Definition and etiology

A stroke is defined as an acute loss of neurological function due to an abnormal perfusion of brain tissue. Most strokes are ischemic (87%) in nature and commonly result from an arterial obstruction by a thrombus or embolus. Hemorrhagic strokes (13%) are caused by rupture or leak of a blood vessel either within the primary brain tissue or subarachnoid space. This chapter provides a clinical approach to the evaluation and management of stroke, with a focus on ischemic stroke.

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Prevalence and risk factors

Because stroke is the leading cause of morbidity and the third-leading cause of death in the United States today, optimal reduction of risk factors is paramount in preventing and managing stroke. Modifiable and nonmodifiable stroke risk factors are listed in Table 1. In 2005, the prevalence of stroke in noninstitutionalized adults was 5.8 million in the United States alone. Based on American Stroke Association data, the estimated direct and indirect cost of stroke for 2008 was $65.5 billion, with an estimated lifetime cost of $140,000 per patient.

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Pathophysiology and natural history

Ischemic Stroke

Based on prior clinical trials, a subclassification scheme of five categories of ischemic stroke has become widely accepted. These categories are based on etiology and are as follows: large-artery atherosclerosis, embolism, small-vessel disease, stroke of other determined etiology, and stroke of undetermined etiology.

Large-Artery Atherosclerosis

High-grade stenosis or occlusion of the major intra- and extracranial arteries, which include the internal carotid artery, the vertebral artery, the basilar artery, and other major branches of the circle of Willis, occur due to deposition of plaque and often leads to a flow-dependent state of perfusion. With interruption of flow due to acute plaque rupture or a prolonged low-flow state due to relative hypotension, a loss of adequate cerebral perfusion results in ischemia and focal neurologic deficit.

Embolism

Turbulent or stagnant flow states in the heart can result in formation of thrombi. These thrombi can dislodge and occlude blood vessels in the intracranial circulation farther downstream. The most common cause of cardioembolic stroke is atrial fibrillation. Other causes include severe left ventricular dysfunction resulting in a low ejection fraction, paradoxical embolus from the venous system due to a shunt through a septal defect such as an aneurysm or patent foramen ovale, or vessel-to-vessel atheroembolism due to atherosclerotic disease in the vertebral arteries, carotid arteries, and aortic arch.

Small-Vessel Disease

Changes in the arterial vasculature of small perforating arteries can result in narrowing of the vessel lumen and eventual occlusion. Chronic hypertension is one state that leads to vessel damage secondary to lipohyalinosis and endothelial damage. Hyperlipidemia, smoking, and diabetes also lead to changes in the vessel wall that result in decreased compliance and intraluminal stenosis. These changes often result in lacunar infarcts, which are small infarcts defined by their size (<15 mm³) and are typically located in deep structures such as the internal capsule, basal ganglia, thalamus, and brainstem.

Stroke of Other Determined Etiology

The majority of ischemic strokes are classified in one of the previous categories. Rarely, other causes must be investigated, particularly in patients who are young and have no risk factors for stroke. Among these causes are coagulopathies, vasculopathies, genetic disorders, and metabolic disorders.

Stroke of Undetermined Etiology

In a significant number of cases (≤40%), no clear explanation can be found for an ischemic stroke despite an extensive diagnostic evaluation. These strokes are classified as strokes of undetermined etiology, or cryptogenic strokes. This is a diagnosis of exclusion, however, and should only be made once a thorough search for both common and uncommon causes of stroke has been completed.

Intracerebral Hemorrhage

Intracerebral hemorrhage occurs when a blood vessel within the brain parenchyma ruptures and causes accumulation of blood within the brain tissue. Weakening of the blood vessel wall is often a result of chronic uncontrolled hypertension or a problem intrinsic to the blood vessel such as amyloid angiopathy or other vascular malformation. In hypertension, microaneurysms in perforating vessels, known as Charcot-Bouchard aneurysms, can rupture and cause bleeding. The thalamus, basal ganglia, pons, and cerebellum are the most common sites for these hypertensive bleeds. Lobar hemorrhages more commonly result from amyloid angiopathy, which is typically seen in older patients. This should be suspected when there is evidence of prior areas of hemorrhage manifested as hemosiderin deposits on magnetic resonance imaging (MRI). Other causes of intracerebral hemorrhage include the use of anticoagulants, thrombolytics, and antiplatelet agents, particularly when levels are supratherapeutic. They may also be caused by an underlying primary or metastatic brain tumor, especially when there are focal areas of necrosis and hemorrhage within the tumor bed.

Subarachnoid Hemorrhage

Subarachnoid hemorrhage is most commonly due to trauma and typically occurs adjacent to areas of bony prominence, such as the temporal poles and the frontal poles. Subarachnoid hemorrhage can also result from rupture of a cerebral aneurysm. Aneurysms are usually located at vulnerable branch points in the circle of Willis and occur due to weakening of the vessel wall. The most common sites of aneurysm formation and rupture are in the distribution of the anterior communicating artery and the posterior communicating artery. Uncontrolled chronic hypertension, smoking, and a family history of aneurysms are risk factors for formation and rupture of aneurysms. In 10% to 20% of cases of spontaneous, nontraumatic subarachnoid hemorrhage, no cause is found despite serial angiography. The prognosis for these patients is typically benign.

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Signs and symptoms

An acute stroke is signified by a sudden onset of focal neurologic deficit and is variable depending on the area of tissue ischemia. Localization can often be made by the pattern of clinical findings. Common stroke syndromes are listed in Table 2 according to vascular distribution. Although headache might accompany an ischemic stroke, an acute and severe headache that is maximal at onset more commonly represents a subarachnoid or intraparenchymal hemorrhage, especially if this is followed by somnolence or decreased mental status. Seizures can also occur at the onset of ischemic or hemorrhagic strokes.

Motor symptoms consist of facial droop, hemiparesis, or isolated weakness of the arm or leg. Dizziness, slurred speech, problems with coordination, or difficulty with gait and balance may also be reported and may be due to involvement of cerebellar fibers. Sensory symptoms include numbness or altered sensation, with tingling paresthesias of one side of the body or face, or both. Vision loss in one eye or both eyes as in a homonymous hemianopsia can also occur.

Patients with an acute stroke might also present with confusion or are sometimes perceived as being confused when there is an expressive or receptive aphasia or a visuospatial neglect phenomenon.

One of the most urgent and potentially devastating stroke syndromes is thrombosis of the basilar artery, which can manifest with acute quadriparesis, loss of consciousness, and respiratory failure.

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Diagnosis

The first step in correctly identifying a stroke is a rapid, thorough neurologic assessment consisting of a focused history and neurologic examination. A differential diagnosis is listed in Box 1. It is of utmost importance to establish a time of symptom onset when eliciting the history from the patient or witnesses. If the patient woke with symptoms, onset is determined at the time the patient was last seen normal, which for many would be when they went to bed the night before.

Vital signs should be assessed frequently, with particular attention to blood pressure and heart rate. It is also necessary to obtain a blood glucose level immediately because both hypo- and hyperglycemia can manifest clinically with acute neurologic deficits, mimicking a stroke.

Regarding the physical examination, a variety of tools in the form of validated scales are available for evaluation of the patient at presentation. The NIH Stroke Scale is a widely accepted and useful tool that is recommended in the acute phase for the purpose of quickly identifying focal neurologic deficits and their severity (Class I, Level B recommendation).

Laboratory Tests

In patients presenting with sudden onset of focal neurologic deficit, baseline laboratory testing should be performed. This consists of point-of-care blood glucose testing, basic metabolic panel, complete blood count, cardiac enzymes, and coagulation studies (Class I, Level B recommendation). A 12-lead electrocardiogram (ECG) should be performed in all stroke patients (Class I, Level B recommendation). If subarachnoid hemorrhage is suspected, cerebrospinal fluid should be obtained and sent for differential red blood cell counts in serial tubes.

Once the patient is stabilized, further testing such as lipid panel and hemoglobin A_1C studies should be sent to assist in identifying risk factors. If no clear etiology is identified, further laboratory testing to assess for a hypercoagulable state, genetic or metabolic disturbance, or inflammatory conditions should be performed.

Imaging

With advances in technology, imaging has become integral in the evaluation and management of acute stroke patients. In all patients who present to the hospital with a suspected stroke, the first imaging study should be an emergent noncontrast computed tomography (CT) scan of the brain to assess for intracranial hemorrhage. CT angiography with and without perfusion studies rapidly provides visualization of blood flow and is used in the acute setting at some tertiary stroke centers to identify the location of vascular occlusion and assess for salvageable brain tissue (Class I, Level A recommendation). However, because the study uses contrast, renal function should ideally be known and documented before proceeding. Cerebral angiography may also be undertaken emergently, particularly in cases when vascular intervention is being considered.

In the last several years, MRI has emerged as an invaluable tool in the care of stroke patients. A specialized MRI sequence that measures the diffusion of water, known as diffusion-weighted imaging (DWI), allows visualization of acute strokes that range in age from a few hours to 1 week. This is especially helpful in stroke patients who present within 24 to 48 hours of symptom onset because an acute ischemic lesion can often be missed on a routine CT scan early on. MR angiography is also a useful method for evaluating intra- and extracranial vasculature, although the degree of stenosis in diseased vessels is often overestimated by this technique. Other studies that assess cerebral blood flow include carotid ultrasound and transcranial Doppler ultrasonagraphy (TCD), which are noninvasive tests that use pulsatility indices and mean flow velocities to evaluate the vasculature.

Other Diagnostic Tests

All patients with ischemic stroke should have a transthoracic echocardiogram (TTE) to assess for a cardioembolic source, which includes left ventricular or valvular dysfunction, intracardiac thrombus, and patent foramen ovale. In patients who are strongly suspected to have a cardioembolic stroke despite a negative TTE, further testing with transesophageal echocardiogram or TCD with breath-holding should be performed as these studies increase the detection of an intra-cardiac shunt. Duplex ultrasonography of the legs should also be considered in patients in whom a paradoxical embolus is suspected.

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Treatment

Acute Management and Interventions

The first step in the appropriate management of acute stroke is early identification at symptom onset. Early notification of emergency medical services (EMS) with use of stroke-identification algorithms, management in the field with stroke protocols, and emergent transport to the nearest center capable of treating acute stroke is recommended (Class I, Level B evidence). Airway, breathing, and circulation should be stabilized, with airway support and ventilatory assistance in the appropriate patients (Class I, Level C evidence). Initial laboratory testing and CT brain scan should be performed as detailed earlier.

In patients who present with stroke symptoms within 3 hours of onset and have no evidence of hemorrhage or infarct size greater than one third of the middle cerebral artery territory on CT brain, treatment with IV recombinant tissue plasminogen activator (rtPA) is recommended at a dose of 0.9 mg/kg (maximum dose, 90 mg) over 1 hour, with the first 10% given as a bolus over 1 minute (Class I, Level A evidence). Studies have demonstrated that 31% to 50% of patients treated with rtPA experienced improved recovery at 3 months as compared to 20% to 38% of patients in the placebo arm. However, strict adherence to national guidelines in the administration of rtPA and postlysis management is critical, given the 6% risk of intracranial hemorrhage. Box 2 lists conditions excluding patients from t-PA therapy.

In selected patients who are not candidates for IV rtPA therapy, intra-arterial thrombolysis by a qualified neuro-interventionalist may be considered in stroke patients who present within 6 hours of onset (Class I, Level B recommendation). However, the availability of intra-arterial thrombolysis should not preclude the administration of IV rtPA in eligible patients (Class III, Level C evidence). Endovascular intervention, including angioplasty and disruption or removal of the clot, is another option available at some specialized stroke centers.

Although used previously, urgent anticoagulation in acute ischemic stroke is not recommended and should not be used to replace IV rtPA therapy in eligible patients (Class III, Level A evidence). Oral aspirin therapy at a dose of 325 mg daily is recommended 24 to 48 hours after stroke onset in most patients (Class I, Level A evidence), but it should not be given within 24 hours following rtPA therapy (Class III, Level A and B).

In patients who are eligible for rtPA, treatment of arterial hypertension is recommended (Class I, Level C evidence) with a goal blood pressure of less than 185/110 mm Hg before rTPA is administered. Close post-lysis monitoring, with antihypertensive treatment given according to the rtPA protocol, is also crucial to prevent hemorrhage (Class I, Level B evidence). In patients who are not candidates for rtPA, blood pressure management in the acute setting is still controversial, but the consensus is that antihypertensive medications should be withheld unless systolic blood pressure is higher than 220 or diastolic blood pressure is higher than 120 (Class I, Level C evidence). After 24 hours, initiation of antihypertensive agents is considered relatively safe for patients with pre-existing hypertension.

Hypoxemia should be treated with supplemental oxygen, and fever should be treated with antipyretic agents (Class I, Level C evidence). Euglycemia should be targeted, because persistent hyperglycemia has been associated with poor outcomes (Class IIa, Level C evidence).

Patients should be admitted to specialized stroke care units incorporating rehabilitation when possible (Class I, Level A evidence). Close monitoring during the first 72 to 96 hours of acute ischemic stroke is important to assess for signs of hemorrhagic transformation or brain edema (Class I, Level B evidence). Decompressive surgery in the setting of malignant edema may be life-saving, but the morbidity is unknown in the setting of major cerebral hemispheric infarctions (Class IIa, Level B evidence).

Treatment of concomitant medical illnesses, pneumonia, and urinary tract infections is recommended (Class I, Level B and C evidence). Screening swallow evaluations should be performed to assess the patient's risk for aspiration pneumonia (Class I, Level B evidence). Subcutaneous anticoagulation or sequential compression devices should be instituted to prevent formation of deep venous thrombosis, especially in patients with decreased mobility (Class I, Level A evidence). Additional early and late complications are listed in Box 3.

Primary Prevention

In 2006, the American Heart Association and American Stroke Association issued a guideline for the primary prevention of ischemic stroke, which is summarized here.

• Each patient should undergo formal assessment of his or her stroke risk (Class I, Level A evidence).
• Those with coronary artery disease, heart failure, or symptomatic peripheral arterial disease are 1.73 times more likely to have a first stroke as compared to those without these conditions. Antiplatelet therapy is recommended in these patients.
• Hypertension has been well documented to increase the risk of stroke, and current recommendations are to perform screening for hypertension at least every 2 years in adults (Class I, Level A evidence). Diet and lifestyle should be modified and pharmacologic treatment should be prescribed according to the JNC 7 recommendations. Currently, guidelines emphasize individualization of therapy, with the overall goal being blood pressure reduction to at least less than 140/90 mm Hg.
• In patients with diabetes, stricter blood pressure control to less than 130/80 mm HG with use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is recommended (Class I, Level A evidence). In these patients, a statin to lower the risk of first stroke is also recommended (Class I, Level A evidence). Tight glycemic control is encouraged to reduce microvascular complications, but evidence showing a reduction in stroke risk is lacking.
• In patients with dyslipidemia, recommendations state that those with known coronary disease and high-risk hypertensive patients be treated with lifestyle measures and a statin, even in the presence of a normal LDL (Class I, Level A evidence). In patients with atrial fibrillation, warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0 is recommended in those without contraindications to oral anticoagulants (Class I, Level of A evidence).
• Smoking doubles the risk of ischemic stroke and doubles or quadruples the risk of hemorrhagic stroke. Smoking cessation is recommended (Class I, Level B evidence) and the use of counseling, nicotine replacement, and oral medications should be considered (Class IIa, Level B evidence).
• Currently, aspirin therapy is not recommended for primary stroke prevention in men (Class III, Level A evidence), but it may be helpful in primary stroke prevention among women older than 65 years who have well-controlled hypertension (Class IIa, Level B evidence).
• Carotid endarterectomy is recommended for patients with symptomatic high-grade carotid artery stenosis because surgery was shown to be beneficial in significantly reducing stroke risk (9%) at 2 years versus medical therapy with aspirin alone (26%). In patients with asymptomatic carotid artery stenosis, screening for other treatable causes of stroke with aggressive control of all risk factors is recommended (Class I, Level C evidence). Aspirin therapy is recommended in the absence of contraindications (Class I, Level of B evidence). Prophylactic carotid endarterectomy is recommended in selected patients with high-grade asymptomatic carotid stenosis; endarterectomy should be performed by surgeons with less than 3% morbidity and mortality postoperative complication rates (Class I, Level of A evidence). Carotid artery angioplasty and stenting may be considered in asymptomatic patients who are at high surgical risk for endarterectomy (Class IIb, Level B evidence).

Secondary Prevention

Following a stroke, lifestyle changes should be made, with particular attention to reducing risk factors for stroke as outlined earlier. In patients with atrial fibrillation, warfarin therapy is recommended for preventing recurrent stroke in the absence of contraindications. In patients with a history of noncardioembolic ischemic stroke, antiplatelet therapy is recommended. Aspirin, clopidogrel, and dipyridamole in combination with low-dose aspirin have all been shown to be beneficial in reducing the risk of recurrent stroke in multiple clinical trials. The most recently published study, the PRoFESS trial from 2008, directly compared clopidogrel alone and dipyridamole in combination with low-dose aspirin for preventing recurrent stroke. Although the results did not meet the predefined statistical criteria for noninferiority, there was no statistically significant difference between the groups in the primary outcome of recurrent stroke. However, there was an increase in the rate of intracranial hemorrhage with the dipyridamole and aspirin arm, which was not seen in prior studies evaluating this combination. Currently there is no clear uniform recommendation of one agent over another, and therapy must be tailored to individual patients based on availability, cost, and side-effect profile.

Considerations in Special Populations

In patients with known medical conditions that increase the risk of stroke, such as sickle cell disease, vasculitis, or cardiomyopathy, the approach to stroke prevention should be a coordinated effort among the patient, the primary care physician, and involved specialists. Often, it is important to aggressively manage the underlying disease state. The risk of ischemic stroke or intracerebral hemorrhage is 2.4 times greater during pregnancy and the first 6 weeks following delivery. Focal neurologic signs in this population merits prompt evaluation by a neurologist. Other special considerations include children or young adults with stroke and patients in whom no clear etiology of stroke is determined. Further workup may include referral to a geneticist for evaluation of potential genetic or metabolic causes of stroke in these populations.

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Outcomes

During the hospitalization for an acute stroke, intensive speech, physical, and occupational therapy should be initiated as soon as the patient is stable enough to participate. Most functional recovery occurs within the first 3 months. After this, further recovery is possible, but it is generally limited. The 1-year mortality in first-time stroke sufferers is 14% to 24% in persons aged 40 to 69 years, and the 1-year mortality increases to 22% to 27% in patients aged 70 years and older. Following a first stroke, the mean survival for persons aged 60 to 79 years ranges from 5.4 to 7.4 years. After age 80 years, the mean survival decreases to 1.8 years for men and 3.1 years for women.

Temporary stroke symptoms due to ischemia that last less than 24 hours are typically referred to as a transient ischemic attack (TIA). After a TIA, the 90-day risk of stroke is 3% to 17.3%, and the risk is highest within the first 30 days. Within a year of a TIA, up to 25% of patients die.

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Summary

• A stroke is defined as a sudden focal loss of neurologic function due to decreased perfusion of brain tissue.
• In patients who present with stroke symptoms, a rapid, focused neurologic history and physical examination should be performed, making every attempt to establish a specific time of onset because this helps to guide further therapy.
• Patients presenting within a 3-hour time window of symptom onset should receive IV rtPA at a dose of 0.9 mg/kg (maximum dose 90 mg) after a CT brain excludes the presence of an intracranial hemorrhage and there are no other contraindications to therapy. The dose is administered over 60 minutes, with 10% of the total dose being given initially as a bolus.
• The remaining hospital course is focused on evaluating potential etiologies of stroke, preventing early complications, and performing intensive rehabilitation.
• Anticoagulation should be considered for patients with a history of cardioembolic stroke, and antiplatelet therapy should be considered for ischemic strokes of noncardiac etiology.
• Optimization of stroke risk factor reduction is critical in both primary and secondary prevention.

The recommendations on early management of adults with ischemic stroke and prevention are based on guidelines from the American Heart Association and American Stroke Association. Data regarding clinical trials in ischemic stroke are available at www.strokecenter.org.

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Suggested Readings

• Adams HP Jr, del Zoppo G, Alberts MJ, et al: Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and theAtherosclerotic Peripheral Vascular Disease and Quality of CareOutcomes in Research Interdisciplinary Working Groups. Stroke. 2007, 38: 1655-1711.
• American Heart Association. Heart Disease and Stroke Statistics—2008 Update. Dallas: American Heart Association, 2008.
• Goldstein LB, Adams R, Alberts MJ, et al: Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research, Interdisciplinary Working Group. Stroke. 2006, 37: 1583.
• National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995, 333: (24): 1581-1587.
• North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991, 325: 445-453.
• Sacco RL, Diener HC, Yusuf S, et al: and the PRoFESS Study Group: Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008, 359: 1238-1251.