ISCHEMIC STROKE: MECHANISMS, EVALUATION, AND TREATMENT

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CHAPTER 42 ISCHEMIC STROKE: MECHANISMS, EVALUATION, AND TREATMENT

Stroke is a major public health problem. An estimated 500,000 new and 200,000 recurrent strokes occur in the United States annually, and the number of stroke survivors is estimated to be about 4.8 million. Stroke is the leading cause of disability and the third leading cause of death in the United States (after coronary heart disease and cancer) and accounts for a health care cost burden estimated at $53 billion spent in the year 2004.1

Of all cases of stroke, 80% are ischemic and 20% are hemorrhagic (parenchymal and subarachnoid hemorrhages). This chapter focuses exclusively on ischemic stroke, discussing underlying causes, syndromes, acute treatment, and strategies for secondary prevention.

TRANSIENT ISCHEMIC ATTACK

Transient ischemic attacks (TIAs) have traditionally been distinguished from ischemic stroke on the basis of symptom duration, with the assumption, largely justified, that otherwise the two entities share risk factors and causes and that evaluation findings and secondary prophylaxis are similar for the two. TIA has traditionally been defined as a focal neurological deficit of abrupt onset, referable to a vascular territory, that lasts less than 24 hours. However, the 24-hour definition is arbitrary and is not based on any plausible biological mechanism. In fact, most TIAs resolve in less than an hour. In addition, studies have demonstrated that a significant proportion of clinically defined TIAs are not necessarily transient at the tissue level; there is evidence of tissue infarction on magnetic resonance imaging (MRI) performed early in the course of the syndrome.2,3 Indeed, in view of the advances in neuroimaging and epidemiological studies, a panel of experts has proposed that TIA be defined as a brief episode of neurological dysfunction caused by retinal or brain ischemia with symptoms lasting less than 1 hour and without evidence of acute infarction on neuroimaging (diffusion-weighted imaging [DWI] or computed tomography [CT] scan).4 When the symptoms and signs do not fit criteria for a TIA—that is, they persist for more than 1 hour and/or there is evidence on neuroimaging of tissue infarction—the syndrome is classified as an ischemic stroke. The modified duration for TIA is of practical benefit, in view of the new time window–dependent strategies for acute stroke management, when a decision for acute intervention should not be contingent on resolution of a patient’s signs and symptoms within 24 hours. However, the neuroimaging component of the proposed new definition is problematic because it sidesteps what is arguably most important about clinically defined TIAs: their reversibility. If symptoms resolve in under an hour but a lesion is identified with DWI, then what is the difference between this entity and ischemic stroke whose symptoms do not resolve? In addition, a definition of TIA based on the absence of a DWI lesion has the odd consequence of eliminating duration as an important distinguishing feature, inasmuch as studies have shown that a substantial proportion of patients with symptoms lasting less than an hour have DWI lesions. Indeed, one DWI study revealed that symptom duration could not distinguish TIA from ischemic stroke.5

Study findings support the contention that it is symptom duration or, more specifically, the rate of symptom reversal from time of onset, that is the essential characteristic of TIA; data indicate that risk of recurrent stroke is substantially higher in patients with rapid recovery than in those with fixed deficits and subsequent slow recovery.68 The largest study of risk of recurrent stroke after TIA showed that 50% of all ischemic strokes after TIA occur within 48 hours of the TIA.9 Thus, the presence or absence of lesions on DWI should not be required for a definition of TIA, only that the deficit substantially reverses, not necessarily fully, in less than an hour. This is not to say that DWI does not provide useful information about TIA mechanisms. For example, it has been shown that patients with deficits that reverse in less than 24 hours but who have DWI lesions have the highest risk of in-hospital recurrent stroke. This subgroup may have made up a substantial proportion of the patients in the large study mentioned previously.

The critical implication of the spate of studies on TIA is that TIA reflects a more unstable condition than does stroke and merits immediate attention. A TIA is to the brain what unstable angina or non–Q-wave myocardial infarction is to the heart, a condition of fluctuating tissue perfusion that is unstable and threatens tissue viability. TIA should be viewed as a medical emergency that necessitates immediate diagnostic workup and treatment. The clinical seriousness of TIA makes accurate diagnosis very important, but because the symptoms have nearly always resolved by the time the patient is seen by a physician, careful history taking is essential. This can be a challenge because a large number of nonischemic conditions, such as migraine, seizures, and multiple sclerosis, cause transient neurological symptoms. TIAs themselves vary in their mode of presentation, variation attributable primarily to the underlying cause. Different TIA presentations are therefore discussed as follows as they relate to each stroke subtype.

ISCHEMIC STROKE

Ischemic strokes usually cause sudden loss of one or more functions as a result of acute damage to specific CNS structures supplied by a particular vessel. However, symptoms can also give patients the sense that something unpleasant, such as vertigo or hiccoughing, has been acquired rather than lost. The presentation can be more or less fulminant and depends on the specific structures involved and the amount of tissue damage.

All strokes are ultimately caused by tissue perfusion failure. The brain goes through a series of autoregulatory protective responses as cerebral perfusion pressure (CPP) drops, as a result of either systemic hypotension or a local arterial stenosis, or both. As CPP falls, arterioles dilate to maintain cerebral blood flow (CBF), which results in an increase in cerebral blood volume. When no further vasodilation is possible, CBF becomes passively dependent on CPP, but over a certain range of low CPP, neuronal metabolism (the cerebral metabolic rate of oxygen) can be maintained by increasing the blood oxygen extraction fraction (OEF). OEF is usually about 30% to 40% but can increase to near 100%.

Experimental studies in nonhuman animals and observations in patients indicate that there are two critical CBF thresholds. Below the first, 16 to 18 mL/100 g/minute, there is loss of neuronal electrical function (electrical failure). Below the second, 10 to 12 mL/100 g/minute, there is loss of cellular ion homeostasis (membrane failure). The concept of the ischemic penumbra is of central importance to therapeutic approaches to stroke and follows directly from the observation that there are separate CBF thresholds for electrical and membrane failure. The ischemic penumbra is a shell of electrically unexcitable but still viable neuronal tissue surrounding a core of ischemic irreversibly damaged tissue. The ischemic penumbra is in a state of misery perfusion where CBF is reduced, OEF is increased, and cerebral metabolic rate of oxygen is relatively preserved. The therapeutic importance is that a state of misery perfusion cannot be sustained indefinitely, and if CBF is not restored, the tissue proceeds to infarction.

In order to salvage penumbral tissue, CBF must be restored in the critical time window between electrical and membrane failure. There is good evidence, obtained mainly with positron emission tomographic (PET) studies,10 that ischemic penumbra exists in human and nonhuman primates and that it remains viable for longer and more variable periods of time than was suggested by initial small mammal experiments. Advances in MRI have made significant inroads in identifying the ischemic penumbra in patients after stroke and making it a target for therapeutic intervention (see “Stroke Evaluation” section). TIA might represent a form of penumbral phenomenon without an infarct core, and new data on the instability of TIA reflect the high risk of proceeding to infarction in this penumbral tissue.

STROKE CLASSIFICATION BY MECHANISM (STROKE SUBTYPES)

Despite the final common pathway for tissue ischemia and infarction, it is important to classify ischemic strokes according to their etiological subtype. This is achieved on the basis of clinical features and results of ancillary tests. Accurate subclassification ensures consistency in terminology for larger registries and clinical trials, and conversely, correct translation to the practice setting of knowledge obtained from clinical trials. Assigning a stroke a subtype designation implies an inference about mechanism and natural history, both crucial for treatment and prognosis. Causes of ischemic strokes are generally subdivided into large-artery atherosclerosis (LAA), penetrating small-artery disease, cardiac embolism, cryptogenic stroke, and strokes of other determined cause such as hypercoagulability, migraine, and cervical artery dissection. These subdivisions are not mutually exclusive in terms of stroke mechanism. For example, atherosclerosis with superimposed thrombus in a large vessel may lead to occlusion of an exiting perforator. Thus, although the underlying cause is LAA, the mechanism of stroke is small-vessel occlusion. Similarly, the mechanisms of stroke in the category of strokes of other determined cause overlap substantially with those of the other four categories, but they nevertheless have unique etiological features that merit individual consideration.

Large-Artery Atherosclerosis

This subtype is characterized by evidence for atherosclerosis (anterior or posterior circulation) in the large-vessel vascular distribution of a brain infarction, in the absence of a cardiac source of embolism. The most common location for atherosclerotic changes is at the bifurcation or proximal takeoff of the large vessels, where the shear stress on the wall, from turbulent flow usually related to long-standing hypertension, is maximal. The arterial narrowing can be either extracranial (in the carotid or vertebral arterial system) or intracranial (in the many tributaries of the circle of Willis and their branches). The pattern of parenchymal involvement can be small or large, cortical or subcortical, and is determined largely by the status of pial-pial collaterals and the circle of Willis. There are two other infarction patterns associated with proximal large vessel disease: border zone and watershed. Border zone infarction corresponds to involvement of areas at the junction of the distal fields of two nonanastomosing arterial systems. Watershed infarctions occur at a zone of pial-pial artery anastomoses between two large vessels: for example, the middle cerebral artery (MCA)–posterior cerebral artery (PCA) watershed. There are internal border zones (misleadingly also referred to as internal watersheds) in the centrum semiovale and paraventricular corona radiata, regions at the junction of subcortical and medullary penetrators off the MCA, and in the subinsular zone, a region between small insular penetrating arteries and the lateral lenticulostriate vessels.11 Thus, for example, critical internal carotid artery (ICA) stenosis or occlusion can cause watershed infarction at (1) the boundary of the anterior cerebral artery (ACA) and MCA, manifesting as a thin wedge extending from the anterior horn of the lateral ventricle to the frontal cortex or a string of infarction at the medial convexity surface; (2) the MCA/ACA/PCA boundary, often more difficult to distinguish from MCA branch occlusion, but again appearing as a cortical wedge extending from the occipital horn of the lateral ventricle to parieto-occipital cortex; and (3) a confluent or discontinuous long lesion in the centrum semiovale running parallel to the lateral ventricle.

Interpretation of patterns of infarction from large vessel disease is based on assumptions about underlying mechanisms: (1) large-vessel stenosis or occlusion by in situ disease or artery-to-artery embolism and (2) flow-failure distally from a more proximal occlusion or hypotension. However, these mechanisms are likely to coexist. A high-grade ICA or MCA stenosis may be both emboligenic and cause a low-flow state. The low-flow state reduces the chances of clearing small embolic particles from distal arterial beds, leading to a border zone or watershed pattern of infarction.12 In addition to producing cortical, subcortical, and watershed patterns of infarction, LAA can occlude the os of a single penetrating small vessel, causing a lacunar infarct (see later discussion). Thus, the variety of infarct patterns possible with LAA makes diagnosis based on clinical examination or infarct pattern alone difficult. A bruit on examination and the presence of other atherosclerotic risk factors or markers such as hypertension, elevated cholesterol, diabetes, smoking history, peripheral arterial disease, and coronary artery disease, are marginally helpful at best. Indeed, it is debatable whether there is any significant difference in modifiable risk factor profile and predisposition to LAA versus small-vessel disease.13 Information regarding race/ethnicity can be helpful, inasmuch as white persons have a higher incidence of extracranial atherosclerosis, whereas Asian, black, and Hispanic persons have a higher incidence of intracranial atherosclerosis.

Interestingly, unlike completed infarction, LAA-associated TIAs do have distinctive features that help make the diagnosis. Intermittent flow-failure through a critical stenosis, often brought on when the patient stands up suddenly or by overly aggressive antihypertensive therapy, can cause focal neurological deficits that reverse when the patient lies down. More rarely, patients manifest a “limb-shaking” TIA, consisting of brief periods of shaking of an extremity brought on by standing or sitting up, easily confused with a focal motor seizure. Another strong clue to LAA is an unstable course in the first 24 hours after stroke onset, manifested by deterioration after improvement.14

Determination of LAA as the underlying cause of a stroke through ancillary testing (see “Stroke Evaluation” section) is important because there is a high rate of early stroke recurrence in this subgroup of patients,15 both for extracranial and intracranial atherosclerosis. This is also true for the long term because patients with symptomatic ICA stenosis with greater than 70% diameter reduction have a stroke recurrence risk of 26% in 2 years.16 The recurrence rate for patients with symptomatic MCA stenosis is about 10% a year.17,18 Because of this relatively high risk of early recurrence and the established benefit of early endarterectomy in long-term stroke prevention for ICA stenosis, identification of this subtype of stroke is critical.19

Small-Vessel Atherosclerosis (Lacunar Strokes)

The definition of lacunar infarction has become quite confused. We believe that it should be a combined clinical and radiological diagnosis that is based on a presentation with one of a handful of typical syndromes (see “Lacunar Syndromes” section) and imaging evidence for a small infarct (2 to 20 mm in diameter) in the deep cerebral white matter, basal ganglia, thalamus, or pons. Evidence suggests that in situ single perforator disease is the cause in the majority of cases. Exclusion of LAA and a cardiac source of embolism is important, because lacunar infarction is estimated to originate from emboli or LAA in about 10% to 15% of cases.20 This may be true particularly for patients who have a lacunar syndrome with evidence of multiple subacute lesions on neuroimaging.21

The lacunar hypothesis remains controversial, and some commentators have gone as far as to recommend abolishing the category and substituting it with “small stroke,” assuming the same risk factors and causes as large strokes. This understandable exasperation stems from the tendency to use the term lacune for any small subcortical stroke, with the associated erroneous assumption that all subcortical strokes are caused by in situ small vessel disease. Thus, it should be emphasized that the term should be reserved for the clinicoradiological definition given at the beginning of this section. Subcortical strokes can also arise from occlusion of medullary penetrators that supply the centrum semiovale, from internal border zone infarctions, and from multiple perforator involvement resulting from embolic or intrinsic large-vessel disease (e.g., striatocapsular infarction from MCA stem disease).

However, despite these concerns, evidence favors preserving the lacunar infarction stroke category from a pathophysiological standpoint. First, the presence of lacunar infarcts is correlated with leukoaraiosis and with subcortical microhemorrhages.22 These correlations suggest that lacunar infarcts are manifestations of a more diffuse abnormality of small cerebral arterioles.23 Second, the proportion of embolic sources identified in patients with lacunar infarction is lower than that of hemispherical ischemic strokes. Third, after a lacunar infarction, a recurrent stroke is more likely to be lacunar than nonlacunar.23a This would not be expected if lacunar infarcts shared the same mechanism with larger cortical strokes. In addition, the early stroke recurrence rate is lower than those for LAA and cardioembolic stroke. Fourth, in a primate model, only 6% of even the smallest particles injected in the carotid artery ended up in the lenticulostriate vessels.23b

The pathology underlying lacunar infarction is still debated, mainly because lacunar infarcts are seldom fatal and cases are thus rarely subjected to autopsy. Nevertheless, it is assumed that lacunar infarction results from occlusion of a small penetrator by atheroma blocking its origin, by embolus, or by an intrinsic process, lipohyalinosis (narrowing the lumen at points along its length). Lenticulostriate pathology after lacunar infarction has been visualized with MRI.24 These images show a linear structure with signal features consistent with perforator occlusion by thrombus or leakage of vessel contents into the surrounding parenchyma. These findings support the idea of a pathological process unique to deep perforating arteries, which can cause lacunar infarction. Occlusion of the vessel itself might cause infarction, or blood vessel contents might be toxic to surrounding parenchyma. A spectrum of perforator disease with luminal thrombus and leakage of contents into the blood vessel wall and then into the perivascular tissue might explain the previously mentioned correlation among lacunar infarcts, leukoaraiosis, and deep microhemorrhages. In addition, a leakage mechanism might also explain an interesting feature of TIAs associated with lacunar infarction: the “capsular warning syndrome.” This consists of a stuttering cluster of stereotypical events over a period of about 72 hours. These events are brief bursts of typical lacunar phenomena that can come and go over minutes. Many of these patients progress to a fixed deficit; it is possible that the capsular warning syndrome evolves because a single penetrator undergoes occlusion or leakage damages surrounding tissue directly.23

Cardioembolic Strokes

Embolism of cardiac origin accounts for about 20% to 40% of ischemic strokes. Atrial fibrillation is the best established cause of cardioembolic stroke, and its identification is extremely important, in view of the relatively high recurrence rates (about 10% a year) and the effective prophylaxis (approximately 60% absolute risk reduction) achieved with chronic oral anticoagulation. Other known emboligenic sources, treated with anticoagulation, are valvular disease (especially prosthetic valves), documented intraventricular thrombus present in severe cardiomyopathies, and recent myocardial infarction. In one study, transesophageal echocardiography (TEE) was used to assess 151 consecutive patients, 1 week after ischemic stroke or TIA.24a Intracardiac thrombus was identified in 26% of the patients (70% in the left atrial appendage). Multivariate analysis showed an association with large stroke, symptomatic coronary artery disease, and evidence for ischemia on electrocardiogram.

Interatrial septal abnormalities, such as patent foramen ovale (PFO) and atrial septal aneurysm (ASA), result from failure of the septum to close at birth and occur in about 25% of the general population.24b Interatrial septal abnormalities are thought to be an important cause of embolic stroke in patients younger than 55. A PFO is an intact interatrial connection through the two overlapping septa that form the interatrial septum. An ASA is a hypermobile piece of the atrial septum that can protrude through the PFO into the left atrium during the cardiac cycle. PFOs can serve as a conduit for embolism originating from the venous circulation (lower extremity or pelvic venous thromboses) to the arterial circulation through right-to-left shunting of blood during the cardiac cycle and especially during Valsalva maneuvers. ASAs seem to enhance the stroke risk of a PFO, possibly by directing flow through the PFO or acting as a nidus for thrombus formation itself. A metaanalysis revealed a 24-fold increased risk of stroke in patients younger than 55 who had both a PFO and an ASA, in comparison with a fivefold risk in patients with only a PFO.25 The high frequency of interatrial septal abnormalities in the general population in comparison with the relatively low incidence of stroke in persons younger than 55 suggests that a second factor needs to combine with PFO in order for stroke to occur. Studies have shown increased frequency of two inherited hypercoagulable disorders, the factor V Leiden and the prothrombin 20210 mutations, in young patients with stroke and PFO.25a,25b Thus, perhaps a combination of PFO and an underlying hypercoagulable state, either acquired or inherited, is required in order for a PFO-related stroke to occur. In contrast to patients younger than 55, it does not seem that interatrial septal abnormalities are a substantial stroke risk in older patients, possibly because left-sided atrial pressures increase with aging. In all patients with stroke and PFO, it is important to emphasize the need for a thorough search for the other potential causes of stroke before attributing it to the PFO.

Prospective studies have shown that aortic arch atheroma is found more often in patients with stroke and that the presence of aortic arch atheroma, detected by TEE, is associated with increased risk of future stroke. A metaanalysis of these prospective studies gave an odds ratio for recurrent stroke of 3.76, similar in magnitude to those for atrial fibrillation and high-grade carotid stenosis.26 Aortic arch atheroma, occurring with increasing age and in people with vascular risk factors,27 may be just a marker for atherosclerosis. However, a number of observations suggest that aortic arch atheroma causes embolic stroke. First, aortic arch atheroma is often present in patients with stroke but without concomitant carotid disease. Second, stroke risk is highest for atheroma with mobile components. Third, stroke is more common in the presence of aortic arch atheroma than with atheroma in the thoracic aorta.28 Fourth, left hemisphere events are more common than right hemisphere events, and most atheroma is found in the middle to distal arch, after takeoff of the innominate artery.29

Less common sources of embolism from the heart are infectious and noninfectious (marantic) endocarditis, fibroelastoma, air, and atrial myxoma. In addition, there are a number of cardiac abnormalities whose embolic potential remains uncertain but is likely to be low. These include mitral valve prolapse, valvular strands, and mitral annulus calcification.

A number of clinical features and radiographic features suggest cardioembolic stroke: (1) sudden onset with rapid progression to maximal focal neurological deficit (<5 minutes); (2) simultaneous or sequential strokes in multiple arterial territories, such as a left homonymous hemianopia and a right hemiparesis; (3) Wernicke’s aphasia (inferior division of the left MCA) and visual field cuts (distal PCA); (4) a large deficit that then rapidly regresses, probably as a result of recanalization of a large proximal vessel; (5) appearance on imaging, especially DWI, of bihemispherical, both anterior and posterior territory, or bilateral or multilevel posterior circulation infarcts (the typical pattern of stroke on MRI is a wedge-shaped lesion with its base at the cortex and the apex located subcortically); (6) hemorrhagic transformation of an ischemic infarct as a result of recanalization and irrigation of infarcted tissue or, less likely, dissection at the site of thrombus impact; and (7) the presence of single or multiple small subcortical infarcts in the absence of cortical infarcts, which makes the diagnosis of embolic stroke less likely.30

Stroke of Other Determined Cause

Other determined causes can be found in about 5% of patients with stroke after extensive diagnostic investigation. Causes include arterial dissection (spontaneous or traumatic), migraine, moyamoya disease, inherited or acquired hypercoagulable states, inflammatory vasculopathy (primary or secondary CNS angiitis), hyperviscosity, and vasospasm (secondary to aneurysmal subarachnoid hemorrhage, vasoconstrictive drugs, or pregnancy). Some of these are discussed in more detail as follows.

Dissection is a tear in the intima or the media that allows luminal blood to be redirected into a false lumen within the blood vessel wall, with formation of an intramural hematoma, which may limit flow (Fig. 42-1) or cause aneurysmal dilatation. Arterial dissection of the extracranial portions of the carotid and vertebral arteries accounts for only about 2% of all ischemic strokes but for up to 25% of ischemic strokes in patients younger than 55. Cervical artery dissection can occur after clear-cut neck trauma (motor vehicle accidents, attempted strangulation, fall with neck injury), after relatively trivial mobilization of the neck (hair washing, chiropractic manipulation),31 or spontaneously, without any obvious precipitant. The latter two scenarios probably reflect an underlying structural weakness of the arterial wall, inasmuch as dermal connective tissue abnormalities have been detected in up to a third of these cases. Approximately 5% of spontaneous dissections can be attributed to inherited disorders of collagen structure, the most common of which is Ehlers-Danlos syndrome type IV. Others include Marfan’s syndrome, autosomal dominant polycystic kidney disease, and osteogenesis imperfecta type I. In addition, about 5% of patients have a family history of dissection. Approximately 15% of patients have angiographic evidence of fibromuscular dysplasia. Infection, migraine, and elevated homocysteine have also been associated with dissection, but these risk factors have mainly been assessed with case-control studies, which are subject to information and selection bias, as well as confounding.32

The extracranial carotid and vertebral arteries are particularly prone to dissection because they are mobile and thus susceptible to injury from bony structures such as the cervical vertebrae or the styloid process. In addition, exposure of the media to blood leads to thrombus formation, which can embolize distally.

Carotid dissection usually occurs 1 to 2 cm above the bifurcation and classically manifests with a subset or with all of the following: unilateral facial, retroorbital, or neck pain; partial Horner’s syndrome (facial anhidrosis is not present because facial sweat glands are innervated by sympathetic nerves traveling on the external carotid artery); and cerebral or retinal ischemia at a delay of hours to days. The lower cranial nerves, most often the hypoglossal, can also be affected.

Vertebral dissection usually occurs either at the level of the first and second cervical vertebrae or proximally, just before entry into the intervertebral foramen, and classically manifests with posterior neck pain radiating to the occiput and delayed ischemia in the posterior circulation; with posterior inferior cerebellar artery (PICA) territory infarction being most common.

There is fairly good evidence of a relationship between migraine and stroke, but proving causality is much more difficult: Does a stroke precipitate a migraine attack in predisposed patients, or does migraine lead to infarction? The truth, as always, is likely to be that both can occur. The best evidence for migraine as a direct cause of stroke is migrainous infarction, defined as a stroke that occurs during a migraine attack, and the deficit is a persistent version of the patient’s typical aura. For example, homonymous hemianopia is a frequent aura in patients with migraine, and the occipital cortex is the most frequent site pf migrainous infarction. Even in this scenario, which is rare, the diagnosis of migrainous infarction should be made only if no other cause of the stroke can be determined. Migrainous infarction tends to occur after prolonged migraine attacks, which suggest that efforts should be made to abort such attacks. In addition to migrainous infarction, migraine with aura is a risk factor in women younger than 45 for stroke occurring outside a period of migraine attack, a risk that is substantially increased by smoking and/or oral contraceptive use.

Moyamoya disease occurs in younger patients and is characterized by a progressive intracranial occlusive noninflammatory vasculopathy of the distal ICA and its bifurcation into the middle and anterior cerebral arteries. Its hallmark is the development of deep intracranial collateral vessels, usually in the lenticulostriate vessels, giving its peculiar characteristic defined by Japanese investigators as “puff-of-smoke” (Fig. 42-2). Its cause is unclear but does not seem to be an inflammatory process, as in the primary CNS vasculitides. A similar pattern can occur with other conditions such as prior pituitary tumor irradiation, Down syndrome, neurofibromatosis, and sickle cell disease. In these situations, the pattern appears secondary to the underlying condition and is described as moyamoya syndrome rather than moyamoya disease. It should be suspected in young patients with deep hemispherical hemorrhage but without the associated risk factors for intracerebral hemorrhage (ICH) and in young patients with cryptogenic ischemic stroke, especially if one of the commonly associated conditions listed previously is present.

CLINICAL SYNDROMES

Lacunar Syndromes

There are five classical lacunar syndromes (Table 42-1): pure motor hemiparesis, pure sensory syndrome, sensorimotor syndrome, dysarthria–clumsy hand syndrome, and ataxic hemiparesis. It should be emphasized however, that many additional, albeit rarer, lacunar syndromes almost certainly exist and that nonlacunar subcortical and cortical strokes can cause the classical syndromes.32a For example, an embolus to the rolandic branch of the MCA could affect the primary sensorimotor cortex and cause sensorimotor syndrome. Another example is occlusion of a paramedian pontine penetrator by basilar artery atheroma, causing pure motor hemiparesis. However, studies have shown an excellent positive predictive value of the lacunar syndromes for the presence of lacunar infarction on brain imaging.

TABLE 42-1 Classic Lacunar Syndromes with Vascular Territories and Anatomical Structures Most Commonly Affected

Lacunar Syndromes (Structures Affected) Vessel Distribution
Pure Sensory Syndrome
Thalamus Thalamic perforators
Pure Motor Hemiparesis
Basis pontis Pontine penetrators (basilar branch)
Posterior limb of internal capsule Lenticulostriate vessels (MCA branches)
Cerebral peduncle Basilar or PCA penetrators
Dysarthria–Clumsy Hand Syndrome
Anterior limb or genu of internal capsule Lenticulostriate vessels (MCA branches)
Basis pontis Pontine penetrators (basilar branch)
Ataxic Hemiparesis
Contralateral basis pontis Pontine penetrators
Contralateral thalamus Thalamic penetrators
Posterior limb of internal capsule Lenticulostriate branches
Sensorimotor Syndrome
Posterior limb of internal capsule and thalamus Lenticulostriate branches

MCA, middle cerebral artery; PCA, posterior cerebral artery.

The typical clinical presentations of a lacunar stroke reflect the most commonly involved structures: putamen, caudate, thalamus, basis pontis, internal capsule, and corona radiata.

Pure Motor Hemiparesis

This is the most common manifestation of a lacunar stroke. In this syndrome, there is motor involvement of the face, arm, and leg, sometimes with more involvement of one than the other, but with absence of sensory, visual, language, or other cortical symptoms. There are often varying degrees of dysarthria and dysphagia, as a result of involvement of corticobulbar tracts. Structures commonly involved in this syndrome reflect the descending course of the corticospinal tract: the corona radiata, the posterior limb of the internal capsule (Fig. 42-3), and the basis pontis. Less often, a midbrain peduncular or medullary pyramidal infarct (with sparing of the face) can also cause this syndrome. The diagnosis of brainstem pure motor hemiparesis requires the absence of all the following: vertigo, deafness, tinnitus, diplopia, nystagmus, and ataxia. Traditionally, it has been taught that isolated monoparesis, usually brachial, is rarely caused by lacunar infarct but instead indicates a cortical or centrum semiovale lesion, regions where the motor homunculus is more spatially separated. However, with the advent of MRI, this has been shown not to be the case. Isolated monoparesis is compatible with small-vessel disease: for example, in the corona radiata and pons.33

Cortical Syndromes

The most commonly encountered clinical syndromes (Table 42-2) are briefly reviewed according to vessel distribution and associated stroke causes.

Anterior Circulation

Middle Cerebral Arteries

The MCAs account for about 80% of the blood flow to the cerebral hemispheres and are the arteries most commonly involved in hemispherical strokes. Also, because of the key structures supplied by them, they give rise to some of the most florid and dramatic ischemic stroke syndromes found in clinical practice.

The mechanisms by which the MCAs can be affected are multiple but most commonly involve either an embolism from a more proximal source such as the heart, aorta, or the large cervical vessels (i.e., cardioembolic and large-artery strokes, progressive intracranial disease from atherosclerosis) or other less common conditions such as sickle cell disease, postirradiation changes, moyamoya syndrome, primary CNS angiitis, and focal intracranial dissection.

The location in which embolic material can lodge is variable and includes the proximal MCA stem (usually associated with a more severe syndrome due to involvement of lenticulostriate arteries), its bifurcation (in which case the deep lenticulostriate branches are spared), or at one of the more distal branches beyond the bifurcation (the superior or inferior division and their smaller distal branches). The site of vessel occlusion and the extent of the collateral supply in a given individual determine the amount of tissue damage and therefore the clinical presentation. Individuals with limited collateral supply (from distal branches of the large vessels in the circle of Willis or from extracranial to intracranial anastomoses) are the more severely affected and have the worst prognosis. These patients usually have very large hemispherical strokes affecting the cortical and subcortical territories and are prone to massive hemispherical swelling and subsequent herniation (the “malignant MCA syndrome”).

Middle Cerebral Artery Stem Occlusion

The proximal syndrome is usually dramatic and reflects damage to the basal ganglia and internal capsule, supplied by the medial and lateral lenticulostriate branches that arise from the dorsal surface of the MCA stem, as well as large areas of cortical infarction in the territories of the superior and inferior divisions of the MCA (Fig. 42-4). The typical patient presents with contralateral hemiplegia with equal involvement of the arm and leg, variable degrees of primary sensory abnormality, dysphagia, and hemianopia. There is forced eye deviation toward the side of the affected hemisphere, sometimes with accompanying ipsilateral head deviation. With dominant hemispherical involvement, there is usually global aphasia, buccofacial apraxia, and ideomotor apraxia. In the first few days there may be frank mutism. With nondominant hemispherical involvement, there is usually contralateral hemineglect, contralateral anosognosia, and delirium. Less frequently, syndromes more often associated with bilateral hemispherical damage, such as prosopagnosia and the reduplicative paramnesias, can be present with unilateral nondominant hemisphere damage. Individuals with an MCA stem occlusion are the most likely to develop massive hemispherical swelling with midline shift, and subfalcine and transtentorial herniation. The prognosis for these patients is guarded, and in complete MCA-distribution strokes, the mortality rate can be as high as 80% despite neurointensive care efforts.

Middle Cerebral Artery Upper Division Occlusion

Isolated involvement is uncommon because the superior trunk is short, but when it occurs, it is usually caused by ICA or MCA atherosclerosis (Fig. 42-5). This division supplies most of the frontal convexity and anterior parietal lobe, and the syndrome resembles stem occlusion with a contralateral hemiparesis, forced eye and head deviation toward the side of the lesion, and variable degrees of aphasia and hemineglect. In contrast to stem occlusion, motor deficits are characterized by a gradient of weakness with the contralateral side of the face and arm (brachiofacial pattern) more severely affected than the leg, reflecting the involvement of the corresponding cortical structures rather than the internal capsule. A visual field defect is usually absent.

With dominant hemispherical involvement, there is language disturbance characterized in the acute phase by global aphasia, which tends to reduce to predominantly Broca’s aphasia and speech apraxia. This highlights the fact that in the acute stroke setting, vascular aphasias are often global and nonclassic in their presentation.35 With nondominant involvement, there may be some degree of visuospatial neglect but usually not as pronounced as with a larger territorial infarct. Acute agitated delirium is usually not present, because this requires infarction of the right middle temporal gyrus and inferior parietal lobule, supplied by the inferior division of the MCA (see later discussion). Because of the smaller volume of tissue infarction, upper-division MCA-distribution strokes do not cause the same high rate of mortality observed with holo-MCA strokes but carry a significant degree of long-term disability that necessitates intensive rehabilitation.

Anterior Cerebral Arteries

In comparison with strokes in the MCA distribution, ACA-distribution strokes are uncommon and are most often secondary to embolism from a proximal source such as the carotid artery or the heart. Less frequent causes of an ACA-distribution stroke include vasospasm from a ruptured saccular aneurysm (anterior communicating artery), in which case the strokes may be bilateral, and inflammatory vasculopathy involving the intracranial vessels. The most common manifestations of an infarct in the distal territory of the ACA are a function of the territories supplied: anterior and medial frontal lobes, including the motor-sensory cortex for the contralateral foot and leg; the supplementary motor area; and the central bladder representation, and also of lesion side36 (Fig. 42-6).

Left-sided infarction causes transient akinetic mutism (abulia), transcortical motor aphasia, contralateral leg and shoulder weakness with sparing of the distal upper extremity and face, and contralateral deficits in higher order sensory functions such as stereognosis (ability to discriminate two simultaneous stimuli) and joint-position sense discrimination. Right-sided infarction causes acute confusional state, motor hemineglect, transient akinetic mutism, contralateral hemiparesis, and sensory deficits in the pattern described for left-sided infarction. Predominant leg weakness is not unique to ACA infarction; it is also present with MCA-territory cortical infarction. It can also be present with capsular and pontine infarcts. In general, lesions that affect the medial premotor cortex, the supplementary motor area, and the rear portion of the medial part of the precentral gyrus, or their projections, can cause leg-predominant hemiparesis.37

Bilateral ACA infarction causes persistent akinetic mutism, sphincter dysfunction (urinary more than defecatory incontinence) and paraplegia or tetraplegia. Bilateral ACA strokes can occur when both ACAs originate from the same carotid system, when only one ACA supplies both medial hemispheres (azygous ACA), in vasospasm from subarachnoid hemorrhage, or in the setting of an extrinsic lesion compressing both the ACAs (intraparenchymal hemorrhage, head trauma, subfalcine herniation).

In addition to abulia and predominant leg weakness, callosal disconnection syndromes can help distinguish ACA from MCA infarcts. The three main syndromes are left unilateral ideomotor apraxia, agraphia, and tactile anomia. All three syndromes affect the left hand in right-handed patients. Left unilateral ideomotor apraxia, also called the anterior disconnection syndrome, is the inability to perform overlearned skilled movements in response to verbal command. Patients with left-hand agraphia have severely impaired handwriting with their left hands but not their right. Patients with unilateral tactile anomia are unable to name objects placed in their left hands. All three syndromes are probably caused by interruption of transcallosal information to or from the language areas in the left hemisphere. They usually result from infarcts in different regions of the corpus callosum caused by interruption of pericallosal branches of the ACA. However, these syndromes, although of phenomenological interest, are overemphasized, in view of their low frequency of occurrence. They are relatively rare probably because the anterior corpus callosum is supplied by both ACAs.

The two to four recurrent arteries of Heubner arise near the junction of the anterior communicating artery and the ACA and supply the inferior part of the head of the caudate nucleus, the adjacent anterior limb of the internal capsule, and the subfrontal white matter. Caudate infarcts cause prominent behavioral abnormalities, including abulia, agitation, aphasia, and hemineglect. Extension of the infarct into the anterior limb of the internal capsule and anterior putamen can lead to dysarthria, movement disorders, and mild hemiparesis. However, the only study to associate symptomatic caudate infarcts with their culprit vascular territory showed that only one infarct was in the territory of Heubner’s arteries; the rest were in the territory of lenticulostriate vessels off the MCA.

Anterior Choroidal Artery

The anterior choroidal artery (AChA) is the most distal branch of the ICA, originates just after the origin of the posterior communicating artery, and courses posterolaterally to supply the anterior medial temporal lobe, the optic tract, the geniculate body, the medial globus pallidus, the medial third of the cerebral peduncle, portions of the ventral and pulvinar thalamus, and the posterior limb of the internal capsule. There is controversy over whether the AChA or the lateral lenticulostriate vessels supply the posterior paraventricular region of the corona radiata. The regions most often infarcted are the posterior limb of the internal capsule, the medial globus pallidus, and the lateral geniculate body. As a result, the most common clinical syndrome includes a contralateral hemiparesis and contralateral visual field defect. The visual field defect can consist of a complete homonymous hemianopsia or may manifest with a distinctive feature—sparing of the meridian, called sectoranopsia—a fact explained by the arrangement of the afferent visual fibers as they course through the geniculate ganglia. There can also be variable degrees of hemisensory loss (proprioception is usually spared) from capsular and ventrolateral thalamic involvement. Traditionally, the absence of a higher cognitive deficit in a patient with a hemiparesis and homolateral visual field deficit has been considered suggestive of involvement of the AChA, as opposed to the MCA. However, apraxia, hemineglect, and aphasia have been described with AChA territory infarction.

The likely cause of AChA infarction is small-artery focal atherosclerosis secondary to long-standing hypertension and diabetes when the infarct is restricted to the posterior limb of the internal capsule and medial globus pallidus, but more extensive infarcts are probably caused by cardiac or ICA disease.

Internal Carotid Artery

When a stroke involves a combination of the syndromes described previously, it can be devastating and probably represents the involvement of the ICA before it branches off into the above divisions. The occlusive process can be extracranial or intracranial and has varied causes. The most common process leading to focal occlusive disease of the ICA is advanced atherosclerosis with progressive narrowing and significant reduction in distal blood flow. As described earlier in this chapter, a focus of atherosclerosis also represents a source of thrombus with potential for distal embolization. Less common processes include extracranial spontaneous or traumatic ICA dissection and postirradiation ICA stenosis. An acute cardiac embolism that lodges at the top of the ICA intracranially, blocking the origins of the ipsilateral MCA and ACA, can also be present and is usually associated with a more sudden dramatic manifestation.

The clinical syndrome observed with an acute ICA-distribution stroke is usually a combination of the syndromes described previously with involvement of both MCA and ACA territories. Sometimes, however, the ACA territory is spared in patients with adequate collateral circulation through an intact circle of Willis, where blood is diverted from the other hemisphere through a functional anterior communicating artery. The manifestation is often stepwise, reflecting slow failure of distal collateral vessels as the ICA occlusive process progresses. When the occlusion is total and hemodynamic reserve is no longer sufficient, the patient has a sudden decline and is prone to rapid deterioration from extensive ongoing ischemia and hemispherical swelling.

Many times, it is difficult to differentiate an ICA-territory infarction, especially when the onset is abrupt, from embolic MCA strokes. The hallmark of a proximal ICA disease is a history of a preceding TIA, either retinal (transient monocular blindness or amaurosis fugax) or hemispherical. Its presence is strongly suggestive of ICA disease proximal to the origin of the ophthalmic artery and should prompt rapid investigation of the extracranial carotid system. ICA dissection is another possible cause (see Table 42-2).

Posterior Circulation

Twenty percent of ischemic events involve areas supplied by the posterior circulation, but they are often incorrectly diagnosed. For example, isolated lightheadedness, syncope, and vertigo are frequently blamed on a posterior circulation process even though it is almost never the cause of these symptoms. Conversely, a patient with multiple stroke risk factors may present with vertigo and gait ataxia resulting from brainstem ischemia, but vestibular neuronitis may be diagnosed. The term vertebrobasilar insufficiency, although popular, is vague with regard to mechanism and should be avoided. Overall, in patients with posterior circulation TIA and minor stroke, the risk of subsequent stroke or death is similar to that in patients presenting with carotid disease, although their risk is probably slightly higher than that of carotid patients in the acute phase. Posterior circulation TIAs carry a higher risk of recurrence than do anterior circulation TIAs.

Vertebrobasilar Territory Strokes

Intracranial Vertebral Arteries

The most common site for ICVA atherosclerosis is the distal segment of the artery near the vertebrobasilar junction, after takeoff of the PICA and lateral medullary penetrators. The most common stroke syndrome associated with focal ICVA disease is the lateral medullary syndrome (Wallenberg’s syndrome), and it usually represents involvement of vertebral artery branches directly supplying the lateral medulla. In contrast, involvement of PICA itself usually causes cerebellar rather than medullary infarction and results from cardiac or ECVA embolism. Lateral medullary syndrome manifests with a subset of the following symptoms and signs: vertigo, dysphagia, hoarseness, ipsilateral facial and contralateral trunk and limb thermoanalgesia, ipsilateral oculosympathetic dysfunction, ipsilateral limb ataxia, gait ataxia, nausea, and vomiting. The specific constellation of symptoms depends on the rostrocaudal and horizontal extent of the medullary lesion. Occlusion of the medial PICA branch causes infarction of the dorsal medulla and the inferior cerebellar vermis. Involvement of the lateral PICA branch causes infarction of the posteroinferior cerebellar hemisphere, with truncal ataxia and ipsilateral limb ataxia. Brainstem signs such as vertigo and dysarthria are usually not present. Full PICA territory infarction causes vomiting, gait and ipsilateral limb ataxia, and truncal lateral pulsion. Multidirectional nystagmus may also be present. A full PICA infarction can lead to considerable edema, usually within 24 to 48 hours, with “pseudotumoral” mass effect. This can be rapidly fatal as a result of progressive pontine and medullary compression. Surgical decompression is necessary. Clues to brainstem compression include headache, vomiting, drowsiness, ipsilateral gaze preference, and ipsilateral hemiparesis.

Basilar Artery Branches

The basilar artery originates from the confluence of the two vertebral arteries at the pontomedullary junction and represents the main vascular supply to the brainstem and rostral cerebellum. Atherosclerosis is by far the most important pathology of the basilar artery, strokes are usually preceded by TIAs, and the paramedian pontine base is the most common site of infarction.

The main branches off the basilar artery arise in pairs: the anterior inferior cerebellar artery, the superior cerebellar artery, and the PCA. Throughout its course, the basilar artery gives rise to multiple penetrating and circumferential branches that supply the brainstem; it is responsible for the whole blood supply of the pons and much of the distal brainstem.

Superior Cerebellar Arteries.

Traditionally, it was thought that isolated superior cerebellar artery territory infarcts were rare but instead occurred in combination with midbrain, thalamic, and PCA territory infarcts, as a result of embolism to the top of the basilar artery. However, modern MRI suggests that the occurrence of isolated superior cerebellar artery infarcts has been underestimated.38 These infarcts can be small or territorial, both most commonly caused by embolism. The superior cerebellar artery supplies most of the cerebellar cortex, the cerebellar nuclei, and the superior cerebellar peduncle. Superior cerebellar artery infarcts result in a combination of the following signs and symptoms: vertigo and dizziness, nystagmus, limb ataxia, gait ataxia, and mild hemiparesis. Clinical brainstem signs are usually absent.

Basilar Artery and Its Penetrators.

The posterior wall of the basilar artery gives rise to small paramedian and short circumferential arteries that supply the paramedian and lateral pontine regions. These arteries can be affected by either microatheroma at their origins or lipohyalinosis along their length. These are believed to be distinct pathological processes. Stroke from basilar artery disease is very variable and can range from a mild lacunar stroke, resulting from a small penetrator disease, to a large, devastating syndrome with extensive destruction of the brainstem from complete or almost complete basilar occlusion (Fig. 42-7). Pontine syndromes reflect the particular structures affected, with a basic division between strokes that predominantly affect the anterior pons and those that affect predominantly the pontine tegmentum. Anterior pontine infarctions can manifest as classic lacunar syndromes with pure motor hemiparesis or ataxic hemiparesis/dysarthria–clumsy hand syndrome, as a result of damage to the corticospinal tract and crossing corticopontocerebellar fibers. Strokes that predominantly affect the pontine tegmentum manifest with a constellation of brainstem signs as a result of involvement of the medial lemniscus, the medial longitudinal fasciculus, the cerebellar peduncles, the abducens nucleus, and the vestibular nuclei.

Top-of-the-Basilar Syndrome.

When an embolic particle arises either from the heart or from the proximal vertebral arteries, it travels all the way downstream until it lodges in a vessel with a diameter equal to or less than that of the particle size. Because of the relatively large diameter of the basilar artery, this usually occurs at the distal segment, where it gives rise to both superior cerebellar arteries and PCAs and leads to a constellation of signs and symptoms commonly referred to as the “top-of-the-basilar” syndrome. Infarction of the rostral midbrain (tectum, posterior commissure, red nucleus) leads to oculomotor abnormalities such as vertical gaze palsies, convergence retractive nystagmus, bilateral hyperconvergence (“pseudo-sixth” nerve palsy), and eyelid retraction. The involvement of the more caudal midbrain results in damage to the cranial nerve III nucleus and fascicle and is responsible for cranial nerve III palsy with bilateral ptosis, midposition and poorly reactive pupils, and internuclear ophthalmoparesis. Midbrain involvement also includes damage to the ascending reticular activating system with consequent somnolence or stupor.

In rare cases, patients may present with vivid, well-formed visual hallucinations after strokes in the distal basilar territory, a phenomenon called peduncular hallucinosis. There exist few pathological studies of the usual location and nature of the lesions causing such a syndrome, but it is thought to occur from rostral midbrain or thalamic involvement.

Other structures that can be affected by an embolus to the distal basilar artery include the occipital lobes, medial temporal lobes, and thalami (Fig. 42-8). Their involvement can be either unilateral or bilateral and gives rise to multiple signs or symptoms referable to the involvement of the PCA territory (see next section).39

Posterior Cerebral Arteries.

The PCAs are the terminal branches arising from the basilar artery. In about 30% of patients, one PCA arises from the ipsilateral ICA; this is a so-called fetal PCA. Infarcts in the PCA territory are mainly caused by emboli, which is perhaps not surprising because the PCAs are the end territory of the posterior circulation. The first, P1, segment of the PCA courses posteriorly around the midbrain and gives off small branches to the midbrain and medial thalamus before it becomes the P2 segment, which supplies the ventral and lateral thalamus, the occipital lobe, and the medial temporal lobe. The three most prominent symptoms and signs after PCA territory infarction are headache, positive and negative visual field defects, and hemisensory disturbances. The most common visual field abnormality is a hemianopia from infarction of the optic radiations or calcarine cortex. If the field cut is transient, release hallucinations can occur at its edges as it clears. Involvement of the lateral thalamus and surrounding afferent white matter tracts is responsible for hemisensory disturbances, which can range from hemibody tingling to frank hemianesthesia in all sensory modalities. Sometimes the sensory complaints are accompanied by clumsiness and ataxia, also probably attributable to thalamic involvement, whereas dense hemiparesis results from infarction of the cerebral peduncle.

In addition to the common symptoms and signs described previously, there are unique neuropsychological deficits in up to 60% of patients with visual field defects. These neuropsychological deficits are hemisphere specific or hemisphere predominant. Some of the neuropsychological deficits are more florid when there is bilateral PCA infarction. Infarction in the territory of the left PCA that extends to the splenium of the corpus callosum or to its neighboring parieto-occipital white matter leads to alexia without agraphia. Visual perception is normal in the preserved left hemifield, but the information cannot reach language areas of the left hemisphere. In addition, there is color anomia because color percepts are purely visual and therefore no other sensory modality can be evoked to provide a clue to the left language region. In addition to alexia without agraphia and color anomia, some patients have visual object agnosia. Alexia with agraphia, along with some anomia, occurs with infarcts in the left temporo-occipital junction. Infarction of the left medial temporal lobe can lead to anterograde and retrograde amnesia, which can last months. Presumably, the contralateral hippocampus can take over with time. It follows that permanent anterograde amnesia can result from bilateral PCA infarcts.

Prosopagnosia can occur with right inferior occipitotemporal lesions. Other behavioral syndromes associated with right PCA infarction are less specific and probably reflect right parietal syndromes, inasmuch as the PCA sometimes supplies parts of the right posterior parietal lobe.

Balint’s syndrome can arise after unilateral or bilateral infarction of the superior parietal lobule at the parieto-occipital junction, supplied by the MCA-PCA watershed. The syndrome, also known as optic ataxia, is characterized by defective directional control of visually guided reaching movements, but motor execution is normal when other sensory modalities are used. On-line control is more impaired than feedforward planning, and errors in reaching are variable with no appreciable constant errors. Anton’s syndrome is denial of blindness despite clear physiological evidence for it after bilateral occipital infarction. This syndrome can be accompanied by agitation/delirium, possibly from the decreased visual input or concomitant involvement of the temporal lobes.

STROKE EVALUATION

Parenchymal Imaging

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