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InternalMed_Harrison. After the clinical diagnosis of stroke is made, an orderly process of evaluation and treatment should follow (Fig. 446-1). The first goal is to prevent or reverse brain injury. Attend to the patient’s airway, breathing, and circulation (ABCs), and treat hypoglycemia or hyperglycemia if identified. Perform an emergency noncontrast head CT scan to differentiate between ischemic stroke and hemorrhagic stroke; there are no reliable clinical findings that conclusively separate ischemia from hemorrhage, although a more depressed level of consciousness, higher initial blood pressure, or worsening of symptoms after onset favor hemorrhage, and a deficit that is maximal at onset, or remits, suggests ischemia. Treatments designed to reverse or lessen the amount of tissue infarction and improve clinical outcome fall within six categories: (1) medical support, (2) IV thrombolysis, (3) endovascular revascularization, (4) antithrombotic treatment, (5) neuroprotection, and (6) stroke centers and


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InternalMed_Harrison. outcome fall within six categories: (1) medical support, (2) IV thrombolysis, (3) endovascular revascularization, (4) antithrombotic treatment, (5) neuroprotection, and (6) stroke centers and rehabilitation.


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InternalMed_Harrison. When ischemic stroke occurs, the immediate goal is to optimize cerebral perfusion in the surrounding ischemic penumbra. Attention is also directed toward preventing the common complications of bedridden patients—infections (pneumonia, urinary, and skin) and deep venous thrombosis (DVT) with pulmonary embolism. Subcutaneous heparin (unfractionated and low-molecular-weight) is safe and can be used concomitantly. Use of pneumatic compression stockings is of proven benefit in reducing risk of DVT and is a safe alternative to heparin.


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InternalMed_Harrison. Because collateral blood flow within the ischemic brain may be blood pressure dependent, there is controversy about whether blood pressure should be lowered acutely. Blood pressure should be lowered if there is malignant hypertension (Chap. 298) or concomitant myocardial ischemia, or if blood pressure is >185/110 mmHg and thrombolytic therapy is anticipated. When faced with the competing demands of myocardium and brain, lowering the heart rate with a β1-adrenergic blocker (such as esmolol) can be a first step to decrease cardiac work and maintain blood pressure. Routine lowering of blood pressure has been found to worsen outcomes. Fever is detrimental and should be treated with antipyretics and surface cooling. Serum glucose should be monitored and kept at <10.0 mmol/L (180 mg/dL) using an insulin infusion if necessary.


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InternalMed_Harrison. Between 5 and 10% of patients develop enough cerebral edema to cause obtundation or brain herniation. Edema peaks on the second or third day but can cause mass effect for ~10 days. The larger the infarct, the greater the likelihood that clinically significant edema will develop. Water restriction and IV mannitol may be used to raise the serum osmolarity, but hypovolemia should be avoided because this may contribute to hypotension and worsening infarction. Combined analysis of three randomized European trials of hemicraniectomy (craniotomy and temporary removal of part of the skull) shows that hemicraniectomy markedly reduces mortality, and the clinical outcomes of survivors are acceptable. The size of the diffusion-weighted imaging volume of brain infarction during the acute stroke is a predictor of deterioration requiring hemicraniectomy.


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InternalMed_Harrison. Special vigilance is warranted for patients with cerebellar infarction. These strokes may mimic labyrinthitis because of prominent vertigo and vomiting; the presence of head or neck pain should alert the physician to consider cerebellar stroke from vertebral artery dissection. Even small amounts of cerebellar edema can acutely increase intracranial pressure (ICP) by obstructing cerebrospinal fluid (CSF) flow leading to hydrocephalus or by directly compressing the brainstem. The resulting brainstem compression can manifest as coma and respiratory arrest and require emergency surgical decompression. Prophylactic suboccipital decompression of large cerebellar infarcts before brainstem compression, although not tested rigorously in a clinical trial, is practiced at most stroke centers.


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InternalMed_Harrison. The National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study showed a clear benefit for IV rtPA in selected patients with acute stroke. The NINDS study used IV rtPA (0.9 mg/kg to a 90-mg maximum; 10% as a bolus, then the remainder over 60 min) versus placebo in ischemic stroke within 3 h of onset. One-half of the patients were treated within 90 min. Symptomatic intra-cranial hemorrhage occurred in 6.4% of patients on rtPA and 0.6% 2562 on placebo. In the rTPA group, there was a significant 12% absolute increase in the number of patients with only minimal disability (32% on placebo and 44% on rtPA) and a nonsignificant 4% reduction in mortality (21% on placebo and 17% on rtPA). Thus, despite an increased incidence of symptomatic intracranial hemorrhage, treatment with IV rtPA within 3 h of the onset of ischemic stroke improved clinical outcome. Three subsequent trials of IV rtPA did not confirm this benefit, perhaps because of the dose of rtPA used, the timing


InternalMed_Harrison

InternalMed_Harrison. IV rtPA within 3 h of the onset of ischemic stroke improved clinical outcome. Three subsequent trials of IV rtPA did not confirm this benefit, perhaps because of the dose of rtPA used, the timing of its delivery, and small sample size. When data from all randomized IV rtPA trails were combined, however, efficacy was confirmed in the <3-h time window, and efficacy likely extended to 4.5 h and possibly to 6 h. Based on these combined results, the European Cooperative Acute Stroke Study (ECASS) III explored the safety and efficacy of rtPA in the 3to 4.5-h time window. Unlike the NINDS study, patients older than 80 years of age and diabetic patients with a previous stroke were excluded. In this 821-patient randomized study, efficacy was again confirmed, although the treatment effect was less robust than in the 0to 3-h time window. In the rtPA group, 52.4% of patients achieved a good outcome at 90 days, compared to 45.2% of the placebo group (odds ratio [OR] 1.34, p = .04). The symptomatic


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InternalMed_Harrison. than in the 0to 3-h time window. In the rtPA group, 52.4% of patients achieved a good outcome at 90 days, compared to 45.2% of the placebo group (odds ratio [OR] 1.34, p = .04). The symptomatic intra-cranial hemorrhage rate was 2.4% in the rtPA group and 0.2% in the placebo group (p = .008). Based on these data, rtPA is approved in the 3to 4.5-h window in Europe and Canada, but is still only approved for 0–3 h in the United States and Canada. Use of IV tPA is now considered a central component of primary stroke centers (see below). It represents the first treatment proven to improve clinical outcomes in ischemic stroke and is cost-effective and cost-saving. Advanced neuroimaging techniques (see neuroimaging section below) may help to select patients beyond the 4.5-h window who will benefit from thrombolysis, but this is currently investigational. The time of stroke onset is defined as the time the patient’s symptoms were witnessed to begin or the time the patient was last seen as


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InternalMed_Harrison. from thrombolysis, but this is currently investigational. The time of stroke onset is defined as the time the patient’s symptoms were witnessed to begin or the time the patient was last seen as normal. Patients who awaken with stroke have the onset defined as when they went to bed. Table 446-1 summarizes eligibility criteria and instructions for administration of IV rtPA.


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InternalMed_Harrison. Ischemic stroke from large-vessel intracranial occlusion results in high rates of mortality and morbidity. Occlusions in such large vessels (middle cerebral artery [MCA], intracranial internal carotid artery, and the basilar artery) generally involve a large clot volume and often fail to open with IV rtPA alone. Therefore, there is growing interest in using thrombolytics via an intraarterial route to increase the concentration of drug at the clot and minimize systemic bleeding complications. The Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial found benefit for intraarterial prourokinase in acute MCA occlusions up to the sixth hour following onset of stroke. Intraarterial treatment of basilar artery occlusions may also be beneficial for selected patients. Intraarterial administration of a thrombolytic agent for acute ischemic stroke (AIS) is not approved by the U.S. Food and Drug Administration (FDA); however, many stroke centers offer this treatment based on these data.


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InternalMed_Harrison. Endovascular mechanical thrombectomy has been studied as an alternative or adjunctive treatment of acute stroke in patients who are ineligible for, or have contraindications to, thrombolytics or in those who failed to achieve vascular recanalization with IV thrombolytics (see Fig. 446-15). The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and multi-MERCI single-arm trials found that an endovascular thrombectomy device restored patency of occluded intracranial vessels within 8 h of ischemic stroke symptoms compared with a historical control group. Recanalization of the target vessel occurred in 48–58% of treated patients and in 60–69% of patients after use of adjuvant endovascular methods, and successful recanalization at 90 days correlated well with favorable outcomes. Based on these nonrandomized data, the FDA approved this device as the first device for revascularization of occluded vessels in AIS even if the patient has been given rtPA and that therapy has failed.


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InternalMed_Harrison. Clinical diagnosis of stroke Sustained BP >185/110 mmHg despite treatment Onset of symptoms to time of drug administration ≤4.5 hb Platelets <100,000; HCT <25%; glucose <50 or >400 mg/dL edema of >1/3 of the MCA territory Use of heparin within 48 h and prolonged PTT, or elevated INR Administration of rtPA IV access with two peripheral IV lines (avoid arterial or central line placement) Administer 0.9 mg/kg IV (maximum 90 mg) IV as 10% of total dose by bolus, followed by remainder of total dose over 1 h For decline in neurologic status or uncontrolled blood pressure, stop infusion, give cryoprecipitate, and reimage brain emergently aSee Activase (tissue plasminogen activator) package insert for complete list of contraindications and dosing. bDepending on the country, IV rtPA may be approved for up to 4.5 h with additional restrictions.


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InternalMed_Harrison. Abbreviations: BP, blood pressure; CT, computed tomography; HCT, hematocrit; INR, international normalized ratio; MCA, middle cerebral artery; PTT, partial thromboplastin time. The Penumbra Pivotal Stroke trial tested another mechanical device that showed even higher rates of recanalization and led to FDA clearance of the tested device as well. More recently, two Stentriever devices (nondetachable stents) were shown to significantly improve vascular recanalization compared to the first approved MERCI device, approaching recanalization rates of 90% in most large intra-cranial vessels.


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InternalMed_Harrison. In 2013, three randomized endovascular trials with nonendovascular controls found no benefits to endovascular therapy. The largest was the Interventional Management of Stroke III trial that randomized 656 AIS patients within 3 h of onset to IV rtPA (0.9 mg/kg) alone versus IV rtPA (0.6 mg/kg) followed by endovascular adjuvant treatment with IA rtPA, or endovascular thrombectomy as soon as possible. Outcomes between these groups were not significantly different, and there were more complications (groin bleeding chiefly) in the endovascular group. The SYNTHESIS trial based in Italy randomized 363 patients to IV rtPA versus intraarterial rtPA for patients within 3 h of stroke onset. No differences were found between the groups at 90 days. These two relatively large trials indicate that endovascular therapy using principally intraarterial rtPA is not better than IV therapy, but many questions remain. Relatively few patients received mechanical clot retraction therapies, and those who did


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InternalMed_Harrison. therapy using principally intraarterial rtPA is not better than IV therapy, but many questions remain. Relatively few patients received mechanical clot retraction therapies, and those who did received what we now know were inferior devices. Trials assessing more efficacious thrombectomy devices are currently ongoing.


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InternalMed_Harrison. Because use of endovascular devices in combination with rtPA appears relatively safe, some centers continue to offer endovascular therapy. This applies to patients who are not eligible for IV rtPA (recent surgery, stroke following cardiac catheterization, etc.), and some continue to use thrombectomy because of perceived better outcomes in patients with more effective devices. Comprehensive stroke centers are now obtaining credentialing to offer this therapy in distinction to primary stroke centers that offer only IV rtPA.


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InternalMed_Harrison. ANTITHROMBOTIC TREATMENT Platelet Inhibition Aspirin is the only antiplatelet agent that has been proven effective for the acute treatment of ischemic stroke; there are several antiplatelet agents proven for the secondary prevention of stroke (see below). Two large trials, the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST), found that the use of aspirin within 48 h of stroke onset reduced both stroke recurrence risk and mortality minimally. Among 19,435 patients in IST, those allocated to aspirin, 300 mg/d, had slightly fewer deaths within 14 days (9.0 vs 9.4%), significantly fewer recurrent ischemic strokes (2.8 vs 3.9%), no excess of hemorrhagic strokes (0.9 vs 0.8%), and a trend toward a reduction in death or dependence at 6 months (61.2 vs 63.5%). In CAST, 21,106 patients with ischemic stroke received 160 mg/d of aspirin or a placebo for up to 4 weeks. There were very small reductions in the aspirin group in early mortality (3.3 vs 3.9%), recurrent


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InternalMed_Harrison. 21,106 patients with ischemic stroke received 160 mg/d of aspirin or a placebo for up to 4 weeks. There were very small reductions in the aspirin group in early mortality (3.3 vs 3.9%), recurrent ischemic strokes (1.6 vs 2.1%), and dependency at discharge or death (30.5 vs 31.6%). These trials demonstrate that the use of aspirin in the treatment of AIS is safe and produces a small net benefit. For every 1000 acute strokes treated with aspirin, about 9 deaths or nonfatal stroke recurrences will be prevented in the first few weeks and ~13 fewer patients will be dead or dependent at 6 months.


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InternalMed_Harrison. Clopidogrel is being tested as a way to prevent stroke following TIA and minor ischemic stroke (see below).


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InternalMed_Harrison. Anticoagulation Numerous clinical trials have failed to demonstrate any benefit of anticoagulation in the primary treatment of atherothrombotic cerebral ischemia. Several trials have investigated antiplatelet versus anticoagulant medications given within 12–24 h of the initial event. The U.S. Trial of Organon 10172 in Acute Stroke Treatment (TOAST), an investigational low-molecular-weight heparin (LMWH), failed to show any benefit over aspirin. Use of SC unfractionated heparin versus aspirin was tested in IST. Heparin given SC afforded no additional benefit over aspirin and increased bleeding rates. Several trials of LMWHs have also shown no consistent benefit in AIS. Furthermore, trials generally have shown an excess risk of brain and systemic hemorrhage with acute anticoagulation. A recent meta-analysis of all forms of heparin found no benefit for acute stroke patients at high or low risk of thrombotic events. Therefore, trials do not support the use of heparin or other


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InternalMed_Harrison. A recent meta-analysis of all forms of heparin found no benefit for acute stroke patients at high or low risk of thrombotic events. Therefore, trials do not support the use of heparin or other anticoagulants for patients with atherothrombotic stroke.


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InternalMed_Harrison. Neuroprotection is the concept of providing a treatment that prolongs the brain’s tolerance to ischemia. Drugs that block the excitatory amino acid pathways have been shown to protect neurons and glia in animals, but despite multiple human trials, they have not yet been proven to be beneficial. Hypothermia is a powerful neuroprotective treatment in patients with cardiac arrest (Chap. 330) and is neuroprotective in animal models of stroke, but it has not been adequately studied in patients with ischemic stroke and is associated with an increase in pneumonia rates that could adversely impact stroke outcomes.


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InternalMed_Harrison. Patient care in stroke units followed by rehabilitation services improves neurologic outcomes and reduces mortality. Use of clinical pathways and staff dedicated to the stroke patient can improve care. This includes use of standardized stroke order sets. Stroke teams that provide emergency 24-h evaluation of acute stroke patients for acute medical management and consideration of thrombolysis or endovascular treatments are essential components of primary and comprehensive stroke centers, respectively.


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InternalMed_Harrison. Proper rehabilitation of the stroke patient includes early physical, occupational, and speech therapy. It is directed toward educating the patient and family about the patient’s neurologic deficit, preventing the complications of immobility (e.g., pneumonia, DVT 2563 and pulmonary embolism, pressure sores of the skin, and muscle contractures), and providing encouragement and instruction in overcoming the deficit. Use of pneumatic compression stockings is of proven benefit in reducing risk of DVT and is a safe alternative to heparin. The goal of rehabilitation is to return the patient to home and to maximize recovery by providing a safe, progressive regimen suited to the individual patient. Additionally, the use of constrained movement therapy (immobilizing the unaffected side) has been shown to improve hemiparesis following stroke, even years after the stroke, suggesting that physical therapy can recruit unused neural pathways. Newer robotic therapies appear promising as well. The


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InternalMed_Harrison. shown to improve hemiparesis following stroke, even years after the stroke, suggesting that physical therapy can recruit unused neural pathways. Newer robotic therapies appear promising as well. The human nervous system is more adaptable than previously thought, and developing physical and pharmacologic strategies to enhance long-term neural recovery is an active area of research.


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InternalMed_Harrison. (Figs. 446-1 and 446-3 and Table 446-2) Although the initial management of AIS often does not depend on the etiology, establishing a cause is essential to reduce the risk of recurrence. Particular focus should be on atrial fibrillation and carotid atherosclerosis, because these etiologies have proven secondary prevention strategies. The clinical presentation and examination findings often establish the cause of stroke or narrow the possibilities to a few. Judicious use of laboratory testing and imaging studies completes the initial evaluation. Nevertheless, nearly 30% of strokes remain unexplained despite extensive evaluation.


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InternalMed_Harrison. Clinical examination should focus on the peripheral and cervical vascular system (carotid auscultation for bruits and blood pressure), the heart (dysrhythmia, murmurs), extremities (peripheral emboli), and retina (effects of hypertension and cholesterol emboli [Hollenhorst plaques]). A complete neurologic examination is performed to localize the anatomic site of stroke. An imaging study of the brain is nearly always indicated and is required for patients being considered for thrombolysis; it may be combined with CTor MRI-based angiography to visualize the vasculature of the neck and intracranial vessels (see “Imaging Studies,” below). A chest x-ray, electrocardiogram (ECG), urinalysis, complete blood count, erythrocyte sedimentation rate (ESR), serum electrolytes, blood urea nitrogen (BUN), creatinine, blood glucose, serum lipid profile, prothrombin time (PT), and partial thromboplastin time (PTT) are often useful and should be considered in all patients. An ECG may demonstrate


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InternalMed_Harrison. (BUN), creatinine, blood glucose, serum lipid profile, prothrombin time (PT), and partial thromboplastin time (PTT) are often useful and should be considered in all patients. An ECG may demonstrate arrhythmias or reveal evidence of recent myocardial infarction (MI). Of all these studies, only brain imaging, blood glucose, and perhaps PTT/international normalized ratio (INR) are necessary prior to IV rtPA; the results of other studies should not delay the rapid administration of IV rtPA if the patient is eligible.


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InternalMed_Harrison. Cardioembolic Stroke Cardioembolism is responsible for ~20% of all ischemic strokes. Stroke caused by heart disease is primarily due to embolism of thrombotic material forming on the atrial or ventricular wall or the left heart valves. These thrombi then detach and embolize into the arterial circulation. The thrombus may fragment or lyse quickly, producing only a TIA. Alternatively, the arterial occlusion may last longer, producing stroke. Embolic strokes tend to occur suddenly with maximum neurologic deficit present at onset. With reperfusion following more prolonged ischemia, petechial hemorrhages can occur within the ischemic territory. These are usually of no clinical significance and should be distinguished from frank intracranial hemorrhage into a region of ischemic stroke where the mass effect from the hemorrhage can cause a significant decline in neurologic function.


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InternalMed_Harrison. Emboli from the heart most often lodge in the intracranial internal carotid artery, the MCA, the posterior cerebral artery (PCA), or one of their branches; infrequently, the anterior cerebral artery (ACA) is involved. Emboli large enough to occlude the stem of the MCA (3–4 mm) lead to large infarcts that involve both deep gray and white matter and some portions of the cortical surface and its underlying white matter. A smaller embolus may occlude a small cortical or penetrating arterial branch. The location and size of an infarct within a vascular territory depend on the extent of the collateral circulation. artery disease Carotid plaque with arteriogenic emboli


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InternalMed_Harrison. FIGURE 446-3 Pathophysiology of ischemic stroke. A. Diagram illustrating the three major mechanisms that underlie ischemic stroke: (1) occlusion of an intracranial vessel by an embolus that arises at a distant site (e.g., cardiogenic sources such as atrial fibrillation or artery-to-artery emboli from carotid atherosclerotic plaque), often affecting the large intracranial vessels; (2) in situ thrombosis of an intracranial vessel, typically affecting the small penetrating arteries that arise from the major intracranial arteries; (3) hypoperfusion caused by flow-limiting stenosis of a major extracranial (e.g., internal carotid) or intracranial vessel, often producing “watershed” ischemia. B. and C. Diagram and reformatted computed tomography angiogram of the common, internal, and external carotid arteries. High-grade stenosis of the internal carotid artery, which may be associated with either cerebral emboli or flow-limiting ischemia, was identified in this patient.


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InternalMed_Harrison. The most significant causes of cardioembolic stroke in most of the world are nonrheumatic (often called nonvalvular) atrial fibrillation, MI, prosthetic valves, rheumatic heart disease, and ischemic cardiomyopathy (Table 446-2). Cardiac disorders causing brain embolism are discussed in the chapters on heart diseases. A few pertinent aspects are highlighted here.


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InternalMed_Harrison. Nonrheumatic atrial fibrillation is the most common cause of cerebral embolism overall. The presumed stroke mechanism is thrombus formation in the fibrillating atrium or atrial appendage, with subsequent embolization. Patients with atrial fibrillation have an average annual risk of stroke of ~5%. The risk of stroke can be estimated by calculating the CHADS2 score (Table 446-3). Left atrial enlargement is an additional risk factor for formation of atrial thrombi. Rheumatic heart disease usually causes ischemic stroke when there is prominent mitral stenosis or atrial fibrillation. Recent MI may be a source of emboli, especially when transmural and involving the anteroapical ventricular wall, and prophylactic anticoagulation following MI has been shown to reduce stroke risk. Mitral valve prolapse is not usually a source of emboli unless the prolapse is severe.


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InternalMed_Harrison. Paradoxical embolization occurs when venous thrombi migrate to the arterial circulation, usually via a patent foramen ovale or atrial septal defect. Bubble-contrast echocardiography (IV injection of agitated saline coupled with either transthoracic or transesophageal echocardiography) can demonstrate a right-to-left cardiac shunt, revealing the conduit for paradoxical embolization. Alternatively, a right-to-left shunt is implied if immediately following IV injection of agitated saline, the ultrasound signature of bubbles is observed during transcranial Doppler insonation of the MCA; pulmonary arteriovenous malformations should be considered if this test is positive yet an echocardiogram fails to reveal an intracardiac shunt. Both techniques are highly sensitive for detection of right-to-left shunts. Besides venous clot, fat and tumor emboli, bacterial endocarditis, IV air, and amniotic fluid emboli at childbirth may occasionally be responsible for paradoxical embolization. The


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InternalMed_Harrison. shunts. Besides venous clot, fat and tumor emboli, bacterial endocarditis, IV air, and amniotic fluid emboli at childbirth may occasionally be responsible for paradoxical embolization. The importance of a patent foramen ovale (PFO) as a cause of stroke is debated, particularly because they are present in ~15% of the general population. Some studies have suggested that the risk is only elevated in the presence of a coexisting atrial septal aneurysm. The presence of a venous source of embolus, most commonly a deep venous thrombus, may provide confirmation of the importance of a PFO with an accompanying right-to-left shunt in a particular case. Three randomized trials of PFO occlusion for secondary prevention of ischemic stroke were negative, although each lacked sufficient power to be conclusive. At present, there is no supportive evidence to offer percutaneous PFO closure for stroke prevention.


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InternalMed_Harrison. Bacterial endocarditis can be a source of valvular vegetations that give rise to septic emboli. The appearance of multifocal symptoms and signs in a patient with stroke makes bacterial endocarditis more likely. Infarcts of microscopic size occur, and large septic infarcts may evolve into brain abscesses or cause hemorrhage into the infarct, which generally precludes use of anticoagulation or thrombolytics. Mycotic aneurysms caused by septic emboli may also present as SAH or intra-cerebral hemorrhage.


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InternalMed_Harrison. Artery-to-Artery Embolic Stroke Thrombus formation on atherosclerotic plaques may embolize to intracranial arteries producing an artery-to-artery embolic stroke. Less commonly, a diseased vessel may acutely thrombose. Unlike the myocardial vessels, artery-to-artery embolism, rather than local thrombosis, appears to be the dominant vascular mechanism causing large-vessel brain ischemia. Any diseased vessel may be an embolic source, including the aortic arch, common carotid, internal carotid, vertebral, and basilar arteries.


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InternalMed_Harrison. cArotiD AtheroScleroSiS Atherosclerosis within the carotid artery occurs most frequently within the common carotid bifurcation and proximal internal carotid artery; the carotid siphon (portion within the cavernous sinus) is also vulnerable to atherosclerosis. Male gender, older age, smoking, hypertension, diabetes, and hypercholesterolemia are risk factors for carotid disease, as they are for stroke in general (Table 446-4). Carotid atherosclerosis produces an estimated 10% of Spontaneous echo contrast Systemic vasculitis (PAN, granuloma- Stimulant drugs: cocaine, tosis with polyangiitis [Wegener’s], amphetamine Takayasu’s, giant cell arteritis) Primary CNS vasculitis Meningitis (syphilis, tuberculosis, fungal, bacterial, zoster) aChiefly cause venous sinus thrombosis. bMay be associated with any hypercoagulable disorder. Abbreviations: CNS, central nervous system; PAN, polyarteritis nodosa.


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InternalMed_Harrison. Abbreviations: CNS, central nervous system; PAN, polyarteritis nodosa. ischemic stroke. For further discussion of the pathogenesis of atherosclerosis, see Chap. 291e. Carotid disease can be classified by whether the stenosis is symptomatic or asymptomatic and by the degree of stenosis (percent narrowing of the narrowest segment compared to a nondiseased segment). Symptomatic carotid disease implies that the patient has experienced a stroke or TIA within the vascular distribution of the artery, and it is associated with a greater risk of subsequent stroke than asymptomatic stenosis, in which the patient is symptom free and the stenosis is detected through screening. Greater degrees of arterial narrowing are generally associated with a higher risk of stroke, except that those with near occlusions are at lower risk of stroke.


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InternalMed_Harrison. other cAuSeS of Artery-to-Artery embolic Stroke Intracranial atherosclerosis produces stroke either by an embolic mechanism or by in situ thrombosis of a diseased vessel. It is more common in patients of Asian 2565 and African-American descent. Recurrent stroke risk is ~15% per year, similar to symptomatic untreated carotid atherosclerosis.


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InternalMed_Harrison. Dissection of the internal carotid or vertebral arteries or even vessels beyond the circle of Willis is a common source of embolic stroke in young (age <60 years) patients. The dissection is usually painful and precedes the stroke by several hours or days. Extracranial dissections do not cause hemorrhage, presumably because of the tough adventitia of these vessels. Intracranial dissections, conversely, may produce SAH because the adventitia of intracranial vessels is thin and pseudoaneu rysms may form, requiring urgent treatment to prevent rerupture. Treating asymptomatic pseudoaneurysms following dissection is likely not necessary. The cause of dissection is usually unknown, and recurrence is rare. Ehlers-Danlos type IV, Marfan’s disease, cystic medial necrosis, and fibromuscular dysplasia are associated with dissections. Trauma (usually a motor vehicle accident or a sports injury) can cause carotid and vertebral artery dissections. Spinal manipulative therapy is associated with


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InternalMed_Harrison. are associated with dissections. Trauma (usually a motor vehicle accident or a sports injury) can cause carotid and vertebral artery dissections. Spinal manipulative therapy is associated with vertebral artery dissection and stroke. Most dissections heal spontaneously, and stroke or TIA is uncommon beyond 2 weeks. Although there are no trials comparing anticoagulation to antiplatelet agents, many physicians treat acutely with anticoagulants and then convert to antiplatelet therapy after demonstration of satisfactory vascular recanalization.


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InternalMed_Harrison. The term lacunar infarction refers to infarction following atherothrombotic or lipohyalinotic occlusion of a small artery in the brain. The term small-vessel stroke denotes occlusion of such a small penetrating artery and is now the preferred term. Small-vessel strokes account for ~20% of all strokes.


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InternalMed_Harrison. Pathophysiology The MCA stem, the arteries comprising the circle of Willis (A1 segment, anterior and posterior communicating arteries, and P1 segment), and the basilar and vertebral arteries all give rise to 30to 300-μm branches that penetrate the deep gray and white matter of the cerebrum or brainstem (Fig. 446-4). Each of these small branches can occlude either by atherothrombotic disease at its origin or by the development of lipohyalinotic thickening. Thrombosis of these vessels causes small infarcts that are referred to as lacunes (Latin for “lake” of fluid noted at autopsy). These infarcts range in size from 3 mm to 2 cm in diameter. Hypertension and age are the principal risk factors.


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InternalMed_Harrison. Clinical Manifestations The most common small-vessel stroke syndromes are the following: (1) Pure motor hemiparesis from an infarct in the posterior limb of the internal capsule or the pons; the face, arm, and leg are almost always involved; (2) pure sensory stroke from an infarct in the ventral thalamus; (3) ataxic hemiparesis from an infarct in the ventral pons or internal capsule; (4) and dysarthria and a clumsy hand or arm due to infarction in the ventral pons or in the genu of the internal capsule. Transient symptoms (small-vessel TIAs) may herald a small-vessel infarct; they may occur several times a day and last only a few minutes. Recovery from small-vessel strokes tends to be more rapid and complete than recovery from large-vessel strokes; in some cases, however, there is severe permanent disability.


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InternalMed_Harrison. A large-vessel source (either thrombosis or embolism) may manifest initially as a small-vessel infarction. Therefore, the search for embolic sources (carotid and heart) should not be completely abandoned in the evaluation of these patients. Secondary prevention of small-vessel stroke involves risk factor modification, specifically reduction in blood pressure (see “Treatment: Primary and Secondary Prevention of Stroke and TIA,” below). (Table 446-2) Hypercoagulable disorders (Chap. 78) primarily increase the risk of venous, including venous sinus, thrombosis. Systemic lupus erythematosus with Libman-Sacks endocarditis can be a cause of embolic stroke. These conditions overlap with the antiphospholipid syndrome, which probably requires long-term anticoagulation to With atrial fibrillation, previous embolization, or atrial appendage thrombus, or left atrial diameter >55 mm Without atrial fibrillation but systemic embolization, or otherwise cryptogenic stroke or TIA


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InternalMed_Harrison. Without atrial fibrillation but systemic embolization, or otherwise cryptogenic stroke or TIA Aortic position, bileaflet or Medtronic Hall tilting disk with normal left atrial size and sinus rhythm Mitral or aortic position, anterior-apical myocardial infarct or left atrial enlargement Mitral or aortic position, with atrial fibrillation, or hypercoagulable state, or low ejection fraction, or atherosclerotic vascular disease VKA INR 2.5, range 2–3 VKA INR 3.0, range 2.5–3.5 VKA INR 3.0, range 2.5–3.5 Aspirin plus VKA INR 3.0, range 2.5–3.5 Add aspirin and/or increase INR: prior target was 2.5 increase to 3.0, range 2.5–3.5; prior target was 3.0 increase to 3.5, range 3–4 aCHADS2 score calculated as follows: 1 point for age >75 years, 1 point for hypertension, 1 point for congestive heart failure, 1 point for diabetes, and 2 points for stroke or TIA; sum of points is the total CHADS2 score.


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InternalMed_Harrison. Note: Dose of aspirin is 50–325 mg/d; target INR for OAC is between 2 and 3 unless otherwise specified. Abbreviations: INR, international normalized ratio; LMWH, low-molecular-weight heparin; OAC, oral anticoagulant (VKA, thrombin inhibitor, oral factor Xa inhibitors); TIA, transient ischemic attack; VKA, vitamin K antagonist. Sources: Modified from DE Singer et al: Chest 133:546S, 2008; DN Salem et al: Chest 133:593S, 2008. prevent further stroke. Homocysteinemia may cause arterial thromboses as well; this disorder is caused by various mutations in the homocysteine pathways and responds to different forms of cobalamin depending on the mutation.


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InternalMed_Harrison. Venous sinus thrombosis of the lateral or sagittal sinus or of small cortical veins (cortical vein thrombosis) occurs as a complication of oral contraceptive use, pregnancy and the postpartum period, inflammatory bowel disease, intracranial infections (meningitis), and dehydration. It is also seen in patients with laboratory-confirmed thrombophilia including polycythemia, sickle cell anemia, deficiencies of proteins C and S, factor V Leiden mutation (resistance to activated protein C), antithrombin III deficiency, homocysteinemia, and the prothrombin G20210 mutation. Women who take oral contraceptives and have the prothrombin G20210 mutation may be at particularly high risk for sinus thrombosis. Patients present with headache and may also have focal neurologic signs (especially paraparesis) and seizures. Often, CT imaging is normal unless an intracranial venous hemorrhage has occurred, but the venous sinus occlusion is readily visualized using magnetic resonance (MR) or CT venography


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InternalMed_Harrison. and seizures. Often, CT imaging is normal unless an intracranial venous hemorrhage has occurred, but the venous sinus occlusion is readily visualized using magnetic resonance (MR) or CT venography or conventional x-ray angiography. With greater degrees of sinus thrombosis, the


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InternalMed_Harrison. Basilar a. Basilar a. Vertebral a. Deep branches Hypertension 2–5 38% 100–300 50–100 Atrial fibrillation 1.8–2.9 68% warfarin, 21% aspirin 20–83 13 Diabetes 1.8–6 No proven effect Smoking 1.8 50% at 1 year, baseline risk at 5 years postcessation Hyperlipidemia 1.8–2.6 16–30% 560 230 Asymptomatic 2.0 53% 85 N/A carotid stenosis aNumber needed to treat to prevent one stroke annually. Prevention of other cardiovascular outcomes is not considered here. Abbreviation: N/A, not applicable. Deep branches of the Anterior cerebral a. middle cerebral a. Anterior cerebral a. Internal carotid a. Middle cerebral a. Internal carotid a. Middle cerebral a. Vertebral a. of the basilar a.


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InternalMed_Harrison. Deep branches of the Anterior cerebral a. middle cerebral a. Anterior cerebral a. Internal carotid a. Middle cerebral a. Internal carotid a. Middle cerebral a. Vertebral a. of the basilar a. FIGURE 446-4 Diagrams and reformatted computed tomography (CT) angiograms in the coronal section illustrating the deep penetrating arteries involved in small-vessel strokes. In the anterior circulation, small penetrating arteries called lenticulostriates arise from the proximal portion of the anterior and middle cerebral arteries and supply deep subcortical structures (upper panels). In the posterior circulation, similar arteries arise directly from the vertebral and basilar arteries to supply the brainstem (lower panels). Occlusion of a single penetrating artery gives rise to a discrete area of infarct (pathologically termed a “lacune,” or lake). Note that these vessels are too small to be visualized on CT angiography. patient may develop signs of increased 2567


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InternalMed_Harrison. patient may develop signs of increased 2567 ICP and coma. Intravenous heparin, regardless of the presence of intracranial hemorrhage, reduces morbidity and mortality, and the long-term outcome is generally good. Heparin prevents further thrombosis and reduces venous hypertension and ischemia. If an underlying hypercoagulable state is not found, many physicians treat with vitamin K antagonists (VKAs) for 3–6 months and then convert to aspirin, depending on the degree of resolution of the venous sinus thrombus. Anticoagulation is often continued indefinitely if thrombophilia is diagnosed.


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InternalMed_Harrison. Sickle cell anemia (SS disease) is a common cause of stroke in children. A subset of homozygous carriers of this hemoglobin mutation develop stroke in childhood, and this may be predicted by documenting high-velocity blood flow within the MCAs using transcranial Doppler ultrasonography. In children who are identified to have high velocities, treatment with aggressive exchange transfusion dramatically reduces risk of stroke, and if exchange transfusion is ceased, their stroke rate increases again along with MCA velocities.


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InternalMed_Harrison. Fibromuscular dysplasia affects the cervical arteries and occurs mainly in women. The carotid or vertebral arteries show multiple rings of segmental narrowing alternating with dilatation. Vascular occlusion is usually incomplete. The process is often asymptomatic but occasionally is associated with an audible bruit, TIAs, or stroke. Involvement of the renal arteries is common and may cause hypertension. The cause and natural history of fibromuscular dysplasia are unknown (Chap. 302). TIA or stroke generally occurs only when the artery is severely narrowed or dissects. Anticoagulation or antiplatelet therapy may be helpful. Temporal (giant cell) arteritis (Chap.


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InternalMed_Harrison. Temporal (giant cell) arteritis (Chap. 385) is a relatively common affliction of elderly individuals in which the external carotid system, particularly the temporal arteries, undergo subacute granulomatous inflammation with giant cells. Occlusion of posterior ciliary arteries derived from the ophthalmic artery results in blindness in one or both eyes and can be prevented with glucocorticoids. It rarely causes stroke because the internal carotid artery is usually not inflamed. Idiopathic giant cell arteritis involving the great vessels arising from the aortic arch (Takayasu’s arteritis) may cause carotid or vertebral thrombosis; it is rare in the Western Hemisphere. Necrotizing (or granulomatous) arteritis, occurring alone or in association with generalized polyarteritis nodosa or granulomatosis with polyangiitis (Wegener’s), involves the distal small


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InternalMed_Harrison. Necrotizing (or granulomatous) arteritis, occurring alone or in association with generalized polyarteritis nodosa or granulomatosis with polyangiitis (Wegener’s), involves the distal small FIGURE 446-5 Cerebral angiogram from a 32-year-old male with central nervous system vasculopathy. Dramatic beading (arrows) typical of vasculopathy is seen.


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InternalMed_Harrison. FIGURE 446-5 Cerebral angiogram from a 32-year-old male with central nervous system vasculopathy. Dramatic beading (arrows) typical of vasculopathy is seen. branches (<2 mm diameter) of the main intracranial arteries and produces small ischemic infarcts in the brain, optic nerve, and spinal cord. The CSF often shows pleocytosis, and the protein level is elevated. Primary central nervous system vasculitis is rare; small or medium-sized vessels are usually affected, without apparent systemic vasculitis. The differential diagnosis includes other inflammatory vasculopathies including infection (tuberculous, fungal), sarcoidosis, angiocentric lymphoma, carcinomatous meningitis, and noninflammatory causes such as atherosclerosis, emboli, connective tissue disease, vasospasm, migraine-associated vasculopathy, and drug-associated causes. Some cases develop in the postpartum period and are self-limited.


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InternalMed_Harrison. Patients with any form of vasculopathy may present with insidious progression of combined white and gray matter infarctions, prominent headache, and cognitive decline. Brain biopsy or high-resolution conventional x-ray angiography is usually required to make the diagnosis (Fig. 446-5). An inflammatory profile found on lumbar puncture favors an inflammatory cause. In cases where inflammation is confirmed, aggressive immunosuppression with glucocorticoids, and often cyclophosphamide, is usually necessary to prevent progression; a diligent investigation for infectious causes such as tuberculosis is essential prior to immunosuppression. With prompt recognition and treatment, many patients can make an excellent recovery.


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InternalMed_Harrison. Drugs, in particular amphetamines and perhaps cocaine, may cause stroke on the basis of acute hypertension or drug-induced vasculopathy. No data exist on the value of any treatment. Phenylpropanolamine has been linked with intracranial hemorrhage, as has cocaine and methamphetamine, perhaps related to a drug-induced vasculopathy. Moyamoya disease is a poorly understood occlusive disease involving large intracranial arteries, especially the distal internal carotid artery and the stem of the MCA and ACA. Vascular inflammation is absent. The lenticulostriate arteries develop a rich collateral circulation around the occlusive lesion, which gives the impression of a “puff of smoke” (moyamoya in Japanese) on conventional x-ray angiography. Other collaterals include transdural anastomoses between the cortical surface branches of the meningeal and scalp arteries. The disease occurs mainly in Asian children or young adults, but the appearance may be identical in adults who have


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InternalMed_Harrison. between the cortical surface branches of the meningeal and scalp arteries. The disease occurs mainly in Asian children or young adults, but the appearance may be identical in adults who have atherosclerosis, particularly in association with diabetes. Intracranial hemorrhage may result from rupture of the transdural and pial anastomotic channels; thus, anticoagulation is risky. Breakdown of dilated lenticulostriate arteries may produce intraparenchymal hemorrhage, and progressive occlusion of large surface arteries can occur, producing large-artery distribution strokes. Surgical bypass of extracranial carotid arteries to the dura or MCAs may prevent stroke and hemorrhage.


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InternalMed_Harrison. Posterior reversible encephalopathy syndrome (PRES) can occur with head injury, seizure, migraine, sympathomimetic drug use, eclampsia, and in the postpartum period (Chap. 463e). The pathophysiology is uncertain but likely involves a hyperperfusion state with widespread segmental vasoconstriction and cerebral edema. Patients complain of headache and manifest fluctuating neurologic symptoms and signs, especially visual symptoms. Sometimes cerebral infarction ensues, but typically the clinical and imaging findings suggest that ischemia reverses completely. MRI findings are characteristic with the edema present within the occipital lobes but can be generalized and do not respect any single vascular territory. A closely related reversible cerebral vasoconstriction syndrome (RCVS) typically presents with sudden, severe headache closely mimicking SAH. Patients may experience ischemic infarction and intracerebral hemorrhage and typically have new-onset, severe hypertension. Conventional


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InternalMed_Harrison. presents with sudden, severe headache closely mimicking SAH. Patients may experience ischemic infarction and intracerebral hemorrhage and typically have new-onset, severe hypertension. Conventional x-ray angiography reveals changes in the vascular caliber throughout the hemispheres resembling vasculitis, but the process is noninflammatory. Oral calcium channel blockers may be effective in producing remission, and recurrence is rare.


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InternalMed_Harrison. Leukoaraiosis, or periventricular white matter disease, is the result of multiple small-vessel infarcts within the subcortical white matter. It is readily seen on CT or MRI scans as areas of white matter injury surrounding the ventricles and within the corona radiata. The pathophysiologic basis of the disease is lipohyalinosis of small penetrating arteries within the white matter, likely produced by chronic hypertension. Patients with periventricular white matter disease may develop a subcortical dementia syndrome, and it is likely that this common form of dementia may be delayed or prevented with antihypertensive medications (Chap. 448).


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InternalMed_Harrison. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited disorder that presents as small-vessel strokes, progressive dementia, and extensive symmetric white matter changes often including the anterior temporal lobes visualized by MRI. Approximately 40% of patients have migraine with aura, often manifest as transient motor or sensory deficits. Onset is usually in the fourth or fifth decade of life. This autosomal dominant condition is caused by one of several mutations in Notch-3, a member of a highly conserved gene family characterized by epidermal growth factor repeats in its extracellular domain. Other monogenic ischemic stroke syndromes include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS). Fabry’s disease also produces both a large-vessel arteriopathy and small-vessel infarctions.


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InternalMed_Harrison. TIAs are episodes of stroke symptoms that last only briefly; the standard definition of duration is <24 h, but most TIAs last <1 h. If a relevant brain infarction is identified on brain imaging, the clinical entity is now classified as stroke regardless of the duration of symptoms. The causes of TIA are similar to the causes of ischemic stroke, but because TIAs may herald stroke, they are an important risk factor that should be considered separately and urgently. TIAs may arise from emboli to the brain or from in situ thrombosis of an intracranial vessel. With a TIA, the occluded blood vessel reopens and neurologic function is restored.


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InternalMed_Harrison. The risk of stroke after a TIA is ~10–15% in the first 3 months, with most events occurring in the first 2 days. This risk can be directly estimated using the well-validated ABCD2 score (Table 446-5). Therefore, urgent evaluation and treatment are justified. Because etiologies for stroke and TIA are identical, evaluation for TIA should parallel that of stroke (Figs. 446-1 and 446-3). The improvement characteristic of TIA is a contraindication to thrombolysis. However, because the risk of subsequent stroke in the first few days after a TIA is high, the opportunity to give rtPA rapidly if a stroke occurs may justify hospital admission for most patients. The combination of aspirin and clopidogrel has been recently reported to prevent stroke following TIA better than aspirin alone in a large Chinese randomized trial and is undergoing similar evaluation in an ongoing National Institutes of Health (NIH)sponsored trial (POINT study). A: Age ≥60 years 1 B: SBP >140 mmHg or DBP >90 mmHg 1


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InternalMed_Harrison. A: Age ≥60 years 1 B: SBP >140 mmHg or DBP >90 mmHg 1 C: Clinical symptoms Unilateral weakness 2 Speech disturbance without weakness 1 D: D: ABCD2 Score Total 3-Month Rate of Stroke (%)a 00 12 23 33 48 5 12 6 17 7 22 aData ranges are from five cohorts. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. Source: SC Johnston et al: Validation and refinement of score to predict very early stroke risk after transient ischaemic attack. Lancet 369:283, 2007.


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InternalMed_Harrison. Source: SC Johnston et al: Validation and refinement of score to predict very early stroke risk after transient ischaemic attack. Lancet 369:283, 2007. A number of medical and surgical interventions, as well as lifestyle modifications, are available for preventing stroke. Some of these can be widely applied because of their low cost and minimal risk; others are expensive and carry substantial risk but may be valuable for selected high-risk patients. Identification and control of modifiable risk factors, and especially hypertension, is the best strategy to reduce the burden of stroke, and the total number of strokes could be reduced substantially by these means (Table 446-4).


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InternalMed_Harrison. The relationship of various factors to the risk of atherosclerosis is described in Chap. 291e. Older age, diabetes mellitus, hypertension, tobacco smoking, abnormal blood cholesterol (particularly, low high-density lipoprotein [HDL] and/or elevated low-density lipoprotein [LDL]), and other factors are either proven or probable risk factors for ischemic stroke, largely by their link to atherosclerosis. Risk of stroke is much greater in those with prior stroke or TIA. Many cardiac conditions predispose to stroke, including atrial fibrillation and recent MI. Oral contraceptives and hormone replacement therapy increase stroke risk, and although rare, certain inherited and acquired hypercoagulable states predispose to stroke.


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InternalMed_Harrison. Hypertension is the most significant of the risk factors; in general, all hypertension should be treated to a target of less than 140– 150/90 mmHg. However, many vascular neurologists recommend that guidelines for secondary prevention of stroke should aim for blood pressure reduction to 130/80 mmHg or lower. The presence of known cerebrovascular disease is not a contraindication to treatment aimed at achieving normotension. Also, the value of treating systolic hypertension in older patients has been clearly established. Lowering blood pressure to levels below those traditionally defining hypertension appears to reduce the risk of stroke even further. Data are particularly strong in support of thiazide diuretics and angiotensin-converting enzyme inhibitors.


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InternalMed_Harrison. Several trials have confirmed that statin drugs reduce the risk of 2569 stroke even in patients without elevated LDL or low HDL. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial showed benefit in secondary stroke reduction for patients with recent stroke or TIA who were prescribed atorvastatin, 80 mg/d. The primary prevention trial, Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), found that patients with low LDL (<130 mg/dL) caused by elevated C-reactive protein benefitted by daily use of this statin. Primary stroke occurrence was reduced by 51% (hazard ratio 0.49, p = .004), and there was no increase in the rates of intracranial hemorrhage. Meta-analysis has also supported a primary treatment effect for statins given acutely for ischemic stroke. Therefore, a statin should be considered in all patients with prior ischemic stroke. Tobacco smoking should be discouraged in all patients (Chap.


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InternalMed_Harrison. effect for statins given acutely for ischemic stroke. Therefore, a statin should be considered in all patients with prior ischemic stroke. Tobacco smoking should be discouraged in all patients (Chap. 470). The use of pioglitazone (an agonist of peroxisome proliferator-activated receptor gamma) in patients with type 2 diabetes and previous stroke may lower risk of recurrent stroke, MI, or vascular death, but no trial sufficiently powered to definitively detect a significant reduction in stroke in the general diabetic population has yet been performed.


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InternalMed_Harrison. Platelet antiaggregation agents can prevent atherothrombotic events, including TIA and stroke, by inhibiting the formation of intraarterial platelet aggregates. These can form on diseased arteries, induce thrombus formation, and occlude or embolize into the distal circulation. Aspirin, clopidogrel, and the combination of aspirin plus extended-release dipyridamole are the antiplatelet agents most commonly used for this purpose. Ticlopidine has been largely abandoned because of its adverse effects but may be used as an alternative to clopidogrel.


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InternalMed_Harrison. Aspirin is the most widely studied antiplatelet agent. Aspirin acetylates platelet cyclooxygenase, which irreversibly inhibits the formation in platelets of thromboxane A2, a platelet aggregating and vasoconstricting prostaglandin. This effect is permanent and lasts for the usual 8-day life of the platelet. Paradoxically, aspirin also inhibits the formation in endothelial cells of prostacyclin, an antiaggregating and vasodilating prostaglandin. This effect is transient. As soon as aspirin is cleared from the blood, the nucleated endothelial cells again produce prostacyclin. Aspirin in low doses given once daily inhibits the production of thromboxane A2 in platelets without substantially inhibiting prostacyclin formation. Higher doses of aspirin have not been proven to be more effective than lower doses.


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InternalMed_Harrison. Ticlopidine and clopidogrel block the adenosine diphosphate (ADP) receptor on platelets and thus prevent the cascade resulting in activation of the glycoprotein IIb/IIIa receptor that leads to fibrinogen binding to the platelet and consequent platelet aggregation. Ticlopidine is more effective than aspirin; however, it has the disadvantage of causing diarrhea, skin rash, and, in rare instances, neutropenia and thrombotic thrombocytopenic purpura (TTP). Clopidogrel rarely causes TTP but does not cause neutropenia. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, which led to FDA approval, found that it was only marginally more effective than aspirin in reducing risk of stroke. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) trial was a large multicenter, randomized, double-blind study that compared clopidogrel in combination with aspirin to clopidogrel alone in the secondary prevention of TIA or stroke. The MATCH


InternalMed_Harrison

InternalMed_Harrison. trial was a large multicenter, randomized, double-blind study that compared clopidogrel in combination with aspirin to clopidogrel alone in the secondary prevention of TIA or stroke. The MATCH trial found no difference in TIA or stroke prevention with this combination, but did show a small but significant increase in major bleeding complications (3 vs 1%). In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, which included a subgroup of patients with prior stroke or TIA along with other groups at high risk of cardiovascular events, there was no benefit of clopidogrel combined with aspirin compared to aspirin alone. Lastly, the SPS3 trial looked at the long-term combination of clopidogrel and aspirin versus clopidogrel alone in small-vessel stroke and found no 2570 improvement in stroke prevention and a significant increase in both hemorrhage and death. Thus, the long-term use of clopidogrel in combination with


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InternalMed_Harrison. alone in small-vessel stroke and found no 2570 improvement in stroke prevention and a significant increase in both hemorrhage and death. Thus, the long-term use of clopidogrel in combination with aspirin is not recommended for stroke prevention. The short-term combination of clopidogrel with aspirin may be effective in preventing second stroke, however. A trial of 5170 Chinese patients enrolled within 24 h of TIA or minor ischemic stroke found that a clopidogrel-aspirin regimen (clopidogrel 300 mg load then 75 mg/d with aspirin 75 mg for the first 21 days) was superior to aspirin (75 mg/d) alone, with 90-day stroke risk decreased from 11.7 to 8.2% (p < .001) and no increase in major hemorrhage. An international NIH-sponsored trial of similar design is ongoing. Dipyridamole is an antiplatelet agent that inhibits the uptake of adenosine by a variety of cells, including those of the vascular endothelium. The accumulated adenosine is an inhibitor of aggregation. At least in part through


InternalMed_Harrison

InternalMed_Harrison. agent that inhibits the uptake of adenosine by a variety of cells, including those of the vascular endothelium. The accumulated adenosine is an inhibitor of aggregation. At least in part through its effects on platelet and vessel wall phosphodiesterases, dipyridamole also potentiates the antiaggregatory effects of prostacyclin and nitric oxide produced by the endothelium and acts by inhibiting platelet phosphodiesterase, which is responsible for the breakdown of cyclic AMP. The resulting elevation in cyclic AMP inhibits aggregation of platelets. Dipyridamole is erratically absorbed depending on stomach pH, but a newer formulation combines timed-release dipyridamole, 200 mg, with aspirin, 25 mg, and has better oral bioavailability. This combination drug was studied in three trials. The European Stroke Prevention Study (ESPS) II showed efficacy of both 50 mg/d of aspirin and extended-release dipyridamole in preventing stroke, and a significantly better risk reduction when the two agents


InternalMed_Harrison

InternalMed_Harrison. Stroke Prevention Study (ESPS) II showed efficacy of both 50 mg/d of aspirin and extended-release dipyridamole in preventing stroke, and a significantly better risk reduction when the two agents were combined. The open-label ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial) trial confirmed the ESPS-II results. After 3.5 years of follow-up, 13% of patients on aspirin and dipyridamole and 16% on aspirin alone (hazard ratio 0.80, 95% confidence index [CI] 0.66– 0.98) met the primary outcome of death from all vascular causes. In the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, the combination of extended-release dipyridamole and aspirin was compared directly with clopidogrel with and without the angiotensin receptor blocker telmisartan; there were no differences in the rates of second stroke (9% each) or degree of disability in patients with median follow-up of 2.4 years. Telmisartan also had no effect on these outcomes. This


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InternalMed_Harrison. there were no differences in the rates of second stroke (9% each) or degree of disability in patients with median follow-up of 2.4 years. Telmisartan also had no effect on these outcomes. This suggests that these anti-platelet regimens are similar and also raises questions about default prescription of agents to block the angiotensin pathway in all stroke patients. The principal side effect of dipyridamole is headache. The combination capsule of extended-release dipyridamole and aspirin is approved for prevention of stroke.


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InternalMed_Harrison. Many large clinical trials have demonstrated clearly that most antiplatelet agents reduce the risk of all important vascular atherothrombotic events (i.e., ischemic stroke, MI, and death due to all vascular causes) in patients at risk for these events. The overall relative reduction in risk of nonfatal stroke is about 25–30% and of all vascular events is about 25%. The absolute reduction varies considerably, depending on the particular patient’s risk. Individuals at very low risk for stroke seem to experience the same relative reduction, but their risks may be so low that the “benefit” is meaningless. Conversely, individuals with a 10–15% risk of vascular events per year experience a reduction to about 7.5–11%.


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InternalMed_Harrison. Aspirin is inexpensive, can be given in low doses, and could be recommended for all adults to prevent both stroke and MI. However, it causes epigastric discomfort, gastric ulceration, and gastrointestinal hemorrhage, which may be asymptomatic or life threatening. Consequently, not every 40or 50-year-old should be advised to take aspirin regularly because the risk of atherothrombotic stroke is extremely low and is outweighed by the risk of adverse side effects. Conversely, every patient who has experienced an atherothrombotic stroke or TIA and has no contraindication should be taking an antiplatelet agent regularly because the average annual risk of another stroke is 8–10%; another few percent will experience an MI or vascular death. Clearly, the likelihood of benefit far outweighs the risks of treatment.


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InternalMed_Harrison. The choice of antiplatelet agent and dose must balance the risk of stroke, the expected benefit, and the risk and cost of treatment. However, there are no definitive data, and opinions vary. Many authorities believe low-dose (30–75 mg/d) and high-dose (650–1300 mg/d) aspirin are about equally effective. Some advocate very low doses to avoid adverse effects, and still others advocate very high doses to be sure the benefit is maximal. Most physicians in North America recommend 81–325 mg/d, whereas most Europeans recommend 50–100 mg. Clopidogrel and extended-release dipyridamole plus aspirin are being increasingly recommended as first-line drugs for secondary prevention. Similarly, the choice of aspirin, clopidogrel, or dipyridamole plus aspirin must balance the fact that the latter are more effective than aspirin but the cost is higher, and this is likely to affect long-term patient adherence. The use of platelet aggregation studies in individual patients taking aspirin is controversial


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InternalMed_Harrison. effective than aspirin but the cost is higher, and this is likely to affect long-term patient adherence. The use of platelet aggregation studies in individual patients taking aspirin is controversial because of limited data.


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InternalMed_Harrison. Several trials have shown that anticoagulation (INR range, 2–3) in patients with chronic nonvalvular (nonrheumatic) atrial fibrillation (NVAF) prevents cerebral embolism and stroke and is safe. For primary prevention and for patients who have experienced stroke or TIA, anticoagulation with a VKA reduces the risk by about 67%, which clearly outweighs the 1–3% risk per year of a major bleeding complication. VKAs are difficult to dose, their effects vary with dietary intake of vitamin K, and they require frequent blood monitoring of the PTT/INR. Several newer oral anticoagulants (OACs) have recently been shown to be more convenient and efficacious for stroke prevention in NVAF. A randomized trial compared the oral thrombin inhibitor dabigatran to VKAs in a noninferiority trial to prevent stroke or systemic embolization in NVAF. Two doses of dabigatran were used: 110 mg/d and 150 mg/d. Both dose tiers of dabigatran were noninferior to VKAs in preventing second stroke and systemic


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InternalMed_Harrison. stroke or systemic embolization in NVAF. Two doses of dabigatran were used: 110 mg/d and 150 mg/d. Both dose tiers of dabigatran were noninferior to VKAs in preventing second stroke and systemic embolization, and the higher dose tier was superior (relative risk 0.66; 95% CI 0.53–0.82; p < .001) and the rate of major bleeding was lower in the lower dose tier of dabigatran compared to VKAs. Dabigatran requires no blood monitoring to titrate the dose, and its effect is independent of oral intake of vitamin K. Newer oral factor Xa inhibitors have also been found to be equivalent or safer and more effective than VKAs in NVAF stroke prevention. In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, patients were randomized between apixaban, 5 mg twice daily, and dose-adjusted warfarin (INR 2–3). The combined endpoint of ischemic or hemorrhagic stroke or system embolism occurred in 1.27% of patients in the apixaban group and in 1.6%


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InternalMed_Harrison. 5 mg twice daily, and dose-adjusted warfarin (INR 2–3). The combined endpoint of ischemic or hemorrhagic stroke or system embolism occurred in 1.27% of patients in the apixaban group and in 1.6% in the warfarin group (p < .001 for non-inferiority and p < .01 for superiority). Major bleeding was 1% less, favoring apixaban (p < .001). Similar results were obtained in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF). Here, patients with NVAF were randomized to rivaroxaban versus warfarin: 1.7% of the factor Xa group and 2.2% of the warfarin group reached the endpoint of stroke and systemic embolism (p < .001 for noninferiority); intracranial hemorrhage was also lower with rivaroxaban. Finally, the factor Xa inhibitor edoxaban was also found to be noninferior to warfarin. Thus, oral factor Xa inhibitors are at least a suitable alternative to VKAs, and likely are


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InternalMed_Harrison. with rivaroxaban. Finally, the factor Xa inhibitor edoxaban was also found to be noninferior to warfarin. Thus, oral factor Xa inhibitors are at least a suitable alternative to VKAs, and likely are superior both in efficacy and perhaps compliance.


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InternalMed_Harrison. For patients who cannot take anticoagulant medications, clopidogrel plus aspirin was compared to aspirin alone in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-A). Clopidogrel combined with aspirin was more effective than aspirin alone in preventing vascular events, principally stroke, but increased the risk of major bleeding (relative risk 1.57, p < .001).


InternalMed_Harrison

InternalMed_Harrison. The decision to use anticoagulation for primary prevention is based primarily on risk factors (Table 446-3). The history of a TIA or stroke tips the balance in favor of anticoagulation regardless of other risk factors. Intermittent atrial fibrillation carries the same risk of stroke as chronic atrial fibrillation, and several ambulatory studies of seemingly “cryptogenic” stroke have found evidence of intermittent atrial fibrillation in nearly 20% of patients monitored for a few weeks. Interrogation of implanted pacemakers also confirms an association between subclinical atrial fibrillation and stroke risk. Therefore, for patients with otherwise cryptogenic embolic stroke (no evidence of any other cause for stroke), ambulatory monitoring for 3–4 weeks is a reasonable strategy to determine the best prophylactic therapy.


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InternalMed_Harrison. Because of the high annual stroke risk in untreated rheumatic heart disease with atrial fibrillation, primary prophylaxis against stroke has not been studied in a double-blind fashion. These patients generally should receive long-term anticoagulation. Dabigatran and the oral Xa inhibitors have not been studied in this population. Anticoagulation also reduces the risk of embolism in acute MI. Most clinicians recommend a 3-month course of anticoagulation when there is anterior Q-wave infarction, substantial left ventricular dysfunction, congestive heart failure, mural thrombosis, or atrial fibrillation. OACs are recommended long-term if atrial fibrillation persists.


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InternalMed_Harrison. Stroke secondary to thromboembolism is one of the most serious complications of prosthetic heart valve implantation. The intensity of anticoagulation and/or antiplatelet therapy is dictated by the type of prosthetic valve and its location. Dabigatran may be less effective than warfarin, and the oral Xa inhibitors have not been studied in this population. If the embolic source cannot be eliminated, anticoagulation should in most cases be continued indefinitely. Many neurologists recommend combining antiplatelet agents with anticoagulants for patients who “fail” anticoagulation (i.e., have another stroke or TIA), but the evidence basis for this is lacking.


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InternalMed_Harrison. Data do not support the use of long-term VKAs for preventing atherothrombotic stroke for either intracranial or extracranial cerebrovascular disease. The Warfarin-Aspirin Recurrent Stroke Study (WARSS) found no benefit of warfarin sodium (INR 1.4–2.8) over aspirin, 325 mg, for secondary prevention of stroke but did find a slightly higher bleeding rate in the warfarin group; a European study confirmed this finding. The Warfarin and Aspirin for Symptomatic Intracranial Disease (WASID) study (see below) demonstrated no benefit of warfarin (INR 2–3) over aspirin in patients with symptomatic intracranial atherosclerosis and also found a higher rate of bleeding complications. Carotid atherosclerosis can be removed surgically (endarterectomy) or mitigated with endovascular stenting with or without balloon angioplasty. Anticoagulation has not been directly compared with antiplatelet therapy for carotid disease.


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InternalMed_Harrison. Symptomatic carotid stenosis was studied in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST). Both showed a substantial benefit for surgery in patients with stenosis of ≥70%. In NASCET, the average cumulative ipsilateral stroke risk at 2 years was 26% for patients treated medically and 9% for those receiving the same medical treatment plus a carotid endarterectomy. This 17% absolute reduction in the surgical group is a 65% relative risk reduction favoring surgery (Table 446-4). NASCET also showed a significant, although less robust, benefit for patients with 50–70% stenosis. ECST found harm for patients with stenosis <30% treated surgically.


InternalMed_Harrison

InternalMed_Harrison. A patient’s risk of stroke and possible benefit from surgery are related to the presence of retinal versus hemispheric symptoms, degree of arterial stenosis, extent of associated medical conditions (of note, NASCET and ECST excluded “high-risk” patients with sig-2571 nificant cardiac, pulmonary, or renal disease), institutional surgical morbidity and mortality, timing of surgery relative to symptoms, and other factors. A recent meta-analysis of the NASCET and ECST trials demonstrated that endarterectomy is most beneficial when performed within 2 weeks of symptom onset. In addition, benefit is more pronounced in patients >75 years, and men appear to benefit more than women.


InternalMed_Harrison

InternalMed_Harrison. In summary, a patient with recent symptomatic hemispheric ischemia, high-grade stenosis in the appropriate internal carotid artery, and an institutional perioperative morbidity and mortality rate of ≤6% generally should undergo carotid endarterectomy. If the perioperative stroke rate is >6% for any particular surgeon, however, the benefits of carotid endarterectomy are questionable.


InternalMed_Harrison

InternalMed_Harrison. The indications for surgical treatment of asymptomatic carotid disease have been clarified by the results of the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST). ACAS randomized asymptomatic patients with ≥60% stenosis to medical treatment with aspirin or the same medical treatment plus carotid endarterectomy. The surgical group had a risk over 5 years for ipsilateral stroke (and any perioperative stroke or death) of 5.1%, compared to a risk in the medical group of 11%. Although this demonstrates a 53% relative risk reduction, the absolute risk reduction is only 5.9% over 5 years, or 1.2% annually (Table 446-4). Nearly one-half of the strokes in the surgery group were caused by preoperative angiograms. ACST randomized asymptomatic patients with >60% carotid stenosis to endarterectomy or medical therapy. The 5-year risk of stroke in the surgical group (including perioperative stroke or death) was 6.4%, compared to 11.8% in the


InternalMed_Harrison

InternalMed_Harrison. patients with >60% carotid stenosis to endarterectomy or medical therapy. The 5-year risk of stroke in the surgical group (including perioperative stroke or death) was 6.4%, compared to 11.8% in the medically treated group (46% relative risk reduction and 5.4% absolute risk reduction).


InternalMed_Harrison

InternalMed_Harrison. In both ACAS and ACST, the perioperative complication rate was higher in women, perhaps negating any benefit in the reduction of stroke risk within 5 years. It is possible that with longer follow-up, a clear benefit in women will emerge. At present, carotid endarterectomy in asymptomatic women remains particularly controversial.


InternalMed_Harrison

InternalMed_Harrison. In summary, the natural history of asymptomatic stenosis is an ~2% per year stroke rate, whereas symptomatic patients experience a 13% per year risk of stroke. Whether to recommend carotid revascularization for an asymptomatic patient is somewhat controversial and depends on many factors, including patient preference, degree of stenosis, age, gender, and comorbidities. Medical therapy for reduction of atherosclerosis risk factors, including cholesterol-lowering agents and antiplatelet medications, is generally recommended for patients with asymptomatic carotid stenosis. As with atrial fibrillation, it is imperative to counsel the patient about TIAs so that therapy can be revised if symptoms develop.


InternalMed_Harrison

InternalMed_Harrison. Balloon angioplasty coupled with stenting is being used with increasing frequency to open stenotic carotid arteries and maintain their patency. These techniques can treat carotid stenosis not only at the bifurcation but also near the skull base and in the intracranial segments. The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial randomized high-risk patients (defined as patients with clinically significant coronary or pulmonary disease, contralateral carotid occlusion, restenosis after endarterectomy, contralateral laryngeal-nerve palsy, prior radical neck surgery or radiation, or age >80) with symptomatic carotid stenosis >50% or asymptomatic stenosis >80% to either stenting combined with a distal emboli-protection device or endarterectomy. The risk of death, stroke, or MI within 30 days and ipsilateral stroke or death within 1 year was 12.2% in the stenting group and 20.1% in the endarterectomy group (p = .055), suggesting that


InternalMed_Harrison

InternalMed_Harrison. The risk of death, stroke, or MI within 30 days and ipsilateral stroke or death within 1 year was 12.2% in the stenting group and 20.1% in the endarterectomy group (p = .055), suggesting that stenting is at the very least comparable to endarterectomy as a treatment option for this patient group at high risk of surgery. However, the outcomes with both interventions may not have been better than leaving the carotid stenoses untreated, particularly for the asymptomatic patients, and much of the benefit seen in the 2572 stenting group was due to a reduction in periprocedure MI. Two randomized trials comparing stents to endarterectomy in lower-risk patients have been published. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) enrolled patients with either asymptomatic or symptomatic stenosis. The 30-day risk of stroke was 4.1% in the stent group and 2.3% in the surgical group, but the 30-day risk of MI was 1.1% in the stent group and 2.3% in the surgery group,


InternalMed_Harrison

InternalMed_Harrison. or symptomatic stenosis. The 30-day risk of stroke was 4.1% in the stent group and 2.3% in the surgical group, but the 30-day risk of MI was 1.1% in the stent group and 2.3% in the surgery group, suggesting relative equivalence of risk between the procedures. At median follow-up of 2.5 years, the combined endpoint of stroke, MI, and death was the same (7.2% stent vs 6.8% surgery). The rate of restenosis at 2 years was also similar in both groups. The International Carotid Stenting (ICSS) trial randomized symptomatic patients to stents versus endarterectomy and found a different result: At 120 days, the incidence of stroke, MI, or death was 8.5% in the stenting group versus 5.2% in the endarterectomy group (p = .006); longer-term follow-up is currently under way. Differences between trial designs, selection of stent, and operator experience may explain these important differences. Until more data are available, there remains controversy as to who should receive a stent or have


InternalMed_Harrison

InternalMed_Harrison. trial designs, selection of stent, and operator experience may explain these important differences. Until more data are available, there remains controversy as to who should receive a stent or have endarterectomy; it is likely that the procedures carry similar risks if performed by experienced physicians.


InternalMed_Harrison

InternalMed_Harrison. Extracranial-to-intracranial (EC-IC) bypass surgery has been proven ineffective for atherosclerotic stenoses that are inaccessible to conventional carotid endarterectomy. In patients with recent stroke, an associated carotid occlusion, and evidence of inadequate perfusion of the brain as measured with positron emission tomography, no benefit from EC-IC bypass was found in a trial stopped for futility.


InternalMed_Harrison

InternalMed_Harrison. The WASID trial randomized patients with symptomatic stenosis (50–99%) of a major intracranial vessel to either high-dose aspirin (1300 mg/d) or warfarin (target INR, 2.0–3.0), with a combined primary endpoint of ischemic stroke, brain hemorrhage, or death from vascular cause other than stroke. The trial was terminated early because of an increased risk of adverse events related to warfarin anticoagulation. With a mean follow-up of 1.8 years, the primary endpoint was seen in 22.1% of patients in the aspirin group and 21.8% of the warfarin group. Death from any cause was seen in 4.3% of the aspirin group and 9.7% of the warfarin group; 3.2% of patients on aspirin experienced major hemorrhage, compared to 8.3% of patients taking warfarin.


InternalMed_Harrison

InternalMed_Harrison. Intracranial stenting of intracranial atherosclerosis was found to be dramatically harmful compared to aspirin in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. This trial enrolled newly symptomatic TIA or minor stroke patients with associated 70–99% intracranial stenosis to primary stenting with a self-expanding stent or to medical management. Both groups received clopidogrel, aspirin, statin, and aggressive control of blood pressure. The endpoint of stroke or death occurred in 14.7% of the stented group and 5.8% of the medically treated groups (p = .002). This low rate of second stroke was significantly lower than in the WASID trial and suggests that aggressive medical management had a marked influence on secondary stroke risk.


InternalMed_Harrison

InternalMed_Harrison. Dural Sinus Thrombosis Limited evidence exists to support short-term use of anticoagulants, regardless of the presence of intracranial hemorrhage, for venous infarction following sinus thrombosis. The long-term outcome for most patients, even those with intracerebral hemorrhage, is excellent. A careful history and neurologic examination can often localize the region of brain dysfunction; if this region corresponds to a particular arterial distribution, the possible causes responsible for the syndrome can be narrowed. This is of particular importance when the patient Uncus Caudate Anterior cerebral a. Internal carotid a. Middle cerebral a. Anterior cerebral a. Middle cerebral a. Deep branches of middle cerebral a. Postcerebral a. Deep branches of ant. cerebral a. FIGURE 446-6 Diagram of a cerebral hemisphere in coronal section showing the territories of the major cerebral vessels that branch from the internal carotid arteries.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 446-6 Diagram of a cerebral hemisphere in coronal section showing the territories of the major cerebral vessels that branch from the internal carotid arteries. presents with a TIA and a normal examination. For example, if a patient develops language loss and a right homonymous hemianopia, a search for causes of left middle cerebral emboli should be performed. A finding of an isolated stenosis of the right internal carotid artery in that patient, for example, suggests an asymptomatic carotid stenosis, and the search for other causes of stroke should continue. The following sections describe the clinical findings of cerebral ischemia associated with cerebral vascular territories depicted in Figs. 446-4 and 446-6 through 446-14. Stroke syndromes are divided into: (1) large-vessel stroke within the anterior circulation, (2) large-vessel stroke within the posterior circulation, and (3) small-vessel disease of either vascular bed.


InternalMed_Harrison

InternalMed_Harrison. Stroke within the Anterior Circulation The internal carotid artery and its branches comprise the anterior circulation of the brain. These vessels can be occluded by intrinsic disease of the vessel (e.g., atherosclerosis or dissection) or by embolic occlusion from a proximal source as discussed above. Occlusion of each major intracranial vessel has distinct clinical manifestations. miDDle cerebrAl Artery Occlusion of the proximal MCA or one of its major branches is most often due to an embolus (artery-to-artery, cardiac, or of unknown source) rather than intracranial atherothrombosis. Atherosclerosis of the proximal MCA may cause distal emboli to the middle cerebral territory or, less commonly, may produce low-flow TIAs. Collateral formation via leptomeningeal vessels often prevents MCA stenosis from becoming symptomatic.


InternalMed_Harrison

InternalMed_Harrison. The cortical branches of the MCA supply the lateral surface of the hemisphere except for (1) the frontal pole and a strip along the superomedial border of the frontal and parietal lobes supplied by the ACA, and (2) the lower temporal and occipital pole convolutions supplied by the PCA (Figs. 446-6, 446-7, 446-8, and 446-9). The proximal MCA (M1 segment) gives rise to penetrating branches (termed lenticulostriate arteries) that supply the putamen, outer globus pallidus, posterior limb of the internal capsule, adjacent corona radiata, and most of the caudate nucleus (Fig. 446-6). In the sylvian fissure, the MCA in most patients divides into superior and inferior divisions Ant. parietal a. Rolandic a. Temporopolar a. Inf. division middle cerebral a. Ant. temporal a. Post. parietal a. Visual radiation Prerolandic a. Angular a. Lateral orbitofrontal a. Sup. division middle cerebral a. Post. temporal a.


InternalMed_Harrison

InternalMed_Harrison. Prerolandic a. Angular a. Lateral orbitofrontal a. Sup. division middle cerebral a. Post. temporal a. FIGURE 446-7 Diagram of a cerebral hemisphere, lateral aspect, showing the branches and distribution of the middle cerebral artery and the principal regions of cerebral localization. Note the bifurcation of the middle cerebral artery into a superior and inferior division. Signs and symptoms: Structures involved Paralysis of the contralateral face, arm, and leg; sensory impairment over the same area (pinprick, cotton touch, vibration, position, two-point discrimination, stereognosis, tactile localization, barognosis, cutaneographia): Somatic motor area for face and arm and the fibers descending from the leg area to enter the corona radiata and corresponding somatic sensory system Motor aphasia: Motor speech area of the dominant hemisphere


InternalMed_Harrison

InternalMed_Harrison. Motor aphasia: Motor speech area of the dominant hemisphere Central aphasia, word deafness, anomia, jargon speech, sensory agraphia, acalculia, alexia, finger agnosia, right-left confusion (the last four comprise the Gerstmann syndrome): Central, suprasylvian speech area and parietooccipital cortex of the dominant hemisphere Conduction aphasia: Central speech area (parietal operculum) Apractagnosia of the nondominant hemisphere, anosognosia, hemiasomatognosia, unilateral neglect, agnosia for the left half of external space, dressing “apraxia,” constructional “apraxia,” distortion of visual coordinates, inaccurate localization in the half field, impaired ability to judge distance, upside-down reading, visual illusions (e.g., it may appear that another person walks through a table): Nondominant parietal lobe (area corresponding to speech area in dominant hemisphere); loss of topographic memory is usually due to a nondominant lesion, occasionally to a dominant one


InternalMed_Harrison

InternalMed_Harrison. Homonymous hemianopia (often homonymous inferior quadrantanopia): Optic radiation deep to second temporal convolution Paralysis of conjugate gaze to the opposite side: Frontal contraversive eye field or projecting fibers (M2 branches). Branches of the inferior division supply the inferior parietal and temporal cortex, and those from the superior division supply the frontal and superior parietal cortex (Fig. 446-7). If the entire MCA is occluded at its origin (blocking both its penetrating and cortical branches) and the distal collaterals are limited, the clinical findings are contralateral hemiplegia, hemianesthesia, homonymous hemianopia, and a day or two of gaze preference to the ipsilateral side. Dysarthria is common because of facial weakness. When the dominant hemisphere is involved, global aphasia is present also, and when the nondominant hemisphere is affected, anosognosia, constructional apraxia, and neglect are found (Chap. 36).


InternalMed_Harrison

InternalMed_Harrison. Complete MCA syndromes occur most often when an embolus occludes the stem of the artery. Cortical collateral blood flow and differing arterial configurations are probably responsible for the development of many partial syndromes. Partial syndromes may also be due to emboli that enter the proximal MCA without complete occlusion, occlude distal MCA branches, or frag-2573 ment and move distally.


InternalMed_Harrison

InternalMed_Harrison. Partial syndromes due to embolic occlusion of a single branch include hand, or arm and hand, weakness alone (brachial syndrome) or facial weakness with nonfluent (Broca) aphasia (Chap. 36), with or without arm weakness (frontal opercular syndrome). A combination of sensory disturbance, motor weakness, and nonfluent aphasia suggests that an embolus has occluded the proximal superior division and infarcted large portions of the frontal and parietal cortices (Fig. 446-7). If a fluent (Wernicke’s) aphasia occurs without weakness, the inferior division of the MCA supplying the posterior part (temporal cortex) of the dominant hemisphere is probably involved. Jargon speech and an inability to comprehend written and spoken language are prominent features, often accompanied by a contralateral, homonymous superior quadrantanopia. Hemineglect or spatial agnosia without weakness indicates that the inferior division of the MCA in the nondominant hemisphere is involved.


InternalMed_Harrison

InternalMed_Harrison. Occlusion of a lenticulostriate vessel produces small-vessel (lacunar) stroke within the internal capsule (Fig. 4466). This produces pure motor stroke or sensory-motor stroke contralateral to the lesion. Ischemia within the genu of the internal capsule causes primarily facial weakness followed by arm and then leg weakness as the ischemia moves posterior within the capsule. Alternatively, the contralateral hand may become ataxic, and dysarthria will be prominent (clumsy hand, dysarthria lacunar syndrome). Lacunar infarction affecting the globus pallidus and putamen often has few clinical signs, but parkinsonism and hemiballismus have been reported.


InternalMed_Harrison

InternalMed_Harrison. Anterior cerebrAl Artery The ACA is divided into two segments: the precommunal (A1) circle of Willis, or stem, which connects the internal carotid artery to the anterior communicating artery, and the postcommunal (A2) segment distal to the anterior communicating artery (Figs. 446-4, 446-6, and 446-8). The A1 seg ment gives rise to several deep penetrating branches that supply the anterior limb of the internal capsule, the anterior perforate substance, amygdala, anterior hypothalamus, and the inferior part of the head of the caudate nucleus (Fig. 446-6).


InternalMed_Harrison

InternalMed_Harrison. Occlusion of the proximal ACA is usually well tolerated because of collateral flow through the anterior communicating artery and collaterals through the MCA and PCA. Occlusion of a single A2 segment results in the contralateral symptoms noted in Fig. 446-8. If both A2 segments arise from a single anterior cerebral stem (contralateral A1 segment atresia), the occlusion may affect both hemispheres. Profound abulia (a delay in verbal and motor response) and bilateral pyramidal signs with paraparesis or quadriparesis and urinary incontinence result. Anterior choroiDAl Artery This artery arises from the internal carotid artery and supplies the posterior limb of the internal capsule and the white matter posterolateral to it, through which pass some of rolandic a. Post. prerolandic a. Secondary Pericallosal a. Sensory parietal a. motor area cortex Medial Splenial a. Lateral posterior Callosomarginal a. choroidal a. Post. thalamic a. Parietooccipital a. Frontopolar a.


InternalMed_Harrison

InternalMed_Harrison. Secondary Pericallosal a. Sensory parietal a. motor area cortex Medial Splenial a. Lateral posterior Callosomarginal a. choroidal a. Post. thalamic a. Parietooccipital a. Frontopolar a. Visual cortex Ant. cerebral a. Medial orbitofrontal a. Calcarine a. Post. communicating a. Post. temporal a. Medial posterior choroidal a. Penetrating thalamosubthalamic Post. Hippocampal As. Ant. paramedian As. cerebral temporal a. FIGURE 446-8 Diagram of a cerebral hemisphere, medial aspect, showing the branches and distribution of the anterior cerebral artery and the principal regions of cerebral localization.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 446-8 Diagram of a cerebral hemisphere, medial aspect, showing the branches and distribution of the anterior cerebral artery and the principal regions of cerebral localization. Signs and symptoms: Structures involved Paralysis of opposite foot and leg: Motor leg area A lesser degree of paresis of opposite arm: Arm area of cortex or fibers descending to corona radiata Cortical sensory loss over toes, foot, and leg: Sensory area for foot and leg Urinary incontinence: Sensorimotor area in paracentral lobule Contralateral grasp reflex, sucking reflex, gegenhalten (paratonic rigidity): Medial surface of the posterior frontal lobe; likely supplemental motor area Abulia (akinetic mutism), slowness, delay, intermittent interruption, lack of spontaneity, whispering, reflex distraction to sights and sounds:


InternalMed_Harrison

InternalMed_Harrison. Uncertain localization—probably cingulate gyrus and medial inferior portion of frontal, parietal, and temporal lobes Impairment of gait and stance (gait apraxia): Frontal cortex near leg motor area Dyspraxia of left limbs, tactile aphasia in left limbs: Corpus callosum the geniculocalcarine fibers (Fig. 446-9). The complete syndrome of in that eye or that the upper or lower half of vision disappeared. In anterior choroidal artery occlusion consists of contralateral hemiple-most cases, these symptoms last only a few minutes. Rarely, ischemia gia, hemianesthesia (hypesthesia), and homonymous hemianopia. or infarction of the ophthalmic artery or central retinal arteries occurs However, because this territory is also supplied by penetrating vessels at the time of cerebral TIA or infarction. of the proximal MCA and the posterior communicating and posterior A high-pitched prolonged carotid bruit fading into diastole is often choroidal arteries, minimal deficits may occur, and patients


InternalMed_Harrison

InternalMed_Harrison. of the proximal MCA and the posterior communicating and posterior A high-pitched prolonged carotid bruit fading into diastole is often choroidal arteries, minimal deficits may occur, and patients frequently associated with tightly stenotic lesions. As the stenosis grows tighter recover substantially. Anterior choroidal strokes are usually the result and flow distal to the stenosis becomes reduced, the bruit becomes of in situ thrombosis of the vessel, and the vessel is particularly vul-fainter and may disappear when occlusion is imminent. nerable to iatrogenic occlusion during surgical clipping of aneurysms common cArotiD Artery All symptoms and signs of internal carotidarising from the internal carotid artery.


InternalMed_Harrison

InternalMed_Harrison. occlusion may also be present with occlusion of the common carotid internAl cArotiD Artery The clinical picture of internal carotid occlu-artery. Jaw claudication may result from low flow in the external sion varies depending on whether the cause of ischemia is propagated carotid branches. Bilateral common carotid artery occlusions at their thrombus, embolism, or low flow. The cortex supplied by the MCA origin may occur in Takayasu’s arteritis (Chap. 385). territory is affected most often. With a competent circle of Willis,


InternalMed_Harrison

InternalMed_Harrison. Stroke Within the Posterior Circulation The posterior circulation is occlusion may go unnoticed. If the thrombus propagates up the composed of the paired vertebral arteries, the basilar artery, and theinternal carotid artery into the MCA or embolizes it, symptoms are paired posterior cerebral arteries. The vertebral arteries join to formidentical to proximal MCA occlusion (see above). Sometimes there is the basilar artery at the pontomedullary junction. The basilar artery massive infarction of the entire deep white matter and cortical surface.


InternalMed_Harrison

InternalMed_Harrison. divides into two posterior cerebral arteries in the interpeduncular fossaWhen the origins of both the ACA and MCA are occluded at the top (Figs. 446-4, 446-8, and 446-9). These major arteries give rise to long of the carotid artery, abulia or stupor occurs with hemiplegia, hemianand short circumferential branches and to smaller deep penetratingesthesia, and aphasia or anosognosia. When the PCA arises from the branches that supply the cerebellum, medulla, pons, midbrain, sub-internal carotid artery (a configuration called a fetal posterior cerebral thalamus, thalamus, hippocampus, and medial temporal and occipitalartery), it may also become occluded and give rise to symptoms refer-lobes. Occlusion of each vessel produces its own distinctive syndrome. able to its peripheral territory (Figs. 446-8 and 446-9).