 hours for 4-12 weeks); corticosteroids appear to be unhelpful and possibly harmful. Differential diagnosis includes primary central nervous system vasculitis (discussed earlier in this chapter) and aneurysmal subarachnoid hemorrhage (see Chapter 6, Headache & Facial Pain), but neither produces recurrent thunderclap headache. Borderzone infarction or vasogenic edema on CT or MRI also argues against these diagnoses.

7. Venous or sinus thrombosis (Figure 13-16) is an uncommon cause of stroke. It affects young women most often and may be associated with a predisposing condition, such as otitis or sinusitis, pregnancy and the puerperium, dehydration, cancer, 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 show edema, infarct, hemorrhage, or filling defect in the superior sagittal sinus (delta sign). MRI with MR angiography is the most definitive diagnostic test. Treatment is with anticoagulants and, for septic thrombosis, antibiotics.

8. Rare Mendelian disorders may also be associated with stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), due to mutations in the NOTCH3 gene, produces small-vessel strokes, migraine, encephalopathy, and seizures. Both small- and large-vessel strokes can be seen with mutations in α-galactosidase A (Fabry disease, X-linked recessive); ATP-binding cassette, subfamily C, member 6 (pseudoxanthoma elasticum, autosomal recessive); neurofibromin (neurofibromatosis 1, autosomal dominant); and cystathionine β-synthase (homocystinuria, autosomal recessive). Arterial dissection leading to stroke may complicate autosomal dominant mutations in the type 3 collagen α-1 chain (Ehlers–Danlos syndrome, type IV) or fibrillin-1 (Marfan syndrome).

CARDIAC DISORDERS

Atrial Fibrillation

Atrial fibrillation is common: its prevalence increases with age and reaches ~5% by 65 years. Formerly associated with rheumatic heart disease, it is now usually due to ischemic or hypertensive heart disease. Atrial fibrillation increases stroke risk 2- to 7-fold and, when valvular heart disease is also present, about 17-fold. Additional risk factors include age >75 years, hypertension or diabetes, and heart failure. Atrial fibrillation predisposes to embolic stroke from thrombi that form in the left atrial appendage due to stasis of blood. Treatment is with oral anticoagulants (see Prevention & Treatment later in this chapter). Tachycardia-bradycardia (sick sinus) syndrome is also associated with cardioembolic stroke, whereas most other arrhythmias are more likely to cause pancerebral hypoperfusion and syncope (see Chapter 12, Seizures & Syncope).

Myocardial Infarction

Myocardial infarction is followed by stroke, usually cardioembolic, within 1 month in ~2.5% of patients. Factors associated with increased risk include left ventricular dysfunction with low cardiac output, left ventricular thrombus or aneurysm, and atrial fibrillation. Treatment with aspirin, other antiplatelet drugs, warfarin, or combinations of these may reduce the risk of stroke after myocardial infarction, but is also associated with a risk for bleeding.

Prosthetic Heart Valves

Patients with prosthetic heart valves are at increased risk for embolic stroke, which varies with the composition and location of the valve. Mechanical valves present the highest risk and require chronic administration of warfarin, with or without aspirin. Transcatheter valves are associated with fewer thromboembolic complications, and antiplatelet treatment with low-dose aspirin and clopidogrel for 6 months after valve replacement is thought to be adequate. Bioprosthetic (bovine or porcine) valves are the least thrombogenic and are usually managed with a 3-month course of warfarin or low-dose aspirin. Mitral valve prostheses are generally associated with a higher risk of thromboembolic complications than are aortic valve prostheses.

Dilated Cardiomyopathy

Dilated cardiomyopathy can be caused by genetic disorders (eg, muscular dystrophies), drugs (eg, alcohol or cytotoxic agents), viral infection, or autoimmunity. Stroke results from embolization of intraventricular thrombi, but additional factors (eg, atrial fibrillation or valvular heart disease) may help account for this association. Neither antiplatelet therapy nor anticoagulation has been shown to be of clear benefit for patients with dilated cardiomyopathy in normal sinus rhythm.

Rheumatic Mitral Stenosis

Stroke incidence is increased in patients with rheumatic heart disease—particularly those with mitral stenosis and atrial fibrillation. Definitive diagnosis is by transthoracic or transesophageal echocardiography. Treatment includes anticoagulation and, for severe symptomatic stenosis, percutaneous mitral balloon valvuloplasty or surgical valve repair or replacement.

Infective Endocarditis

Infective (bacterial or fungal) endocarditis is associated with a 25-50% incidence of systemic embolization. Up to two-thirds of embolic events affect the brain, typically within the middle cerebral artery distribution. Factors that predispose to infectious endocarditis include intravenous drug use, hemodialysis, intravenous catheterization, valvular heart disease, and prosthetic heart valves. Staphylococcus aureus and Streptococcus viridans are the most common organisms in patients with native valves and in community-acquired endocarditis, whereas Staphylococcus aureus predominates in intravenous drug users, hospital-acquired infections, and recent recipients of prosthetic heart valves. Fungal endocarditis is rare, is usually caused by Candida or Aspergillus, and has a worse prognosis.

The risk of embolization in infectious endocarditis is highest with mitral valve infection and with fastidious gram-negative organisms (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, or Kingella). Infectious endocarditis can cause cardioembolic stroke or intracerebral or subarachnoid hemorrhage from rupture of a mycotic aneurysm, which are most common before or soon after the onset of antibiotic treatment.

Signs of infective endocarditis include heart murmur, petechiae, subungual splinter hemorrhages, retinal Roth spots (red spots with white centers), Osler nodes (painful red or purple digital nodules), Janeway lesions (red macules on the palms or soles), and clubbing of the fingers or toes. Diagnosis is by culturing the responsible organism from the blood and imaging vegetations with echocardiography. Treatment is with antibiotics and, for recurrent emboli or large left-sided valvular vegetations, valve repair or replacement surgery. Anticoagulation, thrombolytics, and initiation of antiplatelet agents should be avoided because of the risk of intracranial hemorrhage, although long-term antiplatelet therapy may be continued in some cases if bleeding complications are absent.

Nonbacterial Thrombotic Endocarditis

Nonbacterial thrombotic (marantic) endocarditis is most frequent in patients with cancer and causes the majority of ischemic strokes in this population. The tumors most often associated with this type of stroke are adenocarcinomas of the lung, gastrointestinal tract, or prostate. Vegetations are present on the mitral or aortic valves, but associated murmurs are rare. Vegetations may be detected by transesophageal echocardiography, but failure to demonstrate vegetations does not exclude the diagnosis. Aspirin, other antiplatelet agents, and anticoagulation all appear to reduce the risk of recurrent thromboembolic events after stroke in patients with cancer.

Atrial Myxoma

Atrial myxoma, a rare benign tumor of the heart, can cause embolic stroke, especially when located in the left atrium. It usually presents in young patients and is more common in females. Multiple, bihemispheric strokes may be seen. Atrial myxoma can also obstruct left ventricular outflow, causing syncope. Diagnosis is by echocardiography. Treatment consists of surgical resection of the tumor and, in some cases, anticoagulation or antiplatelet drugs.

Paradoxical Embolus

Congenital anomalies associated with pathologic communication between the right and left sides of the heart, such as patent foramen ovale and atrial or ventricular septal defect, may permit “paradoxical” passage of emboli from the systemic venous circulation to the brain. However, patent foramen ovale is common, and its presence does not necessarily imply a causal link to stroke (see Cryptogenic Stroke later in this chapter).

HEMATOLOGIC DISORDERS

Hemoglobinopathies

1. Sickle cell (hemoglobin S) disease results from a GLU6VAL mutation in the hemoglobin β chain gene and most commonly affects patients of West African descent. The mutation causes sickle-shaped deformation of erythrocytes when the partial pressure of oxygen in blood is reduced, resulting in vascular stasis and endothelial injury. Clinical features include hemolytic anemia and vascular occlusions, which may be extremely painful (sickle cell crisis). Homozygotes are more severely affected than heterozygotes.

   Cerebrovascular complications of sickle cell disease occur in both children and adults and include silent cerebral infarction, ischemic stroke (usually involving the intracranial internal carotid or proximal middle or anterior cerebral artery), aneurysmal subarachnoid hemorrhage, and cerebral venous or sinus thrombosis. Increased cerebral blood flow velocity on transcranial Doppler studies (which should be performed annually from age 2-16 years) can identify patients at increased risk, who may benefit from chronic transfusion therapy to maintain hemoglobin S levels <30%.

   Stroke in patients with sickle cell disease should not be assumed to be due to the hemoglobinopathy, and alternative causes (eg, cardiogenic embolus) should be sought. Acute treatment includes administration of supplemental oxygen, intravenous fluids to correct dehydration, and exchange transfusion to achieve a hemoglobin level of 10 g/L and hemoglobin S level <30%. Patients who satisfy criteria for anticoagulation or thrombolysis (see Prevention & Treatment later in this chapter) should be treated accordingly. Secondary prevention in patients with prior stroke involves blood transfusion every 3-4 weeks to reduce hemoglobin S levels to <30%. Hydroxyurea may be employed as an alternative or adjunct to transfusion.

2. β-Thalassemia can result from a variety of autosomal recessive mutations that interfere with synthesis of the hemoglobin β chain. It is most common in Mediterranean and certain South Asian populations. The disease is clinically heterogeneous, with earlier onset and more severe (β-thalassemia major) and later onset and less severe (β-thalassemia intermedia) phenotypes. Both are associated with a hypercoagulable state and splenectomy-induced thrombocytosis, which may predispose to stroke. Clinically overt ischemic stroke is more common in β-thalassemia major and silent cerebral infarction in β-thalassemia minor. Antiplatelet agents and blood transfusion may have a role in treatment.

Hypercoagulable States

Causes of hypercoagulable states that may be associated with stroke include paraproteinemia (especially macroglobulinemia), estrogen therapy, oral contraceptives, postpartum and postoperative states, cancer, and antiphospholipid antibody syndrome. Treatment is of the underlying disorder, discontinuing the suspect medication if applicable, or (for antiphospholipid antibody syndrome) administration of aspirin.

Myeloproliferative Disorders

Myeloproliferative disorders—especially polycythemia vera and essential thrombocythemia—are associated with increased risk for ischemic stroke, transient ischemic attacks, and cerebral venous or sinus thrombosis. Risk correlates poorly with increased platelet or white blood cell counts, perhaps because these disorders also affect platelet function and coagulation pathways; extremely high platelet counts paradoxically protect against thrombosis because of associated defects in von Willebrand factor. Instead, the best predictors of stroke are age >65 years, previous arterial thrombotic events, and hematocrit >45%. Treatment is with phlebotomy, aspirin, and in some cases cytoreduction.

Secondary Polycythemia

Polycythemia may occur not only in myeloproliferative disorders, but also as a complication of chronic obstructive lung disease or erythropoietin-producing tumors. Polycythemia with hematocrit >45% is associated with reduced cerebral blood flow and increased risk of stroke. Treatments include phlebotomy, antiplatelet drugs, cytoreduction with hydroxyurea, and Janus kinase 2 inhibitors.

CRYPTOGENIC STROKE

In many patients with stroke, no cause can be identified. This condition has been termed cryptogenic stroke. Compared to patients with stroke of known cause, those with cryptogenic stroke tend to be younger, have less severe impairment, and experience fewer recurrences. Cryptogenic stroke is diagnosed when imaging excludes lacunar stroke based on lesion size or location, arteries supplying the affected region show <50% luminal stenosis, high-risk cardioembolic sources (eg, atrial fibrillation, recent myocardial infarction, mechanical prosthetic heart valve, mitral stenosis, endocarditis, atrial myxoma) are absent, and no other specific cause of stroke can be identified.

Cryptogenic stroke is associated with a high incidence of patent foramen ovale, a congenital defect in the interatrial septum that can provide a route for paradoxical embolism from the venous circulation to the brain. Other possible etiologies of cryptogenic stroke include artery-to-artery embolism from atherosclerotic (but nonstenotic) cervical or intracranial vessels, undetected intermittent atrial fibrillation, mitral valve prolapse, and aortic stenosis or calcification.

Patients with cryptogenic stroke should be evaluated and treated for stroke risk factors (see Table 13-1) and given aspirin (eg, 325 mg orally daily). Certain patients with cryptogenic stroke and patent foramen ovale, such as those age ≤60 years with a moderate or large interatrial shunt or atrial septal aneurysm, may derive added benefit from foramenal closure. If a venous source of embolism is present in a patient with TIA or stroke and patent foramen ovale, treatment options include anticoagulation, inferior vena cava filter, and transcatheter closure of the cardiac defect.

CLINICAL FINDINGS

HISTORY

Predisposing Factors

Risk factors (see Table 13-1) such as TIAs, hypertension, diabetes, dyslipidemia, ischemic or valvular heart disease, cardiac arrhythmia, cigarette smoking, and oral contraceptive use should be inquired about. Hematologic and other systemic disorders (see Table 13-4) can 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.

Onset & Course

The history should establish the time of onset of symptoms, whether similar symptoms have occurred before, and whether the clinical picture is that of TIA, stroke in evolution, or completed stroke (see Figure 13-1). The history may also suggest a thrombotic or embolic etiology:

1. Features suggesting thrombotic stroke include stepwise progression of neurologic deficits, antecedent TIAs with identical symptoms, and lacunar infarction.

2. Features suggesting embolic stroke include maximal deficit within 5 minutes of onset, impaired consciousness at onset, sudden regression of deficit, multifocal infarction, Wernicke or global aphasia without associated hemiparesis, top-of-the-basilar syndrome, hemorrhagic transformation of infarct, or associated valvular disease, cardiomegaly, arrhythmia, or endocarditis. However, none of these features is definitive.

Associated Symptoms

1. Headache is present at onset in about 25% of patients with ischemic stroke and is especially common in intracranial arterial dissection and venous or sinus thrombosis.

2. Seizures can accompany the onset of stroke or follow stroke by weeks to years, but do not definitively distinguish embolic from thrombotic stroke.

PHYSICAL EXAMINATION

General Physical Examination

The general physical examination should focus on searching for an underlying systemic (especially treatable) cause of cerebrovascular disease as follows:

1. The blood pressure should be measured to detect hypertension—a major risk factor for stroke.

2. 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.

3. 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.

4. Neck examination may reveal the absence of carotid pulses or the presence of carotid bruits. However, reduced carotid artery pulsation in the neck is a poor indicator of internal carotid artery disease, significant carotid stenosis can occur without an audible bruit, and a loud bruit can occur without stenosis.

5. Cardiac examination can detect arrhythmias, or murmurs related to valvular disease, which may predispose to cardioembolic stroke.

6. Temporal artery palpation is useful in the diagnosis of giant cell arteritis, in which these vessels may be tender, nodular, or pulseless.

7. Skin examination may show signs of a coagulation disorder, such as ecchymoses or petechiae.

Neurologic Examination

Patients with cerebrovascular disorders may or may not have abnormal neurologic findings. A normal examination is expected, for example, after a TIA has resolved. Where deficits are found, the goal is to define the anatomic site of the lesion, which may suggest the cause or optimal management of stroke. For example, evidence of anterior circulation involvement may lead to angiographic evaluation for possible surgical correction of an internal carotid lesion, whereas signs that suggest vertebrobasilar or lacunar infarction will dictate a different course of action.

1. Cognitive deficits such as aphasia, unilateral neglect, or constructional apraxia suggest a cortical lesion in the anterior circulation and exclude vertebrobasilar or lacunar stroke. Coma implies brainstem or bihemispheric involvement.

2. Visual field abnormalities also exclude lacunar infarction, but hemianopia can occur with occlusion of either the middle or posterior cerebral artery, which supply the optic radiation and visual cortex, respectively. Isolated hemianopia suggests posterior cerebral artery stroke, because middle cerebral artery stroke should produce additional (motor and somatosensory) deficits.

3. Ocular palsy, nystagmus, or internuclear ophthalmoplegia assigns the underlying lesion to the brainstem and thus the posterior cerebral circulation.

4. 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 lacunes at subcortical or brainstem sites. Hemiparesis affecting the face, hand, and arm more than the leg is characteristic of middle cerebral artery lesions. Hemiparesis affecting the face, arm, and leg to a similar extent is consistent with large vessel stroke in the internal carotid, middle cerebral stem, or vertebrobasilar distribution, or with lacunar infarction. Crossed hemiparesis, which involves the face on one side and the rest of the body on the other, assigns the lesion to the brainstem between the facial (VII) nerve nucleus in the pons and the decussation of the pyramids in the medulla.

5. Cortical sensory deficits such as astereognosis or agraphesthesia, with preserved primary sensory modalities, imply a cortical deficit within the middle cerebral artery territory. Hemisensory deficits without associated motor involvement are usually lacunar. Crossed sensory deficits result from lesions in the medulla, as seen in the lateral medullary syndrome (Wallenberg syndrome, Chapter 8, Disorders of Equilibrium).

6. Hemiataxia usually points to a lesion in the ipsilateral brainstem or cerebellum but can also be produced by lacunar stroke in the internal capsule.

INVESTIGATIVE STUDIES

BLOOD TESTS

Blood Glucose

Hypoglycemia and hyperglycemia can both present with focal neurologic signs and masquerade as stroke. Hypoglycemia requires immediate administration of glucose to avoid permanent brain injury. Hyperglycemia (hyperosmolar nonketotic hyperglycemia or diabetic ketoacidosis) also requires prompt specific treatment.

Complete Blood Count

This can identify possible causes of stroke (eg, polycythemia, anemia from hemoglobinopathy) or suggest concomitant infection, which may complicate its course. A platelet count less than 100,000/μL contraindicates thrombolytic therapy for stroke (see later).

Coagulation Studies

Coagulation defects due to anticoagulant drugs or liver dysfunction may affect eligibility for thrombolytic therapy and other aspects of management. The prothrombin time (PT) and internationalized normal ratio (INR) are useful for detecting the effects of warfarin and liver disease, but other tests (eg, thrombin time or ecarin clotting time) may be required to detect anticoagulation by direct thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) inhibitors.

Inflammatory Markers

An increased erythrocyte sedimentation rate (ESR) is seen in giant cell arteritis and other systemic vasculitides.

Serologic Assay for Syphilis

A positive serum treponemal assay (FTA-ABS or MHA-TP) establishes, and a negative assay excludes, past or present syphilis infection. Positive CSF serology (VDRL) indicates untreated or inadequately treated neurosyphilis and suggests syphilitic arteritis as the cause of stroke.

Circulating Troponin Level

Myocardial infarction, which requires specific management, should be excluded by measuring troponin as a marker of myocardial ischemia, as well as by electrocardiogram.

ELECTROCARDIOGRAM (ECG)

An ECG should be obtained routinely to detect unrecognized myocardial infarction or cardiac arrhythmias, such as atrial fibrillation, which predispose to stroke.

LUMBAR PUNCTURE

Lumbar puncture (see Chapter 2, Investigative Studies) should be performed only in selected cases, to exclude subarachnoid hemorrhage (manifested by xanthochromia and red blood cells) or to document meningovascular syphilis (reactive CSF VDRL) as the cause of stroke.

BRAIN IMAGING

A noncontrast CT scan or MRI (Figure 13-17) should be obtained routinely (and always prior to thrombolytic therapy) to distinguish between infarction and hemorrhage as the cause of stroke, to exclude other lesions (eg, tumor or abscess) that can mimic stroke, and to localize the lesion. Noncontrast CT is usually preferred for initial diagnosis because it is widely and rapidly available. However, its sensitivity within the first 6 hours is limited, and MRI may be superior for demonstrating early infarcts and brainstem or cerebellar infarcts and for detecting thrombotic occlusion of venous sinuses.

Diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) are additional imaging techniques that may be useful for early detection and prognostication in stroke. DWI is superior to CT for detecting stroke in the first 12 hours after onset and may help predict final infarct volume in anterior circulation stroke. However, diffusion defects are sometimes seen with TIAs, and small strokes or brainstem strokes may escape detection. The difference between DWI and PWI abnormalities (diffusion-perfusion mismatch) may represent tissue at risk of infarction but potentially salvageable by thrombolysis, roughly corresponding to the ischemic penumbra.

VESSEL IMAGING

Imaging techniques can identify underlying causes of cerebrovascular disease (eg, carotid stenosis, vasculitis, fibromuscular dysplasia, arterial dissection, aneurysm, arteriovenous malformation), including operable extracranial carotid lesions.

Doppler ultrasonography can detect operable stenosis of the extracranial carotid artery and is noninvasive. However, it may not distinguish stenosis from occlusion and does not visualize the surrounding vascular anatomy, so is used primarily for screening.

Digital subtraction X-ray angiography is more sensitive and specific, but carries a small (<1%) risk of serious complications, including stroke.

CT angiography (CTA) and MR angiography (MRA) are noninvasive substitutes for digital subtraction angiography and can detect both extracranial and intracranial cerebrovascular disease with high sensitivity and specificity. CTA involves radiation exposure and may be obscured by artifact from calcium in atherosclerotic plaques.

ECHOCARDIOGRAPHY

Echocardiography is useful for demonstrating cardiac lesions that may be responsible for embolic stroke (eg, mural thrombus, valvular disease, atrial myxoma, or patent foramen ovale).

DIFFERENTIAL DIAGNOSIS

In patients presenting with focal central nervous system dysfunction of sudden onset, structural and metabolic processes that can mimic ischemic stroke must be excluded. Such a process should be suspected when the neurologic deficit does not conform to the distribution of any single cerebral artery, or when consciousness is impaired in the absence of severe focal deficits.

Disorders sometimes mistaken for ischemic stroke include intracerebral hemorrhage, subdural or epidural hematoma, subarachnoid hemorrhage, brain tumor, and brain abscess. These can be excluded by CT scan or MRI. Metabolic disturbances such as hypoglycemia and hyperosmolar nonketotic hyperglycemia may present in stroke-like fashion, but the blood glucose level is diagnostic.

PREVENTION & TREATMENT

Antithrombotic drugs used in the prevention or treatment of cerebrovascular disease are listed in Table 13-5. Treatment related to specific underlying vascular, cardiac, and hematologic causes of stroke (eg, anti-inflammatory, antibiotic, or antiarrhythmic drugs) was addressed earlier in this chapter in the section on Etiology.

PRIMARY PREVENTION

Lifestyle

Moderate to vigorous aerobic activity for 30 to 40 min per day, 3 to 4 times per week, is recommended. A diet low in sodium and saturated fats and rich in fruits, vegetables, low-fat dairy products, and nuts may also reduce stroke risk, as may weight reduction in overweight or obese patients, cessation of smoking, and moderation of heavy alcohol use.

Obstructive sleep apnea is associated with atrial fibrillation and increased stroke risk. Treatment with devices that provide continuous positive airway pressure during sleep may reduce this risk, but such an effect has not been proven.

Statins

Treatment with a statin (eg, atorvastatin 20 mg orally daily) is recommended for patients, with or without dyslipidemia, who are at high (>10%) 10-year risk for cardiovascular events, including stroke. Risk is assessed based on sex, age, race, total and HDL-cholesterol, systolic blood pressure, antihypertensive therapy, diabetes, and smoking history (see http://tools.acc.org/ASCVD-Risk-Estimator/). This approach reflects the finding that statins have vasoprotective (eg, anti-inflammatory) actions in addition to their lipid-lowering effects.

Blood Pressure Control

Blood pressure should be reduced by lifestyle modification, antihypertensive drugs, or both for patients with hypertension (>140 mm Hg systolic or >90 mm Hg diastolic pressure).

Glycemic Control

Diabetes increases the risk of stroke and should be treated, although the relationship between intensity of glycemic control and stroke incidence is unclear. In addition to whatever effect glycemic control may have, stroke risk in diabetics can be reduced by statins and antihypertensive treatment.

Antiplatelet Drugs

Low-dose aspirin (81-100 mg/d) may reduce the risk of stroke in patients with increased (>10%) 10-year risk for such events (see http://tools.acc.org/ASCVD-Risk-Estimator/).

Anticoagulation

Anticoagulation is indicated for patients with certain cardiac disorders that predispose to stroke, assuming an acceptably low likelihood of hemorrhagic complications. Algorithms like the CHA₂DS₂-VASc score are sometimes used to assess stroke risk in atrial fibrillation: it assigns 2 points each for age ≥75 years and history of transient ischemic attack or stroke, and 1 point each for congestive heart failure, treated or untreated hypertension, diabetes, peripheral arterial disease or aortic plaque or history of myocardial infarction, age 65-74 years, and female sex. However, this scale does not account for all stroke risk factors, and treatment decisions should always be tailored to the individual patient. Patients with valvular atrial fibrillation and CHA₂DS₂-VASc score ≥2 are commonly designated to receive long-term warfarin treatment targeted to an international normalized ratio (INR) of 2.5 ± 0.5. Options for those with CHA₂DS₂-VASc score = 1 include warfarin, aspirin, and no treatment; no treatment may be indicated for a CHA₂DS₂-VASc score = 0. In patients with nonvalvular atrial fibrillation and CHA₂DS₂-VASc score ≥2, dabigatran, rivaroxaban, apixaban, or edoxaban can be substituted for warfarin. Mitral stenosis with either a history of embolism or associated left atrial thrombus is also an indication for warfarin, and certain patients should be treated with both warfarin and aspirin following mechanical aortic or mitral valve replacement. The role of anticoagulation in reducing stroke risk related to other cardiac disorders—such as bioprosthetic valve replacement, heart failure, severe mitral stenosis, or ST-elevation myocardial infarction with mural thrombus or apical dyskinesis—is less clear.

Asymptomatic Carotid Artery Stenosis

Asymptomatic 70% to 99% stenosis of the extracranial internal carotid artery or carotid bulb (but not total carotid occlusion) is also associated with an increased risk of stroke, and patients with asymptomatic stenosis should be treated with low-dose aspirin and statins. In some cases with >70% stenosis, carotid endarterectomy or carotid artery stenting (discussed later) may be employed, assuming that a surgical complication rate of 3% or less can be anticipated.

TRANSIENT ISCHEMIC ATTACK & ACUTE ISCHEMIC STROKE

Transient ischemic attack, or TIA, is an episode of focal cerebral ischemia that resolves fully and rapidly, usually within 1 hour, without evidence of cerebral infarction. The goal of treatment is to prevent subsequent stroke, which occurs in 3-10% of patients within 2 days and 9-17% within 90 days. In contrast to TIA, acute ischemic stroke implies a persistent focal neurologic deficit, which may be improving, stable, or worsening (stroke in evolution or progressing stroke) when the patient is seen. Evaluation and treatment are similar in both cases; the major difference is that thrombolytic therapy is not usually considered for TIA, in which the vascular occlusion that caused symptoms is thought to have resolved with the resolution of symptoms.

Several algorithms have been developed to predict the acute risk of stroke (and, therefore, the urgency of evaluation and treatment) in patients with TIA. The ABCD2 scale, designed largely for triage in the emergency room, takes into account age, blood pressure, clinical presentation (focal weakness or speech impairment), duration of the event, and concurrent diabetes to determine the need for urgent hospital admission and diagnostic evaluation. Variants like the ABCD3-I scale include additional considerations, such as the occurrence of multiple TIAs and imaging findings, and are tailored for use by specialists after TIA has been diagnosed. Nevertheless, decisions regarding evaluation and treatment of patients with TIA should always be individualized.

Investigative Studies

Patients with suspected TIA or acute ischemic stroke should be evaluated promptly with blood tests (complete blood count, prothrombin and partial thromboplastin time, erythrocyte sedimentation rate, treponemal test for syphilis, glucose) and ECG to identify underlying causes or mimics of cerebrovascular disease and guide subsequent therapy.

Noncontrast CT scan or MRI should be performed immediately to exclude intracerebral hemorrhage and other disorders that can mimic ischemic stroke.

Patients with symptoms or imaging findings consistent with anterior circulation ischemia should undergo CT angiography or MR angiography to detect clinically consistent stenosis or occlusion of the internal carotid or proximal middle cerebral artery, which may be amenable to intraarterial clot retrieval, or operable lesions in the extracranial carotid artery (discussed later in this chapter).

Echocardiography should be performed if there is a predisposing cardiac disorder or if symptoms suggest cardiogenic embolus (eg, recurrent TIAs with symptoms related to different vascular territories).

Medical Treatment

1. Blood pressure should usually not be lowered acutely, except for patients with acute ischemic stroke in whom it is high enough (>185 mm Hg systolic or >110 mm Hg diastolic pressure) to make an otherwise suitable candidate ineligible for thrombolytic therapy (see later). When acute antihypertensive therapy is required, recommended drugs include intravenous labetalol or nicardipine.

2. Hyperthermia, which may adversely affect outcome, should be corrected, and any infectious cause identified.

3. Hypoxia (oxygen saturation ≤94%) should be treated with supplemental oxygen.

4. Hypoglycemia (blood glucose <60 mg/dL) should be corrected.

5. Anticoagulation with heparin, given by continuous intravenous infusion to achieve an activated partial thromboplastin time (aPTT) 1.5 to 2.5 times control, followed by warfarin, given orally daily to achieve an INR of 2.5 ± 0.5, or another oral anticoagulant (see Table 13-5), is indicated if a cardiac embolic source (eg, atrial fibrillation, mitral stenosis, or mechanical valve replacement) appears to be responsible for TIA or acute ischemic stroke.

6. Antiplatelet therapy with aspirin (325 mg orally once, followed by 81-325 mg orally daily) is recommended for presumed noncardiogenic TIA or acute ischemic stroke, unless the patient is to undergo thrombolysis.

7. Statins should be continued for patients receiving long-term statin treatment.

Interventional Treatment

Interventional treatment is an option for selected patients with acute ischemic stroke, but is not used for TIA.

1. Intravenous thrombolysis—Intravenous administration of recombinant tissue-type plasminogen activator (r-tPA or alteplase) within 4.5 hours of the onset of symptoms can reduce disability and mortality from acute ischemic stroke. The drug is administered at 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. Treatment should be started within 60 minutes of the patient’s arrival at the hospital, which provides time for diagnosis and evaluation of possible contraindications. Intravenous r-tPA should be given whether or not subsequent intraarterial thrombectomy is being considered. When the appropriate expertise is not available locally, remote diagnosis of stroke and supervision of intravenous thrombolysis via telemedicine can provide care of similar quality.

   Contraindications to thrombolysis are designed to avoid unnecessarily treating patients who are improving spontaneously or unlikely to benefit, or exacerbating bleeding complications (including intracerebral hemorrhage). Contraindications designed to avert unnecessary or ineffectual treatment include the presence of only minor neurologic deficits and onset of symptoms more than 6 hours prior to initiating treatment. Contraindications related to bleeding complications include recent head trauma, intracranial or spinal surgery, gastrointestinal malignancy or recent hemorrhage, current severe uncontrolled hypertension, and bleeding diathesis.

   Within the first 24 hours after administration of r-tPA, 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 thrombolysis—Intraarterial administration of r-tPA may be beneficial in patients with acute ischemic stroke who are not candidates for intravenous thrombolysis, such as those treated 4.5 to 6 hours after the onset of symptoms or with a recent history of major surgery, and patients in whom intravenous therapy is unsuccessful.

3. Clot retrieval—Mechanical thrombectomy with a stent retriever, typically in combination with intravenous r-tPA, can improve functional outcome for patients with stenosis or occlusion of proximal (internal carotid or proximal middle cerebral) intracranial arteries in the anterior cerebral circulation. Those who are not candidates for or who fail intravenous thrombolysis may also benefit from this procedure, which should be started within 6 hours after the onset of symptoms.

Surgical Treatment

1. Carotid endarterectomy (surgical removal of thrombus from a stenotic common or internal carotid artery in the neck) is indicated for patients with anterior circulation TIAs and high-grade (70-99%) extracranial internal carotid artery stenosis—and for selected patients with moderate (50-70%) stenosis—on the side appropriate to the symptoms. The net benefit of endarterectomy assumes a combined perioperative morbidity and mortality of less than 6%.

2. Carotid artery stenting is as effective as endarterectomy for treating extracranial carotid stenosis, assuming a similar perioperative morbidity and mortality rate. Stenting is associated with an increased risk of periprocedural stroke and death, but a decreased risk of periprocedural myocardial infarction. Considering the generally greater adverse effect of stroke than of myocardial infarction on quality of life, carotid endarterectomy probably remains superior overall, although stenting may be preferable for some (eg, younger) patients.

3. Decompressive craniectomy with dural expansion (loose closure of dura and skin over the bony defect), often with ventriculostomy drainage to treat hydrocephalus, can be lifesaving when cerebellar infarction causes brainstem compression and depressed consciousness. Decompressive craniectomy is also sometimes used to prevent transtentorial herniation and death in patients younger than 60 years who deteriorate within 48 hours after large hemispheric strokes.

SECONDARY PREVENTION

Secondary prevention (ie, prevention of a subsequent cerebrovascular event in patients with prior TIA or ischemic stroke) involves measures similar to those employed in primary prevention, with the following exceptions.

Statins

Treatment with a statin (eg, atorvastatin 80 mg orally daily) is recommended for all patients with prior TIA or ischemic stroke.

Blood Pressure Control

Angiotensin converting enzyme inhibitors and diuretics appear to be more effective than other antihypertensive regimens in reducing the risk of recurrent stroke.

Antiplatelet Drugs

All patients with prior non-cardioembolic TIA or ischemic stroke should receive aspirin (81-325 mg/d); aspirin/dipyridamole (25/200 mg twice daily) or clopidogrel (75 mg/d) alone are alternative options. For patients whose TIA or stroke occurred while taking aspirin, it is unclear if increasing the dose or substituting another antiplatelet drug confers additional benefit. There is no evidence that anticoagulation or the combination of antiplatelet therapy and anticoagulation is effective in this setting.

Anticoagulation

Patients with prior TIA or ischemic stroke and valvular atrial fibrillation or mechanical aortic or mitral valve replacement should be given long-term warfarin treatment targeted to an INR of 2.5 ± 0.5. Low-dose aspirin is added for patients with mechanical valves who are at low risk for bleeding complications. Nonvalvular atrial fibrillation should be treated with warfarin (INR 2.5 ± 0.5), apixaban, dabigatran, rivaroxaban, or edoxaban. Short-term (~3 months) anticoagulation with warfarin is indicated for prior TIA or ischemic stroke with acute myocardial infarction or cardiomyopathy when either is complicated by mural thrombus. Warfarin for 3 to 6 months followed by long-term low-dose aspirin is recommended for recipients of bioprosthetic valves. Either antiplatelet drugs or anticoagulation with warfarin can be used in rheumatic valvular disease without atrial fibrillation.

Surgical Treatment

Surgical treatment for secondary prevention of TIA or stroke (carotid endarterectomy or stenting) is as described earlier for treatment of TIA or acute ischemic stroke.

COMPLICATIONS

Clinical complications are common after stroke and can strongly affect outcome. They may occur either early in the course or during chronic recovery.

1. Aphasia and dysarthria may respond to language and speech training and the use of communication devices.

2. Bladder and bowel incontinence should be investigated and addressed and indwelling urinary catheters should be removed within 24 hours after admission if possible.

3. Cognitive impairment following stroke may benefit from environmental enrichment, physical exercise, and limiting the use of psychoactive medications.

4. Deep vein thrombosis should be prophylaxed with subcutaneous low molecular weight or unfractionated heparin, with or without intermittent pneumatic compression of the legs, if ambulation is impaired.

5. Depression is common after stroke, with physical disability, stroke severity, prior depression, or impaired cognition carrying an increased risk. Poststroke depression may respond to antidepressants, stimulants (eg, methylphenidate), exercise, or brief psychosocial therapy.

6. Dysphagia is observed in about one-half of patients after stroke, and may lead to aspiration, malnutrition, and dehydration. Screening for dysphagia should be conducted early in the course and, if present, swallowing should be assessed by videofluoroscopy or fiberoptic endoscopy. When swallowing is impaired after stroke, nasogastric tube feeding should be started within 1 week and may be continued for up to 3 weeks. If tube feeding is required for a longer period, percutaneous gastrostomy should be employed.

7. Falls can be reduced with balance training, exercise programs, and assistive devices (eg, cane or walker).

8. Hemiplegic shoulder pain should be alleviated by positioning and range-of-motion exercises.

9. Infections, especially pneumonia and urinary tract infections, complicate stroke in 25-65% of patients. Contributing factors include both stroke-induced immunodepression and factors like aspiration and urinary catheterization. However, prophylactic antibiotic therapy does not improve outcome in patients with stroke.

10. Osteoporosis and associated risk of bone fractures may complicate stroke, after which bone mineral density typically declines, especially on the hemiparetic side and in nonambulatory patients. Supplementation with calcium and vitamin D may be indicated.

11. Post-stroke central pain (Dejerine–Roussy or thalamic pain syndrome) is most common after stroke involving the spinothalamic system in the ventral posterior thalamus. It usually begins months after stroke and is experienced in the region of a sensory deficit. Pain may respond to treatment with amitriptyline, lamotrigine, or electrical or repetitive transcranial magnetic stimulation of the motor cortex.

12. Seizures occur within the first few days after stroke in up to 25% of patients, most often in the first 24 hours, and especially following cortical strokes. However, routine poststroke seizure prophylaxis with anticonvulsant drugs is not recommended.

13. Sexual dysfunction is common after stroke, with decreased libido, erection, and ejaculation in men and impaired lubrication and orgasm in women. Interventions include addressing possible psychological factors, limiting the use of medications that interfere with sexual function, and pharmacotherapy (eg, sildenafil).

14. Skin breakdown and contractures should be guarded against by turning and positioning, attention to skin care, use of mattresses and cushions, and orthotic devices where indicated.

15. Spasticity may be relieved by botulinum toxin, oral antispasticity drugs (eg, baclofen, dantrolene, or tizanidine), or intrathecal baclofen.

REHABILITATION

Most patients show some spontaneous improvement in neurologic function in the 3 to 6 months after stroke, reflecting the adaptive plasticity of the brain. However, optimal postacute stroke care involves treatment in an inpatient rehabilitation facility. Recovery of mobility and limb function can be enhanced by training and practice. Effective rehabilitative measures include fitness and strength training, over-ground gait training, pharmacologic modulation of spasticity, speech and language therapy, and perhaps noninvasive transcortical magnetic or direct current stimulation. The efficacy of constraint-induced movement therapy is uncertain. Early commencement of rehabilitative therapy and high-intensity regimens are recommended, and patient motivation is an important factor.

PROGNOSIS

Outcome after stroke is influenced by several factors, the most important being the nature and severity of the resulting neurologic deficit and the patient’s age. The cause of stroke and coexisting medical disorders also affect prognosis. About one-half of stroke survivors are discharged directly home from the hospital, whereas the remainder require at least interim care in an inpatient rehabilitation or skilled nursing facility. Roughly 50% of patients have returned to work by 6-12 months after stroke. Poststroke mortality is ~10% at 30 days, ~20% at 1 year, and ~40% at 5 years.

Intracerebral hemorrhage refers to bleeding in the brain parenchyma, as distinguished from bleeding in the epidural, subdural, or subarachnoid space surrounding the brain. Symptomatic intracerebral hemorrhage usually presents as (focal) stroke, and may be indistinguishable from ischemic stroke except by imaging studies. In contrast, epidural, subdural, and subarachnoid hemorrhages tend to affect the brain more diffusely; headache and altered consciousness are the most prominent features, while focal signs are less conspicuous. However, imaging studies are required for definitive diagnosis in these disorders as well.

Two varieties of intracerebral bleeding are observed. The best characterized—cerebral macrobleeds—are macroscopic, almost always symptomatic, often neurologically devastating, and most often caused by head trauma or chronic hypertension. In recent years, another type of intracerebral hemorrhage—cerebral microbleeds—has been recognized, based largely on imaging studies. Cerebral microbleeds are 1-10 mm in diameter, individually asymptomatic, and reflect cerebral small vessel disease. The most commonly identified causes are hypertension, which is associated with microbleeds in the deep subcortical gray matter and brainstem, and cerebral amyloid angiopathy (discussed below), which tends to produce lobar microbleeds at the cortical gray matter-white matter junction. Less frequent causes of microbleeds include CADASIL, moyamoya, and infective endocarditis (discussed earlier as causes of focal cerebral ischemia), as well as fat embolism and cerebral malaria. Microbleeds are associated with cognitive dysfunction and an increased risk of large intracerebral hemorrhages; nonlobar microbleeds are also predictive of ischemic stroke. Treatment of microbleeds involves controlling hypertension; their presence does not preclude the use of antiplatelet agents, anticoagulants, thrombolytics, or statins for treatment of concurrent ischemic cerebrovascular disease, if otherwise indicated.

Except where noted, the discussion below relates to the larger (macrobleed) variety of intracerebral hemorrhage.

HYPERTENSIVE HEMORRHAGE

EPIDEMIOLOGY

Intracerebral hemorrhage causes ~10% of strokes, independent of age. Hypertension is the most common underlying cause of nontraumatic hemorrhage.

PATHOPHYSIOLOGY

Chronic Hypertension

Chronic hypertension promotes changes in the walls of penetrating small cerebral arteries and arterioles in the subcortical white matter, basal ganglia, thalamus, pons, and cerebellum. These changes consist of lipohyalinosis (collagenous thickening and inflammation of the vessel wall) and fibrinoid necrosis (vessel-wall destruction with perivascular inflammation), which are associated with ischemic (lacunar) stroke and may also lead to the development of miliary (Charcot–Bouchard) aneurysms, which predispose to hemorrhage.

Acute Hypertension

The role of acute elevation of blood pressure in intracerebral hemorrhage is uncertain. Most patients are hypertensive after intracerebral hemorrhage, but this may be due to a combination of baseline chronic hypertension and the vasopressor response to increased intracranial pressure (Cushing reflex). Some patients with intracerebral hemorrhage have no history of hypertension and lack signs of hypertensive end-organ disease, suggesting that acute hypertension might be a precipitant, as does the occurrence of intracerebral hemorrhage following sympathomimetic drug (eg, amphetamine or cocaine) use.

Hematoma Effects

Hypertensive hemorrhage causes both destruction and compression of brain tissue. In addition, breakdown products of extravasated blood may cause inflammation and secondary injury. Perihematoma edema correlates with hematoma size, which predicts a poor outcome. Increased intracranial pressure results in tamponade of the ruptured vessel, but can also lead to brain herniation and death.

Hydrocephalus

Hydrocephalus may result from hematomal compression of the ventricular system or its obstruction by intraventricular or subarachnoid blood. This complication is especially common after cerebellar hemorrhage.

Rebleeding

This occurs in up to ~15% of cases and is associated with clinical worsening.

PATHOLOGY

Most hypertensive hemorrhages originate from long, narrow penetrating arterial branches along which lipohyalinosis, fibrinoid necrosis, and Charcot–Bouchard aneurysms are found at autopsy. These include the caudate and putaminal branches of the middle cerebral arteries, branches of the basilar artery supplying the pons, thalamic branches of the posterior cerebral arteries, branches of the superior cerebellar arteries supplying the dentate nuclei and the deep white matter of the cerebellum, and some white matter branches of the cerebral arteries, especially in the parietooccipital and temporal lobes. In the acute phase after intracerebral hemorrhage, there is edema surrounding the hematoma and often displacement of adjacent brain structures and ventricular effacement (Figure 13-18). About one-half of hemorrhages, especially those arising in the putamen or thalamus, extend into the ventricles. In the chronic phase following intracerebral hemorrhage, the only abnormality may be a slitlike defect corresponding to the resorbed hematoma, with pigmented margins containing hemosiderin-laden macrophages.

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, so normal or low blood pressure in a patient with stroke makes the diagnosis of hypertensive hemorrhage unlikely.

After hemorrhage, increasing edema produces clinical worsening over minutes to days, and rebleeding may occur. Clinical features vary with the site of hemorrhage (Table 13-6).

Deep Cerebral Hemorrhage

The most common sites of hypertensive hemorrhage are the putamen and thalamus, which are separated by the posterior limb of the internal capsule. This segment of the internal capsule is traversed by descending motor and ascending sensory fibers, including the optic radiations (Figure 13-19). Pressure from an expanding lateral (putaminal) or medial (thalamic) hematoma, therefore, produces a contralateral sensorimotor deficit.

Putaminal hemorrhage typically leads to more severe motor deficit and thalamic hemorrhage to more marked sensory disturbance. Homonymous hemianopia may occur transiently after thalamic hemorrhage and is often persistent in putaminal hemorrhage. Putaminal hemorrhage produces tonic eye deviation toward the affected side of the brain, whereas thalamic hemorrhage may cause tonic downward and medial deviation from pressure on the midbrain center for upgaze. Aphasia may occur if putaminal or thalamic hemorrhage exerts pressure on cortical language areas.

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, but can include headache, vomiting, hemiparesis, hemisensory deficits, aphasia, and visual field defects. Seizures are more frequent than with hemorrhages in other locations, whereas coma is less so.

Pontine Hemorrhage

Bleeding into the pons produces coma within seconds to minutes and usually death within 48 hours. Key findings are pinpoint pupils and absent or impaired horizontal eye movements; vertical eye movements may be preserved. There may be ocular bobbing—bilateral downbeating excursion of the eyes at about 5-second intervals. Patients are commonly quadriparetic with decerebrate posturing, and hyperthermia may be present. Pontine hemorrhage usually ruptures into the fourth ventricle, and often extends into the midbrain, producing midposition fixed pupils. Small pontine hemorrhages that spare the reticular activating system are associated with less severe deficits and good recovery.

Cerebellar Hemorrhage

Cerebellar hemorrhage produces headache, dizziness, and vomiting of sudden onset, and inability to stand or walk within minutes. Patients may initially be alert or only mildly confused, but large hemorrhages lead to coma within 12 to 24 hours in most cases. When coma is present at onset, cerebellar hemorrhage may be indistinguishable from pontine hemorrhage.

Findings include impaired gaze toward or forced deviation away from the lesion, caused by pressure on the pontine lateral gaze center. Skew deviation, in which the eye ipsilateral to the lesion is depressed, may occur. The pupils are small and reactive. Impaired upgaze indicates upward transtentorial herniation of the cerebellar vermis and midbrain, and implies a poor prognosis. Ipsilateral facial weakness of lower motor neuron type occurs in ~50% of cases, but limb strength is normal. Despite prominent gait ataxia, limb ataxia is usually minimal. Plantar responses are flexor early, but become extensor with brainstem compression.

Cerebellar hemorrhage is especially important to diagnose early because it is treatable (see later). The main mistake to avoid is failing to consider the diagnosis when limb ataxia is absent and gait is not tested. Accordingly, stance and gait should be examined in any patient who presents acutely with headache, dizziness, or vomiting.

INVESTIGATIVE STUDIES

A noncontrast CT scan should be obtained to confirm the diagnosis of intracerebral hemorrhage and assess the likelihood of a cause other than chronic hypertension. Lobar hemorrhage, deep hemorrhage in an atypical location, or disproportionate subarachnoid blood or perihematomal edema should prompt a search for such alternative etiologies, using CT angiography or MR angiography to detect, for example, intracranial aneurysm or arteriovenous malformation. Conventional cerebral angiography can be used to better characterize potentially operable lesions.

Blood tests should be obtained to identify coagulopathy or thrombocytopenia as a possible cause of hemorrhage or complicating factor. Blood glucose should be measured to detect hyperglycemia or hypoglycemia, which may require treatment. Lumbar puncture yields bloody cerebrospinal fluid, but should not be performed because of the risk of brain herniation.

DIFFERENTIAL DIAGNOSIS

Putaminal, thalamic, and lobar hypertensive hemorrhages may be difficult to distinguish from infarction in the same locations. However, severe headache, nausea and vomiting, and impaired consciousness suggest hemorrhage. CT or MRI (Figure 13-20) provides a definitive diagnosis.

Brainstem stroke and cerebellar infarction can mimic cerebellar hemorrhage, but are readily distinguishable by CT scan or MRI. Acute peripheral vestibulopathy also produces nausea, vomiting, and gait ataxia, but not headache or impaired consciousness.

Hypertensive hemorrhage must also be distinguished from intracerebral hemorrhage due to other causes, which are discussed later in this chapter.

TREATMENT

Medical

1. Initial management of intracerebral hemorrhage includes airway support with ventilatory assistance if required.

2. Hypertension should be treated by reducing systolic blood pressure to 140-179 mm Hg with intravenous nicardipine and, if needed, intravenous labetalol. This is as effective as more intensive reduction to 110-139 mm Hg in improving clinical outcome.

3. Coagulopathy should be reversed by clotting factor replacement with prothrombin complex concentrate or fresh frozen plasma. If coagulopathy is due to anticoagulation with warfarin, warfarin should be discontinued and vitamin K administered. Severe thrombocytopenia should be corrected by platelet transfusion.

4. Hyperglycemia and hypoglycemia should both be avoided and insulin or glucose administered as needed.

5. Fever should be suppressed with antipyretics; when an infectious cause is excluded, fever may be due to inflammation from the hematoma or its subarachnoid or intraventricular extension.

6. Brain edema should not be treated with corticosteroids or osmotic agents, which are ineffective in improving outcome.

7. Seizures may occur, especially with lobar hemorrhages, but prophylactic administration of anticonvulsants is not recommended.

Surgical

1. Cerebellar hemorrhage—Neurologic deterioration, brainstem compression, and hydrocephalus are indications for decompressive posterior fossa surgery, which may avert a fatal outcome. Results are best in conscious patients.

2. Lobar hemorrhage—Surgical evacuation can also be useful for lobar hematomas, especially those larger than 30 mL in volume and located within approximately 1 cm of the brain surface. Patients with good neurologic function who begin to deteriorate are optimal candidates. Prognosis is related to the level of consciousness before surgery.

3. Deep hemorrhage—Surgery is not beneficial for pontine or deep cerebral hypertensive hemorrhage.

COMPLICATIONS

Complications and their treatment are similar to those described previously for ischemic stroke, except that prophylaxis of deep vein thrombosis with subcutaneous heparin is not recommended in the acute phase.

REHABILITATION

Rehabilitation is as described previously for ischemic stroke.

PROGNOSIS

Considerable return of neurologic function can occur after intracerebral hemorrhage, depending on its location and size. Mortality is 30-40% at 1 month; most deaths occur in the first few days. At discharge from the hospital, about 75% of patients have significant disability.

OTHER CAUSES

TRAUMA

Intracerebral hemorrhage is a frequent consequence of closed-head trauma. Traumatic hemorrhages may occur at (coup) or directly opposite (contrecoup) the site of impact. The most common locations are the frontal and temporal lobes. Traumatic hemorrhage is diagnosed by CT or MRI.

HEMORRHAGIC TRANSFORMATION OF CEREBRAL INFARCTS

Hemorrhage into a cerebral infarct is common and usually has no effect on outcome. Factors that predispose to hemorrhagic transformation include thrombolytic therapy, anticoagulation, cardioembolic stroke, massive infarction, cortical gray matter infarction, and thrombocytopenia. Treatment consists of discontinuing thrombolytic or anticoagulant drugs where applicable.

ANTICOAGULATION & THROMBOLYTIC THERAPY

Patients receiving anticoagulants or thrombolytic agents are at increased risk for developing intracerebral hemorrhage.

COAGULOPATHY

Intracerebral hemorrhage can complicate disorders involving either clotting factors (eg, hepatic failure, hemophilia, disseminated intravascular coagulopathy) or platelets (eg, immune thrombocytopenic purpura).

CEREBRAL AMYLOID ANGIOPATHY

Cerebral amyloid (congophilic) angiopathy is characterized by β-amyloid deposits in the walls of leptomeningeal and cortical capillaries, arterioles, and small arteries. The disorder is most common in elderly patients and typically produces lobar hemorrhage, including microbleeds, at multiple sites. Risk factors include apolipoprotein E ε4 and ε2 alleles, anticoagulation or antiplatelet therapy, head trauma, and hypertension. Rare hereditary cases (eg, amyloid βA4 precursor protein mutations) are inherited in autosomal dominant fashion.

VASCULAR MALFORMATIONS

Cerebrovascular malformations can affect arteries (saccular, or berry, aneurysms), veins (cavernous malformations), or their interconnections (arteriovenous malformations, or AVMs), and rupture can cause intracerebral hemorrhage.

AVMs are usually sporadic, but may also be features of Mendelian disorders, such as hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease). They consist of tortuous arteries and dilated veins and arise developmentally when the intervening capillary beds fail to form, but continue to undergo remodeling throughout life (Figure 13-21). They may be asymptomatic or cause hemorrhage, seizures, headache, or focal neurologic deficits. For unruptured AVMs, the risk of rupture is 1-3% per year. However, when rupture occurs it carries a 10-30% mortality rate and, for survivors, a 6% risk of re-rupture over the next year. Anticonvulsants are the treatment of choice for AVMs that present with seizures. In the case of hemorrhage, however, surgical resection, endovascular embolization, or radiosurgery can prevent rebleeding.

Cavernous malformations can be sporadic or familial. In the latter case, they result from autosomal dominant mutations in one of three genes: Krev interaction trapped 1 (KRIT1 or CCM1), malcavernin (CCM2), or programed cell death protein 10 (PDCD10 or CCM3). Like AVMs, cavernous malformations can present with hemorrhage, seizures, headache, or focal neurologic deficits. The risk of bleeding is ~1% per year for previously unruptured lesions, but increases to ~5% per year once bleeding has occurred. Treatment approaches include conservative management (eg, anticonvulsants for patients presenting with seizures), microsurgical resection, and radiosurgery.

Saccular aneurysms are acquired lesions of arterial walls, located especially at branch points around the circle of Willis. When aneurysms bleed, they usually present with subarachnoid hemorrhage, but at some sites (eg, middle cerebral artery) they may bleed into brain parenchyma to produce an intracerebral hematoma. Aneurysms are discussed in detail in Chapter 6, Headache & Facial Pain.

AMPHETAMINE OR COCAINE ABUSE

Amphetamine or cocaine use can cause intracerebral hemorrhage, typically within minutes to hours after the drug is taken. Most such hemorrhages are located in subcortical white matter and may be related to acutely elevated blood pressure, rupture of a preexisting vascular anomaly, or drug-induced arteritis.

HEMORRHAGE INTO TUMORS

Bleeding into primary or metastatic brain tumors is an occasional cause of intracerebral hemorrhage. Tumors associated with hemorrhage include melanoma, lung carcinoma, glioma, breast carcinoma, renal cell carcinoma, and oligodendroglioma. 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.

ACUTE HEMORRHAGIC LEUKOENCEPHALITIS

This rare monophasic demyelinating and hemorrhagic disorder typically follows respiratory infection in children. Multiple small perivascular hemorrhages are found in the brain. Clinical features include fever, headache, confusional state, and coma. CSF shows a polymorphonuclear pleocytosis, and CT or MRI may demonstrate hemorrhage. The classic clinical picture is of a fulminant course leading to death within several days, but some patients respond to corticosteroids or plasma exchange.

ETIOLOGY

Global cerebral ischemia occurs when blood flow is inadequate to meet the metabolic requirements of the brain, as in cardiac arrest. Global ischemia produces more severe brain injury than does pure anoxia with preserved circulation (eg, primary respiratory arrest or carbon monoxide poisoning), presumably because it also impairs glucose delivery and removal of toxic metabolites.

PATHOLOGY

The severity of cerebral pathology is determined by the duration of global ischemia, and its distribution is governed by the preferential vulnerability of certain neuronal populations and arterial watershed (borderzone) regions. Preferentially vulnerable neurons include CA1 pyramidal neurons of the hippocampus; cerebellar Purkinje neurons; pyramidal neurons of neocortical layers 3, 5, and 6; thalamic reticular neurons; and medium-sized neurons in the caudate nucleus and putamen. Arterial watersheds are located at the borders between the anterior, middle, and posterior cerebral arteries (Figure 13-22). Superimposed disease of the craniocervical arteries may lead to asymmetries in the distribution of cerebral damage from global ischemia.

CLINICAL FINDINGS

BRIEF ISCHEMIA

Reversible encephalopathies are common after brief circulatory arrest. In such cases, coma persists for less than 12 hours. Transient confusion or amnesia may occur on awakening, but recovery is typically rapid and complete. Some patients show severe anterograde and variable retrograde amnesia and a bland, unconcerned affect with or without confabulation. This syndrome may reflect reversible bilateral damage to the thalamus or hippocampus.

PROLONGED ISCHEMIA

Coma

Coma lasting for more than 12 hours after cardiac arrest may be associated with lasting focal or multifocal motor, sensory, and cognitive deficits upon awakening. It is discussed in Chapter 3, Coma.

Focal Cerebral Dysfunction

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 and results from ischemia in the border zone between the middle and posterior cerebral arteries. 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.

Myoclonus & Seizures

Posthypoxic action myoclonus (Lance–Adams syndrome) after cardiac arrest produces multifocal myoclonus and is sometimes associated with signs of cerebellar disease, including dysarthria, dysmetria, ataxia, and intention tremor. It occurs in conscious patients without severe ischemic injury and typically improves over time. Treatment with clonazepam, valproic acid, or levetiracetam may be effective. Myoclonic status, which occurs in comatose patients, consists of generalized, bilateral, synchronous twitching that usually affects the face and trunk. It is usually, but not always, associated with a poor outcome. Partial or generalized seizures, including status epilepticus, are also seen after cardiac arrest, and should be treated with anticonvulsants.

Persistent Vegetative or Minimally Responsive State

Some patients who are initially comatose after cardiac arrest survive and awaken, but remain functionally decorticate and unaware of their surroundings. They typically regain spontaneous eye opening, sleep-wake cycles, roving eye movements, and brainstem and spinal cord reflexes. This persistent vegetative or minimally responsive state (see Chapter 3, Coma) is thus distinct from coma and appears to be associated with laminar necrosis of the neocortex. In some apparently unaware patients, however, functional MRI or EEG can demonstrate responsiveness. Most such patients have traumatic rather than ischemic brain injury, but the possibility that a patient without overt behavioral responses remains subclinically aware and responsive should always be explored. 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 3, Coma), in which both cerebral and brainstem functions are absent.

Spinal Cord Syndromes

Spinal cord injury from hypoperfusion is usually seen only with profound cerebral involvement. Although an arterial watershed occurs at the mid-thoracic level of the cord, autopsy studies show that ischemic injury after cardiac arrest affects large neurons in the anterior horns of the lumbar spinal cord most prominently. This may be due to the large size and high metabolic activity of these neurons, and is consistent with the clinical finding of flaccid paraplegia associated with spinal cord injury after cardiac arrest.

TREATMENT

Treatment of global cerebral ischemia involves restoring cerebral circulation, eliminating arrhythmias, maintaining systemic blood pressure, correcting acid-base or electrolyte abnormalities, and detecting and treating clinical and electrographic seizures. Ventilatory assistance and supplemental oxygen may be necessary.

Induced hypothermia to 32 to 34°C for 12 to 24 hours by surface or endovascular cooling can improve 6-month survival and neurologic outcome after out-of-hospital cardiac arrest with ventricular fibrillation. However, some data suggest that maintaining temperature at 36°C may be equally effective.

Seizures, including possible electrographic seizures and status epilepticus, should be investigated by EEG and treated aggressively with anticonvulsants, but prophylactic administration of anticonvulsants is not recommended.

PROGNOSIS

Rates for survival to hospital discharge are ~10% for out-of-hospital and ~20% for in-hospital cardiac arrest. Prognosis is better for patients with ventricular fibrillation or pulseless ventricular tachycardia (~40% survival to discharge) than for asystole or pulseless electrical activity (electromechanical dissociation) (~20% survival to discharge).

The goal of neurologic prognostication after cardiac arrest is to distinguish patients with and without a chance for meaningful recovery. Meaningful recovery is excluded by pupillary areflexia, observed using a magnifying glass, at 72 hours after arrest or rewarming. Other signs, such as myoclonus at 24 hours, or corneal areflexia or absent or decerebrate motor responses to pain at 72 hours, are less reliable. In patients who have undergone therapeutic hypothermia, the effects of hypothermia per se, drugs administered in hypothermia protocols (eg, sedatives and paralytics), and hypothermia-induced changes in drug metabolism can delay recovery. The prognostic value of EEG, somatosensory evoked potentials, or neuroimaging findings is uncertain.