Stroke - ischemic
José Biller, MD, FACP, FAAN, FAHA, Eelco F. M. Wijdicks, MD, Karl E. Misulis, MD, PhD,
and Fred F. Ferri, MD, FACP
Revised: 26 Feb 2014
Last Updated: 05 Mar 2011
Copyright Elsevier BV. All rights reserved.
Latest updates
On February 25, 2014, the American Academy of Neurology published a clinical practice
guideline on stroke prevention in nonvalvular atrial fibrillation. The guideline includes new
information on outpatient diagnosis of atrial fibrillation, and on the use of the newer oral
anticoagulants dabigatran , rivaroxaban , or apixaban . A commentary accompanies the published
guidelines.
Previous updates
Prevention of stroke in women
On February 6, 2014, the journal Stroke published the American Heart Association/American
Stroke Association's guidelines for the prevention of stroke in women. For this first-ever
guideline, the expert panel reviewed published articles on stroke risk factors related to female
reproduction and those conditions that are more common in women, such as migraine with aura,
obesity, metabolic syndrome, and atrial fibrillation.
Key risk factors and recommendations:
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Screen and treat all women with a history of preeclampsia for cardiovascular risk factors,
as preeclampsia is a stroke risk factor even well after pregnancy
Prescribe low-dose aspirin and consider a calcium supplement throughout pregnancy in
women with a history of high blood pressure to help prevent preeclampsia
Screen women for high blood pressure prior to prescribing birth control pills, as the
combination increases the risk of stroke
Discourage women who have migraine headaches with aura from smoking, as stroke risk
is higher in migraine sufferers who smoke than among those who do not smoke
Screen for atrial fibrillation in women, in particular those older than 75 years, as the
arrhythmia is more common among elderly women than among men, and it increases the
risk of stroke five-fold. Anticoagulation is not recommended in women younger than 65
years with atrial fibrillation but who are otherwise at low risk for stroke; consider
antiplatelet therapy in this patient population
The panel also calls for a female-specific stroke risk score
Prevention of atherosclerotic cardiovascular disease
On November 12, 2013, the American College of Cardiology (ACC) and the American Heart
Association (AHA) published four related guidelines on the prevention of atherosclerotic
cardiovascular disease (ASCVD) events, with a focus on cholesterol, obesity, and lifestyle
management tools.
The new guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular
risk in adults recommends a fundamental change in patient management from the National Heart,
Lung, and Blood Institute's (NHLBI) Adult Treatment Panel III (ATP3) recommendations, the
acknowledged leading guideline since 2004. In contrast to the ATP3, the ACC/AHA
recommends treating all patients who fall into one of four statin benefit groups with either
standardized, fixed-dose, high-intensity or moderate-intensity therapies.
As one of the four groups, individuals with clinical ASCVD should receive high-intensity statin
therapy ( atorvastatin 40–80 mg or rosuvastatin 20–40 mg). Patients older than 75 years should
receive moderate-intensity statin therapy (atorvastatin 10–20 mg, rosuvastatin 5–10 mg,
simvastatin 20–40 mg, or pravastatin 40–80 mg, among other statins).
The new AHA/ACC guideline on lifestyle management to reduce cardiovascular risk continues
to recommend any medically recognized heart-healthy dietary program. For lowering LDL-C,
the strongest recommendations advise a reduction in the percentage of calories from saturated
and trans fats, aiming for 5% to 6% of calories from saturated fat. For lowering blood pressure,
the strongest recommendation continues to be reducing sodium intake and following a DASHtype diet.
Key points
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Ischemic stroke is an acute brain injury caused by a reduction or interruption of blood
flow within one or more arterial territories of the brain
There is a wide range of potential signs and symptoms depending on the area(s) of the
brain affected, including severe headache, altered level of consciousness, paralysis or
weakness, speech slurring or aphasia, diplopia, visual loss in either eye or one hemifield
to both eyes, and gait and/or limb ataxia
Symptoms fail to resolve within 24 hours (otherwise, transient ischemic attack [TIA]
should be suspected)
If stroke is suspected, the following steps should be taken:
o Immediately refer the patient to the emergency department
o Ensure that the patient's airway, ventilation, and circulation are stable
o Monitor blood pressure closely
o Do not give the patient anything to eat or drink by mouth until safety can be
ensured
o Establish intravenous line access, and begin normal saline infusion
o
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Obtain a glucose fingerstick test, chemistry panel, coagulation parameters, blood
count, and a 12-lead electrocardiogram (ECG)
First-choice therapy when no contraindications are present is intravenous thrombolytic
therapy with recombinant tissue plasminogen activator (r-tPA; alteplase) within 3 hours
of stroke symptom onset. Intravenous alteplase is also recommended in selected patients
with acute ischemic stroke within 3 to 4.5 hours of symptom onset
The prognosis is highly variable, depending on the size and location of the infarction.
Recovery also depends partially on the patient's enthusiasm and motivation for
rehabilitation
Background
Description
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Caused by a reduction or interruption of blood flow within one or more arterial territories
of the brain
Most often due to embolic or atherothrombotic occlusion of extracranial or intracranial
blood vessels
Focal neurologic symptoms can be dramatic, with abrupt onset
The third leading cause of death and a leading cause of disability in adults
Key elements of management include immediate non-contrast computed tomography
(CT) scan to exclude intracerebral hemorrhage followed by thrombolytic therapy within 3
hours of symptom onset
Patients who recently sustained a TIA or ischemic stroke are at increased risk for
subsequent ischemic events
Epidemiology
Detailed epidemiologic data on heart disease and stroke in the U.S. are available in the American
Heart Association's Heart Disease and Stroke Statistics—2009 Update .
Incidence and prevalence:
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The World Health Organization estimates that approximately 15 million new strokes
occur each year worldwide
On average, someone in the U.S. has a stroke every 40 seconds, and someone in the U.S.
dies of a stroke every 4 minutes
Approximately 795,000 strokes occur in the U.S. each year, 610,000 of which are first
events, and 185,000 of which are recurrent events
Of all strokes, 87% are ischemic strokes
Incidence rates for men and women aged 45 to 84 years are 3.6 and 2.3 per 1,000
persons, respectively, among white patients and 6.6 and 4.9 per 1,000 persons,
respectively, among black patients
The prevalence of stroke in the U.S. (2005 data) was 6,500,000 (approximately 3,900,000
women and 2,600,000 men)
Demographics:
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Stroke occurs most often in patients over age 60, with incidence peaking between the
ages of 80 and 84 years. The prevalence of stroke also increases with age, with a rate of
approximately 3% among patients aged 55 to 64 years, 6.5% among patients aged 65 to
74 years, and 12% among patients aged 75 years
The overall incidence of stroke is 1.25 times greater in men than in women, but the
difference between the sexes declines with increasing age (1.59 at age 65-69 years, 1.46
at age 70-74 years, 1.35 at age 75-79 years, and 0.74 at age 80 and older). Women are
more likely to have atrial fibrillation and arterial hypertension, both of which are potent
risk factors for stroke
Incidence and mortality rates are higher in black, Asian, Pacific Islander, and HispanicAmerican patients compared to white patients. Black patients have twice the risk of firstever stroke compared to white patients, and American Indian, Alaskan Native, and
Mexican American patients also have a higher than average risk of first-ever stroke
Family history is a risk factor, although the genetic basis not yet fully elucidated
Causes and risk factors
Causes:
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The most common causes are atheromatous disease in large- and medium-sized
extracranial and/or intracranial arteries, small vessel disease (lacunar infarcts), and
cardiac embolism (often secondary to atrial fibrillation or other high-risk cardioembolic
conditions)
Rare causes include the following:
o Border zone infarcts due to arterial hypotension and poor cerebral perfusion
o Cervicocephalic arterial dissection (extracranial/intracranial)
o Other nonatherosclerotic vasculopathies ( eg , moyamoya syndrome,
fibromuscular dysplasia)
o Vasculitis ( eg , infectious, necrotizing, associated with collagen vascular disease,
associated with other systemic diseases, giant cell arteritides [Takayasu arteritis,
temporal arteritis], hypersensitivity vasculitides, and primary central nervous
system [CNS] vasculitis)
o Hypercoagulable states ( eg , pregnancy , antiphospholipid antibody syndrome ,
sickle cell disease , homocystinuria, cancer)
Risk factors:
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Advanced age: risk is increased in patients over age 60
Hypertension (defined as persistent blood pressure elevations ≥140/90 mm Hg) is the
single most important modifiable risk factor for ischemic stroke. For each 10-mm Hg
increase in systolic blood pressure or 5-mm Hg increase in diastolic blood pressure, the
relative risk of stroke increases by a factor of 2.3
Atrial fibrillation is an important preventable cause of stroke. The relative risk of stroke
in patients with nonvalvular atrial fibrillation is at least 5-fold greater than that in patients
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with normal sinus rhythm. The risk of stroke increases to 17 fold when atrial fibrillation
complicates rheumatic valvular heart disease
Gender: incidence is higher in men than in women
Heredity: no distinct genetic etiology has been identified, but family history is a risk
factor; thrombophilia may be inherited
Mitral stenosis and left atrial enlargement contribute to the risk of embolic stroke
Myocardial infarction and stroke coexist in 2% to 6% of patients
TIAs are a major independent risk factor for stroke
Diabetes mellitus is an independent risk factor for stroke, increasing the relative risk by a
factor of 2. Diabetes is associated with accelerated atherosclerosis, endothelial
dysfunction, and a prothrombotic state
Dyslipidemia : elevated total cholesterol and low-density lipoprotein (LDL) cholesterol
levels and low plasma levels of high-density lipoprotein (HDL) cholesterol are major
modifiable risk factors for atherothrombotic vascular disease
Cigarette smoking : smokers have a 4- to 6-fold increased risk of stroke compared to
patients who have never smoked
Illicit drug (cocaine, heroin, amphetamines) use
Hematologic disorders (primary or secondary hypercoagulable states)
Low serum potassium levels have been associated with a higher risk of stroke in older
patients
Oral contraceptive use is associated with a small but significant increase of stroke.
Women who smoke and take oral contraceptives are at greater risk for thrombosis.
Estrogen-containing oral contraceptives should not be used in women with a history of
clinical vascular disease, including stroke. Progestin-only hormonal contraceptives can be
used in the setting of stroke, unless the stroke developed while taking these agents
Migraines , particularly those associated with aura, are associated with a 2-fold increased
risk of ischemic stroke
Associated disorders
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TIAs often precede ischemic stroke; hemispheric TIAs are associated with a greater risk
of ipsilateral ischemic stroke than retinal TIAs
Advanced carotid artery stenosis (>70%) increases the risk of stroke
Ischemic heart disease and peripheral vascular disease are also commonly associated with
atherosclerosis and an increased risk of stroke
Atrial fibrillation may cause cardioembolic strokes
Screening
Screening for carotid artery stenosis or carotid bruits can be considered. However, the U.S.
Preventive Service Task Force does not necessarily recommend routine screening for stroke
prevention because far more patients with asymptomatic carotid artery stenosis will experience
cardiovascular events than stroke, and the sensitivity of carotid bruits in detecting carotid artery
stenosis greater than 70% is low.
Primary prevention
Summary approach
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Prevention of an initial event is accomplished mainly by managing risk factors
When modified, the following have been shown to decrease the incidence of first stroke,
either directly or by decreasing risk factors for stroke:
o Hypertension: reduction of blood pressure is more important than the specific
agent or modality used
o Cigarette smoking: persons who smoke cigarettes have a 4- to 6-fold increased
risk of ischemic stroke compared to those who have never smoked
o Recreational drug use: primarily cocaine but also heroin, amphetamines, and
marijuana have been linked to ischemic stroke
o Alcohol: alcohol should be consumed in moderation; light to moderate
consumption may reduce the incidence of stroke by increasing HDL cholesterol
levels and decreasing platelet aggregation, but heavy consumption may increase
the risk of stroke by elevating blood pressure, causing hypercoagulation, inducing
cardiac arrhythmias, and reducing cerebral blood flow
o Diet: long-term dietary changes, including reducing cholesterol and sodium intake
and increasing intake of fruits and vegetables, can help modulate atherosclerosis
and hypertension
o Exercise: increased physical activity helps reduce blood pressure, hyperglycemia,
and obesity
o Risk of embolic events: patients at increased risk for embolic events, such as
those with atrial fibrillation, benefit from the use of warfarin and antiplatelet
agents
o Risk of advanced atherosclerosis: patients at increased risk of developing
advanced atherosclerosis, such as those with diabetes and dyslipidemia, benefit
from control of their primary condition with hypoglycemic agents and statins,
respectively
o Carotid artery stenosis: patients with asymptomatic carotid artery stenosis benefit
from interventional therapy, such as carotid endarterectomy
Evidence
Hypertension:
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A systematic review of data from 29 randomized, controlled trials (RCTs) evaluating the
effects of different antihypertensive regimens in a total of 162,341 patients found that
angiotensin-converting enzyme (ACE) inhibitors reduced blood pressure less than
calcium antagonists, angiotensin receptor blockers, diuretics, and β-blockers, but there
were no significant differences in the rate of total major cardiovascular events among the
drug classes studied. [1] Level of evidence: 1
A systematic review of 23 RCTs evaluating the use of thiazides, β-adrenergic blockers,
calcium-channel blockers, and ACE inhibitors in a total of 50,853 patients with
hypertension concluded that low-dose thiazide therapy is the best option for first-line
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treatment of hypertension, resulting in a significant reduction in the risk of death, stroke,
coronary artery disease, and cardiovascular events. [2] Level of evidence: 1
As summarized in the Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure , there has been consistent
evidence for many years now that control of hypertension is valuable in the primary
prevention of stroke as well as in reducing the risk of other end-organ damage ( eg ,
congestive heart failure and renal failure), and it is likely that the size of the blood
pressure reduction is more important in determining the risk of stroke rather than the
specific antihypertensive agent chosen. [3] Level of evidence: 3
An American Heart Association/American Stroke Association Stroke Council guideline
recommends regular (at least every 2 years in most adults and more frequently in
minority populations and the elderly) screening for hypertension and appropriate
management, including dietary changes, lifestyle modification, and drug therapy. [4]
Level of evidence: 3
Cigarette smoking:
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Epidemiologic studies have found that cigarette smoking is a potent risk factor for
ischemic stroke. [5] , [6] , [7] Level of evidence: 2
An American Heart Association/American Stroke Association Stroke Council guideline
recommends avoidance of environmental tobacco smoke for stroke prevention and states
that the use of counseling, nicotine replacement, and oral smoking cessation medications
have been found to be effective in smokers and should be considered. [4] Level of
evidence: 3
Diet:
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The American Heart Association/American Stroke Association recommends a diet with a
reduced sodium intake and an increased potassium intake that emphasizes fresh fruits,
vegetables, and low-fat dairy products and is low in saturated fat and total fat to lower
blood pressure, as these measures may thereby reduce the risk of stroke. [4] Level of
evidence: 3
Exercise:
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The American Heart Association/American Stroke Association recommends increased
physical activity in patients who can exercise safely because it has been shown to be
associated with a reduction in the risk of stroke in epidemiologic studies. [4] Level of
evidence: 3
Atrial fibrillation:
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Two systematic reviews found that treatment with adjusted-dose warfarin in patients with
atrial fibrillation who are at high risk for stroke but have no previous history of stroke is
associated with a significant reduction in the risk of ischemic stroke compared to placebo
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or control. Adjusted-dose warfarin also significantly reduced the risk of ischemic stroke
compared to aspirin. [8] , [9] Level of evidence: 1
A systematic review of five RCTs comparing oral anticoagulants versus control in a total
of 2,313 patients with chronic nonvalvular atrial fibrillation and no history of TIA or
stroke concluded that treatment with adjusted-dose warfarin significantly reduces the rate
of all strokes; death; and a combined end point of stroke, myocardial infarction, or
vascular death. [10] Level of evidence: 1
A meta-analysis of 29 trials involving more than 28,000 patients with nonvalvular atrial
fibrillation showed that adjusted-dose warfarin and antiplatelet agents reduced the risk of
stroke by 64% and 22%, respectively, with only small increases in the incidence of
hemorrhage. [11] Level of evidence: 1
A systematic review found that the use of aspirin in patients with atrial fibrillation who
are at high risk for stroke but have no previous history of stroke was associated with a
nonsignificant reduction in the incidence of stroke. When the outcome of stroke was
combined with the outcomes of myocardial infarction or vascular death, aspirin was
associated with a significant reduction in the risk of stroke compared to placebo or
control. [12] Level of evidence: 1
A meta-analysis of five RCTs comparing either warfarin or aspirin versus control in
patients with atrial fibrillation at low risk for stroke (under age 65 with no history of
hypertension, stroke, TIA, or diabetes) found that warfarin consistently decreased the risk
of stroke, but the efficacy of aspirin was less consistent and requires further study. The
main adverse effect associated with anticoagulant and antiplatelet therapy is hemorrhage,
with an absolute risk of major bleeding in elderly patients with variable risk factors for
stroke of 1.3% for warfarin and 1.0% for aspirin compared to 1.0% for placebo. [13]
Level of evidence: 1
Two systematic reviews evaluating the use of aspirin for primary prevention of stroke in
patients with atrial fibrillation at low risk for stroke found differing results. [8] , [14]
Level of evidence: 1
A multicenter RCT in 7,554 patients with atrial fibrillation in whom vitamin K antagonist
therapy was considered unsuitable found that the addition of clopidogrel to aspirin
reduced the risk of major vascular events, especially stroke, but increased the risk of
hemorrhage. [15] Level of evidence: 1
Diabetes:
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Epidemiologic studies have shown that the presence of diabetes increases the risk of
ischemic stroke. [16] , [17] Level of evidence: 2
An American Heart Association/American Stroke Association Stroke Council guideline
recommends tight blood pressure control and statin therapy in patients with diabetes,
especially if other risk factors are present. Treatment with an ACE inhibitor or an
angiotensin receptor blocker should be considered. [4] Level of evidence: 3
Dyslipidemia:
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A systematic review and meta-analysis of randomized trials evaluating the use of statins
in more than 90,000 patients, including patients with and without a previous history of
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stroke, TIA, or coronary artery disease, found that statins significantly reduced the risk of
stroke compared to placebo or no treatment after a mean of 4.3 years of follow-up. [18]
Level of evidence: 1
The National Cholesterol Education Program's Third Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults contains
recommendations regarding the management of patients with elevated total cholesterol
levels or elevated non-HDL cholesterol levels in the presence of hypertriglyceridemia but
with no previous history of stroke or TIA. [19] , [20] Level of evidence: 3
The American Heart Association/American Stroke Association recommends that patients
with known coronary heart disease and those with high-risk hypertension, even with
normal LDL cholesterol levels, receive statin therapy and advice on lifestyle
modifications. Weight loss, increased physical activity, smoking cessation, and possibly
treatment with niacin or fibrates ( eg , gemfibrozil) are recommended in patients with
known coronary artery disease and low HDL cholesterol levels. [4] Level of evidence: 3
Carotid artery stenosis:
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A systematic review of three RCTs involving a total of 5,223 patients found that patients
with asymptomatic carotid artery stenosis who underwent carotid endarterectomy had a
reduced risk of perioperative stroke, death, or subsequent ipsilateral stroke over 3 to 4
years compared to those receiving medical therapy alone. The reviewers note that the
absolute risk reduction was small (approximately 1% per year during the first few years
of follow-up in the two largest RCTs included in the review), although it could be higher
with longer follow-up. [21] Level of evidence: 1
References
Diagnosis
Summary approach
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Stroke should be suspected whenever a patient has a sudden onset of altered level of
consciousness or focal neurologic signs, including hemiparesis, hemisensory deficit,
aphasia, or homonymous hemianopia
Non-contrast CT scan should be the initial brain imaging study to differentiate between
ischemic stroke and hemorrhagic stroke
Other imaging studies, including carotid artery imaging, may aid in establishing the
etiology of stroke and may assist in treatment decisions
Cardiac evaluation and monitoring are generally recommended because ischemic stroke
may result from cardiac emboli
Clinical presentation
The clinical presentation differs depending on the affected area(s) of the brain.
Symptoms
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Sudden loss or decline in level of consciousness
Sudden numbness or weakness of the face, arm, or leg (monoparesis or hemiparesis)
Sudden confusion, trouble speaking (aphasia or dysarthria), or difficulty understanding
Sudden difficulty seeing in one or both eyes, including loss of vision or double vision
Sudden difficulty walking, dizziness, or loss of balance and coordination, including limb
ataxia
Sudden, severe headache , which may occur several days before the onset of other
symptoms
Rapid onset of nausea and vomiting
Signs
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Abrupt onset of cognitive, motor, and/or sensory deficits
Aphasia
Dysarthria
Homonymous hemianopia
Facial droop
Hemiparesis
Signs of neglect are consistent with a nondominant parietal lobe lesion
Ataxia, incoordination, nystagmus and gait disturbance may be due to a brainstem or
cerebellar lesion
An irregular pulse may signify atrial fibrillation as a potential embolic cause
Signs of previous ischemic events in other vascular locations
Examination
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Assess the patient's level of consciousness.Patients with a decreased level of
consciousness require urgent management of airway, breathing, and circulation and
assessment with the Glasgow Coma Scale
Evaluate the patient's cognitive function, observing whether the patient is orientated and
alert or confused and drowsy. If the patient is able to speak, observe if the speech is clear,
slurred, or incomprehensible and determine whether the can patient hear
Examine the head, neck, and spine, noting if any abnormalities are present and checking
for trauma
Do a full cardiovascular examination, focusing in particular on the pulse rhythm (atrial
fibrillation) and rate, blood pressure ( hypertension and low pulse rate characteristic of
Cushing response), murmurs ( mitral stenosis and left atrial enlargement), and carotid
bruits
Do a full cranial nerve examination
o Determine if nuchal rigidity is present, as this suggests subarachnoid hemorrhage
or meningitis
o Examine the pupils, visual fields, and fundi, checking for homonymous
hemianopia, Horner syndrome, papilledema, retinal emboli, or hemorrhages
o Examine eye movements, checking for nystagmus or internuclear
ophthalmoplegia
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Check facial sensation and movement. In patients with predominantly facial
weakness, determine if the patient is able to lift the eyebrows, wrinkle the
forehead, and close the eyes. These functions differentiate central (upper motor
neuron) facial weakness from stroke from peripheral lesions, such as Bell palsy .
Patients with peripheral facial paralysis or Bell palsy are unable to lift the
eyebrows, wrinkle the forehead, or close the eyes completely and often have
hypogeusia on the anterior two thirds of the tongue
Determine if the patient is able to swallow and produce a strong cough
Do a full motor, sensory, and coordination examination, assessing tone (flaccid
acutely, increased in later stages), power, sensation, and coordination
Observe the patient's gait and check muscle stretch reflexes for briskness or
asymmetry and plantar response (Babinski sign). Watch the patient walk, and test
for Romberg sign
Calculate the patient's level of neurologic function on the National Institutes of
Health Stroke Scale (NIHSS), which yields a score between 0 (normal) and 42
(maximum score), establishes a baseline to follow the disease course, and is
necessary to determine the patient's eligibility for thrombolytic therapy
 NIHSS score of 1: minor stroke or rapidly improving neurologic
symptoms
 NIHSS score of 2 to 3: mild stroke
 NIHSS score of 4 to 10: moderate stroke
 NIHSS score >10: severe stroke
 NIHSS score >15: typically indicates a large ischemic stroke
 NIHSS score >25: may increase the possibility of hemorrhagic
complications after the administration of intravenous tPA
Questions to ask
Presenting condition:
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What are your symptoms, and what was the duration of their onset? Sudden onset of
motor, sensory, or cognitive deficits (usually in combination) is suggestive of ischemic
stroke
Have you experienced anything like this in the past? TIAs often precede stroke, but
symptoms resolve within 24 hours and usually within 1 hour
When did the symptoms begin? Intravenous thrombolytic therapy, when indicated, must
be initiated within 3 hours of symptom onset and, in selected patients, 3 to 4.5 hours from
the onset of acute stroke symptoms
Contributory or predisposing factors:
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How old are you? Advanced age is associated with an increased risk of ischemic stroke
Do you have high blood pressure? Uncontrolled hypertension is the most important risk
factor for ischemic stroke
Are you taking any drugs that may cause an elevation in blood pressure? Such drugs
include oral contraceptives, adrenal steroids, thyroid hormones, cyclosporine,
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erythropoietin, tricyclic antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs),
nasal decongestants with adrenergic effects, monoamine oxidase inhibitors, alcohol, diet
pills, and cocaine
Do you have a history of cardiac arrhythmias? Atrial fibrillation is a treatable risk factor
for ischemic stroke
Do you smoke, or have you ever smoked? Smokers have a 4- to 6-fold increased risk of
stroke compared to patients who have never smoked
Do you have diabetes or high cholesterol? These are both risk factors for atherosclerosis
Do you use illicit drugs? Cocaine, heroin, and amphetamine abuse have been linked to an
increased risk of ischemic stroke
Do you have any blood disorders? Polycythemia vera , thrombocytosis, thrombotic
thrombocytopenic purpura , disseminated intravascular coagulation , dysproteinemias,
and sickle cell disease are risk factors for ischemic stroke. Prior history of deep vein
thrombosis or pulmonary embolism may suggest an underlying hypercoagulable state
Family history:
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Has anyone in your family had a stroke? Family history is a risk factor for ischemic
stroke
Diagnostic testing
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Anticoagulation studies, including prothrombin time and international normalized ratio
(INR) and activated partial thromboplastin time (aPTT) , may show a coagulopathy and
are useful if thrombolytics or anticoagulants are used
Chemistry panel findings serve as a baseline and may be suggestive of conditions that
mimic stroke
Complete blood count (CBC) with platelet count serves as a baseline and may suggest an
etiology of the stroke or provide evidence of another illness ( eg , infection or anemia)
Creatine kinase and creatine kinase–MB fraction and cardiac troponins provide evidence
of concurrent myocardial infarction
ECG findings may provide evidence of cardiac ischemia or rhythm change, which can
predispose patients to stroke
Chest radiograph may indicate an underlying infectious process and can be used to rule
out aspiration or cardiac enlargement or aortic calcifications
Pulse oximetry findings may indicate hypoxia and need for oxygenation
CT scan and/or CT perfusion is mandatory for distinguishing ischemic stroke from
hemorrhagic stroke and may define the anatomic distribution of stroke. If cerebellar or
brainstem symptoms are present, imaging should include thin cuts through the posterior
fossa. CT perfusion is useful to visualize the ischemic penumbra and delineates
irreversible and reversible cerebral ischemia with a higher degree of sensitivity and
specificity than traditional CT scan
CT angiography is a noninvasive alternative to catheter cerebral angiography for
visualization of intracranial and extracranial arteries and has largely replaced catheter
angiography
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MRI with diffusion-weighted imaging or perfusion-weighted imaging is useful to
delineate ischemic strokes, especially those involving the brainstem or cerebellum, or
lacunar strokes. MRI with diffusion-weighted imaging or perfusion-weighted imaging is
useful to visualize the ischemic penumbra
Multimodal neuroimaging ( eg , CT/CT angiography/CT perfusion or diffusion-weighted
imaging/perfusion-weighted imaging with MRI) may be used to determine if the patient
is a candidate for thrombolysis
Magnetic resonance angiography (MRA) can visualize blood flow in the major cerebral
arteries at the level of the circle of Willis and the extracranial carotid and vertebral
arteries in the neck. MRA tends to overestimate the degree of stenosis. Specificity and
sensitivity can be improved with the administration of gadolinium
Carotid duplex ultrasound is commonly done when the clinical findings could be due to
carotid artery disease
Transcranial Doppler ultrasound can assess intracranial vascular anatomy but is not part
of the routine evaluation, except to identify high-risk patients with sickle cell anemia.
Continuous transcranial Doppler ultrasound, with or without the administration of
microbubbles, may also enhance the effect of ultrasound on thrombolysis, presumably by
improving exposure of thrombi to the thrombolytic agent
Echocardiography (transthoracic and/or transesophageal) is commonly used when the
clinical findings could be due to cardiogenic emboli; the findings are usually interpreted
by a cardiologist
Catheter cerebral angiography is useful in patients in whom characterization of
cerebrovascular anatomy may lead to alterations in medical management, such as those
with occlusive disease or arterial dissection
Additional studies that can be done in selected patients include the following:
o Antithrombin activity; protein C and total and free protein S antigen levels; factor
V Leiden; prothrombin gene ( G20210A ) mutation; cardiolipin (immunoglobulin
[Ig] G, IgM, IgA) antibodies; β2 glycoprotein 1 (IgG, IgM, IgA) antibodies; lupus
anticoagulant; fibrinogen; plasminogen; plasminogen activator inhibitor; plasmin
functional activity; factors V, VII, VIII, IX, X, XI, and XIII; hemoglobin
electrophoresis; plasma homocysteine; MTHFR gene mutation (particularly
MTHFR 677TT polymorphism); and lipoprotein(a) to check for an inherited or
acquired hypercoagulable state
o Antinuclear antibody testing to detect underlying antiphospholipid antibody
syndrome
o Erythrocyte sedimentation rate to rule out CNS vasculitis
o Glycosylated hemoglobin in patients with diabetes or in those in whom diabetes is
suspected, as chronic hyperglycemia is associated with an increased risk of
cardiovascular disease in these patients
Prothrombin time and INR
Description

Venous blood sample
Normal results


Prothrombin time: approximately 12 seconds
INR: 0.8 to 1.2
Comments





An elevated prothrombin time suggests abnormalities of the extrinsic clotting system
Therapeutic INR is typically targeted at 2.0 to 3.0; the bleeding risk increases with
supratherapeutic INR values
Warfarin increases the prothrombin time/INR. Some antibiotics also can increase the
prothrombin time/INR, and barbiturates, oral contraceptives, hormone replacement
therapy, and St. John wort can decrease the prothrombin time/INR
Certain foods that contain large amounts of vitamin K, such as broccoli, soybean
products, and green tea, can alter the prothrombin time
Other causes of abnormal results include coagulopathies, liver disease, and vitamin K
deficiency
aPTT
Description

Venous blood sample
Normal result

35 seconds
Comments






Monitors bleeding times of the intrinsic coagulation system
Responsive to decreased levels of or inhibition of factors II, IX, and X
The bleeding risk increases with supratherapeutic aPTT values
Heparin increases the aPTT, and warfarin may increase the aPTT
Other causes of abnormal results include coagulopathies, liver disease, end-stage renal
disease, and vitamin K deficiency
Keep in mind the possibility of a false-positive result, particularly in morbidly obese
patients managed according to weight-based heparin dosing nomograms
Chemistry panel
Description

Venous blood sample
Normal ranges






Sodium: 136 to 142 mEq/L
Potassium: 3.5 to 5.0 mEq/L
Chloride: 96 to 106 mEq/L
Carbon dioxide: 22 to 28 mEq/L
Blood urea nitrogen: 8 to 23 mg/dL
Glucose (fasting): 70 to 110 mg/dL
Comments








Particular attention should be paid to serum glucose and sodium concentrations because
hypoglycemia , hyperglycemia, or hyponatremia may mimic symptoms of stroke
Provides insight into serum electrolytes, acid-base status, renal function, and metabolic
state
Hypoglycemia may result from diabetes, lack of dietary carbohydrates, or excessive use
of insulin or oral hypoglycemic agents
Hyperglycemia may be due to diabetes
Dilutional hyponatremia may result from liver cirrhosis , congestive heart failure ,
nephrosis, or use of osmotically active agents ( eg , mannitol)
Alcohol abuse is a common cause of hyponatremia and other electrolyte disorders
Depletion of sodium may result from mineralocorticoid deficiencies or sodium-wasting
renal disease
Use of diuretics may alter results
CBC with platelet count
Description

Venous blood sample
Normal ranges





Hematocrit: 39.0% to 49.1% in men; 33.0% to 43.1% in women
Hemoglobin: 14 to 18 g/dL in men; 11.5 to 15.5 g/dL in women
o Mean corpuscular hemoglobin: 26 to 34 pg/cell
o Mean corpuscular hemoglobin concentration: 33 to 37 g/dL
o Mean corpuscular volume: 80 to 100 μm3
Leukocyte count: 4,500 to 11,000/μL
Erythrocyte count: 4.3 to 5.9 × 106/μL in men; 3.5 to 5.0 × 106/μL in women
Platelet count: 150 to 350 × 103/μL
Comments

Provides a baseline and may suggest the cause of stroke (polycythemia, thrombocytosis,
thrombocytopenia, leukemia)





An elevated leukocyte count may result from infection, although it does not indicate the
location of infection or identify the causative microorganism. A normal leukocyte count
allows infection to be ruled out as cause of symptoms
An increase in the hemoglobin concentration (polycythemia) may be due to a decrease in
the total plasma volume or to an increase in the total number of erythrocytes and may
result from various respiratory or circulatory conditions
A decrease in the number of platelets (thrombocytopenia) may occur with viral
infections; bone marrow tumors; immune destruction; pregnancy; chemotherapy;
radiation therapy; and use of ethanol, some antibiotics, anti-inflammatory agents,
antihistamines, antiarrhythmics, antihypertensives, and anticonvulsants
An increase in the number of platelets (thrombocytosis) may occur with chronic
infections, cancers, and certain blood diseases
The presence of anemia may alter results
Creatine kinase and creatine kinase–MB fraction
Description



Venous blood sample
Creatine kinase is an enzyme found in tissues that consume large amounts of energy
The creatine kinase–MB isoenzyme is found primarily in cardiac tissue
Normal ranges


Creatine kinase: 40 to 150 U/L
Creatine kinase–MB fraction: 0 to 7 ng/mL
Comments





Allows evaluation of cardiac muscle damage, as stroke and myocardial events often
occur simultaneously
The absolute amount of creatine kinase–MB varies with the assay technique; in general,
the MB fraction is determined to be elevated if it exceeds 6% of the total creatinine
kinase concentration
Elevated levels indicate myocardial injury
Serum creatine kinase levels typically are not elevated until 4 to 8 hours after myocardial
infarction and peak 12 to 24 hours after myocardial damage has occurred. Therefore,
these levels should be monitored every 8 to 12 hours for 1 to 2 days
Falls, injections, and recent muscle exertion can result in elevated creatine kinase levels
Cardiac troponins
Description

Measurement of cardiac troponin I and cardiac troponin T in venous blood sample 6 to 72
hours after the onset of symptoms
Normal ranges


Cardiac troponin I: 0 to 0.15 ng/mL
Cardiac troponin T: 0 to 0.10 ng/mL
Comments






Very high specificity and sensitivity for cardiac muscle
Necrosis of cardiac muscle causes release of cardiac troponins into the blood; results
become positive in 3 to 12 hours
Prolonged time course of decay (cardiac troponin I levels do not return to normal for 5-10
days and cardiac troponin T levels do not return to normal for 5-14 days) allows late
diagnosis or confirmation of myocardial infarction
Levels may be elevated in patients with chronic renal insufficiency (cardiac troponin T
elevation is more marked), acute myopericarditis, heart failure , acute pulmonary
embolism , cardiac trauma, generalized hypoxemia, or severe stress reactions ( eg ,
burns , sepsis or subarachnoid hemorrhage ) and in those taking cardiotoxic drugs
Normal values may vary by laboratory
Keep in mind the possibility of a false-negative result, particularly if the sample was not
obtained within the time span in which troponin levels increase
ECG
Description

Investigation of cardiac abnormalities
Comments







Should be done because of the strong correlation between acute ischemic stroke and the
presence of heart disease
May detect cardiac arrhythmias, which could have contributed to stroke, and myocardial
infarction
ST-T–segment elevation is present in the early stages of Q-wave myocardial infarction;
ST-segment depression suggests non–Q-wave myocardial infarction
New Q waves may be diagnostic of myocardial infarction and may occur in patients with
prolonged ischemia or myocarditis
ST-segment elevation and evolution of Q waves may result from pre-excitation
syndromes, pericarditis , cardiomyopathy , chronic obstructive pulmonary disease , and
pulmonary embolism
Rhythm abnormalities, especially those consistent with atrial fibrillation , may be seen in
patients with stroke
Findings are extremely useful for future reference
Chest radiograph
Description

Investigation of cardiac abnormalities
Comments


Should be done because of the strong correlation between acute ischemic stroke and the
presence of heart disease
May detect concurrent abnormalities, such as cardiac chamber enlargement or congestive
heart failure
Pulse oximetry
Description

Noninvasive method of monitoring the percentage of hemoglobin saturated with oxygen
Normal result

Oxygen saturation >95%
Comments





Accurate for oxygen saturations in the range of 70% to 100%
May detect problems with ventilation and hypoxia before symptoms are observed
clinically
Longstanding respiratory disease or cyanotic congenital heart disease may cause oxygen
saturation readings to be low, thereby reflecting the severity of the disease
Inaccurate if the oxygen saturation is <70%; if there is peripheral vasoconstriction
(resulting from hypovolemia, severe hypotension, cold, heart failure , some cardiac
arrhythmias); if venous congestion is present; if the probe is poorly positioned; when
used under bright overhead lights; and if methemoglobinemia, methylene blue, or nail
polish is present
Cannot distinguish between different forms of hemoglobin
CT scan and/or CT perfusion
Description


Non-contrast head CT scan is usually among the initial studies done in patients
presenting with symptoms and signs of acute stroke in order to exclude hemorrhage
CT perfusion provides images as well as information about cerebral perfusion
Comments









Detects the anatomic distribution of stroke and may provide clues to its etiology (clot in
intracranial artery) and severity (edema, midline shift)
Rapidly distinguishes ischemic stroke from hemorrhagic stroke
Detects most other life-threatening conditions, such as hematomas, abscesses, and
neoplasms
With CT perfusion, imaging and perfusion data can be acquired simultaneously
Approximately 6 hours after the onset of symptoms, edema in the stroke region produces
a hypodense region on scan. A large, hypodense region within the first 6 hours after
symptom onset should prompt questioning regarding the time of stroke onset
Other findings include insular ribbon sign, obscuration of lentiform nucleus, sulcal
effacement, loss of differentiation between gray and white matter, and hyperdense vessel
sign
Parenchymal low density on CT perfusion may be due to abnormal perfusion
May miss subtle hemorrhages, lesions near the skull due to artifact, small subcortical or
cortical infarctions or lesions in the posterior fossa, and small infarcts adjacent to the
skull in the brainstem
May not visualize the ischemic lesion if done within first few hours after stroke
CT angiography
Description

Minimally invasive, contrast-enhanced, X-ray–based technique used to evaluate the
vascular system (both arteries and veins) from the aortic arch to the vertex
Normal result

No evidence of arterial stenosis, arterial occlusion, or aneurysm
Comments





Provides three-dimensional images of the arterial and venous system
Abnormalities are seen in patients with atherosclerosis, dissection, intracranial aneurysms
larger than 2 to 3 mm, or cerebral venous thrombosis
Rapid, accurate, less prone to motion artifact, and can be done in the outpatient setting
Accommodates patients with metal implants and those with claustrophobia
Disadvantages include exposure of the patient to radiation, inability to define the
direction of flow of the intracranial circulation, risk of renal failure due to administration
of contrast, and the need for premedication (administration of antihistamines and
steroids) in patients allergic to iodinated contrast media
MRI with diffusion-weighted imaging or perfusion-weighted imaging
Description

High-resolution scan of the brain using magnetic fields


Diffusion-weighted imaging and perfusion-weighted imaging are new magnetic
resonance techniquesincreasingly used in patients with acute stroke
May be combined with continuous bedside monitoring of cerebral perfusion and cerebral
function ( eg , electroencephalography) for true multimodal neurologic imaging
Normal result

No evidence of ischemia
Comments











More sensitive than CT scan, especially in the first few hours after symptom onset and
for small vessel infarctions
Aids in establishing the diagnosis, especially when a brainstem or cerebellar infarction is
suspected
Does not utilize ionizing radiation
Diffusion-weighted imaging illustrates the degree of diffusion of water molecules and is
most useful early on in distinguishing TIA from stroke
Evidence of restricted diffusion on diffusion-weighted imaging is the most sensitive
marker of acute cerebral ischemia
Hyperintensity on diffusion-weighted imaging indicates inflammation and edema that
typically evolve into infarction
Perfusion-weighted imaging detects impairedperfusion and complements information
derived from diffusion-weighted imaging
Signs of acute hemorrhage may be nonspecific
Claustrophobia may be problematic for some patients
Contraindicated in patients with cardiac pacemakers and a variety of other implanted
medical devices, especially when the exact device and the compatibility with the
procedure are unknown
Associated with a risk of nephrogenic systemic fibrosis in patients with renal disease
MRA
Description

Provides noninvasive visualization of the intracranial and extracranial circulation
Normal result

No stenosis of extracranial or intracranial vessels
Comments


Can show significant stenosis of large vessels resulting from arteriosclerotic lesions,
aneurysms, or other vascular defects
Resolution is usually good, except for smaller vessels, but may overestimate stenosis

Presence of ferromagnetic objects in the patient's body can cause artifacts in scanning and
may cause injury to the patient
Carotid duplex ultrasound
Description

Noninvasive alternative to preoperative angiography in patients with carotid artery
disease
Normal result

Normal blood velocity through carotid vessels
Comments





High sensitivity for detecting carotid artery stenosis
The more narrow the lumen of the artery, the higher the velocities during the systolic and
diastolic phases of the cardiac cycle
May show further thrombotic disease of the carotid vasculature
Can be used in patients who are not candidates for MRI ( eg , those with a pacemaker or
aneurysm clips) or invasive testing
Accuracy is dependent on operator technique; technical difficulty increases when
visualizing the upper portion of the carotid arteries
Transcranial Doppler ultrasound
Description


Measures the velocity of blood flow through the carotid arteries or the arteries at the base
of the brain
Done by insonating the main intracranial arteries through regions of the skull with thinner
walls
Normal result

Normal blood velocity through cerebral vessels
Comments



Most accurate in identifying an embolus to the middle cerebral artery
Decreased blood flow can suggest carotid bifurcation disease
Provides limited information and is seldom used as a first-line test for assessing patients
in whom carotid artery disease is suspected
Echocardiography (transthoracic and/or transesophageal)
Description


Allows noninvasive assessment of cardiac valve areas and function
Useful in patients with stroke to assess concomitant heart disease
Comments





Establishes the diagnosis of structural disease, including valvular heart disease and left
atrial myxoma
Documents left atrial size and left ventricular systolic function and, thus, predicts the
likely success of cardioversion
Can help predict stroke through the identification of independent predictors, including
left ventricular dysfunction and left atrial dilation
Transesophageal echocardiography is particularly useful in identifying an intra-atrial
thrombus
Requires specialized equipment and training to interpret
Catheter cerebral angiography
Description

Provides excellent detail of structural abnormalities of the carotid arteries
Normal result

Normal contrast flow through cerebral vessels
Comments







Of great value when other tests cannot be done or fail to provide enough information to
make an accurate diagnosis
Essential in the endovascular treatment of carotid artery disease
Embolic or stenotic lesions (see figure Stroke: angiographic view of occlusion of main
carotid artery ) may be seen and the extent of involvement visualized
May show structural abnormalities of the cerebral arteries
Decreased contrast delivery can suggest carotid bifurcation disease
Invasive; requires contrast media; and is associated with a risk of vascular injury,
embolization, neurologic deficits (1% risk of any neurologic deficit; 0.5% risk of
persistent neurologic deficit), and allergic reaction and renal failure due to contrast media
Seldom used solely for the diagnosis of carotid artery disease
Differential diagnosis
TIA





TIA is defined as a transient episode of neurologic dysfunction caused by focal brain,
spinal cord, or retinal ischemia, without acute infarction
Focal neurologic deficit resolves rapidly (usually within 1 hour)
Normal examination findings between attacks
The conventional boundary in differentiating between TIA and stroke has been 24 hours,
although patients with transient deficits lasting longer 1 hour are more likely to have
some abnormalities on diffusion-weighted magnetic resonance imaging (MRI)
The ABCD2 score (Age ≥60 years = 1 point;Blood pressure ≥140/90 mm Hg = 1
point;Clinical unilateral weakness = 2 points; speech impairment = 1 point;Duration ≥60
minutes = 2 points, <60 minutes = 1 point;Diabetes = 1 point) identifies patients with
TIA who are at high risk for stroke, with a score of 0 to 3 representing low risk, a score of
4 to 5 representing moderate risk, and a score of 6 to 8 representing high risk; prompt
hospital admission is indicated in patients with an ABCD2 score >4
Migraine






A migraine is a recurrent, throbbing headache that characteristically affects one side of
the head
May be preceded by focal weakness or numbness, which has a progressive and marching
quality as opposed to the acute onset of stroke or TIA
May be associated with an aura, consisting of blurred vision or flickering bright lights
May be accompanied by vomiting and prostration
Hemiplegic and basilar migraines are associated with focal weakness or other stroke-like
symptoms
Pseudomigraine with temporary neurologic deficits and cerebrospinal fluid
lymphocytosis is a frequently underdiagnosed syndrome of unknown etiology that may
mimic complicated migraine or stroke
Seizure disorders







Tonic stiffening, clonic activity of extremities, or myoclonic jerks
Focal ictal paralysis is uncommon but can occur
Focal slowing or epileptiform discharges on electroencephalography
Focal symptoms and Todd paralysis after the seizure
Loss of consciousness in patients with generalized seizures. Incontinence and tongue
biting may occur in patients with generalized tonic-clonic seizures
Postictal headache, confusion
Uncommon in patients with acute stroke but may be a delayed complication of stroke in
5% to 10% of patients
Intracranial hemorrhage


Intracranial hemorrhage may involve the brain tissue itself or the subarachnoid, subdural,
or epidural space
Patients may present with sudden, severe headache with no known cause; nausea and
vomiting; sudden confusion or altered level of consciousness; sudden numbness or

weakness of the face, arm, or leg, particularly on one side of body; sudden difficulty
speaking or understanding speech; sudden visual disturbances; or sudden difficulty
walking, dizziness, and loss of balance or coordination
Bleeding into or around the brain is seen on brain imaging studies
Brain neoplasm






Progressive focal neurologic deficit(s)
Headache
Seizures
Personality change
Cognitive impairment
Gait disturbance
Hyponatremia



Hyponatremia is defined as a serum sodium level <135 mEq/L
Patients may present with confusion, lethargy, disorientation, or seizures
Serum sodium levels may be as low as 100 mEq/L, with minimal symptoms and a
chronic decrease in sodium levels over days or weeks, but an acute decrease in 24 to 48
hours may lead to coma, severe cerebral edema, or brainstem herniation
Hypoglycemia



Hypoglycemia is defined as a serum glucose level <45 to 50 mg/dL in men or <35 to 40
mg/dL in women
Patients may present with sweating, tachycardia, anxiety, tremor, dizziness, blurred
vision, confusion, convulsions, syncope, or coma
Focal neurologic deficits may occur
Vertigo







Illusion of self or environment spinning
Nausea, emesis
Pallor
Diaphoresis
Nystagmus
Postural unsteadiness
Gait ataxia
Consultation


As soon as stroke is suspected, the patient should be referred to a neurologist or a
multidisciplinary stroke team in the emergency department for evaluation
If hemorrhage is suspected or imaging studies show a hemorrhage or another surgical
lesion, the patient should be referred to a neurosurgeon



All patients with intracerebral hemorrhage should be referred to a neurosurgeon and
admitted to the hospital
Patients in whom subarachnoid hemorrhage is suspected on the basis of clinical findings
should be referred to a neurosurgeon and admitted to the hospital, even if CT scan
findings are normal
Telemedicine for stroke ('telestroke') can enable the initiation of cost-effective
interventions and facilitate transfer of patients in the community for specific tertiary care
stroke interventions
Treatment
Summary approach



The goals of treatment are as follows:
o Confirm ischemic stroke and rule out other causes of neurologic symptoms
o Initiate appropriate treatment
o Predict and prevent complications
o Facilitate rehabilitation as needed
o Minimize the risk of future recurrence
Pre-hospital care:
o Initial treatment with basic life support measures, including ensuring that the
patient's airway, ventilation, and circulation are stable, is important when stroke is
suspected
o Oxygen should be administered to all patients in whom hypoxemia (oxygen
saturation <94%) is suspected
o Patients may be transferred to a specifically designated stroke unit depending on
the results of initial assessment
Acute hospital management:
o First-choice therapy is intravenous thrombolysis with alteplase initiated within 3
hours of the onset of ischemic symptoms, adhering to the eligibility criteria and
therapeutic regimen established by the National Institute of Neurological
Disorders and Stroke . Candidates for thrombolytic therapy must have no
evidence of hemorrhage on non-contrast head CT scan and no other
contraindications to alteplase. There are now data to suggest that intravenous
thrombolytic therapy can be initiated within 4 to 4.5 hours of the onset of acute
ischemic stroke symptoms in selected patients; exceptions include patients over
age 80, those with a combination of previous stroke and diabetes mellitus, those
receiving oral anticoagulants (regardless of INR values), those with an NIHSS
score >25, and those with evidence of major infarct on CT scan with compromise
of more than one third of the middle cerebral artery territory
o Certain patients in whom intravenous thrombolytic therapy is deemed unsuitable,
such as those with acute large artery occlusion, may be candidates for intraarterial thrombolysis and/or intra-arterial mechanical thrombectomy, which may
be considered within the first 6 hours (or longer in patients with basilar artery
occlusive disease) after the onset of symptoms at hospitals with appropriate
facilities
o
o


Aspirin may be used when thrombolytic therapy is contraindicated
Elevated blood pressure should be treated with labetalol or another appropriate
parenteral agent ( eg , nicardipine). However, Guidelines for the Early
Management of Patients With Ischemic Stroke authored by the Stroke Council of
the American Heart Association state that antihypertensive agents should be
withheld in patients with acute ischemic stroke unless the diastolic blood pressure
is >120 mm Hg or the systolic blood pressure is >220 mm Hg
o Blood glucose levels should be monitored, and subcutaneous or intravenous
insulin should be administered in patients with blood glucose levels >10 mmol/L
(approximately 200 mg/dL)
o Cardiac monitoring ( eg , for the detection of atrial fibrillation and other
arrhythmias) is valuable in all patients
Surgical treatment:
o Carotid endarterectomy or percutaneous atherectomy is indicated following acute
stroke in patients who require revascularization and should only be considered by
stroke specialists. Percutaneous atherectomy is an alternative to open
endarterectomy that aims to clear the lumen of the atheromatous carotid artery by
means of a sharp, rotating blade; the procedure may be done in conjunction with
carotid angioplasty and stenting
o Surgery is highly beneficial in patients who have already had a stroke or
experienced the warning signs of a stroke and have severe stenosis (70%-99%)
o Carotid angioplasty and stenting (with or without mechanical thrombectomy) may
be an alternative to carotid endarterectomy
Prevention of recurrent stroke:
o Although not curative, antiplatelet therapy is an integral component of effective
secondary prevention (risk reduction) following non-cardioembolic stroke
o A systematic review comparing antiplatelet therapy versus placebo or no
antiplatelet therapy in patients at high risk for vascular disease, including those
with a previous stroke or TIA, found that patients receiving antiplatelet therapy
experienced a significant reduction in serious vascular events (myocardial
infarction, stroke, or vascular death) after 3 years compared to control subjects
with previous stroke or TIA
o Antiplatelet agents, such as aspirin, aspirin and extended-release dipyridamole , or
clopidogrel , may be used to prevent stroke recurrence. Cilostazol , a
phosphodiesterase III inhibitor, is often used for stroke prevention in Japan and
other Asian countries. Triflusal, which is chemically related to aspirin, is
considered to be acceptable first-line antiplatelet agent in some European
countries
o Important factors to consider when choosing an antiplatelet regimen include the
presence of concomitant coronary artery disease or peripheral arterial disease,
history of recent acute coronary syndrome, coronary artery or other arterial
stenting, other cardiovascular risk factors, stroke subtype, comorbid factors
potentially predisposing the patient to bleeding, and any socioeconomic
limitations
o The American Heart Association/American Stroke Association evidence-based
guidelines on non-cardioembolic ischemic stroke recommend treatment with an


antiplatelet agent, including aspirin, 50 to 325 mg/d; the combination of aspirin,
25 mg, plus extended-release dipyridamole, 200 mg, twice daily; and clopidogrel,
75 mg/d. Clopidogrel is a reasonable alternative in patients allergic to aspirin. The
addition of aspirin to clopidogrel increases the risk of hemorrhage and is not
routinely recommended in patients with ischemic stroke or TIA, unless a specific
indication ( ie , coronary artery stent or acute coronary syndrome) exists
o In patients who have an ischemic stroke while taking aspirin, there is no evidence
that increasing the dose of aspirin provides additional benefit. Although
alternative antiplatelet agents are often used, no single agent or combination of
agents has been prospectively evaluated in patients who have had an ischemic
event while receiving aspirin therapy
o Antiplatelet agents should be avoided in the first 24 hours following
administration of intravenous alteplase for acute ischemic stroke
o Antiplatelet therapy is recommended over oral anticoagulants in patients with
non-cardioembolic ischemic stroke or TIA. However, warfarin may be used to
prevent stroke recurrence in patients with atrial fibrillation , other causes of
cardiac emboli, and some coagulopathies
o Dabigatran, a reversible oral thrombin inhibitor recently approved by the U.S.
Food and Drug Administration (FDA_, has shown great promise as a substitute
for adjusted-dose warfarin in the prevention of stroke in patients with atrial
fibrillation
o Heparins, including unfractionated heparin and low-molecular-weight heparins,
may be used to prevent pulmonary embolism or deep vein thrombosis after a
stroke in immobilized patients. However, the value of heparins in preventing
arterial stroke is limited and controversial; routine use is not recommended.
Patients with cerebral venous thrombosis often receive anticoagulation with
heparin
o Antihypertensive therapy is recommended for the prevention of recurrent stroke
following ischemic stroke beyond the hyperacute period
o Statins should be considered in all patients following stroke, even in the absence
of dyslipidemia
o Lifestyle modifications may improve overall health and aid in the prevention of
stroke recurrence and cardiac disease
Rehabilitation:
o Rehabilitation therapy involves a combination of different modalities and may
include physical therapy, occupational therapy, and speech therapy
o Newer approaches based on motor learning include constraint-induced movement
therapy, electromyography-triggered neuromuscular stimulation, impairmentoriented training, robotic interactive therapy, and virtual reality therapies. To
achieve optimal results, rehabilitation should be geared toward a patient's specific
deficits
Resolution of stroke and stroke-related complications may be a lifelong process for many
patients
Medications
Oxygen
Alteplase
Labetalol
Aspirin
Clopidogrel
Aspirin and extended-release dipyridamole
Cilostazol
Warfarin
Statins
Non-drug treatments
Carotid endarterectomy or percutaneous atherectomy
Carotid angioplasty and stenting (with or without mechanical thrombectomy)
Lifestyle modifications
Rehabilitation therapy
Special circumstances
Thrombolytic therapy with alteplase may be initiated within 3 hours of onset of ischemic stroke
and within 3 to 4.5 hours of stroke onset in selected patients. However, many exclusionary and
precautionary criteria exist to determine patient eligibility for this therapy. Strict adherence to
protocols that have been refined by pivotal trials is strongly recommended to achieve a favorable
risk-benefit profile.
Comorbidities
Coexisting disease:

Patients with myocardial infarction or pericarditis within the previous 6 weeks, subacute
bacterial endocarditis, or severe renal or hepatic disease may be at increased risk during
treatment with thrombolytic agents
Coexisting medication:

Patients with an elevated aPTT receiving heparin within previous 48 hours and those with
a prothrombin time >15 second (INR >1.7) receiving warfarin are excluded from
receiving thrombolytic therapy
Special patient groups:

The following populations are considered to be at increased risk during treatment with
thrombolytic agents:
o Pregnant or lactating women
o Comatose patients or those with severe neurologic deficit
o

Patients with sustained hypotension (systolic blood pressure <90 mm Hg or
diastolic blood pressure <50 mm Hg)
o Patients who underwent lumbar puncture within the previous week
o Patients under age 18 (not included in the National Institute of Neurological
Disorders and Stroke r-tPA study) or over age 80
The following exclude patients from receiving intravenous thrombolytic therapy (within
3 hours of stroke onset):
o Minor or rapidly improving neurologic deficits (controversial)
o Seizure at the onset of symptoms (if residual impairments are postictal)
o Symptoms suggestive of subarachnoid hemorrhage
o Systolic blood pressure ≥185 mm Hg or diastolic blood pressure ≥110 mm Hg
o Aggressive antihypertensive therapy
o Stroke or serious head trauma in the previous 3 months
o Major surgery in the previous 14 days
o History of intracranial hemorrhage
o Gastrointestinal or genitourinary bleeding in the last 21 days
o Arterial puncture at a noncompressible site in the previous 7 days
o Elevated aPTT and anticoagulant or heparin therapy within the preceding 48
hours
o INR >1.7 or prothrombin time >15 seconds
o Platelet count <100,000/μL
o Glucose level <50 mg/dL
o Myocardial infarction in the previous 3 months
Patient satisfaction/lifestyle priorities


Many cognitive, emotional, and physical changes may occur after stroke, including
confusion, apathy, depression , emotional lability, neglect of the side corresponding to
that of the brain injury, memory loss, communication deficits, inability to perform
activities of daily living, decubitus ulcers, and pain
Patients need support from caregivers and rehabilitation specialists to manage and
overcome these obstacles
Consultation





Patients in whom stroke is suspected should be referred to the emergency department
immediately for diagnostic testing and treatment
The multidisciplinary stroke team should be alerted to screen the patient for eligibility for
thrombolytic therapy
Patients in whom carotid endarterectomy is indicated should be referred to a
neurosurgeon or vascular surgeon
Patients with concurrent cardiac abnormalities should be referred to a cardiologist
Patients who have had a stroke should be referred to rehabilitative services for physical
therapy, occupational therapy, and speech therapy, as needed
Follow-up
Plan for review:




Cardiovascular parameters, including blood pressure, should be monitored closely for 24
hours in the acute setting
Patients with atherothrombotic stroke should receive an antiplatelet agent regularly unless
contraindicated
Long-term oral anticoagulation with warfarin (target INR, 2.0-3.0) is recommended for
stroke prevention in patients with atrial fibrillation and is also indicated for prevention of
stroke recurrence in patients with mechanical heart valves, severe left ventricular
dysfunction, or left ventricular thrombus; long-term oral anticoagulation with warfarin is
not recommended in symptomatic patients with intracranial arterial stenosis
Periodic blood monitoring for bleeding times is required
Prognosis:


The prognosis is highly variable, depending on the size and location of the infarction
Recovery also depends partially on the patient's enthusiasm and motivation for
rehabilitation: 10% of patients recover almost completely, 25% recover with minor
impairments, 40% experience impairments requiring special care, 10% require long-term
care, and 15% die shortly after stroke
Recurrence:




The rate of stroke recurrence is 25% to 45% within 5 years; thus, it is important to
identify risk factors for stroke and take appropriate measures to reduce the risk of
additional strokes, including:
o Controlling hypertension
o Initiating warfarin therapy in patients with atrial fibrillation
o Initiating aspirin therapy in patients with previous myocardial infarction
o Managing diabetes ( type 1 or type 2 )
o Treating hypercholesterolemia
o Educating patients about the risk factors for stroke and emphasizing the
importance of making lifestyle changes ( eg , smoking cessation, reducing alcohol
consumption, increased physical activity, and dietary modification), if needed
Carotid endarterectomy may prevent recurrence in selected patients
Aspirin and other antiplatelet agents, such as aspirin plus extended-release dipyridamole
and clopidogrel, may reduce the risk of subsequent ischemic stroke
At-risk patients and/or their caregivers should be advised of the following symptoms of
stroke, as outlined by the American Stroke Association, and instructed to urgently contact
emergency services if some or all of these symptoms are present:
o Sudden numbness or weakness of the face, arm, or leg, especially on one side of
the body
o Sudden confusion and/or difficulty in speaking or understanding
o Sudden deterioration of vision in one or both eyes
o Sudden difficulty walking, dizziness, and loss of balance or coordination
o Sudden, severe headache with no known cause
Complications:






Cerebral edema and elevated intracranial pressure: may be treated with mannitol or
hypertonic saline in an intensive care setting
Seizures: carbamazepine or another antiepileptic drug can be used for treatment;
lorazepam or diazepam can be used to treat status epilepticus
Hemorrhage: treatment depends on the amount of bleeding and symptoms
Deep vein thrombosis and pulmonary embolism : because of the increased risk,
particularly in immobilized patients, venous thromboembolism prophylaxis with lowdose subcutaneous heparin, low-molecular-weight heparins, or pneumatic compression
devices is recommended
Spasticity: stretching exercises, casts, or medications ( eg , baclofen, dantrolene sodium,
tizanidine, and botulinum toxin) may be helpful
Pressure sores: may occur if there is chronic immobility; a district nurse should be
involved for dressing, and any infection will require treatment
Evidence
Secondary prevention of recurrent TIA or stroke is a major aim of stroke treatment; thus, much
of the evidence cited under the various treatment modalities is applicable to secondary
prevention. Selected evidence dealing with specific long-term therapies is provided below.
Anticoagulant therapy:



A systematic review of 11 RCTs involving nearly 2,500 patients attempted to evaluate
chronic anticoagulation therapy after stroke or TIA. The reviewers limited their search to
studies in which the original incident (either stroke or TIA) was believed not to be of
cardiac or embolic origin. There was no evidence of an effect on death, nonfatal stroke,
myocardial infarction, or physical dependency. However, there was a significant increase
in intracranial and extracranial hemorrhage associated with the use of prolonged
anticoagulant therapy in this setting. [51] Level of evidence: 1
A systematic review identified two trials comparing anticoagulants versus antiplatelet
agents for secondary prevention of stroke in patients with nonrheumatic atrial fibrillation
and recent TIA or minor ischemic stroke. Meta-analysis showed that anticoagulants were
significantly more effective than antiplatelet agents both in preventing all vascular events
and in preventing recurrent stroke. Major extracranial bleeding complications occurred
more often in patients taking anticoagulants than in those taking antiplatelet agents. [52]
Level of evidence: 1
A pooled analysis of data from six RCTs comparing aspirin versus oral anticoagulants in
a total 4,052 patients with a wide range of cardiovascular risk factors showed that the risk
of ischemic stroke, as well as the risk of all stroke, was significantly lower among
patients receiving oral anticoagulants; this finding was consistent across the different risk
groups. There was no significant difference in the risk of other cardiovascular events, but
the rate of serious bleeding was higher among patients receiving oral anticoagulants. [53]
Level of evidence: 1
Antihypertensive therapy:


A systematic review of seven RCTs comparing antihypertensive therapy with β-receptor
antagonists, diuretics, or angiotensin-converting enzyme inhibitors versus placebo or no
treatment in patients with a previous history of stroke or TIA found that antihypertensive
therapy significantly reduced the risk of stroke, myocardial infarction, and total vascular
events after a mean of 3 years but did not result in any significant reduction in vascular
death or all-cause mortality compared to control. [54] Level of evidence: 1
An American Heart Association/American Stroke Association Stroke Council guideline
recommends the use of antihypertensive therapy for both prevention of recurrent stroke
and prevention of other vascular events in patients who have had an ischemic stroke or
TIA and are beyond the hyperacute period. [4] Level of evidence: 3
Statin therapy:




A systematic review and meta-analysis of randomized trials evaluating the use of statins
in more than 90,000 patients, including patients with and without a previous history of
stroke, TIA, or coronary artery disease, found that statins significantly reduced the risk of
stroke compared to placebo or no treatment after a mean of 4.3 years of follow-up. [18]
Level of evidence: 1
An RCT in 4,731 patients with LDL cholesterol levels of 100 to 190 mg/dL who had
experienced a stroke or TIA but had no evidence of coronary artery disease showed that
atorvastatin, 80 mg/d, decreased the incidence of stroke and cardiovascular disease but
was associated with a small increase in the incidence of hemorrhagic stroke. [55] Level of
evidence: 1
An RCT in 89 patients receiving statins who experienced a stroke showed that there was
a higher incidence of death or dependency at 90 days in patients in whom the statin was
withdrawn compared to those in whom the statin was continued. [56] Level of evidence: 1
The American Heart Association and American Stroke Association have published
detailed recommendations concerning the use of statins and other non-statin cholesterollowering treatments. [4] Level of evidence: 3
Carotid endarterectomy:


An analysis of pooled data from RCTs evaluating carotid endarterectomy in patients with
symptomatic carotid artery stenosis showed that surgery was of marginal benefit in those
with 50% to 69% stenosis and was highly beneficial in those with 70% stenosis or greater
but without near occlusion. Benefit in patients with near occlusion of the carotid artery
was marginal in the short term and is uncertain in the long term. In symptomatic patients
with less than 30% stenosis, carotid endarterectomy increased the risk of any stroke or
surgical death. [39] Level of evidence: 1
A systematic review of two trials comparing carotid endarterectomy plus medical therapy
versus medical therapy alone in a total of 5,950 patients with a recent neurologic event in
the territory of a stenosed ipsilateral carotid artery found that carotid endarterectomy
resulted in a significant reduction in the risk of major stroke or death in patients with
severe stenosis; patients with moderate stenosis also benefited from surgery. However,
patients with mild stenosis did not benefit from surgery and were noted to have an
increased risk of stroke. [40] Level of evidence: 1
Lifestyle modifications:

American Heart Association/American Stroke Association guidelines for the prevention
of stroke recommend health care advice to quit smoking and to reduce exposure to
environmental tobacco smoke; advice to reduce alcohol consumption to light-to-moderate
levels; and encouragement to maintain a healthy weight through an appropriate balance
of caloric intake, physical activity, and behavioral counseling. [32] Level of evidence: 3
References
Patient education


Patients should be advised of the following:
o Ischemic stroke is essentially a 'brain attack' that occurs when a blood clot blocks
a blood vessel that oxygenates the brain; if oxygen cannot get to brain cells, the
cells die
o The warning signs of stroke include sudden visual disturbances, numbness or
weakness in one arm or hand, language problems, facial droop or weakness, or
severe headache
o Ischemic stroke occurs most commonly in patients over age 65, but it may occur
at any age
o Stroke may be disabling, resulting in paralysis, weakness, or a loss of sensation;
balance, coordination, and communication difficulties are also possible
o After experiencing a stroke, many patients improve either spontaneously or after
rehabilitation, which may include speech and language therapy to assist with
aphasia, memory, and thought problems; occupational therapy to help with
activities of daily living; and physical therapy to aid in restoring physical
functions through strengthening and range of motion exercises
o Stroke recovery continues throughout life
o Depression is nearly universal among patients who have had a stroke because of
the effect on the patient's confidence; individual counseling, group therapy, or
antidepressant medications may be necessary
o Stroke recurs within 5 years in 25% to 45% of patients
In addition to adhering to the medication regimen, patients should be encouraged to make
lifestyle modifications, including controlling blood pressure, smoking cessation, eating a
healthy diet, and exercising regularly, to prevent subsequent strokes; surgery may also be
an option to reduce the risk of stroke recurrence
Online information for patients

American Academy of Family Physicians:
o Stroke: Warning Signs and Tips for Prevention
o Stroke Rehabilitation






American Academy of Neurology: Stroke
American Association of Neurological Surgeons: Stroke
American Stroke Association: About Stroke
Centers for Disease Control and Prevention: Stroke
National Institute of Neurological Disorders and Stroke:
o Know Stroke
o NINDS Stroke Information Page
National Stroke Association
Resources
Summary of evidence
Evidence
Prevention
Hypertension:




A systematic review of data from 29 RCTs evaluating the effects of different
antihypertensive regimens in a total of 162,341 patients found that ACE inhibitors
reduced blood pressure less than calcium antagonists, angiotensin receptor blockers,
diuretics, and β-blockers, but there were no significant differences in the rate of total
major cardiovascular events among the drug classes studied. [1] Level of evidence: 1
A systematic review of 23 RCTs evaluating the use of thiazides, β-adrenergic blockers,
calcium-channel blockers, and ACE inhibitors in a total of 50,853 patients with
hypertension concluded that low-dose thiazide therapy is the best option for first-line
treatment of hypertension, resulting in a significant reduction in the risk of death, stroke,
coronary artery disease, and cardiovascular events. [2] Level of evidence: 1
As summarized in the Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure , there has been consistent
evidence for many years now that control of hypertension is valuable in the primary
prevention of stroke as well as in reducing the risk of other end-organ damage ( eg ,
congestive heart failure and renal failure), and it is likely that the size of the blood
pressure reduction is more important in determining the risk of stroke rather than the
specific antihypertensive agent chosen. [3] Level of evidence: 3
An American Heart Association/American Stroke Association Stroke Council guideline
recommends regular (at least every 2 years in most adults and more frequently in
minority populations and the elderly) screening for hypertension and appropriate
management, including dietary changes, lifestyle modification, and drug therapy. [4]
Level of evidence: 3
Cigarette smoking:

Epidemiologic studies have found that cigarette smoking is a potent risk factor for
ischemic stroke. [5] , [6] , [7] Level of evidence: 2

An American Heart Association/American Stroke Association Stroke Council guideline
recommends avoidance of environmental tobacco smoke for stroke prevention and states
that the use of counseling, nicotine replacement, and oral smoking cessation medications
have been found to be effective in smokers and should be considered. [4] Level of
evidence: 3
Diet:

The American Heart Association/American Stroke Association recommends a diet with a
reduced sodium intake and an increased potassium intake that emphasizes fresh fruits,
vegetables, and low-fat dairy products and is low in saturated fat and total fat to lower
blood pressure, as these measures may thereby reduce the risk of stroke. [4] Level of
evidence: 3
Exercise:

The American Heart Association/American Stroke Association recommends increased
physical activity in patients who can exercise safely because it has been shown to be
associated with a reduction in the risk of stroke in epidemiologic studies. [4] Level of
evidence: 3
Atrial fibrillation:





Two systematic reviews found that treatment with adjusted-dose warfarin in patients with
atrial fibrillation who are at high risk for stroke but have no previous history of stroke is
associated with a significant reduction in the risk of ischemic stroke compared to placebo
or control. Adjusted-dose warfarin also significantly reduced the risk of ischemic stroke
compared to aspirin. [8] , [9] Level of evidence: 1
A systematic review of five RCTs comparing oral anticoagulants versus control in a total
of 2,313 patients with chronic nonvalvular atrial fibrillation and no history of TIA or
stroke concluded that treatment with adjusted-dose warfarin significantly reduces the rate
of all strokes; death; and a combined end point of stroke, myocardial infarction, or
vascular death. [10] Level of evidence: 1
A meta-analysis of 29 trials involving more than 28,000 patients with nonvalvular atrial
fibrillation showed that adjusted-dose warfarin and antiplatelet agents reduced the risk of
stroke by 64% and 22%, respectively, with only small increases in the incidence of
hemorrhage. [11] Level of evidence: 1
A systematic review found that the use of aspirin in patients with atrial fibrillation who
are at high risk for stroke but have no previous history of stroke was associated with a
nonsignificant reduction in the incidence of stroke. When the outcome of stroke was
combined with the outcomes of myocardial infarction or vascular death, aspirin was
associated with a significant reduction in the risk of stroke compared to placebo or
control. [12] Level of evidence: 1
A meta-analysis of five RCTs comparing either warfarin or aspirin versus control in
patients with atrial fibrillation at low risk for stroke (under age 65 with no history of
hypertension, stroke, TIA, or diabetes) found that warfarin consistently decreased the risk


of stroke, but the efficacy of aspirin was less consistent and requires further study. The
main adverse effect associated with anticoagulant and antiplatelet therapy is hemorrhage,
with an absolute risk of major bleeding in elderly patients with variable risk factors for
stroke of 1.3% for warfarin and 1.0% for aspirin compared to 1.0% for placebo. [13]
Level of evidence: 1
Two systematic reviews evaluating the use of aspirin for primary prevention of stroke in
patients with atrial fibrillation at low risk for stroke found differing results. [8] , [14]
Level of evidence: 1
A multicenter RCT in 7,554 patients with atrial fibrillation in whom vitamin K antagonist
therapy was considered unsuitable found that the addition of clopidogrel to aspirin
reduced the risk of major vascular events, especially stroke, but increased the risk of
hemorrhage. [15] Level of evidence: 1
Diabetes:


Epidemiologic studies have shown that the presence of diabetes increases the risk of
ischemic stroke. [16] , [17] Level of evidence: 2
An American Heart Association/American Stroke Association Stroke Council guideline
recommends tight blood pressure control and statin therapy in patients with diabetes,
especially if other risk factors are present. Treatment with an ACE inhibitor or an
angiotensin receptor blocker should be considered. [4] Level of evidence: 3
Dyslipidemia:



A systematic review and meta-analysis of randomized trials evaluating the use of statins
in more than 90,000 patients, including patients with and without a previous history of
stroke, TIA, or coronary artery disease, found that statins significantly reduced the risk of
stroke compared to placebo or no treatment after a mean of 4.3 years of follow-up. [18]
Level of evidence: 1
The National Cholesterol Education Program's Third Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults contains
recommendations regarding the management of patients with elevated total cholesterol
levels or elevated non-HDL cholesterol levels in the presence of hypertriglyceridemia but
with no previous history of stroke or TIA. [19] , [20] Level of evidence: 3
The American Heart Association/American Stroke Association recommends that patients
with known coronary heart disease and those with high-risk hypertension, even with
normal LDL cholesterol levels, receive statin therapy and advice on lifestyle
modifications. Weight loss, increased physical activity, smoking cessation, and possibly
treatment with niacin or fibrates ( eg , gemfibrozil) are recommended in patients with
known coronary artery disease and low HDL cholesterol levels. [4] Level of evidence: 3
Carotid artery stenosis:

A systematic review of three RCTs involving a total of 5,223 patients found that patients
with asymptomatic carotid artery stenosis who underwent carotid endarterectomy had a
reduced risk of perioperative stroke, death, or subsequent ipsilateral stroke over 3 to 4
years compared to those receiving medical therapy alone. The reviewers note that the
absolute risk reduction was small (approximately 1% per year during the first few years
of follow-up in the two largest RCTs included in the review), although it could be higher
with longer follow-up. [21] Level of evidence: 1
Treatment
Alteplase:




A systematic review of 26 RCTs involving more than 7,000 patients assessed the efficacy
of thrombolytic therapy in treating acute ischemic stroke. Thrombolytic therapy
significantly decreased physical dependence 3 to 6 months after stroke and also increased
the risk of bleeding in the brain. Symptomatic intracerebral hemorrhage occurred in 6.4%
of patients receiving intravenous alteplase compared to 0.6% of patients receiving
placebo. Treatment within a 3-hour window after stroke was associated with the greatest
benefit and the least risk, with no adverse outcomes or death. Thrombolysis reduces the
overall risk of dependency in the long term, although the incidence of fatal intracranial
hemorrhage is increased compared to in patients receiving placebo. [22] Level of
evidence: 1
Another systematic review combining data from six RCTs involving 2,775 patients
compared outcomes in patients receiving alteplase versus those receiving placebo within
3 hours of onset of stroke symptoms. The reviewers found that the sooner alteplase is
administered following the onset of stroke symptoms, the greater the benefit, especially if
initiated within 90 minutes. [23] Level of evidence: 1
A multicenter RCT evaluating the safety and efficacy of alteplase administered between 3
and 4.5 hours of onset of acute stroke symptoms in 821 patients found that more patients
receiving alteplase had a favorable outcome, defined as a score of 0 to 1 on the modified
Rankin scale at 3 months, than those receiving placebo (52% vs 45%). For every 100
patients with acute ischemic stroke receiving intravenous alteplase in the 0- to 3-hour
window, 32 patients benefit, and 3 patients are harmed. For every 100 patients with acute
ischemic stroke receiving intravenous alteplase in the 3- to 4.5-hour window, 16 patients
benefit, and 3 are harmed. [24] Level of evidence: 1
American Heart Association guidelines recommend the use of intravenous alteplase in
adult patients with acute ischemic stroke less than 3 hours from the onset of symptoms in
hospitals with appropriate facilities and protocols. [25] Level of evidence: 3
Labetalol:

Details regarding the appropriate treatment of high blood pressure in the setting of acute
ischemic stroke remain controversial. Expert guidelines recommend that antihypertensive
agents be withheld unless the diastolic blood pressure is >120 mm Hg or the systolic
blood pressure is >220 mm Hg. [26] Level of evidence: 3
Aspirin:



A systematic review of 12 RCTs comparing aspirin, 160 to 300 mg/d, versus placebo for
the treatment of stroke in more than 40,000 patients found that initiation of aspirin
therapy within 48 hours of acute ischemic stroke significantly reduced the risk of death or
dependency at the end of follow-up (maximum, 6 months). Aspirin therapy also was
found to increase the chances of complete recovery from stroke. There was a small
increase in the incidence of symptomatic intracranial hemorrhage among patients
receiving aspirin versus those receiving placebo, but the reviewers considered this effect
to be outweighed by the reduction in recurrent ischemic stroke and pulmonary embolism
compared to placebo. [27] Level of evidence: 1
A systematic review of four RCTs involving 16,558 patients found that, overall,
anticoagulants (both unfractionated and low-molecular-weight heparin) offered no net
advantage over aspirin alone in the treatment of acute ischemic stroke. Subgroup analysis
suggested that the combination of low-dose unfractionated heparin plus aspirin may have
benefits compared to aspirin alone, but further research is necessary. [28] Level of
evidence: 1
According to practice guidelines from the American College of Chest Physicians, early
aspirin therapy (160-325 mg/d) is recommended in patients with ischemic stroke who are
not receiving thrombolytic therapy. Aspirin may be used safely in combination with low
doses of subcutaneous heparin for venous thromboembolism prophylaxis. Antiplatelet
agents are recommended in patients without contraindications who have experienced a
non-cardioembolic stroke or TIA to reduce the risk of recurrent stroke and other
cardiovascular events. [29] Level of evidence: 3
Clopidogrel:



An RCT comparing clopidogrel versus aspirin plus dipyridamole in more than 20,000
patients found no difference in recurrent stroke or a composite outcome of stroke,
myocardial infarction, or death after 2.5 years of follow-up, but the rate of hemorrhagic
complications was higher among patients receiving aspirin plus dipyridamole. [30] Level
of evidence: 1
An RCT comparing clopidogrel versus placebo once daily in addition to aspirin in 7,554
patients with atrial fibrillation in whom warfarin was contraindicated found that patients
receiving clopidogrel plus aspirin had fewer strokes and other vascular events after 3.6
years of follow-up, but the risk of hemorrhage was greater. [31] Level of evidence: 1
The American Heart Association/American Stroke Association evidence-based
guidelines for patients with non-cardioembolic ischemic stroke recommend treatment
with an antiplatelet agent, including aspirin, 50 to 325 mg/d; aspirin, 25 mg, plus
extended-release dipyridamole, 200 mg, twice daily; and clopidogrel, 75 mg/d.
Clopidogrel is deemed a reasonable alternative for patients allergic to aspirin. The
addition of aspirin to clopidogrel increases the risk of hemorrhage and is not routinely
recommended in patients with ischemic stroke or TIA, unless a specific indication ( ie ,
coronary artery stent or acute coronary syndrome) exists. [29] , [32] Level of evidence: 3
Aspirin and extended-release dipyridamole:





In the second European Stroke Prevention Study, low-dose aspirin plus dipyridamole
reduced the risk of recurrent stroke by 37%, whereas aspirin alone and dipyridamole
alone reduced the risk of stroke by only 18% and 16%, respectively. The combined risk
of stroke and death was reduced by 13% with aspirin alone, 15% with dipyridamole
alone, and 24% with combined therapy compared to placebo. The incidence of
intracranial hemorrhage was 0.6% among patients receiving aspirin plus dipyridamole,
0.5% among patients receiving extended-release dipyridamole alone, 0.4% among
patients receiving aspirin alone, and 0.4% among patients receiving placebo. [33] Level
of evidence: 1
The European/Australasian Stroke Prevention in ReversibleIschemia Trial, which
enrolled 2,739 patients with TIA or minor ischemic stroke, was ended prematurely after
the investigators found that the combination of aspirin and dipyridamole was more
effective than aspirin alone in the prevention of a composite of vascular events and death
among patients with a history of cardiovascular disease. [34] Level of evidence: 1
A systematic review of 29 trials involving 23,019 patients with vascular disease found no
evidence to support the use of dipyridamole alone over aspirin alone. [35] Level of
evidence: 1
An RCT comparing aspirin plus dipyridamole versus clopidogrel in more than 20,000
patients found no difference in recurrent stroke or a composite outcome of stroke,
myocardial infarction, or death after 2.5 years of follow-up, but the rate of hemorrhagic
complications was higher among patients receiving aspirin plus dipyridamole. [30] Level
of evidence: 1
The American Heart Association/American Stroke Association evidence-based
guidelines for patients with non-cardioembolic ischemic stroke recommend treatment
with an antiplatelet agent, including aspirin, 50 to 325 mg/d; aspirin, 25 mg, plus
extended-release dipyridamole, 200 mg, twice daily; and clopidogrel, 75 mg/d.
Clopidogrel is deemed a reasonable alternative for patients allergic to aspirin. The
addition of aspirin to clopidogrel increases the risk of hemorrhage and is not routinely
recommended in patients with ischemic stroke or TIA, unless a specific indication ( ie ,
coronary artery stent or acute coronary syndrome) exists. [29] , [32] Level of evidence: 3
Cilostazol:

A systematic review and meta-analysis of 12 trials involving 5,674 patients with
atherosclerotic disease showed that treatment with cilostazol decreased the incidence of
cerebrovascular events compared to placebo, without a difference in cardiovascular
events or serious bleeding complications. [36] Level of evidence: 1
Warfarin:


A systematic review of 24 trials involving more than 23,000 patients showed no short- or
long-term benefit of warfarin in patients with acute ischemic stroke. Warfarin reduced the
rate of recurrent stroke and other thromboembolic complications but was associated with
an increased bleeding risk. [37] Level of evidence: 1
An RCT comparing warfarin versus aspirin in 569 patients with TIA or stroke and known
intracranial arterial stenosis showed that warfarin was no better than aspirin in preventing

recurrent stroke and was associated with a higher risk of adverse effects, including
hemorrhage. [38] Level of evidence: 1
Expert guidelines recommend that long-term anticoagulation (target INR, 2.5 [range, 2.03.0]) be initiated in patients with atrial fibrillation who have experienced a recent stroke
or TIA.[ [29] ] Level of evidence: 3
Statins:

A systematic review and meta-analysis of randomized trials evaluating the use of statins
in more than 90,000 patients, including patients with and without a previous history of
stroke, TIA, or coronary artery disease, found that statins significantly reduced the risk of
stroke compared to placebo or no treatment after a mean of 4.3 years of follow-up. [18]
Level of evidence: 1
Carotid endarterectomy:



A systematic review of pooled data from RCTs evaluating carotid endarterectomy in a
total of 6,902 patients with symptomatic carotid artery stenosis showed that surgery was
highly beneficial in patients with 70% stenosis or greater without near occlusion (string
sign) and of less but some benefit in patients with 50% to 69% stenosis. When carotid
endarterectomy was done within 2 weeks of the index carotid territory ischemic event,
the absolute risk reduction was 18.5%, with a number needed to treat of 5, translating to
185 strokes prevented at 5 years per 1,000 carotid endarterectomies. The benefit of
surgery in patients with near occlusion (string sign) of the internal carotid artery was
marginal in the short term and is uncertain in the long term. The 5-year risk of ischemic
stroke in patients with near occlusion undergoing surgery was 22.4% compared to a 5year risk of 22.3% in those receiving medical therapy (absolute risk reduction, 0.1%) .
Carotid endarterectomy increased the risk of any stroke or surgical death in symptomatic
patients with less than 30% stenosis and had marginal benefit in those with 30% to 49%
stenosis. [39] Level of evidence: 1
Another systematic review of RCTs comparing carotid endarterectomy plus medical
therapy versus medical therapy alone in a total of 5,950 patients with a recent neurologic
event in the territory of a stenosed ipsilateral carotid artery also found that carotid
endarterectomy was beneficial in selected patients. Patients with severe stenosis
undergoing carotid endarterectomy experienced a significant reduction in the risk of
major stroke or death. Patients with moderate stenosis also benefited from surgery.
Patients with mild stenosis did not benefit from surgery and were noted to have an
increased risk of stroke. [40] Level of evidence: 1
An RCT comparing carotid endarterectomy versus carotid artery stenting in 2,502
symptomatic and asymptomatic patients with carotid artery stenosis found that there was
no significant difference between the two procedures in the composite primary outcome
of stroke, myocardial infarction, or death after 4 years (6.8% vs 7.2%; P = .51),
regardless of symptomatic or asymptomatic presentation. More strokes occurred in
patients undergoing carotid artery stenosis, more myocardial infarctions occurred in
patients undergoing carotid endarterectomy, and younger patients undergoing carotid
artery stenosis had a slightly better outcome than older patients. The investigators




attributed the improved periprocedural outcomes to surgeon credentialing and overall
improved technology. [41] Level of evidence: 1
A RCT comparing carotid endarterectomy versus carotid artery stenting in 527
symptomatic patients found that carotid artery stenting was associated with a higher 30day rate of stroke or death. The cumulative probability of periprocedural stroke or death
plus ipsilateral stroke after 4 years of follow-up was 6.2% in patients undergoing carotid
endarterectomy versus 11.1% in those undergoing carotid artery stenting, with a hazard
ratio of 1.97 (95% CI, 1.06-3.67; P = .03). However, the higher risk in patients
undergoing carotid artery stenting was primarily due to the higher 30-day incidence of
stroke or death; there was a similarly low 4-year risk of ipsilateral stroke in both groups.
[42] Level of evidence: 1
Another RCT comparing carotid endarterectomy versus carotid artery stenting in more
than 1,200 patients with symptomatic severe carotid artery stenosis found no significant
difference in periprocedural stroke or death and in ipsilateral ischemic stroke up to 2
years after the procedures (8.8% vs 9.5%; hazard ratio, 1.10; P = .31), although recurrent
asymptomatic stenosis was significantly more frequent in patients undergoing carotid
artery stenting than in those undergoing carotid endarterectomy (intention-to-treat group:
10.7% vs 4.6%; P = .0009). The investigators suggested that ultrasound may slightly
overestimate in-stent stenosis. [43] Level of evidence: 1
An RCT compared carotid endarterectomy versus carotid artery stenting in 504 patients
presenting with carotid artery stenosis (90% whom were symptomatic) between 1992 and
1997. By day 30, there were more minor strokes in the group undergoing carotid
endarterectomy (8 vs 1), but the overall number of strokes was the same in both groups
(25 vs 25). The rate of ipsilateral non-perioperative stroke after 8 years was low in both
groups (15.4% for carotid endarterectomy vs. 21.1% for carotid artery stenting), and no
difference in outcome measures was statistically significant. The investigators admit that
the study was underpowered, and the confidence intervals were wide. [44] Level of
evidence: 1
An interim report was recently published on an international RCT comparing the 120-day
postprocedural rate of stroke, death, or perioperative myocardial infarction in more than
1,700 patients with symptomatic carotid artery stenosis undergoing either carotid
endarterectomy or carotid artery stenting; the primary outcome measure will be the 3year rate of major stroke. At the time of publication, there were 34 events (4.0%) of
disabling stroke or death in the group undergoing carotid artery stenting compared to 27
events (3.2%) in the group undergoing carotid endarterectomy (hazard ratio, 1.28 [95%
CI, 0.77-2.11]). The overall incidence of stroke, death, or procedural myocardial
infarction was 8.5% after carotid artery stenting and 5.2% after carotid endarterectomy
(hazard ratio, 1.92 [95% CI, 1.27-2.89]). The risk of stroke and death was higher in
patients undergoing carotid artery stenting than in those undergoing carotid
endarterectomy; three fatal myocardial infarctions occurred in the carotid artery stenting
group versus four nonfatal myocardial infarctions in the carotid endarterectomy group.
Current results reaffirm that carotid endarterectomy is safer than carotid artery stenting in
symptomatic patients with respect to cardiovascular mortality and nondisabling strokes,
although carotid endarterectomy was associated with many more (nondisabling) cranial
nerve injuries (85 events vs 1 event). [45] Level of evidence: 1
Percutaneous atherectomy:

A systematic review of four trials involving 350 patients with acute stroke showed that
percutaneous vascular procedures produced better outcomes than urokinase in spite of an
increased risk of hemorrhage in the first 24 hours after treatment. However, most data
came from trials in which treatment was initiated up to 6 hours after stroke. [46] Level of
evidence: 1
Carotid angioplasty and stenting (with or without mechanical thrombectomy):





An RCT comparing carotid endarterectomy versus carotid artery stenting in patients with
greater than 70% stenosis found no significant difference in outcomes in terms of death
or cerebral ischemia between the two interventions. [47] Level of evidence: 1
An RCT comparing carotid endarterectomy versus carotid artery stenting in 2,502
symptomatic and asymptomatic patients with carotid artery stenosis found that there was
no significant difference between the two procedures in the composite primary outcome
of stroke, myocardial infarction, or death after 4 years (6.8% vs 7.2%; P = .51),
regardless of symptomatic or asymptomatic presentation. More strokes occurred in
patients undergoing carotid artery stenosis, more myocardial infarctions occurred in
patients undergoing carotid endarterectomy, and younger patients undergoing carotid
artery stenosis had a slightly better outcome than older patients. The investigators
attributed the improved periprocedural outcomes to surgeon credentialing and overall
improved technology. [41] Level of evidence: 1
A RCT comparing carotid endarterectomy versus carotid artery stenting in 527
symptomatic patients found that carotid artery stenting was associated with a higher 30day rate of stroke or death. The cumulative probability of periprocedural stroke or death
plus ipsilateral stroke after 4 years of follow-up was 6.2% in patients undergoing carotid
endarterectomy versus 11.1% in those undergoing carotid artery stenting (hazard ratio,
1.97 [95% CI, 1.06-3.67]; P = .03). However, the higher risk in patients undergoing
carotid artery stenting was primarily due to the higher 30-day incidence of stroke or
death; there was a similarly low 4-year risk of ipsilateral stroke in both groups. [42] Level
of evidence: 1
Another RCT comparing carotid endarterectomy versus carotid artery stenting in more
than 1,200 patients with symptomatic severe carotid artery stenosis found no significant
difference in periprocedural stroke or death and in ipsilateral ischemic stroke up to 2
years after the procedures (8.8% vs 9.5%; hazard ratio, 1.10; P = .31), although recurrent
asymptomatic stenosis was significantly more frequent in patients undergoing carotid
artery stenting than in those undergoing carotid endarterectomy (intention-to-treat group:
10.7% vs 4.6%; P = .0009). The investigators suggested that ultrasound may slightly
overestimate in-stent stenosis. [43] Level of evidence: 1
An RCT compared carotid endarterectomy versus carotid artery stenting in 504 patients
presenting with carotid artery stenosis (90% whom were symptomatic) between 1992 and
1997. By day 30, there were more minor strokes in the group undergoing carotid
endarterectomy (8 vs 1), but the overall number of strokes was the same in both groups
(25 vs 25). The rate of ipsilateral non-perioperative stroke after 8 years was low in both
groups (15.4% for carotid endarterectomy vs. 21.1% for carotid artery stenting), and no

difference in outcome measures was statistically significant. The investigators admit that
the study was underpowered, and the confidence intervals were wide. [44] Level of
evidence: 1
An interim report was recently published on an international RCT comparing the 120-day
postprocedural rate of stroke, death, or perioperative myocardial infarction in more than
1,700 patients with symptomatic carotid artery stenosis undergoing either carotid
endarterectomy or carotid artery stenting; the primary outcome measure will be the 3year rate of major stroke. At the time of publication, there were 34 events (4.0%) of
disabling stroke or death in the group undergoing carotid artery stenting compared to 27
events (3.2%) in the group undergoing carotid endarterectomy (hazard ratio, 1.28 [95%
CI, 0.77-2.11]). The overall incidence of stroke, death, or procedural myocardial
infarction was 8.5% after carotid artery stenting and 5.2% after carotid endarterectomy
(hazard ratio, 1.92 [95% CI, 1.27-2.89]). The risk of stroke and death was higher in
patients undergoing carotid artery stenting than in those undergoing carotid
endarterectomy; three fatal myocardial infarctions occurred in the carotid artery stenting
group versus four nonfatal myocardial infarctions in the carotid endarterectomy group.
Current results reaffirm that carotid endarterectomy is safer than carotid artery stenting in
symptomatic patients with respect to cardiovascular mortality and nondisabling strokes,
although carotid endarterectomy was associated with many more (nondisabling) cranial
nerve injuries (85 events vs 1 event). [45] Level of evidence: 1
Lifestyle modifications:

The American Heart Association Nutritional Committee has produced recommendations
concerning diet and lifestyle. [48] Level of evidence: 3
Rehabilitation therapy:


A systematic review of two RCTs evaluating the effect of cognitive training for attention
deficits following stroke in a total of 56 patients found that patients assigned to training
experienced improvements in measures of alertness and sustained attention compared to
control subjects. However, no improvements in day-to-day functionality could be
attributed to the intervention. [49] Level of evidence: 1
A systematic review of five trials involving 487 patients failed to identify any evidence of
benefit from rehabilitation 1 year after stroke. Specifically, there was no conclusive
finding of improvements in self-care, independence of living, or diminished need for
care. [50] Level of evidence: 1
Follow-up (secondary prevention)
Secondary prevention of recurrent TIA or stroke is a major aim of stroke treatment; thus, much
of the evidence cited under the various treatment modalities is applicable to secondary
prevention. Selected evidence dealing with specific long-term therapies is provided below.
Anticoagulant therapy:



A systematic review of 11 RCTs involving nearly 2,500 patients attempted to evaluate
chronic anticoagulation therapy after stroke or TIA. The reviewers limited their search to
studies in which the original incident (either stroke or TIA) was believed not to be of
cardiac or embolic origin. There was no evidence of an effect on death, nonfatal stroke,
myocardial infarction, or physical dependency. However, there was a significant increase
in intracranial and extracranial hemorrhage associated with the use of prolonged
anticoagulant therapy in this setting. [51] Level of evidence: 1
A systematic review identified two trials comparing anticoagulants versus antiplatelet
agents for secondary prevention of stroke in patients with nonrheumatic atrial fibrillation
and recent TIA or minor ischemic stroke. Meta-analysis showed that anticoagulants were
significantly more effective than antiplatelet agents both in preventing all vascular events
and in preventing recurrent stroke. Major extracranial bleeding complications occurred
more often in patients taking anticoagulants than in those taking antiplatelet agents. [52]
Level of evidence: 1
A pooled analysis of data from six RCTs comparing aspirin versus oral anticoagulants in
a total 4,052 patients with a wide range of cardiovascular risk factors showed that the risk
of ischemic stroke, as well as the risk of all stroke, was significantly lower among
patients receiving oral anticoagulants; this finding was consistent across the different risk
groups. There was no significant difference in the risk of other cardiovascular events, but
the rate of serious bleeding was higher among patients receiving oral anticoagulants. [53]
Level of evidence: 1
Antihypertensive therapy:


A systematic review of seven RCTs comparing antihypertensive therapy with β-receptor
antagonists, diuretics, or angiotensin-converting enzyme inhibitors versus placebo or no
treatment in patients with a previous history of stroke or TIA found that antihypertensive
therapy significantly reduced the risk of stroke, myocardial infarction, and total vascular
events after a mean of 3 years but did not result in any significant reduction in vascular
death or all-cause mortality compared to control. [54] Level of evidence: 1
An American Heart Association/American Stroke Association Stroke Council guideline
recommends the use of antihypertensive therapy for both prevention of recurrent stroke
and prevention of other vascular events in patients who have had an ischemic stroke or
TIA and are beyond the hyperacute period. [4] Level of evidence: 3
Statin therapy:


A systematic review and meta-analysis of randomized trials evaluating the use of statins
in more than 90,000 patients, including patients with and without a previous history of
stroke, TIA, or coronary artery disease, found that statins significantly reduced the risk of
stroke compared to placebo or no treatment after a mean of 4.3 years of follow-up. [18]
Level of evidence: 1
An RCT in 4,731 patients with LDL cholesterol levels of 100 to 190 mg/dL who had
experienced a stroke or TIA but had no evidence of coronary artery disease showed that
atorvastatin, 80 mg/d, decreased the incidence of stroke and cardiovascular disease but


was associated with a small increase in the incidence of hemorrhagic stroke. [55] Level of
evidence: 1
An RCT in 89 patients receiving statins who experienced a stroke showed that there was
a higher incidence of death or dependency at 90 days in patients in whom the statin was
withdrawn compared to those in whom the statin was continued. [56] Level of evidence: 1
The American Heart Association and American Stroke Association have published
detailed recommendations concerning the use of statins and other non-statin cholesterollowering treatments. [4] Level of evidence: 3
Carotid endarterectomy:


An analysis of pooled data from RCTs evaluating carotid endarterectomy in patients with
symptomatic carotid artery stenosis showed that surgery was of marginal benefit in those
with 50% to 69% stenosis and was highly beneficial in those with 70% stenosis or greater
but without near occlusion. Benefit in patients with near occlusion of the carotid artery
was marginal in the short term and is uncertain in the long term. In symptomatic patients
with less than 30% stenosis, carotid endarterectomy increased the risk of any stroke or
surgical death. [39] Level of evidence: 1
A systematic review of two trials comparing carotid endarterectomy plus medical therapy
versus medical therapy alone in a total of 5,950 patients with a recent neurologic event in
the territory of a stenosed ipsilateral carotid artery found that carotid endarterectomy
resulted in a significant reduction in the risk of major stroke or death in patients with
severe stenosis; patients with moderate stenosis also benefited from surgery. However,
patients with mild stenosis did not benefit from surgery and were noted to have an
increased risk of stroke. [40] Level of evidence: 1
Lifestyle modifications:

American Heart Association/American Stroke Association guidelines for the prevention
of stroke recommend health care advice to quit smoking and to reduce exposure to
environmental tobacco smoke; advice to reduce alcohol consumption to light-to-moderate
levels; and encouragement to maintain a healthy weight through an appropriate balance
of caloric intake, physical activity, and behavioral counseling. [32] Level of evidence: 3
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Guidelines
The U.S. Preventive Services Task Force has produced the following:

Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force
recommendation statement . Ann Intern Med. 2009;150:396-404
The National Heart, Lung, and Blood Institute has produced the following:


The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure . Bethesda, MD: National Heart,
Lung, and Blood Institute; 2004
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III): Final Report . Bethesda, MD: National Heart, Lung, and Blood
Institute; 2002
The American Heart Association has produced numerous scientific statements and guidelines
pertaining to stroke, all of which can be accessed here .
The American Heart Association also has produced the following statement regarding
cardiovascular disease risk reduction in the general population:

American Heart Association Nutrition Committee, Lichtenstein AH, Appel LJ, et al. Diet
and lifestyle recommendations revision 2006: a scientific statement from the American
Heart Association Nutrition Committee . Circulation. 2006;114:82-96
The American Heart Association and the American College of Cardiology have produced the
following:

Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for
patients with coronary and other atherosclerotic vascular disease: 2006 update . Endorsed
by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-72
The American Stroke Association has produced the following:

Schwamm LH, Pancioli A, Acker JE 3rd, et al. Recommendations for the establishment
of stroke systems of care: recommendations from the American Stroke Association's
Task Force on the Development of Stroke Systems . Stroke. 2005;36:690-703
The American College of Chest Physicians has produced the following:

Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P; American College of Chest
Physicians. Antithrombotic and thrombolytic therapy for ischemic stroke: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) .
Chest. 2008;133(Suppl):630S-69S
The American Academy of Neurology has produced the following:


Chaturvedi S, Bruno A, Feasby T, et al. Carotid endarterectomy—an evidence-based
review: report of the Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology . Neurology. 2005;65:794-801
Messé SR, Silverman IE, Kizer JR, et al. Practice parameter: recurrent stroke with patent
foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee
of the American Academy of Neurology . Neurology. 2004;62:1042-50
The Canadian Stroke Network and the Heart and Stroke Foundation of Canada have produced
the following:


Canadian Best Practice Recommendations for Stroke Care: 2006 . Ottawa, Canada:
Canadian Stroke Network and the Heart and Stroke Foundation of Canada; 2006
CSS Information & Evaluation Working Group. Performance Measurement Manual. A
supplement to the Canadian Stroke Strategy Canadian Best Practices Recommendations
for Stroke Care (Update 2008) . Ottawa, Canada: Canadian Stroke Network and the Heart
and Stroke Foundation of Canada; 2008
The Royal College of Physicians has produced the following:

Intercollegiate Stroke Working Party. National clinical guideline for stroke, 3rd edition .
London: Royal College of Physicians; 2008
Further reading
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Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients
with symptomatic moderate or severe stenosis. North American Symptomatic Carotid
Endarterectomy Trial Collaborators. N Engl J Med. 1998;339:1415-25
European Carotid Surgery Trialists' Collaborative Group. Randomised trial of
endarterectomy for recently symptomatic carotid stenosis: final results of the MRC
European Carotid Surgery Trial (ECST). Lancet. 1998;351:1379-87
Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults:
national implications for rhythm management and stroke prevention: the
AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA.
2001;285:2370-5
Kearon C, Johnston M, Moffat K, McGinnis J, Ginsberg JS. Effect of warfarin on
activated partial thromboplastin time in patients receiving heparin. Arch Intern Med.
1998;158:1140-3
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Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomized trials
of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high
risk patients. BMJ. 2002;324:71-86
Bushnell CD, Goldstein LB. Homocysteine testing in patients with acute ischemic stroke.
Neurology. 2002;59:1541-6
Green DM, Ropper AH, Kronmal RA, Psaty BM, Burke GL; Cardiovascular Health
Study. Serum potassium level and dietary potassium intake as risk factors for stroke.
Neurology. 2002;59:314-20
Hankey GJ. Stroke. Warfarin-Aspirin Recurrent Stroke Study (WARSS) trial: is warfarin
really a reasonable therapeutic alternative to aspirin for preventing recurrent
noncardioembolic ischemic stroke? 2002;33:1723-6
Derksen RH, de Groot PG, Kappelle LJ. Low dose aspirin after ischemic stroke
associated with antiphospholipid syndrome. Neurology. 2003;61;111-4
Løkkegaard E, Jovanovic Z, Heitmann BL, et al. Increased risk of stroke in hypertensive
women using hormone therapy: analyses based on the Danish Nurse Study. Arch Neurol.
2003;60:1379-84
Engelter ST, Reichhart M, Sekoranja L, et al. Thrombolysis in stroke patients aged 80
years and older: Swiss survey of IV thrombolysis. Neurology. 2005;65:1795-8
Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in
acute ischemic stroke: results of the MERCI trial. Stroke. 2005;36:1432-8
Finley Caulfield A, Wijman CA. Critical care of acute ischemic stroke. Crit Care Clin.
2006;22:581-606; abstract vii
Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update:
a report from the American Heart Association Statistics Committee and Stroke Statistics
Subcommittee. Circulation. 2008;117:e25-146
Urrutia VC, Wityk RJ. Blood pressure management in acute stroke. Crit Care Clin.
2006;22:695-711
Elkind MS, Prabhakaran S, Pittman J, Koroshetz W, Jacoby M, Johnston KC; GAIN
Americas Investigators. Sex as a predictor of outcomes in patients treated with
thrombolysis for acute stroke. Neurology. 2007;68:842-8
Hankey GJ, Spiesser J, Hakimi Z, Carita P, Gabriel S. Time frame and predictors of
recovery from disability following recurrent ischemic stroke. Neurology. 2007;68:202-5
Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of
scores to predict very early stroke risk after transient ischaemic attack. Lancet.
2007;369:283-92
Stroke Unit Trialists' Collaboration. Organised inpatient (stroke unit) care for stroke.
Cochrane Database Syst Rev. 2007:CD000197
White-Bateman SR, Schumacher HC, Sacco RL, Appelbaum PS. Consent for intravenous
thrombolysis in acute stroke: review and future directions. Arch Neurol. 2007;64:785-92
Biller J. The role of antiplatelet therapy in the management of ischemic stroke:
implementation of guidelines in current practice. Neurol Res. 2008;30:669-77
Diener HC, Sacco RL, Yusuf S, et al. Effects of aspirin plus extended-release
dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after
recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for
Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and
placebo-controlled study. Lancet Neurol. 2008;7:875-84
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Codes
Naylor AR. Stenting versus endarterectomy: the debate continues. Lancet Neurol.
2008;7:862-64
Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke:
final results of the Multi MERCI trial. Stroke. 2008;39:1205-12
Biller J. Antiplatelet therapy in ischemic stroke: variability in clinical trials and its impact
on choosing the appropriate therapy. J Neurol Sci. 2009;284:1-9
American Heart Association. Heart Disease and Stroke Statistics – 2009 Update . Dallas,
TX: American Heart Association; 2009
Mazighi M, Serfaty JM, Labreuche J, et al. Comparison of intravenous alteplase with a
combined intravenous-endovascular approach in patients with stroke and confirmed
arterial occlusion (RECANALISE study): a prospective cohort study. Lancet Neurol.
2009;8:802-9
Uchiyama S, Demaerschalk BM, Goto S, et al. Stroke prevention by cilostazol in patients
with atherothrombosis: meta-analysis of placebo-controlled randomized trials. J Stroke
Cerebrovas Dis. 2009;18:482-90
Wintermark M. Brain perfusion-CT in acute stroke patients. Eur Radiol. 2005;15(Suppl
4):D28-31
Srinivasan A, Goyal M, Al Azri F, Lum C. State-of-the-art imaging of acute stroke.
Radiographics. 2006;26(Suppl 1):S75-95
Breuer L, Schellinger PD, Huttner HB, et al. Feasibility and safety of magnetic resonance
imaging-based thrombolysis in patients with stroke on awakening: initial single-centre
experience. Int J Stroke. 2010;5:68-73
Breuer L, Huttner HB, Dörfler A, Schellinger PD, Köhrmann M. Wake up stroke:
overview on diagnostic and therapeutic options for ischemic stroke on awakening [in
German]. Fortschr Neurol Psychiatr. 2010;78:101-6
Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of
laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events:
a systematic review and meta-analysis. Arch Intern Med. 2007;167:1593-9
Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin 'resistance' and risk of
cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008;336:195-8
Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction
between proton pump inhibitors and clopidogrel. CMAJ. 2009;180:713-8
Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19
genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA.
2009;302:849-57
Costa J, Ferro JM, Matias-Guiu J, Alvarez-Sabin J, Torres F. Triflusal for preventing
serious vascular events in people at high risk. Cochrane Database Syst Rev.
2005:CD004296
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med. 2009;361:1139-51
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after
acute ischemic stroke. N Engl J Med. 2008;359:1317-29
Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase 3-4.5 h after acute
ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008;372:1303-9
ICD-9 code
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433 Occlusion and stenosis of precerebral arteries
433.0 Basilar artery
433.1 Carotid artery
433.2 Vertebral artery
433.3 Multiple and bilateral
433.8 Other specified precerebral artery
433.9 Unspecified precerebral artery
434 Occlusion of cerebral arteries
434.0 Cerebral thrombosis
434.1 Cerebral embolism
434.9 Cerebral artery occlusion, unspecified
435 Transient cerebral ischemia
435.0 Basilar artery syndrome
435.1 Vertebral artery syndrome
435.2 Subclavian steal syndrome
435.3 Vertebrobasilar artery syndrome
435.8 Other specified transient cerebral ischemias
435.9 Unspecified transient cerebral ischemias
436 Acute, but ill-defined, cerebrovascular disease
437.1 Other generalized ischemic cerebrovascular disease
FAQ
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Should all patients who have had an ischemic stroke be evaluated for eligibility to
receive thrombolytic therapy with alteplase?Yes, all patients presenting within 3 hours
of symptoms should be considered candidates for intravenous thrombolytic therapy if
they meet the inclusion criteria and have no contraindications. In addition, selected
patients presenting within 3 to 4.5 hours of symptoms may benefit from intravenous
alteplase
Do all patients who have had a stroke have to be admitted to the hospital?Yes, all
patients presenting with a new stroke should be admitted to the hospital to facilitate rapid
evaluation and allow for observation. Many patients will experience clinical deterioration
within the first 24 to 48 hours after a stroke, which can be reduced by inpatient
management
What are the most common clinical findings associated with stroke?Stroke can have
a broad spectrum of clinical findings, but the most common are hemiparesis,
homonymous hemianopia, hemisensory loss, aphasia, diplopia, and ataxia. Stroke will
not always prove to be the ultimate diagnosis, but the sudden onset of any of these
findings or almost any other neurologic deficit should raise the suspicion of stroke
Are all hospitals equipped to provide acute intervention with thrombolytic
therapy?No, in order to provide thrombolytic therapy, a medical center must have an
integrated multidisciplinary team to permit early diagnosis, CT scan analysis, and use of
specific protocols that have been refined by pivotal trials. Strict adherence to protocols is
strongly recommended to achieve a favorable risk-benefit profile
Contributors
José Biller, MD, FACP, FAAN, FAHA
Eelco F. M. Wijdicks, MD
Karl E. Misulis, MD, PhD
Fred F. Ferri, MD, FACP
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