Cerebrovascular diseases include some of the most common and devastating disorders: ischemic stroke and hemorrhagic stroke. Stroke is the second leading cause of death worldwide, causing 6.2 million deaths in 2011, and is double the rate of heart disease in China. Strokes cause ~200,000 deaths each year in the United States and are a major cause of disability. The incidence of cerebrovascular diseases increases with age, and the number of strokes is projected to increase as the elderly population grows, with a doubling in stroke deaths in the United States by 2030. A stroke, or cerebrovascular accident, is defined as an abrupt onset of a neurologic deficit that is attributable to a focal vascular cause. Thus, the definition of stroke is clinical, and laboratory studies including brain imaging are used to support the diagnosis. The clinical manifestations of stroke are highly variable because of the complex anatomy of the brain and its vasculature. Cerebral ischemia is caused by a reduction in blood flow that lasts longer than several seconds. Neurologic symptoms are manifest within seconds because neurons lack glycogen, so energy failure is rapid. If the cessation of flow lasts for more than a few minutes, infarction or death of brain tissue results. When blood flow is quickly restored, brain tissue can recover fully and the patient’s symptoms are only transient: this is called a transient ischemic attack (TIA). The definition of TIA requires that all neurologic signs and symptoms resolve within 24 h without evidence of brain infarction on brain imaging. Stroke has occurred if the neurologic signs and symptoms last for >24 h or brain infarction is demonstrated. A generalized reduction in cerebral blood flow due to systemic hypotension (e.g., cardiac arrhythmia, myocardial infarction, or hemorrhagic shock) usually produces syncope (Chap. 11). If low cerebral blood flow persists for a longer duration, then infarction in the border zones between the major cerebral artery distributions may develop. In more severe instances, global hypoxia-ischemia causes widespread brain injury; the constellation of cognitive sequelae that ensues is called hypoxic-ischemic encephalopathy (Chap. 33). Focal ischemia or infarction, conversely, is usually caused by thrombosis of the cerebral vessels themselves or by emboli from a proximal arterial source or the heart. Intracranial hemorrhage is caused by bleeding directly into or around the brain; it produces neurologic symptoms by producing a mass effect on neural structures, from the toxic effects of blood itself, or by increasing intracranial pressure.
APPROACH TO THE PATIENT: Cerebrovascular Disease
Rapid evaluation is essential for use of time-sensitive treatments such as thrombolysis. However, patients with acute stroke often do not seek medical assistance on their own because they are rarely in pain and also may lose the appreciation that something is wrong (anosognosia); it is often a family member or a bystander who calls for help. Therefore, patients and their family members should be counseled to call emergency medical services immediately if they experience or witness the sudden onset of any of the following: loss of sensory and/or motor function on one side of the body (nearly 85% of ischemic stroke patients have hemiparesis); change in vision, gait, or ability to speak or understand; or a sudden, severe headache.
Other causes of sudden-onset neurologic symptoms that may mimic stroke include seizure, intracranial tumor, migraine, and metabolic encephalopathy. An adequate history from an observer that no convulsive activity occurred at the onset usually excludes seizure, although ongoing complex partial seizures without tonic-clonic activity can on occasion mimic stroke. Tumors may present with acute neurologic symptoms due to hemorrhage, seizure, or hydrocephalus. Surprisingly, migraine (Chap. 34) can mimic stroke, even in patients without a significant migraine history. When migraine develops without head pain (acephalgic migraine), the diagnosis can be especially difficult. Patients without any prior history of migraine may develop acephalgic migraine even after age 65. A sensory disturbance is often prominent, and the sensory deficit, as well as any motor deficits, tends to migrate slowly across a limb, over minutes rather than seconds as with stroke. The diagnosis of migraine becomes more secure as the cortical disturbance begins to cross vascular boundaries or if typical visual symptoms are present such as scintillating scotomata. At times it may be impossible to make the diagnosis of migraine until there have been multiple episodes with no residual symptoms or signs and no changes on brain magnetic resonance imaging (MRI). Metabolic encephalopathies typically produce fluctuating mental status changes without focal neurologic findings. However, in the setting of prior stroke or brain injury, a patient with fever or sepsis may manifest a recurrent hemiparesis, which clears rapidly when the infection is treated. The metabolic process serves to “unmask” a prior deficit.
Once the diagnosis of stroke is made, a brain imaging study is necessary to determine if the cause of stroke is ischemia or hemorrhage (Fig. 32-1). Computed tomography (CT) imaging of the brain is the standard imaging modality to detect the presence or absence of intracranial hemorrhage (see “Imaging Studies,” below). If the stroke is ischemic, administration of recombinant tissue plasminogen activator (rtPA) or endovascular mechanical thrombectomy may be beneficial in restoring cerebral perfusion (see “Treatment: Acute Ischemic Stroke”). Medical management to reduce the risk of complications becomes the next priority, followed by plans for secondary prevention. For ischemic stroke, several strategies can reduce the risk of subsequent stroke in all patients, while other strategies are effective for patients with specific causes of stroke such as cardiac embolus and carotid atherosclerosis. For hemorrhagic stroke, aneurysmal subarachnoid hemorrhage (SAH) and hypertensive intracerebral hemorrhage are two important causes. The treatment and prevention of hypertensive intracerebral hemorrhage are discussed later in this chapter. SAH is discussed in Chap. 33.
FIGURE 32-1
Medical management of stroke and TIA. Rounded boxes are diagnoses; rectangles are interventions. Numbers are percentages of stroke overall. ABCs, airway, breathing, circulation; BP, blood pressure; CEA, carotid endarterectomy; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage; TIA, transient ischemic attack.
Acute occlusion of an intracranial vessel causes reduction in blood flow to the brain region it supplies. The magnitude of flow reduction is a function of collateral blood flow, and this depends on individual vascular anatomy (which may be altered by disease), the site of occlusion, and systemic blood pressure. A decrease in cerebral blood flow to zero causes death of brain tissue within 4–10 min; values <16–18 mL/100 g tissue per minute cause infarction within an hour; and values <20 mL/100 g tissue per minute cause ischemia without infarction unless prolonged for several hours or days. If blood flow is restored to ischemic tissue before significant infarction develops, the patient may experience only transient symptoms, and the clinical syndrome is called a TIA. Another important concept is the ischemic penumbra, defined as the ischemic but reversibly dysfunctional tissue surrounding a core area of infarction. The penumbra can be imaged by perfusion-diffusion imaging using MRI or CT (see below and Figs. 32-15 and 32-16). The ischemic penumbra will eventually progress to infarction if no change in flow occurs, and hence saving the ischemic penumbra is the goal of revascularization therapies.
Focal cerebral infarction occurs via two distinct pathways (Fig. 32-2): (1) a necrotic pathway in which cellular cytoskeletal breakdown is rapid, due principally to energy failure of the cell; and (2) an apoptotic pathway in which cells become programmed to die. Ischemia produces necrosis by starving neurons of glucose and oxygen, which in turn results in failure of mitochondria to produce ATP. Without ATP, membrane ion pumps stop functioning and neurons depolarize, allowing intracellular calcium to rise. Cellular depolarization also causes glutamate release from synaptic terminals; excess extracellular glutamate produces neurotoxicity by activating postsynaptic glutamate receptors that increase neuronal calcium influx. Free radicals are produced by degradation of membrane lipids and mitochondrial dysfunction. Free radicals cause catalytic destruction of membranes and likely damage other vital functions of cells. Lesser degrees of ischemia, as are seen within the ischemic penumbra, favor apoptotic cellular death causing cells to die days to weeks later. Fever dramatically worsens brain injury during ischemia, as does hyperglycemia (glucose >11.1 mmol/L [200 mg/dL]), so it is reasonable to suppress fever and prevent hyperglycemia as much as possible. The value of induced mild hypothermia to improve stroke outcomes is the subject of continuing clinical research.
TREATMENT: Acute Ischemic Stroke
After the clinical diagnosis of stroke is made, an orderly process of evaluation and treatment should follow (Fig. 32-1). 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 rehabilitation.
MEDICAL SUPPORTWhen 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.
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 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.
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.
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.
INTRAVENOUS THROMBOLYSISThe 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 intracranial hemorrhage occurred in 6.4% of patients on rtPA and 0.6% 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 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 3- to 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 0- to 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 intracranial 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 3- to 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 normal. Patients who awaken with stroke have the onset defined as when they went to bed. Table 32-1 summarizes eligibility criteria and instructions for administration of IV rtPA.
ENDOVASCULAR REVASCULARIZATIONIschemic 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.
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. 32-15). 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. 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 intracranial vessels.
In 2015, five open-label randomized control trials each demonstrated that rapid thrombectomy with Stentriever devices was superior to treatment with intravenous thrombolysis alone. These trials studied patients with proven anterior circulation large-vessel occlusions demonstrated on early vascular imaging, typically with CT angiography. Patients were treated at least up to six hours from time last seen well, and those eligible for intravenous thrombolysis received IV rtPA prior to thrombectomy. A recent meta-analysis of individual patient data from these five trials showed significantly reduced disability at 90 days with a number needed to treat of 2.6 to reduce disability by at least one level on the modified Rankin scale. Mortality at 90 days and risk of intracerebral hemorrhage did not differ between the groups.
In the setting of these results, patients with acute stroke presenting within six hours of their last time seen normal should receive vascular imaging to identify those patients with a large-vessel occlusion amenable to thrombectomy. Patients eligible for IV rtPA should receive it quickly and prior to thrombectomy. The role of perfusion imaging in patient selection remains unclear and additional trials are underway to examine this approach. Although there is not widespread availability of interventionalists who can perform these procedures, comprehensive stroke centers are now obtaining credentialing to offer this therapy in distinction to primary stroke centers that are only required to provide treatment with IV rtPA.
ANTITHROMBOTIC TREATMENT Platelet inhibitionAspirin 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 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.
Clopidogrel is being tested as a way to prevent stroke following TIA and minor ischemic stroke (see below).
AnticoagulationNumerous 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 anticoagulants for patients with atherothrombotic stroke.
NEUROPROTECTIONNeuroprotection 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. 33) 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.
STROKE CENTERS AND REHABILITATIONPatient 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.
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 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 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.
| INDICATION | CONTRAINDICATION | |
|---|---|---|
Clinical diagnosis of stroke Onset of symptoms to time of drug administration ≤4.5 hb CT scan showing no hemorrhage or edema of >1/3 of the MCA territory Age 18 ≥ years Consent by patient or surrogate | Sustained BP >185/110 mmHg despite treatment Platelets <100,000; HCT <25%; glucose <50 or >400 mg/dL Use of heparin within 48 h and prolonged PTT, or elevated INR Rapidly improving symptoms Prior stroke or head injury within 3 months; prior intracranial hemorrhage Major surgery in preceding 14 days Minor stroke symptoms Gastrointestinal bleeding in preceding 21 days Recent myocardial infarction Coma or stupor | |
| Administration of rtPA | ||
IV access with two peripheral IV lines (avoid arterial or central line placement) Review eligibility for rtPA 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 Frequent cuff blood pressure monitoring No other antithrombotic treatment for 24 h For decline in neurologic status or uncontrolled blood pressure, stop infusion, give cryoprecipitate, and reimage brain emergently Avoid urethral catheterization for ≥2 h | ||
(Figs. 32-1 and 32-3 and Table 32-2) 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.
FIGURE 32-3
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.
| COMMON CAUSES | UNCOMMON CAUSES |
|---|---|
|
|
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 CT- or 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 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.
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.
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.
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 32-2). Cardiac disorders causing brain embolism are discussed in the chapters on heart diseases. A few pertinent aspects are highlighted here.
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 32-3). 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.
| CONDITION | RECOMMENDATION |
|---|---|
| Nonvalvular atrial fibrillation | Calculate CHADS2a score |
| • CHADS2 score 0 | Aspirin or no antithrombotic |
| • CHADS2 score 1 | Aspirin or OAC |
| • CHADS2 score >1 | OAC |
| Rheumatic mitral valve disease | |
| • With atrial fibrillation, previous embolization, or atrial appendage thrombus, or left atrial diameter >55 mm | OAC |
| • Embolization or appendage clot despite OAC | OAC plus aspirin |
| Mitral valve prolapse | |
| • Asymptomatic | No therapy |
| • With otherwise cryptogenic stroke or TIA | Aspirin |
| • Atrial fibrillation | OAC |
| Mitral annular calcification | |
| • Without atrial fibrillation but systemic embolization, or otherwise cryptogenic stroke or TIA | Aspirin |
| • Recurrent embolization despite aspirin | OAC |
| • With atrial fibrillation | OAC |
| Aortic valve calcification | |
| • Asymptomatic | No therapy |
| • Otherwise cryptogenic stroke or TIA | Aspirin |
| Aortic arch mobile atheroma | |
| • Otherwise cryptogenic stroke or TIA | Aspirin or OAC |
| Patent foramen ovale | |
| • Otherwise cryptogenic ischemic stroke or TIA | Aspirin |
| • Indication for OAC (deep venous thrombosis or hypercoagulable state) | OAC |
| Mechanical heart value | |
| • Aortic position, bileaflet or Medtronic Hall tilting disk with normal left atrial size and sinus rhythm | VKA INR 2.5, range 2–3 |
| • Mitral position tilting disk or bileaflet valve | VKA INR 3.0, range 2.5–3.5 |
| • Mitral or aortic position, anterior-apical myocardial infarct or left atrial enlargement | VKA INR 3.0, range 2.5–3.5 |
| • Mitral or aortic position, with atrial fibrillation, or hypercoagulable state, or low ejection fraction, or atherosclerotic vascular disease | Aspirin plus VKA INR 3.0, range 2.5–3.5 |
| • Systemic embolization despite target INR | 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 |
| Bioprosthetic valve | |
| • No other indication for VKA therapy | Aspirin |
| Infective endocarditis | Avoid antithrombotic agents |
| Nonbacterial thrombotic endocarditis | |
| • With systemic embolization | Full-dose unfractionated heparin or SC LMWH |
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 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.
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 intracerebral hemorrhage.
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.
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 32-4). Carotid atherosclerosis produces an estimated 10% of ischemic stroke.
| NUMBER NEEDED TO TREATa | ||||
|---|---|---|---|---|
| RISK FACTOR | RELATIVE RISK | RELATIVE RISK REDUCTION WITH TREATMENT | PRIMARY PREVENTION | SECONDARY PREVENTION |
| 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 carotid stenosis | 2.0 | 53% | 85 | N/A |
| Symptomatic carotid stenosis (70–99%) | 65% at 2 years | N/A | 12 | |
| Symptomatic carotid stenosis (50–69%) | 29% at 5 years | N/A | 77 | |
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.
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 and African-American descent. Recurrent stroke risk is ~15% per year, similar to symptomatic untreated carotid atherosclerosis.
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 pseudoaneurysms 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 vertebral artery dissection and stroke. Most dissections heal spontaneously, and stroke or TIA is uncommon beyond 2 weeks. Recent trials comparing anticoagulation to antiplatelet agents have shown no significant differences between these approaches.
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.
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 30- to 300-μm branches that penetrate the deep gray and white matter of the cerebrum or brainstem (Fig. 32-4). 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.
FIGURE 32-4
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.
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.
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 32-2) Hypercoagulable disorders 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 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.
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 or conventional x-ray angiography. With greater degrees of sinus thrombosis, the patient may develop signs of increased 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.
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.
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. 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 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 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.
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. 32-5). 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.
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 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.
Posterior reversible encephalopathy syndrome (PRES) can occur with head injury, seizure, migraine, sympathomimetic drug use, eclampsia, and in the postpartum period (Chap. 58). 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 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.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
