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Table of Contents

Christopher T.
Skidmore, MD

Department of
Neurology

Irene L.
Katzan, MD

Department of
Neurology

Print Chapter

Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Prevention

Outcomes

References

A stroke is defined as a sudden loss of brain function caused by a blockage or rupture of a blood vessel to the brain. Stroke can be subdivided into two types: ischemic and hemorrhagic. Ischemic stroke accounts for 85% of all cases. Hemorrhagic stroke can be further subclassified as intracerebral and subarachnoid. This chapter provides an overview of the broad field of stroke, with particular emphasis on ischemic stroke.

Stroke is the leading cause of morbidity and the third-leading cause of mortality in the United States. Approximately 150,000 deaths per year are attributed to stroke. It is also the most common neurologic reason for hospitalization. Although we have made great strides in the treatment of stroke, the overall incidence will continue to rise as our population ages. Primary and secondary prevention of stroke is important to decrease its incidence and its associated morbidity.

Ischemic Stroke
In ischemic stroke, interruption of the blood supply to the brain results in tissue hypoperfusion, hypoxia, and eventual cell death secondary to a failure of energy production. Three main mechanisms are involved in the development of ischemic stroke, and they are associated with atherothrombotic, embolic, and small-vessel diseases. Less common causes include coagulopathies, vasculitis, dissection, and venous thrombosis (Figure 1).

Atherothrombotic Disease
In atherothrombotic disease, lipid deposition leads to the formation of plaque, which narrows the vessel lumen and results in turbulent blood flow through the area of stenosis. The turbulence of the flow and the resultant alterations in flow velocities lead to intimal disruption or plaque rupture, both of which activate the clotting cascade. This causes platelets to become activated and adhere to the plaque surface, where they eventually form a fibrin clot. As the lumen of the vessel becomes more occluded, ischemia develops distal to the obstruction and can eventually lead to an infarction of the tissue that is dependent on the parent vessel for oxygen delivery.

Unenhanced computed tomography (CT) detects evidence of remote embolic ischemic stroke in the left frontal cortex (middle cerebral artery distribution) and in the left mesial occipital lobe (posterior cerebral artery distribution).

Figure 2

Embolic Disease
Embolic stroke occurs when dislodged thrombi travel distally and occlude vessels downstream (Figure 2).One-half of all embolic strokes are caused by atrial fibrillation; the rest are attributable to a variety of causes, including (1) left ventricular dysfunction secondary to acute myocardial infarction or severe congestive heart failure, (2) paradoxical emboli secondary to a patent foramen ovale, and (3) atheroemboli. These latter vessel-to-vessel emboli often arise from atherosclerotic lesions in the aortic arch, carotid arteries, and vertebral arteries.

CT demonstrates the lacunar infarcts that are typical of small-vessel ischemic stroke.

Figure 3

Small-Vessel Disease
Small-vessel ischemia can occur when microatheromata occlude the orifice of penetrating arteries (Figure 3). Another mechanism is associated with lipohyalinosis, in which pathologic changes in the tunica media and the adventitia of penetrating arteries occur in the presence of chronic hypertension. Elevated blood pressure causes endothelial injury that disrupts the blood-brain barrier. This in turn leads to a deposition of plasma proteins and eventually degeneration of the tunica media smooth muscle. The smooth muscle is replaced with collagenous fibers, which inhibit the elasticity of the blood vessel. This causes the vessel lumen to narrow and eventually activates the clotting cascade, leading to thrombosis. Small-vessel ischemic disease typically results in lacunar infarcts, which were named for the small "lakes" (lacunae) that are found at autopsy in affected patients.

Hypoperfusion can occur as a result of (1) atherosclerotic disease that limits distal flow or (2) systemic hypotension, such as seen in patients who experience acute cardiacarrhythmia or cardiac arrest. A reduction in cerebral perfusion pressure activates the autoregulatory system. As the small arterioles constrict in an attempt to maintain pressure, ischemia can develop in the distal branches of the vascular tree. Areas of the brain that lies between two major vascular supplies (eg, the middle and anterior cerebral arteries) is known as a watershed area. These areas are especially prone to ischemia during episodes of systemic hypotension.

Hemorrhagic Stroke
Intracerebral hemorrhage is the result of the rupture of a vessel within the brain parenchyma. The primary causes of these ruptures are hypertension and amyloid angiopathy; secondary precipitating factors are listed in Table 1. As with ischemic stroke, the location of an intracerebral hemorrhage determines the type of symptoms and the patient's overall outcome. For example, a small lobar hemorrhage might cause only a mild headache and subtle motor deficits, while a hemorrhage of the same size in the pons might result in a coma. Outcomes are also correlated with the volume of blood; hemorrhages greater than 60 ml are almost always fatal, regardless of their location.

Unenhanced CT shows a hypertensive hemorrhage in the right thalamus in addition to remote lacunar ischemic infarcts in the basal ganglia bilaterally.

Figure 4

Hypertension is a major cause of hemorrhages of the basal ganglia and brainstem (Figure 4). Chronic hypertension can lead to the formation of Charcot-Bouchard aneurysms in lipohyalinotic vessels, which can rupture. Common locations of hypertensive hemorrhages include the putamen, caudate, thalamus, pons, and cerebellum.

Amyloid angiopathy is a common cause of lobar hemorrhage (Figure 5). This disease process occurs in the elderly and is caused by a deposition of beta amyloid sheets in the tunica media of the vessel wall. The deposition of amyloid protein causes the vessels to become more rigid, fragile, and prone to rupture. Evidence of hemosiderin deposition in other areas of the brain on magnetic resonance imaging (MRI) might also be seen. This deposition indicates that the patient has experienced previous hemorrhage and provides indirect support for the presence of amyloid angiopathy; however, pathologic examination is necessary before a definitive diagnosis can be made.

Unenhanced CT demonstrates a left parietal intracranial hemorrhage, which is believed to have been caused by amyloid angiopathy.

Figure 5

There is tremendous variability in the signs and symptoms of stroke, but they have all been well documented. Depending on the severity of the stroke, patients can experience a loss of consciousness, cognitive deficits, speech dysfunction, limb weakness, hemiplegia, vertigo, diplopia, lower cranial nerve dysfunction, gaze deviation, ataxia, hemianopia, and aphasia, among others.

Four classic syndromes that are characteristically caused by lacunar-type stroke are: pure motor hemiparesis, pure sensory syndrome, ataxic hemiparesis syndrome, and clumsy-hand dysarthria syndrome.

Pure Motor Hemiparesis
Patients with pure motor hemiparesis present with face, arm, and leg weakness. This condition usually affects the extremities equally, but in some cases it affects one extremity more than the other. The most common stroke location in affected patients is the posterior limb of the internal capsule, which carries the descending corticospinal and corticobulbar fibers. Other stroke locations include the pons, midbrain, and medulla.

Pure Sensory Syndrome
Pure sensory syndrome is characterized by hemibody sensory symptoms that involve the face, arm, leg, and trunk. It is usually the result of an infarct in the thalamus.

Ataxic Hemiparesis Syndrome
Ataxic hemiparesis syndrome features a combination of cerebellar and motor symptoms on the same side of the body. The leg is typically more affected than the arm. This syndrome can occur as a result of a stroke in the pons, the internal capsule, or the midbrain, or in the anterior cerebral artery distribution.

Clumsy-Hand Dysarthria Syndrome
Patients with clumsy-hand dysarthria syndrome experience unilateral hand weakness and dysarthria. The dysarthria is often severe, whereas the hand involvement is more subtle, and patients may describe their hand movements as "awkward." This syndrome is usually caused by an infarct in the pons.

It should be remembered that not all focal neurologic symptoms are a result of stroke. Common stroke "mimickers" include hyper- and hypoglycemia, seizure, multiple sclerosis, hyperventilation, tumor, and complicated migraine.

Finally, emphasis should be placed on educating patients on the warning signs of stroke and the importance of reaching a health care provider within 2 hours of symptom onset. With the significant advances that have improved the management of acute stroke, early treatment might reduce the degree of morbidity that is associated with first-ever strokes.

The evaluation of stroke should focus on determining its cause in order to tailor appropriate therapy. Different patterns of signs can provide clues as to both the location and the mechanism of a particular stroke. Symptoms suggestive of a brainstem stroke include vertigo, diplopia, bilateral abnormalities, lower cranial nerve dysfunction, gaze deviation (toward the side of weakness), and ataxia. Indications of higher cortical dysfunction-such as neglect, hemianopsia, aphasia, and gaze preference (opposite the side of weakness)-suggest hemispheric dysfunction with involvement of a superficial territory from an atherothrombotic or embolic occlusion of a mainstem vessel or peripheral branch.

The pattern of motor weakness is also a helpful clue. Ischemia of the cortex supplied by the middle cerebral artery typically causes weakness that (1) is more prominent in the arm than in the leg and (2) involves the distal muscles more than the proximal muscles. Conversely, involvement of an area supplied by the superficial anterior cerebral artery results in weakness that (1) is more prominent in the leg than the arm and (2) involves proximal upper extremity (shoulder) muscles more than distal upper extremity muscles. Flaccid paralysis of both the arm and leg (unilateral) suggests ischemia of the descending motor tracts in the basal ganglia or brainstem. This is often caused by an occlusion of a penetrating artery as a result of small-vessel disease.

All patients should undergo an imaging study of the brain. The development of MRI has been a significant advancement in all phases of stroke management. It can often identify small strokes that cannot be seen on CT. Diffusion-weighted imaging can generally detect acute ischemic infarcts that are less than 7 days old; this can be especially useful in patients who have experienced multiple previous strokes. Magnetic resonance angiography (MRA) is a noninvasive means of evaluating the status of both intra- and extracranial vessels; however, it can overestimate the presence and degree of stenosis, and studies are under way to determine its accuracy. Other noninvasive methods of assessing the cerebral circulation include Transcranial Doppler Ultrasonography and CT angiography. For now, cerebral angiography remains the gold standard for visualizing the intra- and extracranial circulation. The risk of angiographic complications is approximately 1%.

Patients with an ischemic stroke that is potentially referable to the carotid circulation should undergo either carotid duplex sonography or MRA of the extracranial carotids in an effort to identify the presence of significant carotid artery stenosis. A transthoracic echocardiogram (TTE) should be performed to evaluate the possibility of a cardioembolic source. The use of contrast or agitated saline should be considered in order to increase the yield in the detection of a patent foramen ovale (PFO). A transesophageal echocardiogram is superior to a TTE for evaluating the atrial appendage and aortic arch and for identifying the presence of a PFO or an atrial septal aneurysm.

Early Drug Treatment
Intravenous (IV) tissue plasminogen activator (t-PA) was approved for use in ischemic stroke in 1996, and it radically changed our approach to acute stroke. Because it must be given within 3 hours of symptom onset, rapid and efficient evaluation is essential for all patients with stroke-like symptoms who are potential t-PA candidates. In the National Institute of Neurological Diseases and Stroke (NINDS) trial, on which the approval was based, patients who were treated with recombinant t-PA were 30% more likely to experience an excellent recovery at 3 months than were patients who received placebo.¹ This benefit was seen in patients with all stroke subtypes. However, t-PA was also associated with a 6.4% incidence of symptomatic intracranial hemorrhage, which represents a 10-fold increase in risk. To minimize this risk, strict adherence to national guidelines is essential.² Some of the contraindications to t-PA therapy include uncontrolled blood pressure (>185/110 mm Hg on repeated measurements), a history of brain hemorrhage, abnormal coagulation factors (international normalized ratio [INR] >1.7; partial thromboplastin time >1.5 times normal; platelet count <100 K/uL), and a history of major surgery during the previous 14 days. The nationally recommended inclusion and exclusion criteria should be reviewed for each stroke patient for whom t-PA is being considered.

An accurate assessment of the timing of the stroke is also crucial. If the onset of the stroke was not witnessed, then the time the patient was last known to be neurologically at baseline should be used. For example, if a patient went to bed neurologically normal and awoke with stroke symptoms, the moment of stroke onset is considered to be the time the patient went to bed (assuming that the patient did not get up during the night). Patients older than 77 years of age and those whose strokes are severe (National Institutes of Health stroke scale score >22) are at increased risk for symptomatic intracerebral hemorrhage. Even so, these patients benefited from t-PA in the NINDS trial.

Inpatient Management
The inpatient management during the weeks following a stroke also has a significant impact on outcomes. For example, caring for patients in a stroke unit rather than in a general ward prevents 1 additional death for every 32 patients treated. The impressive benefit of stroke unit care is believed to be attributable to the adherence to standard stroke-specific management practices. One of these practices is an evaluation of swallowing function, which should be performed routinely. If dysphagia is present, steps to avoid aspiration should be taken. Another important precaution is to deliver prophylaxis against deep venous thrombosis (DVT) to nonambulatory patients with either subcutaneous heparin or intermittent compression stockings. Stroke patients have an increased risk of DVT and the subsequent life-threatening complication of pulmonary embolism, which is the most common cause of death during the 2 to 4 weeks following a stroke. Careful control of the patient's blood glucose levels and temperature should also be a priority because hyperglycemia and fever have been shown to result in poorer outcomes.

Aspirin has been found to be of modest but significant benefit during the acute phase of stroke. According to the combined results of two large trials that enrolled a total of 35,580 patients, aspirin therapy resulted in 9 fewer deaths or nonfatal strokes per 1000 patients during the first few weeks poststroke among patients who were treated within 48 hours of the onset of their initial stroke.^3,4

In contrast, there is no evidence from trials that supports the use of intravenous heparin or heparin-like products during the acute phase of stroke. The efficacy of these medications in acute stroke has been evaluated in two randomized controlled trials. In the International Stroke Trial (IST), researchers used a factorial design to randomize 19,435 patients with ischemic stroke to treatment with one of six regimens: (1) subcutaneous heparin at 5,000 IU twice daily, (2) subcutaneous heparin at 12,500 IU twice daily, or (3) no heparin; in addition, patients on each of these three regimens either did or did not also receive 300 mg/day of aspirin.³ The investigators found no significant differences in the rates of recurrent stroke, death at 14 days, or death or dependency at 6 months between patients who did and did not receive heparin.

The other study, the Trial of ORG 10172 in Acute Stroke Treatment (TOAST), was a smaller but more detailed study.⁵ The TOAST investigators randomized 1281 patients to receive either the IV low-molecular-weight heparinoid ORG 10172 or placebo. They found no statistically significant difference between the two groups with respect to the primary criterion of a favorable outcome, which was a Glasgow Outcome Scale score of 1 or 2 at 3 months. Although a post hoc analysis of the TOAST data revealed that ORG 10172 provided a significant benefit for patients with atherothrombotic disease, this finding must be viewed with caution and must be confirmed by randomized studies that are specifically targeted to this population. It is also possible that anticoagulation might benefit other specific patient populations-such as those with multiple embolic risk factors, prosthetic valves, or vertebrobasilar insufficiency-but more data are needed.

Risk Factor Control
Risk factors for stroke are either modifiable or non-modifiable. Among the latter are age, sex, race/ethnicity, and family history (Table 2). Beginning at age 55 years, the rate of stroke doubles every decade. Men are more likely than women to experience early stroke (prior to age 65 yr) and carotid artery stenosis. With respect to race, blacks have a higher incidence of both ischemic and hemorrhagic stroke than do non-Hispanic whites. This difference has been ascribed to the higher prevalence of hypertension and diabetes among blacks.

The modifiable risk factors for stroke include hypertension, diabetes, cigarette smoking, hyperlipidemia, carotid artery stenosis, atrial fibrillation, excessive alcohol consumption, and physical inactivity (Table 3).

Hypertension
The most important modifiable risk factor is hypertension, which increases the risk of stroke 2- to 4-fold. This higher risk is seen in both systolic and diastolic hypertension as well as in isolated systolic hypertension in the elderly. Blood pressure control significantly reduces the risk of stroke; it has been shown to prevent 30 strokes for every 1000 patients treated. According to the current recommendation of the Stroke Council of the American Heart Association (AHA), blood pressure should be maintained at less than 140/90 mm Hg.⁶

Diabetes
Diabetes increases stroke risk 1.8- to 6-fold. Although there is no clear evidence that normalizing blood glucose values itself specifically reduces stroke risk, the Stroke Council's guidelines clearly state that hyperglycemia should be controlled to reduce the risk of microvascular complications.⁶

Smoking
Approximately 27% of men and 22% of women in the United States smoke cigarettes. Smokers have a relative risk of stroke in the range of 1.8, and the estimated population attributable risk of stroke due to smoking is 18%. Fortunately, this increased risk disappears within 5 years of smoking cessation.

Hyperlipidemia
Lipid disorders have been shown to increase the risk of stroke by 1.8- to 2.6-fold.⁶ Most of the information regarding the effect of lowering cholesterol on stroke risk comes from secondary analyses of trials on the prevention of coronary disease, but it is prudent to use these guidelines when evaluating patients for stroke risk. The recently issued third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) provides age- and gender-specific weighting algorithms to guide treatment decisions on the use of lipid-lowering agents. Tools for the immediate assessment of a particular individual's risk can be downloaded for use with personal digital assistants. In general, for primary prevention in the absence of cardiovascular disease, total cholesterol levels should be maintained below 240 mg/dL, LDL levels at less than 160 mg/dL (in patients who have <2 cardiovascular risk factors), and HDL concentrations at greater than 40 mg/dL. Tighter control of hyperlipidemia is indicated for patients who have a history of stroke or cardiovascular disease; their goal LDL level is less than 100 mg/dL, their target HDL level is greater than 40 mg/dL, and their recommended total cholesterol level is less than 200 mg/dL. Keep in mind, however, that total cholesterol levels lower than 160 mg/dL have been associated with an increased risk of intracerebral hemorrhage.

Asymptomatic Carotid Artery Stenosis
The Asymptomatic Carotid Atherosclerosis Study (ACAS) showed that carotid endarterectomy is beneficial in primary stroke prevention in patients who have high-grade asymptomatic carotid stenosis.⁷ In this trial, investigators compared medical management with endarterectomy plus medical management in 1662 patients who had stenoses greater than 60%. Endarterectomy was associated with a 53% reduction in 5-year relative risk, which amounts to an absolute risk reduction of 1% per year. Moreover, the combined rate of surgical and angiographic complications in this trial was very low (2.3%); a complication rate greater than 4.5%, which is closer to the rates seen in other studies, would have negated the benefit of endarterectomy seen in this trial. Therefore, the current AHA guidelines recommend carotid endarterectomy for patients with an asymptomatic stenosis greater than 60% only if (1) the surgeon performing the procedure has a morbidity/mortality rate of less than 3% and (2) the patient has a life expectancy of at least 5 years.^6,8

Symptomatic Carotid Artery Stenosis
The benefit of carotid endarterectomy in patients with symptomatic high-grade carotid artery stenosis was well demonstrated in two large trials. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) was a rigorously performed, randomized, controlled trial that compared carotid endarterectomy with medical management in 659 symptomatic patients who had angiographically proven stenosis of 70% to 99%.⁹ The researchers found that the risk of ipsilateral stroke at 2 years was 9% in the surgical group and 26% in the medical group, a difference that translated into a 51% reduction in relative risk of stroke or death over 2 years in the endarterectomy group. The European Carotid Surgery Trial was another randomized controlled study of patients with symptomatic carotid artery stenosis, and it yielded similar results.¹⁰ A third trial-a Veterans Affairs Cooperative Studies Program trial¹¹-was prematurely stopped after the results of the previous two trials became known.

The benefit of carotid endarterectomy is much greater in symptomatic patients than in asymptomatic patients. According to data from NASCET and ACAS, in which the same method was used to measure stenosis, carotid endarterectomy prevented one stroke or death in 1 year for every 12 symptomatic patients who were so treated; the corresponding figure for asymptomatic patients was 1 for every 85 patients treated.

The NASCET investigators also compared endarterectomy with medical treatment in patients with symptomatic disease whose stenoses were only moderate (50% to 69%).¹² They found that the 5-year stroke rates were 15.7% in the endarterectomy group and 22.2% in the medical group (p=.045). In this group, carotid endarterectomy would prevent one stroke or death in 1 year in for every 77 patients treated.

According to current guidelines, surgical treatment should be offered to all patients with symptomatic stenosis greater than 70% who are good candidates for surgery.^8,13 Patients with a 50% to 69% stenosis should be selected carefully, and the decision to operate should be based on symptoms and stroke risk factors.¹³

Carotid angioplasty and stenting are exciting new and less invasive therapies for carotid artery stenosis. These procedures might be especially useful in patients who are at high surgical risk. However, they are still investigational.

Atrial Fibrillation
The incidence of stroke among patients with atrial fibrillation is approximately 5% per year. Adjusted-dose warfarin has been shown in numerous trials to be the treatment of choice for prevention of stroke in these patients. Warfarin reduces stroke risk by approximately 68%, while antiplatelet agents reduce this risk by only 21%. A target INR of 2.5 (range: 2.0 to 3.0) is generally recommended. An exception to this recommendation applies to patients with "lone atrial fibrillation," defined as those who are younger than 65 years of age who have no history of stroke, transient ischemic attack, poor ventricular function, rheumatic heart disease, hypertension, or diabetes mellitus. In these patients, antiplatelet therapy may be just as effective as warfarin. Elderly patients with atrial fibrillation have a higher risk of serious hemorrhagic complications with warfarin, but they also have a greater reduction in the risk of embolic stroke.

Aspirin is recommended for atrial fibrillation in patients in whom warfarin is contraindicated and in those in whom warfarin would pose too high a risk for hemorrhagic complications. However, there is no evidence to support the use of antiplatelet agents in the primary prevention of noncardiac-related stroke. Although aspirin has been shown to reduce the incidence of first cardiac events, it has not been shown to affect the occurrence of first-time stroke.

For secondary prevention, antithrombotic therapy (either an antiplatelet or an anticoagulant) should be administered to all patients with ischemic stroke, barring a contraindication. Warfarin should be strongly considered for patients with stroke due to atrial fibrillation. The risk of recurrent stroke in these patients is extremely high: up to 12% during the first year.¹⁴ There is no evidence that warfarin is superior to aspirin in patients with noncardiac stroke. Ongoing studies are evaluating the efficacy of warfarin in other subgroups of stroke patients, such as those with intracranial stenoses, antiphospholipid antibodies, and PFO.

Intracerebral Hemorrhage
Blood pressure control is strongly recommended to prevent intracerebral hemorrhage (the current guidelines for blood pressure treatment can be found in the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure).¹⁵ The AHA also recommends that patients with stroke (as well as those with acute myocardial infarction) be carefully considered for thrombolytic therapy to reduce the risk of intracerebral hemorrhage.¹⁶ Some evidence suggests that excessive alcohol consumption also increases a patient's risk for intracerebral hemorrhage, but this evidence is still incomplete; in the meantime, the AHA recommends that at-risk patients should be particularly conscious in avoiding heavy alcohol consumption.

Stroke survivors show significant functional improvement during the first 3 months of recovery. Further improvement can occur during the succeeding 3 months, especially in patients whose initial impairment was severe. Even so, most stroke survivors are left with some disability. For example, 48% are hemiparetic at 6 months and 22% cannot walk. As many as one-half of all stroke survivors are partially dependent on others to perform activities of daily living.¹⁸ The rate of recurrent noncardioembolic stroke is 3% to 7% per year.

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