Ischemic Stroke

A cerebrovascular disorder caused by insufficient blood flow in an area of the brain.

Ischemia accounts for about 80% of strokes. Risk factors include hypertension, heart disease, arrhythmias (eg, atrial fibrillation), hyperlipidemia, and the effects of age on the cerebral vessels.

Brain tissue malfunctions rapidly when deprived of adequate blood flow. Temporary disruption of blood flow may result in ischemia without infarction and thus produce only temporary symptoms. When ischemia is prolonged, infarction occurs and localized brain function is irrevocably lost. However, brain function is plastic, and other, nearby areas may eventually take over the lost function.

Ischemia is caused by an impediment to blood flow, almost always due to a narrowed or occluded artery supplying a local brain region. Arterial occlusion triggers a chain of events; some tend to promote the ischemia and worsen the neurologic deficit, and others (ie, compensatory body reactions) limit the ischemia and the deficit. During the first week after ischemia begins, a thrombus gradually adheres to the arterial wall and becomes organized, diminishing the early tendency of the loosely attached clot to embolize or propagate distally. Similarly, the collateral circulation needs time to become established and stabilized. For these reasons, about one fourth to one half of ischemic strokes are generally presaged by at least one TIA. Strokes may occur days or months after a TIA.

Ischemic strokes are classified on the basis of their site and causes: atherosclerosis of the large arteries in the neck and in the cranium, penetrating artery disease, brain embolization, and systemic hypoperfusion or general circulatory failure.

Large-Vessel Atherosclerosis

Atherosclerosis is a major cause of ischemic stroke. Among whites, atherosclerosis of the cerebrovascular bed is most common at the origins of the internal carotid and the vertebral arteries in the neck and in the intracranial vertebral and basilar arteries. The large intracranial arteries (middle, anterior, and posterior cerebral arteries) and their superficial convexal artery branches are affected much less often (see Figure 44-2).

Atherosclerosis of the extracranial internal carotid and vertebral arteries is twice as common among white men as among white women; it correlates highly with coronary and peripheral vascular occlusive disease and hyperlipidemia. A history of angina pectoris, myocardial infarction, or leg claudication in patients who have had a TIA strongly suggests extracranial atherosclerosis.

Atherosclerosis of the extracranial internal carotid and vertebral arteries is less common among blacks and Asians than among whites, but atherosclerosis of the major intracranial arteries is more common. Among blacks and Asians, intracranial atherosclerosis does not have a strong male preponderance, does not correlate epidemiologically with coronary or peripheral vascular disease or with hyperlipidemia, and occurs at a younger age than does extracranial atherosclerosis. Among persons with diabetes or hypertension, prevalence of intracranial atherosclerosis is also high.

Sometimes occlusions are caused by hematologic abnormalities, alone or superimposed on a stenotic lumen. Polycythemia and thrombocytosis are major causes of vascular occlusion. A hypercoagulable state, which can complicate cancer and other systemic disorders, may lead to obstruction of a narrowed vessel.

Symptoms and Signs

The most common presenting symptom is at least one prior TIA, which is often brief; but TIAs, if untreated, may recur for weeks or months. Some patients present with sudden-onset stroke, probably caused by embolization of intra-arterial clot or plaque material originating in regions of extracranial atherosclerosis and traveling distally to block intracranial recipient arteries. Headache is also common and is probably caused by dilation of collateral arterial channels. Specific symptoms and signs relate to the anatomy of the involved artery and the area it supplies. They may be sensory, motor, or both.

Internal carotid artery in the neck: Transient decreases in arterial flow cause attacks of transient monocular blindness (amaurosis fugax) on the side of the lesion. These attacks are usually described as being like a shade falling or a curtain moving across the eye from the side. They usually last 30 seconds to a few minutes and are sometimes precipitated by sudden standing or bending or by exposure to bright natural light.

Hemispheric ischemia may produce weakness or numbness of the contralateral limbs and the face. The hand and arm are involved more often than the face or leg, but the part affected may vary with each attack. Aphasia is common when the left internal carotid artery is involved. When both transient monocular blindness and attacks of numbness or weakness in the contralateral limbs occur, the diagnosis is internal carotid artery disease in the neck or in the carotid siphon, proximal to the ophthalmic artery branch. Plaque disease and stenosis are most severe at the origin of the internal carotid artery, where it branches from the common carotid artery. Table 44-5 lists some signs of internal carotid artery atherosclerosis.

Subclavian artery: Atherosclerosis usually affects the subclavian arteries proximal to the origin of the vertebral artery branches. The left artery is stenosed more often than the right. The most common symptoms involve the ischemic arm, which often aches, is cool, and becomes fatigued easily during exercise. The radial pulse in the ischemic arm is usually weak or delayed, and the blood pressure is lower than that in the opposite arm. At times, a bruit is audible in the supraclavicular fossa. TIAs related to the subclavian arteries are much more common than stroke; they produce evanescent dizziness, blurred vision, diplopia, or staggering; sometimes they are provoked by exercising the ischemic arm. Patients with subclavian artery atherosclerosis usually do well, unless they use the ischemic arm vigorously in sports (eg, golf). Surgery is usually not indicated.

Vertebral artery: Typical characteristics of ischemia related to vertebral artery disease in the neck are evanescent dizziness, vertigo, diplopia, and blurred vision. These symptoms may occur when the person moves the head in certain positions. The clinical findings are identical to those of subclavian artery disease, except that the arm is not ischemic and the pulses and blood pressures in the upper limbs are equal. Some patients with a vertebral artery occlusion in the neck present with a sudden posterior circulation stroke; the ischemia is caused by blockage of the intracranial vertebral artery or the posterior cerebral artery or its branches. The blockage results from embolic material originating in the proximal vertebral artery. The most common site of vertebral artery atherosclerosis is the origin and first few centimeters of the artery. The distal portion of the vertebral artery in the neck is vulnerable to tearing or dissection during trauma, sudden movement, or manipulation of the neck.

Occlusion or severe stenosis of an intracranial vertebral artery blocks flow through the posterior inferior cerebellar artery branch and causes ischemia of the lateral medulla and the cerebellum. The most common symptoms and signs of lateral medullary ischemia are listed in Table 44-6. Cerebellar ischemia is manifested by staggering gait, ataxia, sensations of disequilibrium, and nausea. Large cerebellar infarcts can increase pressure in the posterior cranial fossa and cause coma due to compression of the brain stem; this potentially fatal complication is treated with surgical decompression of the lesion and removal of infarcted tissue.

Basilar artery: The most common symptoms and signs of basilar artery atherosclerosis are listed in Table 44-7. Occlusion can be fatal unless collateral circulation develops. The basilar artery supplies the pons; the region most vulnerable to ischemia is the base of the pons, which contains the long motor tracts. Ischemia causes bilateral weakness of the trunk and limbs with exaggerated reflexes and extensor plantar signs. Sometimes premonitory episodes of dizziness and diplopia occur, especially when the occlusion begins in the vertebral artery and spreads to the basilar artery.

Intracranial carotid artery: When stenosis affects the intracranial carotid artery proximal to the ophthalmic artery branch, the syndrome is similar to that affecting the internal carotid artery origin. No neck bruit is heard, and results of noninvasive studies of the internal carotid artery are normal. Stenosis of the intracranial carotid artery beyond the ophthalmic artery origin is accompanied by attacks of hemispheric ischemia occurring as lateralized weakness, sensory loss, or visual neglect, but transient monocular blindness does not occur. Also lacking are signs and ultrasonographic evidence of decreased ophthalmic artery flow. Aphasia is common among patients with left hemispheric ischemia; defective drawing and copying ability and left-sided visual neglect are common among patients with right hemispheric ischemia.

Middle, anterior, and posterior cerebral arteries: Middle cerebral artery disease is usually most severe in the proximal segment or the upper trunk branch. Anterior cerebral artery disease is less common and usually affects the proximal segment. Posterior cerebral artery disease usually affects the proximal segment.

Middle cerebral artery disease usually causes weakness and numbness of the contralateral limbs, trunk, and especially the face. When the left middle cerebral artery is affected, aphasia usually occurs; when the right middle cerebral artery is affected, visuospatial dysfunction and left-sided neglect (lack of attention to all activity on the left side) occur.

Anterior cerebral artery disease causes weakness and numbness of the contralateral lower extremity and weakness of the contralateral shoulder. At times, the patient may lack spontaneity, be disinterested, or be incontinent.

The cardinal symptoms and signs of posterior cerebral artery atherosclerosis relate to the visual fields. Patients may have transient attacks of hemianopia or scotomata; the hemianopia often develops suddenly. Memory loss, alexia, and agitated delirium also occur when the lesion is large and includes the temporal lobe territory supplied by the posterior cerebral artery.

Diagnosis

A CBC count, prothrombin time test, and platelet count should be performed and the fibrinogen level measured routinely in every patient who has had a TIA or stroke. ECG and echocardiography are also important, especially for patients with heart disease or cardiac symptoms.

CT and MRI: These tests should be routinely performed for all patients who have had a stroke. CT and MRI can delineate the affected vascular territory when an infarct is present and help differentiate ischemia from hemorrhage. Negative results indicate that the ischemia may be reversible; a large infarct indicates a poor prognosis. The distribution of infarction yields clues to the likely location of the vascular lesion. CT and MRI also can show zones of edema and shifts of intracranial contents.

Ultrasonography: Duplex ultrasonography of the internal carotid and vertebral artery origins in the neck has a high sensitivity and specificity for showing severe occlusive lesions. Color-flow Doppler ultrasonography accurately shows occlusive lesions of these arteries. Transcranial Doppler ultrasonography provides useful information about flow velocities in the major intracranial basilar arteries; it can show whether occlusive extracranial lesions reduce intracranial flow, and it can detect severe occlusive disease in the major intracranial arteries.

Angiography: Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) can be used to screen for extracranial and intracranial occlusive disease and aneurysms. The combination of extracranial and intracranial ultrasonography plus CTA or MRA is very effective in showing most important occlusive lesions in large arteries.

Catheterization angiography is the definitive test for imaging extracranial and intracranial arteries and veins. With small amounts of contrast material, computer-generated high-resolution images can be produced.

In younger patients, angiography is warranted only if surgery is planned or considered. In the elderly, angiography is needed when the clinical examination and noninvasive testing cannot provide a clear diagnosis. However, for many patients, ultrasonography, CTA, and MRA provide sufficient information to preclude the need for angiography or to limit standard angiography to one or two vessels.

Angiography has definite risks (eg, stroke, injury to the artery in which the catheter is placed, allergic reactions); the combined morbidity and mortality rate is about 1%. These tests are particularly risky for patients with diabetes or renal failure. Risks can be minimized by providing adequate hydration and using the smallest amount of dye and the least number of injections needed for accurate diagnosis. The expertise of the angiographer and the information supplied by the responsible clinician are vital to reducing risk. The angiographer begins by injecting the artery most likely to harbor the lesion. When sufficient information is obtained to determine treatment, no further angiography should be performed.

Treatment

General treatment considerations are discussed at the beginning of this chapter.

During the relatively unstable period of a few days to 2 weeks after arterial occlusion, any decrease in brain perfusion should be avoided. Blood pressure should not be lowered unless it is >= 170/110 mm Hg, and cardiac output should be maximized. Hypovolemia, a common problem among stroke patients who do not eat and drink enough, should be avoided. Because sitting or standing may worsen the ischemia early in its course, patients should be closely observed, and their blood pressure checked when they first sit or stand. Patients whose neurologic signs fluctuate or worsen usually should remain supine to maximize cerebral blood flow until the instability passes.

There are seven specific treatment options:

Endarterectomy is the procedure of choice if an extracranial artery is severely stenotic (ie, residual lumen < 2 mm). The lesion must be surgically accessible. This procedure is not warranted if the patient has had a severe stroke affecting the area of brain tissue supplied by the artery.

Angioplasty (often with stenting) is used mainly for patients with extracranial carotid or vertebral artery occlusive disease when an artery is severely stenotic and the patient is not a surgical candidate or the arterial lesion is not surgically accessible. Angioplasty is also used for patients with intracranial artery disease when symptoms of brain ischemia in the territory of the stenotic artery persist despite maximal medical treatment.

Thrombolysis is an option when patients can be treated soon after the onset of symptoms of brain ischemia and when an arterial occlusion is identified by diagnostic tests (CTA, MRA, extracranial and transcranial ultrasonography, or catheterization angiography) before extensive brain infarction has occurred. IV thrombolysis is used when intracranial branch arteries are occluded, but it is ineffective for carotid artery occlusion. Intra-arterial thrombolysis is often effective for patients with intracranial vertebral, basilar, or middle cerebral artery occlusions. Thrombolysis poses a risk of brain hemorrhage and is contraindicated in patients with uncontrolled hypertension, bleeding disorders, or large infarcts.

Short-term (2- to 3-week) heparin therapy is prescribed for patients with complete occlusion of large arteries. Low-molecular-weight heparins or heparinoids can be used instead of heparin. These drugs prevent propagation and embolization of a clot, allowing the loosely adherent thrombus to become organized on the vascular wall and collateral circulation to become well established.

Low-molecular-weight heparins have a more favorable bioavailability and pharmacokinetic profile than standard heparin. They are thought to cause fewer hemorrhagic complications than standard heparin because they have a less pronounced effect on platelet function and vascular permeability. They also cause fewer cases of thrombocytopenia, skin necrosis, and white-clot syndromes.

Heparins may also be used when the neurologic signs are fluctuating, the occluding lesion is undefined, or definitive information is not yet available. Heparin should be given in a continuous IV infusion, keeping the activated partial thromboplastin time at 1.5 to 2 times the control value. Low-molecular-weight heparins and heparinoids can be given intravenously or subcutaneously.

Warfarin should be started 2 to 4 days after initiation of heparin and is usually continued for 1 to 3 months. Longer-term warfarin therapy should be used when the vascular lesion is severely stenotic and inaccessible (eg, in the internal carotid artery siphon or middle cerebral artery) or the patient is not a candidate for or declines surgery. The international normalized ratio (INR) should be kept between 2 and 3.5. Warfarin is most effective in preventing red clots, composed of erythrocytes and thrombin, which may form in regions of very reduced blood flow (eg, severely stenotic arteries or veins or dilated cardiac chambers). Warfarin is continued as long as the condition that promotes red clots persists.

Antiplatelet drugs, such as aspirin, are prescribed when the vascular lesion is not severely stenotic. The optimal dose is undetermined; 1.3 g/day in divided doses (eg, 325 mg qid, 650 mg bid) has been effective in trials, but 300 to 325 mg/day is probably just as effective. Theoretically, 100 mg/day might work as well, if not better. Clopidogrel, another drug that affects platelet aggregation and function, is given in a dose of 75 mg/day to patients who cannot take aspirin. Clopidogrel is as effective as ticlopidine and has less hematologic toxicity. Aspirin and other antiplatelet drugs are used to prevent white clots, composed of fibrin-platelet clumps that form on irregular surfaces in areas with fast-moving blood flow (eg, craggy plaques in nonstenosed arteries). Dipyridamole alone has not been shown to be effective, but a combination of aspirin 25 mg bid and modified-release dipyridamole 200 mg bid has been shown to be effective. Drugs that inhibit the platelet glycoprotein IIb/IIIa complex and its binding to fibrinogen have been developed; they include abciximab, which consists of monoclonal antibodies to the complex; eptifibatide, which is a cyclic peptide; and lamifiban and tirofiban, which are parenteral nonpeptide mimetics. Platelet glycoprotein IIb/IIIa inhibitors may be able to lyse white clots and to prevent their formation.

Extracranial-intracranial bypass surgery may be performed, but its indications are undetermined. In one major study, the procedure was no better than medical therapy for most patients with an inaccessible occlusive vascular lesion in the anterior circulation. Bypass may be considered for isolated patients who have been thoroughly investigated, who have persistent hypoperfusion and brain ischemia, and who are refractory to medical treatment.

Penetrating Artery Disease

(Lacunar Infarcts)

Small, deep infarcts caused by occlusion of penetrating brain arteries.

The small arteries that penetrate deeper brain structures (eg, basal gray nuclei, internal capsule, thalamus, pons) are especially susceptible to degenerative changes caused by hypertension: Medial hypertrophy, fibrinoid changes, and lipohyalinosis gradually narrow the lumens of these arteries, impeding blood flow. Plaques within arteries, blocking or extending into the orifices of penetrating arteries, and microatheromas are more common among patients with diabetes. A high Hct causes increased blood viscosity, which increases the risk of lacunar infarction and large artery occlusion.

When a penetrating artery becomes occluded, a small, deep infarct (lacune) results. Lacunes are < 2 cm at their greatest diameter and affect only deeper structures. Microatheromas or microdissections may occlude the origin of the penetrating arteries, causing infarcts in identical distributions. Lacunes are relatively more common in the posterior circulation; prevalence increases with age but does not appear to be correlated with race or sex.

Symptoms and Signs

Because the lesions are small and deep, patients do not have symptoms related to vasodilation or increased intracranial pressure (eg, headache, vomiting, decreased alertness). The clinical syndrome develops over a short period, usually in < 1 week. Although less common in penetrating artery disease than in large-artery atherosclerosis, TIAs are characteristic and brief. The most common syndromes are pure motor hemiparesis and pure sensory stroke (see Table 44-8). Often, the symptoms are subtle, so the patient and family members may not notice every event. Symptoms often result from the cumulative effects of multiple lacunes. Multiple lacunes may lead to dementia or parkinsonism.

When lacunes are located deep in the cerebral hemisphere, weakness or numbness is not accompanied by hemianopia, visual field loss or neglect, or abnormal cognitive function or behavior. When the brain stem is involved, the signs are seldom limited to dysfunction of tegmental structures (cranial nerve nuclei and eye movements).

Diagnosis

A typical patient has a history of hypertension or diabetes, rapidly evolving symptoms, and signs characteristic of one of the lacunar syndromes (see Table 44-8). CT or MRI shows lacunes or no relevant lesion. With this combination of findings, no further testing is needed. Lacunes may not be visible on CT or MRI scans.

EEGs are rarely helpful, usually showing normal function or minor symmetric abnormalities. Computed tomography angiography and magnetic resonance angiography usually show normal results or unrelated regions of stenosis. Catheterization angiography is usually not indicated for patients with typical lacunar infarcts.

Treatment

Hypertension should be controlled when the patient is no longer vulnerable to ischemia. For the first 1 to (at most) 3 weeks, changes in position, blood pressure, blood volume, and blood flow can increase the ischemic deficit. Because deep penetrating arteries are end vessels, any decrease in flow through adjacent arteries can enlarge the infarct. Blood pressure should be immediately lowered only when it is > 200/120 mm Hg, although several weeks after the acute event, normotension is the goal. Blood glucose levels should be controlled in patients with diabetes. Phlebotomy is important for patients with a Hct of > 45%. Reduction of blood fibrinogen levels may help prevent the development of other lacunes and ischemic damage to white matter. Patients who smoke should be encouraged to stop.

Brain Embolization

Emboli can arise from the aortic arch or from plaques or dissections in the proximal portions of the large extracranial and intracranial arteries. The heart is also a common source of emboli, especially among the elderly. The most important cardiac causes of cerebral embolization are all varieties of valvular heart disease, myocardial ischemia, and atrial fibrillation. (Epidemiologic and clinical findings are the same as those for large-vessel atherosclerosis.)

Symptoms and Signs

Neurologic symptoms usually begin abruptly, often while the patient is awake and active. Most often, the deficit is maximal at or near onset, because the sudden blockage of a distal artery does not allow adequate time for collateral circulation to become established. When emboli pass distally, the deficit may worsen or improve. Stepwise worsening usually occurs within 48 hours. When angiography is performed > 2 days after the onset of symptoms, emboli are usually no longer visible in intracranial arteries. In the anterior circulation, emboli most often reach branches of the anterior and middle cerebral arteries. In the posterior circulation, emboli most often reach the long circumferential cerebellar arteries and branches of the posterior cerebral arteries. When emboli cause a large infarct, headache and decreased alertness are common. Neurologic signs are identical to those of large-vessel atherosclerosis.

Diagnosis

CT and MRI usually show superficial wedge-shaped infarcts in the cerebral hemisphere or cerebellum in the territories of the anterior cerebral, middle cerebral, posterior cerebral, or cerebellar arteries. Many infarcts, some unexpected, scattered in different vascular territories, may be detected. Ultrasonography, computed tomography angiography, and magnetic resonance angiography show embolic sources within the proximal extracranial arteries. Angiography shows abrupt distal cutoff of intracranial branch arteries without underlying local atherostenosis, filling defects in the form of thromboemboli, and proximal regions of atherostenosis.

ECG may be useful for detecting myocardial ischemia, chamber hypertrophy, or arrhythmias. Echocardiography detects valvular heart disease, regions of decreased contractility, tumors such as myxomas, and chamber hypertrophy. Holter monitoring can detect intermittent arrhythmias.

Treatment

Specific medical treatment may be available for the cardiac disorder--eg, antiarrhythmic drugs or coronary vasodilators for ischemia. Some cardiac lesions require surgical correction.

Thrombolytic treatment can be given if the patient is seen soon after the embolic event and the thromboembolus is blocking an intracranial artery.

Anticoagulants are usually indicated when the patient is vulnerable to further emboli. For some patients (eg, those with recent myocardial infarction or reversible arrhythmia), this risk is transient; for others (eg, those with intractable atrial fibrillation), it is lifelong. With heparin, the partial thromboplastin time should be kept to 1.5 to 2 times the control value. Heparin is gradually replaced with warfarin for long-term therapy; the INR should be kept between 2 and 3.5. Anticoagulants are contraindicated if the infarct is large or if the patient is hypertensive, unless blood pressure can be reduced without increasing the neurologic deficit.

If patients with artificial valves develop new emboli while taking warfarin, the addition of dipyridamole (75 to 100 mg po qid) or another antiplatelet drug may be helpful. Investigation of the risk/benefit ratio of prophylactic anticoagulation for patients with potential cardiac embolic sources (eg, atrial fibrillation) has shown that warfarin is indicated for most patients with atrial fibrillation. Warfarin plus dipyridamole may produce less bleeding than warfarin plus aspirin, but dipyridamole may cause orthostatic hypotension in the elderly.

Systemic Hypoperfusion

Brain ischemia due to inadequate cardiac output with systemic hypoperfusion can be caused by acute myocardial infarction, cardiac arrest, and life-threatening ventricular arrhythmias. Less common causes are pulmonary embolism, acute gastrointestinal or systemic bleeding, and shock.

Symptoms, Signs, and Diagnosis

Most often, the patient is pale, sweating, and hypotensive when first examined. Neurologic dysfunction is usually abrupt in onset and follows systemic symptoms related to the underlying disorder. The most prominent findings are decreased alertness and symmetric depression of hemispheric functions.

When ischemia is severe, brain stem function may be abnormal and brain stem reflexes (pupillary, corneal, doll's eye, and pharyngeal) may be absent. Bilateral weakness or decorticate or decerebrate rigidity indicates that the motor system is involved. The arms may be most severely affected, with relative sparing of the face and legs--a distribution described as "a man in a barrel." Severe or prolonged impairment of cerebral perfusion usually results in coma. When stupor lightens, patients may have deficits in visual function and memory. CT results are usually normal during the acute period in all but the most severely affected patients, but EEGs usually show severe bilateral slowing.

Prognosis and Treatment

Loss of brain stem reflexes for > 24 hours indicates a poor prognosis, as does persistent coma. Treatment is directed at the underlying cardiac or systemic process.