Table 13-1. Well-documented risk factors for stroke.¹

Table 13-2. Some monogenic disorders associated with stroke.

APPROACH TO DIAGNOSIS

Stroke is a syndrome characterized by 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 central nervous system involvement is suggested by the nature of the symptoms and signs, delineated more precisely by the neurologic examination, and confirmed by imaging studies (computed tomography [CT] scans or magnetic resonance imaging [MRI]).

3. Lack of rapid resolution—The duration of neurologic deficits is documented by the history. In the past, the standard definition of stroke required 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. When this is confirmed by imaging studies, further investigations can be undertaken to identify a more specific etiology, such as arterial thrombosis, cardiogenic embolus, or clotting disorder.

Strokes begin abruptly. Neurologic deficits may be maximal at onset, as is common in embolic stroke, or may progress over seconds to hours (or occasionally days), which may occur with progressive arterial thrombosis or recurrent emboli.

Figure 13-1. Time course of cerebral ischemic events. A transient ischemic attack (TIA) produces neurologic deficits that resolve completely within a short period, usually within 1 hour. Stroke-in-evolution, or progressing stroke, causes deficits that continue to worsen even as the patient is seen. Completed stroke is defined by the presence of persistent deficits, which may be stable or improving when the patient is seen; it does not necessarily imply that the entire territory of the involved vessel is affected or that no improvement has occurred since the onset.

Focal cerebral deficits that develop slowly (over weeks to months) are unlikely to be due to stroke and are more suggestive of another process, 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 (discussed in more detail later), 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.

Figure 13-2. Major cerebral arteries. The anterior and posterior cerebral circulations comprise arteries that arise anterior and posterior to the posterior communicating arteries, respectively. The circle of Willis is formed by the anterior communicating artery and the anterior cerebral, internal carotid, posterior communicating, and posterior cerebral arteries. (Reproduced, with permission, from Waxman S. Clinical Neuroanatomy. 26th ed. New York, NY: McGraw-Hill; 2010.)

Table 13-3. Territories of the principal cerebral arteries.

Table 13-4. Symptoms and signs of anterior and posterior circulation ischemia.

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 accounts for approximately 90% and hemorrhage for approximately 10% of strokes in typical American and European series. It may not be possible to distinguish between ischemia and hemorrhage from the history and neurologic examination, but CT scan or MRI permits a definitive diagnosis.

ISCHEMIA

Interruption of blood flow to the brain deprives neurons, glia, and vascular cells of substrate glucose and oxygen. Unless blood flow is promptly restored, this leads to ischemic 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 may occur in cardiac arrest with reperfusion, selective vulnerability of certain neuronal populations result in their preferential loss. More severe ischemia produces selective neuronal necrosis, in which all neurons die but glia and vascular cells are preserved. Complete, permanent ischemia, such as occurs in stroke, causes pannecrosis, affecting all cell types. If the patient survives, this ultimately produces chronic cavitary brain lesions.

Where ischemia is incomplete (20%-40% of normal)—as in the border zone or penumbra surrounding the core of an ischemic brain region—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.

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 recurrently.

Embolism

Embolism produces stroke when cerebral arteries are occluded by the distal passage of thrombus from the heart, aortic arch, or large cerebral arteries. Emboli in the anterior cerebral circulation most often occlude the middle cerebral artery or its branches, because approximately 85% of the hemispheric blood flow is carried by this vessel. Emboli in the posterior cerebral circulation usually lodge at the apex of the basilar artery or in the posterior cerebral arteries. Embolic strokes characteristically produce neurologic deficits that are maximal at onset. When TIAs precede embolic strokes, especially those arising from a cardiac source, symptoms typically vary between attacks 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 and compression of vascular structures, leading to secondary ischemia and edema. Intracranial hemorrhage is classified by its location as intracerebral, subarachnoid, subdural, or epidural, all of which—except subdural hemorrhage—are usually caused by arterial bleeding.

Intracerebral Hemorrhage

Intracerebral hemorrhage causes symptoms by compressing adjacent tissue (which can then produce local ischemia) and, to a lesser extent, by destroying tissue. Unlike ischemic stroke, intracerebral hemorrhage tends to cause more severe headache and depression of consciousness as well as neurologic deficits that do not correspond to the distribution of any single blood vessel.

Subarachnoid Hemorrhage

Calcium Dysregulation

Ca²⁺ is maintained at low cytoplasmic levels by a variety of sequestration and extrusion mechanisms. Ischemia-induced elevation of extracellular K⁺ causes membrane depolarization and triggers Ca²⁺ entry through voltage-gated Ca²⁺ channels, voltage-sensitive glutamate receptor-gated channels, and transient receptor potential channels. Ca²⁺ also enters through acid-sensitive ion channels activated by H⁺ produced by glycolysis. The rise in intracellular Na⁺ that results from loss of Na⁺/K⁺-ATPase activity causes the Na⁺/Ca²⁺ exchanger, which normally exports Ca²⁺ from cells against its concentration gradient, to operate in reverse and import Ca²⁺. In addition, Ca²⁺ induces further Ca²⁺ release from endoplasmic reticulum.

As intracellular Ca²⁺ levels rise, the Ca²⁺-buffering capacity of organelles (mitochondria and endoplasmic reticulum) and Ca²⁺-binding proteins is overwhelmed. Catabolic proteases, lipases, and nucleases are activated, mitochondrial function is compromised, and cell death pathways are mobilized.

Excitotoxicity

The term excitotoxicity refers to the pathogenic effects of excitatory neurotransmitters, especially glutamate, on central neurons. Ischemia promotes excitotoxicity by stimulating depolarization-induced synaptic release of neuronal glutamate, releasing glutamate through reversal of astrocytic glutamate uptake, and activating voltage-sensitive glutamate receptor-gated channels. The receptors primarily involved in excitotoxicity are N-methyl-D-aspartate (NMDA)-preferring, ionotropic (ion channel-coupled) receptors, especially those that are extrasynaptic and contain an NR2B subunit. In contrast, synaptic NMDA receptors are thought to be involved in normal glutamate-mediated neurotransmission.

Influx of Ca²⁺ through NMDA receptor-coupled channels contributes to the Ca²⁺ dysregulation described previously. In addition, this route of Ca²⁺ entry is closely linked to the activation of neuronal nitric oxide synthase (NOS1), which generates the gaseous transmitter (gasotransmitter), nitric oxide (NO). Neuronally derived NO contributes to nitrosative injury, as described later. In contrast, NO generated by endothelial nitric oxide synthase (NOS3) confers protection in ischemia, at least partly through its vasodilator properties.

Oxidative and Nitrosative Injury

Some of the toxic effects of ischemia are mediated through the production of highly reactive oxygen-containing species (ROS) and nitrogen-containing species (RNS). These include superoxide anion (O₂^–) and NO, which can combine to generate peroxynitrite (ONOO^–). Because these compounds contain oxygen, they are thought to act primarily during the reperfusion phase that follows ischemia. Their effects are protean, but 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 probably proceeds by several mechanisms, depending partly on location and time course. Death is thought to occur most rapidly in the infarct core and more slowly in the penumbra and during reperfusion. Rapid cell death in the ischemic core is epitomized by necrosis, in which cells and organelles swell, membranes rupture, and cellular contents spill into the extracellular space. However, slower and more regulated modes of cell death (programmed cell death), which require energy and protein synthesis, may predominate in the penumbra and during reperfusion injury.

The best characterized form of programmed cell death is apoptosis, which is associated with cell shrinkage, membrane blebbing without rupture, and DNA fragmentation. Apoptosis may be triggered by extracellular (extrinsic pathway) or intracellular (intrinsic pathway) signals; the latter predominate in stroke. Cell death via the intrinsic pathway can be subdivided further based on its dependence on cysteine-aspartic proteases (caspases). Both caspase-dependent and caspase-independent cell death prominently involve mitochondria. In both cases, Ca²⁺ overload and movement of proapoptotic proteins from cytoplasm to mitochondria alter the permeability of the outer mitochondrial membrane, permitting the release of additional proapoptotic factors. In caspase-dependent cell death, the major factor involved is cytochrome c, which translocates from mitochondria to the cytoplasm and activates caspase-9 and then the executioner caspase, caspase-3. In caspase-independent cell death, apoptosis-inducing factor (AIF) translocates from mitochondria to the nucleus, where it promotes DNA degradation.

Inflammation

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, and the observation that patients with total occlusion of a major vessel may sometimes be asymptomatic indicates that these pathways can be clinically functional. However, the fact that stroke occurs at all indicates that this is not always the case. Examples of collateral routes for cerebral blood flow 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

As noted previously, ischemic brain tissue is characterized by excessive excitation, caused by a combination of gluta-mate, extracellular K⁺, and other factors. This appears to be mitigated early in the course of stroke by enhanced tonic inhibition mediated through extrasynaptic GABA_A receptors. Later, however, this inhibitory effect may be detrimental to recovery.

Transcriptional Hypoxia Response

The cellular response to hypoxia is mediated partly by hypoxia-inducible protein-1 (HIF-1) and its transcriptional activation of proteins that promote cell survival and tissue recovery. These include glycolytic enzymes, erythropoietin (EPO), and vascular endothelial growth factor (VEGF). In addition to their respective effects on erythropoiesis and angiogenesis (discussed later), EPO and VEGF also exert direct protective effects on ischemic cells. Other cytoprotective proteins induced after ischemia include antiapoptotic proteins, growth factors, and heat-shock proteins.

Neurogenesis

New neurons and astrocytes continue to be produced in the adult brain in at least two regions: the hippocampal dentate gyrus and the subventricular zone surrounding the lateral ventricles. Cerebral ischemia stimulates neurogenesis, and some of the cells generated migrate from the subventricular zone to ischemic striatum and cerebral cortex. The extent to which they can replace the large numbers of cells lost after stroke is likely limited, but these cells may promote the survival and repair of ischemic brain tissue by releasing growth factors, suppressing inflammation, or other effects.

Angiogenesis

Ischemia also stimulates the sprouting of existing blood vessels to enhance local blood supply, which is mediated largely through the hypoxia response discussed previously and specifically by VEGF. Because this process takes at least several days, it probably has little impact in the acute phase of stroke, but may help to protect against subsequent ischemic episodes.

Ischemic Tolerance

Another mechanism through which ischemia may protect against a subsequent bout of ischemia is ischemic tolerance. In this process, mild ischemia preconditions brain tissue so it is better able to survive more severe ischemia for a few days thereafter. Ischemic tolerance appears to involve 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 the formation of new neuronal circuits. Not all of these changes are necessarily beneficial, however. For example, increased activation of the contralesional hemisphere may in some cases simply reflect more severe injury.

PATHOLOGY

LARGE VESSEL TERRITORY INFARCTION

On gross inspection, a recent infarct is a swollen, softened area of brain that usually affects both gray and white matter. Microscopy shows acute ischemic changes in neurons (shrinkage, microvacuolization, dark staining), destruction of glial cells, necrosis of small blood vessels, disruption of nerve axons and myelin, and accumulation of interstitial fluid from vasogenic edema. In some cases, perivascular hemorrhages are observed in the infarcted area.

LACUNAR INFARCTION

In contrast to infarcts associated with major cerebral blood vessels, smaller lacunar infarcts result from lipohyalinosis of small resistance vessels, usually in patients with chronic hypertension. Lacunar infarcts—often multiple—are found in approximately 10% of brains at autopsy. The pathologic appearance is of small cavities ranging in size from 0.5 to 15 mm in diameter.

CLINICAL-ANATOMIC CORRELATION

Infarction in the distribution of different cerebral arteries often produces distinctive clinical syndromes. Recognizing these syndromes can facilitate anatomic and sometimes etiologic diagnosis and thereby help guide treatment.

ANTERIOR CEREBRAL ARTERY

Anatomy

Figure 13-3. Arterial supply of the primary motor and sensory cortex (lateral view). The middle cerebral artery supplies parts of the primary motor and sensory cortex related to face and arm function, whereas the anterior cerebral artery supplies parts of the primary motor and sensory cortex related to leg function. This explains why middle cerebral artery strokes affect the face and arm most severely, whereas anterior cerebral artery strokes affect the leg. (Reproduced, with permission, from Waxman S. Clinical Neuroanatomy. 26th ed. New York, NY: McGraw-Hill; 2010.)

Figure 13-4. Arterial supply of the primary motor and sensory cortex (coronal view). (Reproduced, with permission, from Waxman S. Clinical Neuroanatomy. 26th ed. New York, NY: McGraw-Hill; 2010.)

Clinical Syndrome

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

Anatomy

Figure 13-5. Anatomic basis of middle cerebral artery syndromes. Stroke in the distribution of the middle cerebral artery causes hemiparesis affecting especially the face and arm (due to involvement of the primary motor area), hemisensory deficit affecting especially the face and arm (due to involvement of the primary sensory area), gaze preference toward the affected hemisphere (due to involvement of the frontal eye field), aphasia (due to involvement of Broca area, Wernicke area, or both, if in the dominant hemisphere), and hemianopia (due to involvement of the optic radiations leading to the primary visual area. (Reproduced, with permission, from Waxman S. Clinical Neuroanatomy. 26th ed. New York, NY: McGraw-Hill; 2010.)

Clinical Syndrome

The middle cerebral artery is the vessel most commonly involved in large vessel ischemic stroke. 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, contralateral hemisensory deficit in the same distribution, but no homonymous hemianopia. If the dominant hemisphere is involved, these features are combined with Broca (expressive) aphasia, which is characterized by impairment of language expression with intact comprehension.

2. Inferior division stroke is less common in isolation and 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, lack of awareness that a deficit exists [anosognosia], neglect of and failure to recognize the contralateral limbs, neglect of the contralateral side of external space, dressing apraxia, and constructional apraxia). If the dominant hemisphere is involved, Wernicke (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 involves a lesion situated at the point where the artery splits into two (superior and inferior) or three (superior, middle, and inferior) major divisions. This severe stroke syndrome combines the features of superior and inferior division stroke. Its clinical features include contralateral hemiparesis and hemisensory deficit involving the face and arm far more than the leg, homonymous hemianopia, and—if the dominant hemisphere is affected—global (combined expressive and receptive) aphasia.

INTERNAL CAROTID ARTERY

Anatomy

The internal carotid artery arises where the common carotid artery divides into internal and external carotid branches in the neck. In addition to its anterior cerebral and middle cerebral branches discussed previously, the internal carotid artery also gives rise to the ophthalmic artery, which supplies the retina. The severity of internal carotid artery strokes is highly variable, depending on the adequacy of collateral circulation, which tends to develop in compensation for a slowly evolving occlusion.

Clinical Syndrome

Intra- or extracranial internal carotid artery occlusion is responsible for approximately one-fifth of ischemic strokes. In approximately 15% of cases, progressive atherosclerotic occlusion of the internal carotid artery is preceded by premonitory TIAs or by transient monocular blindness caused by ipsilateral retinal artery ischemia.

Carotid artery occlusion may be asymptomatic. Symptomatic occlusion results in a syndrome similar to that of middle cerebral artery stroke (contralateral hemiplegia, hemisensory deficit, and homonymous hemianopia, together with aphasia if the dominant hemisphere is involved).

POSTERIOR CEREBRAL ARTERY

Anatomy

Figure 13-6. Sites of thrombotic and embolic occlusions in the vertebrobasilar circulation. A: Thrombotic occlusion of the basilar artery. B: Thrombotic occlusion of both vertebral arteries. C: Embolic occlusion at the apex of the basilar artery. D: Embolic occlusion of both posterior cerebral arteries.

Clinical Syndrome

Figure 13-7. Arterial supply of the brainstem. A: Midbrain. The basilar artery gives off paramedian branches that supply the oculomotor (III) nerve nucleus and the red nucleus (RN). A larger branch, the posterior cerebral artery, courses laterally around the midbrain, giving off a basal branch that supplies the cerebral peduncle (CP) and a dorsolateral branch supplying the spinothalamic tract (ST) and medial lemniscus (ML). The posterior cerebral artery continues (upper arrows) to supply the thalamus, occipital lobe, and medial temporal lobe. B: Pons. Paramedian branches of the basilar artery supply the abducens (VI) nucleus and the medial lemniscus (ML). The anterior inferior cerebellar artery gives off a basal branch to the descending motor pathways in the basis pontis (BP) and a dorsolateral branch to the trigeminal (V) nucleus, the vestibular (VIII) nucleus, and the spinothalamic tract (ST), before passing to the cerebellum (upper arrows). C: Medulla. Paramedian branches of the vertebral arteries supply descending motor pathways in the pyramid (P), the medial lemniscus (ML), and the hypoglossal (XII) nucleus. Another vertebral branch, the posterior inferior cerebellar artery, gives off a basal branch to the olivary nuclei (ON) and a dorsolateral branch that supplies the trigeminal (V) nucleus, the vestibular (VIII) nucleus, and the spinothalamic tract (ST), on its way to the cerebellum (upper arrows). (Reproduced, with permission, from Waxman S. Clinical Neuroanatomy. 26th ed. New York, NY: McGraw-Hill; 2010.)

Major stenosis or occlusion of the subclavian artery before it has given rise to the vertebral artery can lead to the subclavian steal syndrome, in which blood passes from the vertebral artery into the distal subclavian artery with physical activity of the ipsilateral arm. The syndrome is a manifestation of generalized atherosclerosis and is not predictive of stroke in the vertebrobasilar system. Patients are usually asymptomatic, and stroke, when it occurs, is typically due to coexisting carotid lesions.