STROKE MEDSCAPE Background

Stroke is the clinical term for acute loss of perfusion to vascular territory of the brain, resulting in ischemia and a corresponding loss of neurologic function. Classified as either hemorrhagic or ischemic, strokes typically manifest with the sudden onset of focal neurologic deficits, such as weakness, sensory deficit, or difficulties with language. Ischemic strokes have a heterogeneous group of causes, including thrombosis, embolism, and hypoperfusion, whereas hemorrhagic strokes can be either intraparenchymal or subarachnoid. Only in recent years have advances allowed for significant improvement in the outcome of this devastating disease. A new era in acute stroke care began in 1995, when the National Institute of Neurologic Disorders and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Study Group first presented data indicating that early administration of t-PA benefited a carefully selected patient group with acute ischemic stroke (AIS).1 While newer recanalization approaches are being explored, all modalities are faced with the issue of time, for "time is brain."2 For related information, see Medscape's Stroke Resource Center.

Pathophysiology
The brain is the most metabolically active organ in the body. While representing only 2% of the body's mass, it requires 15-20% of the total resting cardiac output to provide the necessary glucose and oxygen for its metabolism. Ischemic strokes result from events that limit or stop blood flow, such as embolism, thrombosis in situ, or relative hypoperfusion. As blood flow decreases, neurons cease functioning, and irreversible neuronal ischemia and injury begin at blood flow rates of less than 18 mL/100 mg/min. Ischemic cascade The processes involved in stroke injury at the cellular level are referred to as the ischemic cascade. Many factors are thought to result in cell death and dysfunction, and others are being discovered at a rapid rate. Within seconds to minutes of the loss of glucose and oxygen delivery to neurons, the cellular ischemic cascade begins. This is a complex process that begins with cessation of the normal electrophysiologic function of the cells. The resultant neuronal and glial injury produces edema in the ensuing hours to days after stroke, causing further injury to the surrounding tissues. Ischemic penumbra An acute vascular occlusion produces heterogeneous regions of ischemia in the dependent vascular territory. The quantity of local blood flow is comprised of any residual flow in the major arterial source and the collateral supply, if any. Regions of the brain without significant flow are referred to collectively as the core, and these cells are presumed to die within minutes of stroke onset. Zones of decreased or marginal perfusion are collectively called the ischemic penumbra. Tissue in the penumbra can remain viable for several hours because of marginal tissue perfusion, and currently studied pharmacologic interventions for preservation of neuronal tissue target this penumbra.

Recanalization strategies, including IV rt-PA and intra-arterial approaches attempt to establish revascularization so that cells in the penumbra can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of ischemia only if performed quickly. Neuroprotective strategies are intended to both preserve the penumbral tissues and extend the time window for revascularization techniques. While no neuroprotective agent has demonstrated benefit in definitive clinical trials, several studies are underway.

Mechanisms of Stroke
Embolic strokes Emboli may either be of cardiac or arterial origin. Cardiac sources include atrial fibrillation, recent myocardial infarction, prosthetic valves, native valvular disease, endocarditis, mural thrombi, dilated cardiomyopathy, or patent foramen ovale allowing passage of venous circulation emboli. Arterial sources are atherothrombolic or cholesterol emboli that develop in the arch of the aorta and in the extracranial arteries (ie, carotid and vertebral arteries). Embolic strokes tend to have a sudden onset, and neuroimaging may demonstrate previous infarcts in several vascular territories or calcific emboli. Thrombotic strokes Thrombotic strokes include large-vessel strokes and small-vessel or lacunar strokes. They are due to in situ occlusions on atherosclerotic lesions in the carotid, vertebrobasilar, and cerebral arteries, typically proximal to major branches. Thrombogenic factors may include injury to and loss of endothelial cells exposing the subendothelium and platelet activation by the subendothelium, activation of the clotting cascade, inhibition of fibrinolysis, and blood stasis. Thrombotic strokes are generally thought to originate on ruptured atherosclerotic plaques. Intracranial atherosclerosis may be the cause in patients with widespread atherosclerosis. In other patients, especially younger patients, other causes should be considered, including hypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein S deficiency), sickle cell disease, fibromuscular dysplasia, arterial dissections, and vasoconstriction associated with substance abuse. Lacunar stroke Lacunar strokes represent 20% of all ischemic strokes. They occur when the penetrating branches of the middle cerebral artery (MCA), the lenticulostriate arteries, or the penetrating branches of the circle of Willis, vertebral artery, or basilar artery become occluded. Causes of lacunar infarcts include microatheroma, lipohyalinosis, fibrinoid necrosis secondary to hypertension or vasculitis, hyaline arteriosclerosis, and amyloid angiopathy. The great majority are related to hypertension. Watershed infarcts These infarcts, also known as border zone infarcts, develop from relative hypoperfusion in the most distal arterial territories and can produce bilateral symptoms. Frequently, these occur perioperatively or in situations of prolonged hypotension.

Frequency

United States Approximately 795,000 strokes occur each year, including both new and recurrent cases. Of these strokes, approximately 625,000 are ischemic strokes. By the year 2025, the annual number of strokes is expected to reach 1 million. Currently, more than 4.4 million people in the United States are stroke survivors. International As in the United States, stroke is the third leading cause of death in the industrialized countries of Europe and the leading cause of adult disability. The global incidence of stroke will only increase, since the population older than 65 years will rise from 390 million now to 800 million by 2025, representing 10% of the total population. The World Health Organization estimates that 15 million people suffer a stroke worldwide each year, resulting in 5 million deaths and 5 million people permanently disabled.

Mortality/Morbidity

Stroke is the third leading cause of death in the United States (46.6 per 100,000 in 2005), following cardiac and cancer-related deaths. Worldwide in 1990, more than 4.3 million people died of cerebrovascular disorders. Stroke is the leading cause of disability in the United States; 26% of stroke survivors need assistance with daily living, 30% need some type of assistance for walking, and 26% require admission to a long-term care facility. Furthermore, at least one third of stroke survivors have depression as well as many of their care providers. The direct costs (ie, treatment) and indirect costs (ie, lost productivity) of stroke in the United States are approximately $68.9 billion/year in 2009.

Race
In the United States, stroke has a higher incidence in the black population than in the white population.3

Blacks have an age-adjusted risk of death from stroke that is 1.49 times that of whites. White males have a stroke incidence of 62.8 per 100,000, with death being the final outcome in 26.3% of cases, compared with women who have a stroke incidence of 59 per 100,000 and a death rate of 39.2%. Hispanics have a lower overall incidence of stroke than whites and blacks but more frequent lacunar strokes and stroke at an earlier age.

Sex
In patients younger than 60 years, the incidence of stroke is greater in males (3:2 ratio).

Age

Stroke can occur in patients of all ages, including children. Risk of stroke increases with age, especially in patients older than 64 years, in whom 75% of all strokes occur.

Clinical
History

The American Stroke Association advises the public to be aware of the symptoms of stroke that are easily recognized and to call 911 immediately. These symptoms include the following: o Sudden numbness or weakness of face, arm, or leg, especially on one side of the body o Sudden confusion, difficulty in speaking or understanding o Sudden deterioration of vision of one or both eyes o Sudden difficulty in walking, dizziness, and loss of balance or coordination o Sudden, severe headache with no known cause A focused medical history aims to identify risk factors for atherosclerotic and cardiac disease, including hypertension, diabetes mellitus, tobacco use, high cholesterol, and a history of coronary artery disease, coronary artery bypass, or atrial fibrillation. Consider stroke in any patient presenting with acute neurological deficit or any alteration in level of consciousness. Common signs of stroke include the following: o Acute hemiparesis or hemiplegia o Complete or partial hemianopia, monocular or binocular visual loss, or diplopia o Dysarthria or aphasia o Ataxia, vertigo, or nystagmus o Sudden decrease in consciousness In younger patients, elicit a history of recent trauma, coagulopathies, illicit drug use (especially cocaine), migraines, or use of oral contraceptives. Family members, bystanders, and especially prehospital personnel can provide invaluable information regarding the time and events surrounding the onset of symptoms or when the patient was last seen normal. Establishing the time the patient was last normal is especially critical when thrombolytic therapy is an option. If the patient awakens with the symptoms, then the time of onset is defined as the time the patient was last seen without symptoms. Family members, coworkers, or bystanders may be required to help establish the exact time of onset, especially in right hemispheric strokes accompanied by neglect or left hemispheric strokes with aphasia. If the patient is a candidate for thrombolytic therapy, a thorough review of the inclusion and exclusion criteria must be performed. The exclusion criteria largely focus on identifying risk of hemorrhagic complication associated with thrombolytic use.

Physical
Physical examination is directed toward 5 major areas: (1) assessing the airway, breathing, and circulation (ABCs), (2) defining the severity of the patient's neurologic deficits, (3) identifying potential causes of the stroke (4) identifying potential stroke mimics, and (5) identifying comorbid conditions.

The physical examination must encompass all the major organ systems, starting with the ABCs and the vital signs. Patients with stroke, especially hemorrhagic, can

clinically deteriorate quickly; therefore, constant reassessment is critical. Ischemic strokes, unless large or involving the brainstem, do not tend to cause immediate problems with airway patency, breathing, or circulation compromise. On the other hand, patients with intracerebral or subarachnoid hemorrhage frequently require intervention for both airway protection and ventilation. o Vital signs, while nonspecific, can point to impending clinical deterioration and may assist in narrowing the differential diagnosis. Many patients with stroke are hypertensive at baseline, and their blood pressure may become more elevated after stroke. While hypertension at presentation is common, blood pressure decreases spontaneously over time in most patients. Acutely lowering blood pressure has not proven to be beneficial in these stroke patients in the absence of signs and symptoms of associated malignant hypertension, AMI, congestive heart failure (CHF), or aortic dissection. o Head, ears, eyes, nose, and throat examination: A careful examination of the head and neck is essential. Contusions, lacerations, and deformities may suggest trauma as the etiology for the patient's symptoms. Auscultation of the neck may elicit a bruit, suggesting carotid disease as the cause of the stroke. o Cardiac: Cardiac arrhythmias, such as atrial fibrillation, are found commonly in patients with stroke. Similarly, strokes may occur concurrently with other acute cardiac conditions, such as AMI and acute CHF; thus, auscultation for murmurs and gallops is recommended. o Extremities: Carotid or vertebrobasilar dissections, and less commonly, thoracic aortic dissections, may cause ischemic stroke. Unequal pulses or blood pressures in the extremities may reflect the presence of aortic dissections. The neurologic examination must be thorough, and yet this is perhaps the weakest area of training for primary care and emergency providers. A directed and focused examination can be performed in minutes and not only provides great insight into the potential cause of the patient's deficits, but also helps determine the intensity of treatment required. A useful tool in quantifying neurological impairment is the National Institutes of Health Stroke Scale (NIHSS). This scale easily used, is reliable and valid, provides insight to the location of vascular lesions, and is correlated with outcome in patients with ischemic stroke. It focuses on 6 major areas of the neurologic examination: (1) level of consciousness, (2) visual function, (3) motor function, (4) sensation and neglect, (5) cerebellar function, and (6) language. The NIHSS is used most by stroke teams. It enables the consultant to rapidly determine the severity and possible location of the stroke. A patient's score on the NIHSS is strongly associated with outcome, and it can help identify those patients who are likely to benefit from thrombolytic therapy and those who are at higher risk to develop hemorrhagic complications of thrombolytic use.

Table 1. NIH Stroke Scale (For a printable version, see Media file 1.) Open table in new window [ CLOSE WINDOW ]
Table

Category 1a level of consciousness (LOC)

1b LOC questions (month, age)

1c Answers both correctly Answers 1 correctly Incorrect on both 2 Best gaze (follow finger)

3 Best visual (visual fields)

4 Facial palsy (show teeth, raise brows, squeeze eyes shut)

Description Alert Drowsy Stuporous Coma Answers both correctly Answers 1 correctly Incorrect on both Obeys both correctly Obeys 1 correctly Incorrect on both Normal Partial gaze palsy Forced deviation No visual loss Partial hemianopia Complete hemianopia Bilateral hemianopia Normal Minor Partial Complete

5 Motor arm left* (raise 90, hold 10 seconds)

6 Motor arm right* (raise 90, hold 10 seconds)

7 Motor leg left* (raise 30, hold 5 seconds)

8 Motor leg right* (raise 30, hold 5 seconds)

9 Limb ataxia (finger-nose, heel-shin)

10 Sensory (pinprick to face, arm, leg)

No drift Drift Cannot resist gravity No effort against gravity No movement No drift Drift Cannot resist gravity No effort against gravity No movement No drift Drift Cannot resist gravity No effort against gravity No movement No drift Drift Cannot resist gravity No effort against gravity No movement Absent Present in 1 limb Present in 2 limbs Normal Partial loss

Score 0 1 2 3 0 1 2 0 1 2 0 1 2 0 1 2 3 0 1 2 3 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 0 1

Severe loss 2 11 Extinction/neglect (double simultaneous testing) No neglect 0 Partial neglect 1 Complete neglect 2 12 Dysarthria (speech clarity to "mama, baseball, Normal articulation 0 huckleberry, tip-top, fifty-fifty") Mild to moderate 1 dysarthria 2 Near to unintelligible or worse 13 Best language** (name items, describe pictures) No aphasia 0 Mild to moderate 1 aphasia 2 Severe aphasia 3 Mute Total 0-42 * For limbs with amputation, joint fusion, etc, score 9 and explain. ** For intubation or other physical barriers to speech, score 9 and explain. Do not add 9 to the total score. Category Description Score 1a level of consciousness (LOC) Alert 0 Drowsy 1 Stuporous 2 Coma 3 1b LOC questions (month, age) Answers both correctly 0 Answers 1 correctly 1 Incorrect on both 2 1c Answers both correctly Answers 1 correctly Incorrect on Obeys both correctly 0 both Obeys 1 correctly 1 Incorrect on both 2 2 Best gaze (follow finger) Normal 0 Partial gaze palsy 1 Forced deviation 2 3 Best visual (visual fields) No visual loss 0 Partial hemianopia 1 Complete hemianopia 2 Bilateral hemianopia 3 4 Facial palsy (show teeth, raise brows, squeeze eyes shut) Normal Minor 0 Partial Complete 1 2 3 5 Motor arm left* (raise 90, hold 10 seconds) No drift 0 Drift 1 Cannot resist gravity 2 No effort against gravity 3 No movement 4 6 Motor arm right* (raise 90, hold 10 seconds) No drift 0 Drift 1

Cannot resist gravity 2 No effort against gravity 3 No movement 4 7 Motor leg left* (raise 30, hold 5 seconds) No drift 0 Drift 1 Cannot resist gravity 2 No effort against gravity 3 No movement 4 8 Motor leg right* (raise 30, hold 5 seconds) No drift 0 Drift 1 Cannot resist gravity 2 No effort against gravity 3 No movement 4 9 Limb ataxia (finger-nose, heel-shin) Absent 0 Present in 1 limb 1 Present in 2 limbs 2 10 Sensory (pinprick to face, arm, leg) Normal 0 Partial loss 1 Severe loss 2 11 Extinction/neglect (double simultaneous testing) No neglect 0 Partial neglect 1 Complete neglect 2 12 Dysarthria (speech clarity to "mama, baseball, Normal articulation 0 huckleberry, tip-top, fifty-fifty") Mild to moderate 1 dysarthria 2 Near to unintelligible or worse 13 Best language** (name items, describe pictures) No aphasia 0 Mild to moderate 1 aphasia 2 Severe aphasia 3 Mute Total 0-42 * For limbs with amputation, joint fusion, etc, score 9 and explain. ** For intubation or other physical barriers to speech, score 9 and explain. Do not add 9 to the total score.

Causes
Risk factors for ischemic stroke comprise both modifiable and nonmodifiable etiologies. Identification of risk factors in each patient can uncover clues to the cause of the stroke and the most appropriate treatment and secondary prevention plan.

Nonmodifiable risk factors include age, race, sex, ethnicity, history of migraine headaches, sickle cell disease, fibromuscular dysplasia, and heredity. Modifiable risk factors include the following:

Hypertension (the most important) Diabetes mellitus Cardiac disease - Atrial fibrillation, valvular disease, mitral stenosis, and structural anomalies allowing right to left shunting, such as a patent foramen ovale and atrial and ventricular enlargement o Hypercholesterolemia o Transient ischemic attacks (TIAs) o Carotid stenosis o Hyperhomocystinemia o Lifestyle issues - Excessive alcohol intake, tobacco use, illicit drug use, obesity, physical inactivity Oral contraceptive use

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