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Ischemic Stroke

Stroke is characterized by the sudden loss of blood circulation to an area of the brain,

resulting in a corresponding loss of neurologic function. Strokes are classified as either

hemorrhagic or ischemic. Acute ischemic stroke refers to stroke caused by thrombosis or

embolism and is more common than hemorrhagic stroke.

Essential update: New AHA/ASA guidelines for acute stroke treatment

The American Heart Association (AHA) and American Stroke Association (ASA) released

new guidelines for the early management of acute ischemic stroke in January 2013. New

features of the guidelines include a focus on the importance of stroke systems of care, a

recommendation for the use of tissue plasminogen activator (t-PA) in selected patients

presenting within 3 to 4.5 hours of symptom onset, and a recommendation for door-to-needle

times within 60 minutes of hospital arrival in patients eligible for thrombolysis.[1, 2]

Signs and symptoms

Although signs and symptoms of stroke can occur alone, they are more likely to occur incombination. Common stroke signs and symptoms include the following:

Abrupt onset of hemiparesis, monoparesis, or quadriparesis Acute hemisensory loss Complete or partial hemianopia, monocular or binocular visual loss, or diplopia Visual field deficits Diplopia Dysarthria Ataxia Vertigo Nystagmus Aphasia Sudden decrease in the level of consciousness

In younger patients, a history of recent trauma, coagulopathies, illicit drug use (especially

cocaine), migraines, or use of oral contraceptives should be elicited.

SeeClinical Presentationfor more detail.

Diagnosis

With the availability of thrombolytic therapy for acute ischemic stroke in selected patients,

the physician must be able to perform a brief, but accurate, neurologic examination on

patients with suspected stroke syndromes. Essential components of the neurologicexamination include evaluations of the following:

Cranial nerves Motor function Sensory function Cerebellar function Gait Deep tendon reflexes Mental status level of consciousness

The patients skull and spine also should be examined, and signs of meningismus should besought.
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Laboratory studies

Laboratory tests performed in the diagnosis and evaluation of ischemic stroke include the

following:

Complete blood cell count: The CBC count serves as a baseline study and may reveal acause for the stroke (eg, polycythemia, thrombocytosis, thrombocytopenia, leukemia) or

provide evidence of concurrent illness (eg, anemia)

Basic chemistry panel: The chemistry panel serves as a baseline study and may reveal astroke mimic (eg, hypoglycemia, hyponatremia) or provide evidence of concurrent illness

(eg, diabetes, renal insufficiency)

Coagulation studies: Coagulation studies may reveal a coagulopathy and are useful whenthrombolytics or anticoagulants are to be used

Cardiac biomarkers: Cardiac biomarkers are important because of the association ofcerebral vascular disease and coronary artery disease

Toxicology screening: Toxicology screening may assist in identifying intoxicated patientswith symptoms/behavior mimicking stroke syndromes

Pregnancy testing: A urine pregnancy test should be obtained for all women of childbearingage with stroke symptoms; recombinant tissue-type plasminogen activator (rt-PA) is a

pregnancy class C agent

Arterial blood gas analysis: Although infrequent in patients with suspected hypoxemia,arterial blood gas defines the severity of hypoxemia and may be used to detect acid-base

disturbances

Imaging studies

Imaging in ischemic stroke can involve the following modalities:

Several types of magnetic resonance imaging Several types of computed tomography scanning Angiography Ultrasonography Radiology Echocardiography Nuclear imaging

Lumbar puncture

A lumbar puncture is required to rule out meningitis or subarachnoid hemorrhage when the

CT scan is negative but the clinical suspicion remains high

SeeWorkupfor more detail.Management

Ischemic stroke therapies include the following:

Thrombolytic therapy: Thrombolytics restore cerebral blood flow among some patients withacute ischemic stroke and may lead to improvement or resolution of neurologic deficits

Antiplatelet agents: The International Stroke Trial and the Chinese Acute Stroke Trial(CAST) demonstrated modest benefit from the use of aspirin in the setting of acute

ischemic stroke[3, 4]

Mechanical thrombolysis: Involves the endovascular treatment of acute ischemic strokeStroke prevention
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Primary stroke prevention refers to the treatment of individuals with no previous history of

stroke. Measures may include use of the following:

Platelet antiaggregants 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (ie, statins)

ExerciseSecondary prevention refers to the treatment of individuals who have already had a stroke.

Measures may include use of the following:

Platelet antiaggregants Antihypertensives HMG-CoA reductase inhibitors (statins) Lifestyle interventions

SeeTreatmentandMedicationfor more detail.

Image library

Vascular distributions: ACA infarction. Diffusion-weighted image on the left

demonstrates high signal in the paramedian frontal and high parietal regions. The opposite

diffusion-weighted image in a different patient demonstrates restricted diffusion in a larger

ACA infarction involving the left paramedian frontal and posterior parietal regions. There is

also infarction of the lateral temporoparietal regions bilaterally (both MCA distributions),

greater on the left indicating multivessel involvement suggesting emboli.

Background

Stroke is characterized by the sudden loss of blood circulation to an area of the brain,

resulting in a corresponding loss of neurologic function. Also previously called

cerebrovascular accident (CVA) or stroke syndrome, stroke is a nonspecific term

encompassing a heterogeneous group of pathophysiologic causes.

Broadly, however, strokes are classified as either hemorrhagic or ischemic. Acute ischemic

stroke refers to stroke caused by thrombosis or embolism and is more common than

hemorrhagic stroke. (Prior literature indicated that only 8-18% of strokes are hemorrhagic,

but a retrospective review from a stroke center found that 40.9% of 757 strokes included in

the study were hemorrhagic.[5] )

Based on the system of categorizing stroke developed in the multicenter Trial of Org 10172

in Acute Stroke Treatment (TOAST), ischemic strokes may be divided into the following 3

major subtypes[6] :

Large artery infarction: Thrombotic strokes are caused by in situ occlusions onatherosclerotic lesions in the carotid, vertebrobasilar, and cerebral arteries, typically

proximal to major branches.

Small-vessel, or lacunar, infarction Cardioembolic infarction: Cardiogenic emboli are a common source of recurrent stroke.

They may account for up to 20% of acute strokes and have been reported to have the

highest 1-month mortality. (See Pathophysiology.)

The National Institute of Neurologic Disorders and Stroke (NINDS) recombinant tissue-type

plasminogen activator (rt-PA) stroke study group first reported that the early administration

of rt-PA benefited carefully selected patients with acute ischemic stroke.[7] The trials

outcome led to the long-standing goal of t-PA administration within a 3-hour window for a

patient deemed likely to benefit from thrombolytic intervention. Encouraged by this
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breakthrough study and the subsequent approval by the US Food and Drug Administration

(FDA) of the use of t-PA in acute ischemic stroke, many medical professionals now consider

acute ischemic stroke to be a medical emergency that may be amenable to treatment.

Thrombolytic therapyadministered between 3 and 4.5 hours after the onset of symptoms was

found to be efficacious in improving neurologic outcomes in the European Cooperative AcuteStroke Study III (ECASS III), suggesting a wider time window for the administration of

thrombolytics.[8] Based on this and other data, in May 2009, the American Heart Association

and the American Stroke Association guidelines for the administration of rt-PA were revised

to expand the treatment window from 3 to 4.5 hours.[9] This indication has not yet been FDA

approved.

Understanding of the pathophysiology, clinical presentation, and evaluation of the stroke

patient is essential, as is knowledge of the therapeutic armamentarium currently available to

treat acute ischemic stroke, which includes supportive care, treatment of neurologic

complications, antiplatelet therapy, glycemic control, blood pressure control, prevention of

hyperthermia, and thrombolytic therapy.

Anatomy

The brain is the most metabolically active organ in the body. While representing only 2% of

the body's mass, it requires 15-20% of the total resting cardiac output to provide the

necessary glucose and oxygen for its metabolism. See theCardiac Outputcalculator.

Knowledge of cerebrovascular arterial anatomy and the territories supplied by each is useful

in determining which vessels are involved in acute stroke. Atypical patterns that do not

conform to a vascular distribution may indicate a diagnosis other than ischemic stroke, such

as venous infarction.

Arterial distributions

The cerebral hemispheres are supplied by 3 paired major arteries, specifically, the anterior,

middle, and posterior cerebral arteries.

The anterior and middle cerebral arteries carry the anterior circulation and arise from the

supraclinoid internal carotid arteries. The anterior cerebral artery (ACA) supplies the medial

portion of the frontal and parietal lobes and anterior portions of basal ganglia and anterior

internal capsule. The middle cerebral artery (MCA) supplies the lateral portions of the frontal

and parietal lobes, as well as the anterior and lateral portions of the temporal lobes, and gives

rise to perforating branches to the globus pallidus, putamen and internal capsule.

The posterior cerebral arteries arise from the basilar artery and carry the posterior circulation.The posterior cerebral artery (PCA) gives rise to perforating branches that supply the thalami

and brainstem and the cortical branches to the posterior and medial temporal lobes and

occipital lobes. The cerebellar hemispheres are supplied inferiorly by the posterior inferior

cerebellar artery (PICA) arising from the vertebral artery, superiorly by the superior

cerebellar artery, and anterolaterally by the anterior inferior cerebellar artery (AICA) from

the basilar artery.

Pathophysiology

Acute ischemic strokes are the result of vascular occlusion secondary to thromboembolic

disease (see Etiology). Ischemia results in cell hypoxia and depletion of cellular adenosine

triphosphate (ATP). Without ATP, energy failure results in an inability to maintain ionic
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gradients across the cell membrane and cell depolarization. With an influx of sodium and

calcium ions and passive inflow of water into the cell, cytotoxic edema results.[10, 11, 12]

Ischemic core and penumbra

An acute vascular occlusion produces heterogeneous regions of ischemia in the affected

vascular territory. The quantity of local blood flow is made up of any residual flow in themajor arterial source and the collateral supply, if any.

Regions of the brain with CBF lower than 10 mL/100g of tissue/min are referred to

collectively as the core, and these cells are presumed to die within minutes of stroke onset.

Zones of decreased or marginal perfusion (CBF < 25 mL/100g of tissue/min) are collectively

called the ischemic penumbra. Tissue in the penumbra can remain viable for several hours

because of marginal tissue perfusion.

Ischemic cascade

On the cellular level, the ischemic neuron becomes depolarized as ATP is depleted andmembrane ion-transport systems fail. The resulting influx of calcium leads to the release of a

number of neurotransmitters, including large quantities of glutamate, which in turn

activatesN-methyl-D-aspartate (NMDA) and other excitatory receptors on other neurons.

These neurons then become depolarized, causing further calcium influx, further glutamate

release, and local amplification of the initial ischemic insult. This massive calcium influx also

activates various degradative enzymes, leading to the destruction of the cell membrane and

other essential neuronal structures.[13]

Free radicals, arachidonic acid, and nitric oxide are generated by this process, which leads to

further neuronal damage.

Ischemia also directly results in dysfunction of the cerebral vasculature, with breakdown ofthe blood-brain barrier occurring within 4-6 hours after infarction. Following the barriers

breakdown, proteins and water flood into the extracellular space, leading to vasogenic edema.

Vasogenic edema produces greater levels of brain swelling and mass effect that peaks at 3-5

days and resolves over the next several weeks with resorption of water and proteins.[14, 15]

Within hours to days after a stroke, specific genes are activated, leading to the formation of

cytokines and other factors that, in turn, cause further inflammation and microcirculatory

compromise.[13] Ultimately, the ischemic penumbra is consumed by these progressive insults,

coalescing with the infarcted core, often within hours of the onset of the stroke.

Infarction results in the death of astrocytes as well as the supporting oligodendroglia andmicroglia cells. The infarcted tissue eventually undergoes liquefaction necrosis and is

removed by macrophages with the development of parenchymal volume loss. A well-

circumscribed region of cerebrospinal fluidlike low density is eventually seen, consisting of

encephalomalacia and cystic change. The evolution of these chronic changes may be seen in

the weeks to months following the infarction.

Hemorrhagic transformation of ischemic stroke

Hemorrhagic transformation represents the conversion of a bland infarction into an area of

hemorrhage. This is estimated to occur in 5% of uncomplicated ischemic strokes, in the

absence of thrombolytics. Hemorrhagic transformation is not always associated with

neurologic decline and ranges from small petechial hemorrhages to hematomas requiringevacuation.


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Proposed mechanisms for hemorrhagic transformation include reperfusion of ischemically

injured tissue, either from recanalization of an occluded vessel or from collateral blood

supply to the ischemic territory or disruption of the blood-brain barrier. With disruption of

the blood-brain barrier, red blood cells extravasate from the weakened capillary bed

producing petechial hemorrhage or more frank intraparenchymal hematoma.[10, 16, 17]

Hemorrhagic transformation of an ischemic infarct occurs within 2-14 days post ictus,

usually within the first week. It is more commonly seen following cardioembolic strokes and

is more likely with larger infarct size.[10, 18, 7]Hemorrhagic transformation is also more likely

following administration of t-PA, with noncontrast computed tomography (NCCT) scanning

demonstrating areas of hypodensity.[19, 20, 21]

Poststroke cerebral edema and seizures

Although significant cerebral edema can occur after anterior circulation ischemic stroke, it is

thought to be somewhat rare (10-20%).[22] Edema and herniation are the most common causes

of early death in patients with hemispheric stroke.

Seizures occur in 2-23% of patients within the first days after stroke.[22] A fraction of patients

who have experienced stroke develop chronic seizure disorders.

Etiology

Ischemic strokes result from events that limit or stop blood flow, such as extracranial or

intracranial thrombosis embolism, thrombosis in situ, or relative hypoperfusion. As blood

flow decreases, neurons cease functioning, and irreversible neuronal ischemia and injury

begin at blood flow rates of less than 18 mL/100 g of tissue/min.

Risk factors

Risk factors for ischemic stroke include modifiable and nonmodifiable etiologies.Identification of risk factors in each patient can uncover clues to the cause of the stroke and

the most appropriate treatment and secondary prevention plan.

Nonmodifiable risk factors include the following:

Age Race Sex Ethnicity History of migraine headaches Sickle cell disease Fibromuscular dysplasia Heredity

Modifiable risk factors include the following:

Hypertension (the most important) Diabetes mellitus Cardiac disease - Atrial fibrillation, valvular disease, mitral stenosis, and structural

anomalies allowing right to left shunting, such as a patent foramen ovale and atrial and

ventricular enlargement

Hypercholesterolemia Transient ischemic attacks (TIAs) Carotid stenosis Hyperhomocystinemia


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Lifestyle issues - Excessive alcohol intake, tobacco use, illicit drug use, obesity, physicalinactivity

Oral contraceptive useAmong the types of cardiac disease that increase stroke risk are atrial fibrillation, valvular

disease, mitral stenosis, and structural anomalies allowing right-to-left shunting, such as a

patent foramen ovale and atrial and ventricular enlargement.

TIA is a transient neurologic deficit with no evidence of an ischemic lesion on neuroimaging.

Roughly 80% resolve within 60 minutes.[23]

TIA can result from the aforementioned mechanisms of stroke. Data suggest that roughly

10% of patients with TIA suffer stroke within 90 days and half of these patients suffer stroke

within 2 days.[24, 25]

Genetic and inflammatory mechanisms

Evidence continues to accumulate to suggest important roles for inflammation and genetic

factors in the process ofatherosclerosisand, specifically, in stroke. According to the currentparadigm, atherosclerosis is not a bland cholesterol storage disease, as previously thought,

but a dynamic, chronic, inflammatory condition caused by a response to endothelial injury.

Traditional risk factors, such as oxidized low-density lipoprotein (LDL) and smoking,

contribute to this injury. It has been suggested, however, that infections may also contribute

to endothelial injury and atherosclerosis.

Host genetic factors, moreover, may modify the response to these environmental challenges,

although inherited risk for stroke is likely multigenic. Even so, specific single-gene disorders

with stroke as a component of the phenotype demonstrate the potency of genetics in

determining stroke risk.

Flow disturbances

Stroke symptoms can result from inadequate cerebral blood flow due to decreased blood

pressure (and specifically, decreased cerebral perfusion pressure) or as a result of

hematologic hyperviscosity due to sickle cell disease or other hematologic illnesses, such as

multiple myeloma and polycythemia vera. In these instances, cerebral injury may occur in the

presence of damage to other organ systems.

Large-artery occlusion

Large-artery occlusion typically results from embolization of atherosclerotic debris

originating from the common or internal carotid arteries or from a cardiac source. A smaller

number of large-artery occlusions may arise from plaque ulceration and in situ thrombosis.Large-vessel ischemic strokes more commonly affect the MCA territory with the ACA

territory affected to a lesser degree.

Lacunar strokes

Lacunar strokes represent 13-20% of all ischemic strokes. They occur when the penetrating

branches of the MCA, the lenticulostriate arteries, or the penetrating branches of the circle of

Willis, vertebral artery, or basilar artery become occluded.

Causes of lacunar infarcts include the following:

Microatheroma

Lipohyalinosis
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Fibrinoid necrosis secondary to hypertension or vasculitis Hyaline arteriosclerosis Amyloid angiopathy

The great majority are related to hypertension.

Embolic strokesCardiogenic emboli may account for up to 20% of acute strokes.

Emboli may arise from the heart, the extracranial arteries, or, rarely, the right-sided

circulation (paradoxical emboli) with subsequent passage through a patent foramen ovale.

The sources of cardiogenic emboli include the following:

Valvular thrombi (eg, inmitral stenosisorendocarditisor from use of a prosthetic valve) Mural thrombi (eg, inmyocardial infarction[MI],atrial fibrillation[AF],dilated

cardiomyopathy, or severe congestive heart failure [CHF])

Atrial myxomaMI is associated with a 2-3% incidence of embolic strokes, of which 85% occur in the firstmonth after MI.[26] Embolic strokes tend to have a sudden onset, and neuroimaging may

demonstrate previous infarcts in several vascular territories or calcific emboli.

Risk factors include atrial fibrillation and recent cardiac surgery. Cardioembolic strokes may

be isolated, multiple and in a single hemisphere, or scattered and bilateral; the latter 2 types

indicate multiple vascular distributions and are more specific for cardioembolism. Multiple

and bilateral infarcts can be the result of embolic showers or recurrent emboli. Other

possibilities for single and bilateral hemispheric infarctions include emboli originating from

the aortic arch and diffuse thrombotic or inflammatory processes that can lead to multiple

small-vessel occlusions.

Thrombotic strokes

Thrombogenic factors may include injury to and loss of endothelial cells, exposing the

subendothelium, and platelet activation by the subendothelium, activation of the clotting

cascade, inhibition of fibrinolysis, and blood stasis. Thrombotic strokes are generally thought

to originate on ruptured atherosclerotic plaques. Arterial stenosis can cause turbulent blood

flow, which can increase the risk for thrombus formation, atherosclerosis (ie, ulcerated

plaques), and platelet adherence; all cause the formation of blood clots that either embolize or

occlude the artery.

Intracranial atherosclerosis may be the cause in patients with widespread atherosclerosis. In

other patients, especially younger patients, other causes should be considered, including the

following[29, 10] :

Hypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein S

deficiency, pregnancy)

Sickle cell disease Fibromuscular dysplasia Arterial dissections Vasoconstriction associated with substance abuse

Watershed infarcts
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Vascular watershed, or border-zone, infarctions occur at the most distal areas between arterial

territories. They are believed to be secondary to embolic phenomenon or due to severe

hypoperfusion, such as in carotid occlusion or prolonged hypotension.

Epidemiology

Stroke is the leading cause of disability and the third leading cause of death in the UnitedStates.[33]

More than 700,000 persons per year suffer a first-time stroke in the United States, with 20%

of these individuals dying within the first year after the stroke. If current trends continue, this

number is projected to reach 1 million per year by the year 2050.[34]

The global incidence of stroke is unknown.

Stroke incidence by race and sex

In the United States, blacks have an age-adjusted risk of death from stroke that is 1.49 times

that of whites.[35]

Hispanics have a lower overall incidence of stroke than whites and blacks but more frequent

lacunar strokes and stroke at an earlier age.

Men are at higher risk for stroke than women; white males have a stroke incidence of 62.8

per 100,000, with death being the final outcome in 26.3% of cases, while women have a

stroke incidence of 59 per 100,000 and a death rate of 39.2%.

Stroke and age

Although stroke often is considered a disease of elderly persons, one third of strokes occur in

persons younger than 65 years.[34] Risk of stroke increases with age, especially in patients

older than 64 years, in whom 75% of all strokes occur.

Prognosis

The prognosis after acute ischemic stroke varies greatly, depending on the stroke severity and

on the patients premorbid condition, age, and poststroke complications.[6]

Some patients experience hemorrhagic transformation of their infarct (See Pathophysiology).

This is estimated to occur in 5% of uncomplicated ischemic strokes, in the absence of

thrombolytics. Hemorrhagic transformation is not always associated with neurologic decline

and ranges from small petechial hemorrhages to hematomas requiring evacuation.

In the Framingham and Rochester stroke studies, the overall mortality rate at 30 days afterstroke was 28%, the mortality rate at 30 days after ischemic stroke was 19%, and the 1-year

survival rate for patients with ischemic stroke was 77%.

In the United States, 20% of individuals die within the first year after a first-time stroke, as

previously mentioned.

Cardiogenic emboli are associated with the highest 1-month mortality in patients with acutestroke.

In stroke survivors from the Framingham Heart Study, 31% needed help caring for

themselves, 20% needed help when walking, and 71% had impaired vocational capacity in

long-term follow-up.


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The presence of CT scan evidence of infarction early in presentation has been associated with

poor outcome and with an increased propensity for hemorrhagic transformation after

thrombolytics.[7, 36, 37]

Acute ischemic stroke has been associated with acute cardiac dysfunction and arrhythmia,

which then correlate with worse functional outcome and morbidity at 3 months.Data suggest that severe hyperglycemia is independently associated with poor outcome and

reduced reperfusion in thrombolysis, as well as extension of the infarcted territory.[38, 39, 40]

To see complete information on Motor Recovery in Stroke, please go to the main article by

clickinghere.

Patient Education

Public education must involve all age groups. Incorporating stroke into basic life support

(BLS) and cardiopulmonary resuscitation (CPR) curricula is just one way to reach a younger

audience. Avenues to reach an audience with a higher stroke risk include using local

churches, employers, and senior organizations to promote stroke awareness.

The American Stroke Association advises the public to be aware of the symptoms of stroke

that are easily recognized and to call 911 immediately. These symptoms include the

following:

Sudden numbness or weakness of face, arm, or leg, especially on 1 side of the body Sudden confusion Sudden difficulty in speaking or understanding Sudden deterioration of vision in 1 or both eyes Sudden difficulty in walking, dizziness, and loss of balance or coordination

Sudden, severe headache with no known cause

History

A focused medical history for patients with ischemic stroke aims to identify risk factors for

atherosclerotic and cardiac disease, including hypertension, diabetes mellitus, tobacco use,

high cholesterol, and a history of coronary artery disease, coronary artery bypass, or atrial

fibrillation (see Etiology). Consider stroke in any patient presenting with acute neurologic

deficit or any alteration in level of consciousness. Common signs of stroke include the

following:

Acute hemiparesis or hemiplegia Acute hemisensory loss Complete or partial hemianopia, monocular or binocular visual loss, or diplopia Dysarthria or aphasia Ataxia, vertigo, or nystagmus Sudden decrease in consciousness

In younger patients, elicit a history of recent trauma, coagulopathies, illicit drug use

(especially cocaine), migraines, or use of oral contraceptives.

Establishing the time at which the patient was last without stroke symptoms is especially

critical when thrombolytic therapy is an option. If the patient awakens with symptoms, then

the time of onset is defined as the time at which the patient was last seen to be without

symptoms. Family members, coworkers, and bystanders may be required to help establish the


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exact time of onset, especially in right hemispheric strokes accompanied by neglect or left

hemispheric strokes with aphasia.

Physical Examination

The goals of the physical examination include detecting extracranial causes of stroke

symptoms, distinguishing stroke from stroke mimics, determining and documenting for futurecomparison the degree of deficit, and localizing the lesion.

The physical examination always includes a careful head and neck examination for signs of

trauma, infection, and meningeal irritation.

Stroke should be considered in any patient presenting with an acute neurologic deficit (focal

or global) or altered level of consciousness. No historical feature distinguishes ischemic from

hemorrhagic stroke, although nausea, vomiting, headache, and change in level of

consciousness are more common in hemorrhagic strokes.

Common symptoms of stroke include the following:

Abrupt onset of hemiparesis, monoparesis, or quadriparesis Hemisensory deficits Monocular or binocular visual loss Visual field deficits Diplopia Dysarthria Ataxia Vertigo Aphasia Sudden decrease in the level of consciousness

Although such symptoms can occur alone, they are more likely to occur in combination.

A careful search for the cardiovascular causes of stroke requires examination of the ocular

fundi (retinopathy, emboli, hemorrhage), heart (irregular rhythm, murmur, gallop), and

peripheral vasculature (palpation of carotid, radial, and femoral pulses, auscultation for

carotid bruit).

Patients with a decreased level of consciousness should be assessed to ensure that they are

able to protect their airway.

The physical examination must encompass all of the major organ systems, starting with the

airway, breathing, and circulation (ABC) and the vital signs. Patients with stroke, especially

hemorrhagic stroke, can clinically deteriorate quickly; therefore, constant reassessment iscritical. Ischemic strokes, unless large or involving the brainstem, do not tend to cause

immediate problems with airway patency, breathing, or circulation compromise. On the other

hand, patients with intracerebral or subarachnoid hemorrhage frequently require intervention

for airway protection and ventilation.

Vital signs, while nonspecific, can point to impending clinical deterioration and may assist in

narrowing the differential diagnosis. Many patients with stroke are hypertensive at baseline,

and their blood pressure may become more elevated after stroke. While hypertension at

presentation is common, blood pressure decreases spontaneously over time in most patients.

Acutely lowering blood pressure has not proven to be beneficial in these stroke patients in the

absence of signs and symptoms of associated malignant hypertension, acute myocardialinfarction, CHF, or aortic dissection.


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Head and neck examination

A careful examination of the head and neck is essential. Contusions, lacerations, and

deformities may suggest trauma as the etiology for the patient's symptoms. Auscultation of

the neck may elicit a bruit, suggesting carotid disease as the cause of the stroke.

Cardiac examination

Cardiac arrhythmias, such as atrial fibrillation, are found commonly in patients with stroke.

Similarly, strokes may occur concurrently with other acute cardiac conditions, such as acute

myocardial infarction and acute CHF; thus, auscultation for murmurs and gallops is

recommended.

Examination of the extremities

Carotid or vertebrobasilar dissections and, less commonly, thoracic aortic dissections may

cause ischemic stroke. Unequal pulses or blood pressures in the extremities may reflect the

presence of aortic dissections.

Neurologic examination

With the availability of thrombolytic therapy for acute ischemic stroke in selected patients,

the physician must be able to perform a brief, but accurate, neurologic examination on

patients with suspected stroke syndromes. The goals of the neurologic examination include

the following:

Confirming the presence of a stroke syndrome (to be defined further by cranial computedtomography [CT] scanning)

Distinguishing stroke from stroke mimics Establishing a neurologic baseline should the patient's condition improve or deteriorate

Essential components of the neurologic examination include the evaluation of cranial nerves,motor function, sensory function, cerebellar function, gait, and deep tendon reflexes, as well

as of mental status and level of consciousness. The skull and spine also should be examined,

and signs of meningismus should be sought.

Central facial weakness from a stroke should be differentiated from the peripheral weakness

ofBell palsy. With peripheral lesions (Bell palsy), the patient is unable to lift the eyebrows,

wrinkle the forehead, or or close the eye on the affected side.

A useful tool in quantifying neurological impairment is the National Institutes of Health

Stroke Scale (NIHSS). The NIHSS (see Table 2, below and theNIH Stroke Scorecalculator)

is used mostly by stroke teams. It enables the consultant to rapidly determine the severity and

possible location of the stroke. A patient's score on the NIHSS is strongly associated with

outcome, and it can help to identify those patients who are likely to benefit from thrombolytic

therapy and those who are at higher risk of developing hemorrhagic complications of

thrombolytic use.

This scale is easily used and focuses on the following 6 major areas of the neurologic

examination:

level of consciousness Visual function Motor function Sensation and neglect Cerebellar function
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LanguageThe NIHSS is a 42-point scale, with minor strokes usually being considered to have a score

less than 5. An NIHSS score greater than 10 correlates with an 80% likelihood of visual flow

deficits on angiography. However, discretion must be used in assessing the magnitude of the

clinical deficit; for instance, if a patient's only deficit is being mute, the NIHSS score will be

3. Additionally, the scale does not measure some deficits associated with posterior circulationstrokes (ie, vertigo, ataxia).

Middle cerebral artery stroke

MCA occlusion commonly produces contralateral hemiparesis, contralateral hypesthesia,

ipsilateral hemianopsia, and gaze preference toward the side of the lesion. Agnosia is

common, and receptive or expressive aphasia may result if the lesion occurs in the dominant

hemisphere. Neglect, inattention, and extinction of double simultaneous stimulation mayoccur in nondominant hemisphere lesions. Since the MCA supplies the upper extremity

motor strip, weakness of the arm and face is usually worse than that of the lower limb.

Anterior cerebral artery stroke

ACA occlusions primarily affect frontal lobe function and can result in disinhibition and

speech perseveration, producing primitive reflexes (eg, grasping, sucking reflexes), altered

mental status, impaired judgment, contralateral weakness (greater in legs than arms),

contralateral cortical sensory deficits gait apraxia, and urinary incontinence.

Posterior cerebral artery stroke

PCA occlusions affect vision and thought, producing contralateral homonymoushemianopsia, cortical blindness, visual agnosia, altered mental status, and impaired memory.

Vertebrobasilar artery occlusions are notoriously difficult to detect because they cause a wide

variety of cranial nerve, cerebellar, and brainstem deficits. These include the following:

Vertigo Nystagmus Diplopia Visual field deficits Dysphagia

Dysarthria Facial hypesthesia Syncope Ataxia

A hallmark of posterior circulation stroke is that there are crossed findings: ipsilateral cranial

nerve deficits and contralateral motor deficits. This is contrasted to anterior stroke, which

produces only unilateral findings.

Lacunar stroke

Lacunar strokes result from occlusion of the small, perforating arteries of the deep subcortical

areas of the brain. The infarcts are generally from 2-20 mm in diameter. The most common

lacunar syndromes include pure motor, pure sensory, and ataxic hemiparetic strokes. By


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virtue of their small size and well-defined subcortical location, lacunar infarcts do not lead to

impairments in cognition, memory, speech, or level of consciousness.

Treatment

Thrombolytic Therapy

Thrombolytics restore cerebral blood flow among some patients with acute ischemic stroke

and may lead to improvement or resolution of neurologic deficits. Unfortunately,

thrombolytics can also cause symptomatic intracranial hemorrhage, defined as radiographic

evidence of hemorrhage combined with escalation of the NIHSS score by 4 or more points

(see theNIH Stroke Scorecalculator). Therefore, if the patient is a candidate for thrombolytic

therapy, a thorough review of the inclusion and exclusion criteria must be performed. The

exclusion criteria largely focus on identifying risk of hemorrhagic complication associated

with thrombolytic use.

While streptokinase and rt-PA have been shown to benefit patients with acute MI, only

alteplase (rt-PA) has been shown to benefit selected patients with acute ischemic stroke.

In May 2009, the American Heart Association/American Stroke Association (AHA/ASA)

guidelines for the administration of rt-PA following acute stroke were revised to expand the

window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity

to receive benefit from this effective therapy.[8, 9, 61] Eligibility criteria for treatment in the 3-

4.5 hours after acute stroke are similar to those for treatment at earlier time periods, with any

1 of the following additional exclusion criteria:

Patients older than 80 years All patients taking oral anticoagulants are excluded regardless of the international

normalized ratio (INR)

Patients with baseline NIHSS greater than 25 Patients with a history of stroke and diabetes

Caution should be exercised in the administration of rt-PA to patients with major deficits.

Patients with evidence of low attenuation (edema or ischemia) involving more than a third of

the distribution of the MCA on their initial NCCT scan are less likely to have favorable

outcome after thrombolytic therapy and are thought to be at higher risk for hemorrhagic

transformation of their ischemic stroke.[36] In addition to the risk of symptomatic intracranial

hemorrhage (6.4% in the NINDS trial), other complications include potentially

hemodynamically significant hemorrhage and angioedema or allergic reactions.[22]

Streptokinase has not been shown to benefit patients with acute ischemic stroke, but it has

been shown to increase their risk of intracranial hemorrhage and death.

Researchers have studied the use of transcranial ultrasound as a means of assisting rt-PA in

thrombolysis. By delivering mechanical pressure waves to the thrombus, ultrasound can

theoretically expose more of its surface to the circulating thrombolytic agent. Further

research is necessary to determine the exact role of transcranial Doppler ultrasound in

assisting thrombolytics in acute ischemic stroke.

No human trials comparing the IV versus intra-arterial administration of thrombolytics exist.

Theoretic advantages to intra-arterial delivery may include the possibility that higher local

concentrations of thrombolytic would allow lower total doses of the agent (and theoretically

less risk of systemic bleed) and a longer therapeutic window; however, the longer time to

administration via the intra-arterial approach versus the IV approach may mitigate some of

this advantage.
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For more information, seeThrombolytic Therapy.

For more information, seeReperfusion Injury in Stroke.

Antiplatelet Agents

The International Stroke Trial and the Chinese Acute Stroke Trial (CAST) demonstrated

modest benefit from the use of aspirin in the setting of acute ischemic stroke. The

International Stroke Trial randomized 20,000 patients within 48 hours of stroke onset to

treatment with aspirin 325 mg, subcutaneous heparin in 2 different dose regimens, aspirin

with heparin, and a placebo. The study found that aspirin therapy reduced the risk of early

stroke recurrence.[3, 4]

CAST evaluated 21,106 patients and had a 4-week mortality reduction of 3.3% contrasted to

3.9%. A separate study also found that the combination of aspirin and lowmolecular-weight

heparin did not significantly improve outcomes.[3]

The early initiation of aspirin plus extended-release dipyridamole is likely to be as safe and

effective in preventing disability as is later initiation after 7 days following stroke onset,according to a German study. The studys authors attempted to assess the precise time to

initiate dipyridamole following ischemic stroke or TIA.[62] Patients from 46 stroke units who

presented with an NIHSS score of 20 or less were randomly assigned to receive aspirin 25 mg

plus extended-release dipyridamole 200 mg bid (early dipyridamole regimen) (n=283) or

aspirin monotherapy (100 mg once daily) for 7 days (n=260). Therapy in either group was

initiated within 24 hours of stroke onset.

After 2 weeks, all patients received aspirin plus dipyridamole for up to 90 days. At day 90,

154 (56%) patients in the early dipyridamole group and 133 (52%) in the aspirin plus later

dipyridamole group had no or mild disability (P= .45).

Other antiplatelet agents are also under evaluation for use in the acute presentation of

ischemic stroke. In a preliminary pilot study, abciximab was given within 6 hours to establish

a safety profile. A trend toward improved outcome at 3 months for the treatment versus the

placebo group was noted.[63] Further clinical trials are necessary.

Neuroprotective Agents

Despite very promising results in several animal studies, as of yet no single neuroprotective

agent in ischemic stroke is supported by randomized, placebo-controlled human studies.

Nevertheless, substantial research is underway evaluating different neuroprotective strategies,

including hypothermia.

For more information, seeNeuroprotective Agents in Stroke.

Mechanical Thrombolysis

Studies have evaluated the efficacy of mechanical clot disruption in the setting of acute

stroke. In most cases, these technologies were used in combination with thrombolysis. In an

investigation by Berlis et al, mechanical disruption via an endovascular photoacoustic device

was found to be more effective than thrombolysis alone in recanalization rates.[64]

There are currently 2 FDA-approved devices for the endovascular treatment of acute

ischemic stroke: the Concentric Retriever, which is mainly a grasping device, and the

Penumbra device, which employs an aspiration function to remove clots.[65, 66, 67] The

Penumbra trial demonstrated 82% recanalization in patients when using the aspirationfunction of the Penumbra device.
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Successful recanalization occurred in 12 of 28 patients in the Mechanical Embolus Retrieval

in Cerebral Ischemia (MERCI) 1 pilot trial, a study of the Merci Retrieval System.[68]

In a second MERCI study, recanalization was achieved in 48% of those in which the device

was deployed. Clot was successfully retrieved from all major cerebral arteries; however, the

recanalization rate for the MCA was lowest. A further study of clot extraction, the Prolyse inAcute Cerebral Thromboembolism II (PROACT II) study, identified a recanalization rate of

66%.[69, 70]

The Multi MERCI trial used the newer generation Concentric retrieval device (L5).

Recanalization was demonstrated in approximately 55% of patients who did not receive t-PA

and in 68% of those for whom t-PA was given in a group of patients with acute ischemic

stroke presenting within 8 hours of onset of symptoms. Seventy-three percent of patients who

failed IV t-PA therapy had recanalization following mechanical embolectomy.[71] However,

based on these results, the FDA has cleared the use of the MERCI device in patients who are

either ineligible for or who have failed IV thrombolytics.

According to the 2011 AHA/ASA statement on CVT, evidence is insufficient to drawconclusions about the value of endovascular thrombolysis in patients with CVT. For that

reason, the statement recommends this therapy only in patients with progressive neurological

deterioration that persists despite medical treatment.[44]

For more information, seeMechanical Thrombolysis in Acute Stroke.

For more information, seeCerebral Revascularization.

Fever Control

Antipyretics are indicated for febrile stroke patients, since hyperthermia accelerates ischemic

neuronal injury. Substantial experimental evidence suggests that mild brain hypothermia isneuroprotective. The use of induced hypothermia is currently being evaluated in phase I

clinical trials.[72, 73, 74]

High body temperature in the first 12-24 hours after stroke onset has been associated with

poor functional outcome. Results from the Paracetamol (Acetaminophen) In Stroke (PAIS)

trial did not support the routine use of high-dose acetaminophen in patients with acute stroke.

The study assessed whether early treatment with paracetamol improves functional outcome in

patients with acute stroke by reducing body temperature and preventing fever. Patients

(n=1400) were randomly assigned to receive acetaminophen (6 g daily) or placebo within 12

hours of symptom onset. After 3 months, improvement on the modified Rankin scale was not

beyond what was expected.[75]

Cerebral Edema Control

Significant cerebral edema after ischemic stroke is thought to be somewhat rare (10-20%);

maximum severity of edema is reached 72-96 hours after the onset of stroke.

Early indicators of ischemia on presentation and on NCCT scans are independent indicators

of potential swelling and deterioration. Mannitol and other therapies to reduce ICP may be

used in emergency situations, although their usefulness in swelling secondary to ischemic

stroke is unknown. No evidence exists supporting the use of corticosteroids to decrease

cerebral edema in acute ischemic stroke. Prompt neurosurgical assistance should be sought

when indicated.[22]
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Patient position, hyperventilation, hyperosmolar therapy, and, rarely, barbiturate coma may

be used, as in patients with increased ICP secondary to closed head injury. Hemicraniectomy

has shown to decrease mortality and disability among patients with large hemispheric

infarctions associated with life-threatening edema.[76, 77, 78, 79]

Seizure ControlSeizures occur in 2-23% of patients within the first days after stroke. Although seizure

prophylaxis is not indicated, prevention of subsequent seizures with standard antiepileptic

therapy is recommended.[22]

The 2011 AHA/ASA CVT statement notes a lack of clinical trials on the use of

anticonvulsants to control seizures, which occur in 37% of adults, 48% of children, and 71%

of newborns who present with CVT. Therefore, opinions on their use vary greatly. However,

because seizures increase the risk of anoxic damage, anticonvulsant treatment after even a

single seizure is reasonable.[44]

Post-ischemia strokes are usually focal, but they may be generalized. A fraction of patients

who have experienced stroke develop chronic seizure disorders. Seizures secondary to

ischemic stroke should be managed in the same manner as other seizure disorders that arise

as a result of neurologic injury.[22]

Acute Decompensation or Escalation

In the case of the rapidly decompensating patient or the patient with deteriorating neurologic

status, reassessment of ABCs as well as hemodynamics and reimaging are indicated. Many

patients who develop hemorrhagic transformation or progressive cerebral edema will

demonstrate acute clinical decline. Rarely, a patient may have escalation of symptoms

secondary to increased size of the ischemic penumbra. Some advocate resetting the time

window to zero in this circumstance and encourage consideration of reperfusion strategies.Anticoagulation and Prophylaxis

Heparin is known to prolong the lytic state caused by t-PA. Currently, data are inadequate to

justify the utilization of heparin or other anticoagulants in the acute management of patients

with ischemic stroke. Patients with embolic stroke who have another indication for

anticoagulation (eg, atrial fibrillation) may be placed on anticoagulation therapy with the goal

of preventing further embolic disease; however, the potential beneficial effects from that

decision must be weighted against the risk of hemorrhagic transformation.[22]

Immobilized stroke patients who are not receiving anticoagulants, such as IV heparin or an

oral anticoagulant, may benefit from the administration of low-dose, subcutaneous

unfractionated or lowmolecular-weight heparin, which reduces the risk of deep venous

thrombosis.[22]

For more information, seeStroke Anticoagulation and Prophylaxis.

Induced Hypothermia

Hypothermia is fast becoming the standard of care for the ongoing treatment of patients

surviving cardiac arrest due to ventricular tachycardia or ventricular fibrillation. However, no

major clinical study has demonstrated a role for hypothermia in the early treatment of

ischemic stroke.[22]

Carotid Endarterectomy


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Many surgical and endovascular techniques have been studied in the treatment of acute

ischemic stroke. Carotid endarterectomy has been used with some success in the acute

management of internal carotid artery occlusions, but no evidence supports its use in acute

stroke.

Stroke PreventionPrimary prevention refers to the treatment of individuals with no previous history of stroke.

Measures may include the use of platelet antiaggregants; 3-hydroxy-3-methylglutaryl

coenzyme A (HMG-CoA) reductase inhibitors (ie, statins); and exercise. In February 2011,

AHA/ASA guidelines for the primary prevention of stroke were published. The guideline

emphasizes the importance of lifestyle changes to reduce well-documented modifiable risk

factors, citing an 80% lower risk of a first stroke in people who follow a healthy lifestyle

compared with those who do not.[80]

Secondary prevention refers to the treatment of individuals who have already had a stroke.

Measures may include the use of platelet antiaggregants, antihypertensives, HMG-CoA

reductase inhibitors (statins), and lifestyle interventions.

Smoking cessation, blood pressure control, diabetes control, a low-fat diet, weight loss, and

regular exercise should be encouraged as strongly as the medications described above.

Written prescriptions for exercise and medications for smoking cessation (nicotine patch,

bupropion, varenicline) increase the likelihood of success with these interventions.

In addition to these well-documented factors, the 2011 AHA/ASA guidelines for primary

stroke prevention indicate that it is reasonable to avoid exposure to environmental tobacco

smoke despite a lack of stroke-specific data.

The use of aspirin for primary stroke prevention is not recommended for persons at low risk.

Aspirin is recommended for this purpose only in persons with at least a 6-10% risk ofcardiovascular events over 10 years.[80]

For patients with stroke risk due to asymptomatic carotid artery stenosis, the 2011 AHA/ASA

primary prevention guidelines state that older studies that showed revascularization surgery

as more beneficial than medical treatment may now be obsolete due to improvements in

medical therapies. Therefore, individual patient comorbidities, life expectancy, and

preferences should determine whether medical treatment alone or carotid revascularization is

selected.[80]

Atrial fibrillation is a major risk factor for stroke. The 2011 ACC Foundation

(ACCF)/AHA/Heart Rhythm Society (HRS) atrial fibrillation guideline update on dabigatran

states that the new anticoagulant dabigatran is useful as an alternative to warfarin in patients

with atrial fibrillation who do not have a prosthetic heart valve or hemodynamically

significant valve disease.[81]

The 2011 AHA/ASA primary stroke prevention guideline recommends that EDs screen for

AF and assess patients for anticoagulation therapy if AF is found.[80]

For patients with atrial fibrillation after stroke or TIA, the 2010 AHA/ASA secondary stroke

prevention guideline is in accord with the standard recommendation of warfarin, with aspirin

as an alternative for patients who cannot take oral anticoagulants. However, clopidogrel

should not be used in combination with aspirin for such patients because the bleeding risk of

the combination is comparable to that of warfarin. The guideline states that the benefit ofwarfarin after stroke or TIA in patients without atrial fibrillation has not been established.[82]


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The 2011 AHA/ASA guideline recommends ED-based smoking cessation interventions, and

considers it reasonable for EDs to screen patients for hypertension and drug abuse.[80]

Specialized Stroke Centers

Given the multitude of factors that go into the care of a patient with acute stroke, the concept

of the specialized stroke center has evolved. The Brain Attack Coalition providedrecommendations for the establishment of 2 tiers of stroke centers: primary stroke centers

(PSCs) and comprehensive stroke centers (CSCs).[22] The Joint Commission for the

Accreditation of Hospital Organizations (JCAHO) now provides accreditation for PSC, and

efforts to establish the requirements that distinguish CSC are currently ongoing.

The PSC is designed to maximize the timely provision of stroke-specific therapy, including

the administration of rt-PA, and is also capable of providing care to patients with

uncomplicated stroke. The CSC shares the commitment that the PSC has to acute delivery of

rt-PA and also provides care to patients with hemorrhagic stroke and intracranial hemorrhage

and all patients with stroke requiring ICU level of care.[22]

Once patients have been identified as potential stroke patients, their ED evaluation must be

fast-tracked to allow for the completion of required laboratory tests and requisite noncontrast

head CT scanning, as well as the notification and involvement of neurologic consultation.

These requirements have led to the development of "stroke codes" or "stroke activations" in

which EMS crews have been trained to identify possible stroke patients and arrange for their

speedy, preferential transport to a PSC or CSC.

Additionally, Stroke Centers should have personnel versed at monitoring stroke vital signs,

which include the following:

Blood pressure Glucose levels Temperature Oxygenation Change in neurologic status

Hospitals with specialized stroke teams have demonstrated significantly increased rates of

thrombolytic administration and decreased mortality. Cumulatively, the center should

identify performance measures and include mechanisms for evaluating the effectiveness of

the system as well as its component parts. The acute care of the stroke patient is more than

anything a systems-based team approach requiring the cooperation of the ED, radiology,

pharmacy, neurology, and ICU staff.

A stroke system should ensure effective interaction and collaboration among the agencies,services, and people involved in providing prevention and the timely identification, transport,

treatment, and rehabilitation of stroke patients.

For more information, seeStroke Team Creation and Primary Stroke Center Certification.

Palliative Care

Palliative care is an important component of comprehensive stroke care. Some stroke patients

will simply not recover, and others will be in a state of debilitation such that the most humane

and appropriate therapeutic concern is the comfort of the patient. Some patients have

advanced directives providing instructions for medical providers in the event of severe

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Consultations are tailored to individual patient needs.

An experienced professional who is sufficiently familiar with stroke or a stroke team should

be available within 15 minutes of the patient's arrival in the ED. Often, occupational therapy,

physical therapy, speech therapy, and physical medicine and rehabilitation experts are

consulted within the first day of hospitalization. Consultation of cardiology and vascularsurgery or neurosurgery may be warranted based on the results of carotid duplex

scanning, neuroimaging, transthoracic and transesophageal echocardiography, and clinical

course. During hospitalization, additional useful consultations include the following:

Home health care coordinator Rehabilitation coordinator Social worker Psychiatrist (commonly for depression) Dietitian

Hemorrhagic Stroke

The terms intracerebral hemorrhage and hemorrhagic stroke are used interchangeably in this

article and are regarded as separate entities from hemorrhagic transformation of ischemicstroke. Hemorrhagic stroke is less common than ischemic stroke (ie, stroke caused by

thrombosis or embolism); epidemiologic studies indicate that only 8-18% of strokes are

hemorrhagic.[1]However, hemorrhagic stroke is associated with higher mortality rates than is

ischemic stroke. (See Epidemiology.)[2]

Patients with hemorrhagic stroke present with focal neurologic deficits similar to those of

ischemic stroke but tend to be more ill than are patients with ischemic stroke. However,

though patients with intracerebral bleeds are more likely to have headache, altered mental

status, seizures, nausea and vomiting, and/or marked hypertension, none of these findings

reliably distinguishes between hemorrhagic and ischemic stroke. (See Presentation.)[3]

Brain imaging is a crucial step in the evaluation of suspected hemorrhagic stroke and must be

obtained on an emergent basis (see the image below). Brain imaging aids in excluding

ischemic stroke, and it may identify complications of hemorrhagic stroke such as

intraventricular hemorrhage, brain edema, and hydrocephalus. Either noncontrast computed

tomography (NCCT) scanning or magnetic resonance imaging (MRI) is the modality of

choice

Pathophysiology

In intracerebral hemorrhage, bleeding occurs directly into the brain parenchyma. The usual

mechanism is thought to be leakage from small intracerebral arteries damaged by chronic

hypertension. Other mechanisms include bleeding diatheses, iatrogenic anticoagulation,cerebral amyloidosis, and cocaine abuse.


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Intracerebral hemorrhage has a predilection for certain sites in the brain, including the

thalamus, putamen, cerebellum, and brainstem. In addition to the area of the brain injured by

the hemorrhage, the surrounding brain can be damaged by pressure produced by the mass

effect of the hematoma. A general increase in intracranial pressure may occur.

Subarachnoid hemorrhageThe pathologic effects of subarachnoid hemorrhage (SAH) on the brain are multifocal. SAH

results in elevated intracranial pressure and impairs cerebral autoregulation. These effects can

occur in combination with acute vasoconstriction, microvascular platelet aggregation, and

loss of microvascular perfusion, resulting in profound reduction in blood flow and cerebral

ischemia.[4]

Etiology

The etiologies of stroke are varied, but they can be broadly categorized into ischemic or

hemorrhagic. Approximately 80-87% of strokes are from ischemic infarction caused by

thrombotic or embolic cerebrovascular occlusion. Intracerebral hemorrhages account for most

of the remainder of strokes, with a smaller number resulting from aneurysmal subarachnoidhemorrhage.[5, 6, 7, 8]

In 20-40% of patients with ischemic infarction, hemorrhagic transformation may occur within

1 week after ictus.[9, 10]

Differentiating between the different types of stroke is an essential part of the initial workup

of patients with stroke, as the subsequent management of each disorder will be vastly

different.

Risk factors

The risk of hemorrhagic stroke is increased with the following factors:

Advanced age Hypertension (up to 60% of cases) Previous history of stroke Alcohol abuse Use of illicit drugs (eg, cocaine, other sympathomimetic drugs)

Causes of hemorrhagic stroke include the following[8, 9, 11, 12, 13] :

Hypertension Cerebral amyloidosis Coagulopathies Anticoagulant therapy Thrombolytic therapy for acute myocardial infarction (MI) or acute ischemic stroke (can

cause iatrogenic hemorrhagic transformation)

Arteriovenous malformation(AVM), aneurysms, and other vascular malformations (venousand cavernous angiomas)

Vasculitis Intracranial neoplasm

Amyloidosis

Cerebral amyloidosis affects people who are elderly and may cause up to 10% of

intracerebral hemorrhages. Rarely, cerebral amyloid angiopathy can be caused by mutations

in the amyloid precursor protein and is inherited in an autosomal dominant fashion.
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Coagulopathies

Coagulopathies may be acquired or inherited. Liver disease can result in a bleeding diathesis.

Inherited disorders of coagulation such as factor VII, VIII, IX, X, and XIII deficiency can

predispose to excessive bleeding, and intracranial hemorrhage has been seen in all of these

disorders.Anticoagulant therapy

Anticoagulant therapy is especially likely to increase hemorrhage risk in patients who

metabolize warfarin inefficiently. Warfarin metabolism is influenced by polymorphism in

the CYP2C9 genes. Three known variants have been described.CYP2C9*1 is the normal

variant and is associated with typical response to dosage of warfarin. Variations *2 and *3 are

relatively common polymorphisms that reduce the efficiency of warfarin metabolism.[14]

Atrioventricular malformations

Numerous genetic causes may predispose to AVMs in the brain, although AVMs are

generally sporadic. Polymorphisms in theIL6gene increase susceptibility to a number of

disorders, including AVM. Hereditary hemorrhagic telangiectasia (HHT), previously known

as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that causes dysplasia of

the vasculature. HHT is caused by mutations inENG,ACVRL1, or SMAD4 genes. Mutations

in SMAD4 are also associated with juvenile polyposis, so this must be considered when

obtaining the patients history.

HHT is most frequently diagnosed when patients present with telangiectasias on the skin and

mucosa or with chronic epistaxis from AVMs in the nasal mucosa. Additionally, HHT can

result in AVMs in any organ system or vascular bed. AVM in the gastrointestinal tract, lungs,

and brain are the most worrisome, and their detection is the mainstay of surveillance for this

disease.

Hypertension

The most common etiology of primary hemorrhagic stroke (intracerebral hemorrhage) is

hypertension. At least two thirds of patients with primary intraparenchymal hemorrhage are

reported to have preexisting or newly diagnosed hypertension. Hypertensive small-vessel

disease results from tiny lipohyalinotic aneurysms that subsequently rupture and result in

intraparenchymal hemorrhage. Typical locations include the basal ganglia, thalami,

cerebellum, and pons.

Aneurysms and subarachnoid hemorrhageThe most common cause of atraumatic hemorrhage into the subarachnoid space is rupture of

an intracranial aneurysm. Aneurysms are focal dilatations of arteries, with the most

frequently encountered intracranial type being the berry (saccular) aneurysm. Aneurysms

may less commonly be related to altered hemodynamics associated with AVMs, collagen

vascular disease, polycystic kidney disease, septic emboli, and neoplasms.

Nonaneurysmal perimesencephalic subarachnoid hemorrhage may also be seen. This

phenomenon is thought to arise from capillary or venous rupture. It has a less severe clinical

course and, in general, a better prognosis.

Berry aneurysms are most often isolated lesions whose formation results from a combination

of hemodynamic stresses and acquired or congenital weakness in the vessel wall. Saccular


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aneurysms typically occur at vascular bifurcations, with more than 90% occurring in the

anterior circulation. Common sites include the following:

The junction of the anterior communicating arteries and anterior cerebral arteriesmostcommonly, the middle cerebral artery (MCA) bifurcation

The supraclinoid internal carotid artery at the origin of the posterior communicating artery

The bifurcation of the internal carotid artery (ICA)Genetic causes of aneurysms

Intracranial aneurysms may result from genetic disorders. Although rare, several families

have been described that have a predispositioninherited in an autosomal dominant

fashionto intracranial berry aneurysms. A number of genes, all categorized asANIB genes,

are associated with this predisposition. Presently,ANIB1 throughANIB11 are known.

Autosomal dominant polycystic kidney disease (ADPKD) is another cause of intracranial

aneurysm. Families with ADPKD tend to show phenotypic similarity with regard to

intracranial hemorrhage or asymptomatic berry aneurysms.[15]

Loeys-Dietz syndrome (LDS) consists of craniofacial abnormalities, craniosynostosis,

marked arterial tortuosity, and aneurysms and is inherited in an autosomal dominant manner.

Although intracranial aneurysms occur in LDS of all types, saccular intracranial aneurysms

are a prominent feature of LDS type IC, which is caused by mutations in the SMAD3 gene.[16]

Ehlers-Danlos syndrome is a group of inherited disorders of the connective tissue that feature

hyperextensibility of the joints and changes to the skin, including poor wound healing,

fragility, and hyperextensibility. However, Ehlers-Danlos vascular type (type IV) also is

known to cause spontaneous rupture of hollow viscera and large arteries, including arteries in

the intracranial circulation.

Patients with Ehlers-Danlos syndrome may also have mild facial findings, including lobeless

ears, a thin upper lip, and a thin, sharp nose. The distal fingers may appear prematurely aged

(acrogeria). In the absence of a suggestive family history, it is difficult to separate Ehlers-

Danlos vascular type from other forms of Ehlers-Danlos. Ehlers-Danlos vascular type is

caused by mutations in the COL3A1 gene; it is inherited in an autosomal dominant manner.

Hemorrhagic transformation of ischemic stroke

Hemorrhagic transformation represents the conversion of a bland infarction into an area of

hemorrhage. Proposed mechanisms for hemorrhagic transformation include reperfusion of

ischemically injured tissue, either from recanalization of an occluded vessel or from collateral

blood supply to the ischemic territory or disruption of the blood-brain barrier. With disruptionof the blood-brain barrier, red blood cells extravasate from the weakened capillary bed,

producing petechial hemorrhage or frank intraparenchymal hematoma.[8, 9, 17] (For more

information, seeReperfusion Injury in Stroke.)

Hemorrhagic transformation of an ischemic infarct occurs within 2-14 days postictus, usually

within the first week. It is more commonly seen following cardioembolic strokes and is more

likely with larger infarct size.[8, 10, 18]Hemorrhagic transformation is also more likely

following administration of tissue plasminogen activator (tPA) in patients whose noncontrast

computed tomography (CT) scans demonstrate areas of hypodensity.

Prognosis


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The prognosis in patients with hemorrhagic stroke varies depending on the severity of stroke

and the location and the size of the hemorrhage. Lower Glasgow Coma Scale (GCS) scores

are associated with poorer prognosis and higher mortality rates. A larger volume of blood at

presentation is also associated with a poorer prognosis. Growth of the hematoma volume is

associated with a poorer functional outcome and increased mortality rate.

The intracerebral hemorrhage score is the most commonly used instrument for predicting

outcome in hemorrhagic stroke. The score is calculated as follows:

GCS score 3-4: 2 points GCS score 5-12: 1 point GCS score 13-15: 0 points Age 80 years: Yes, 1 point; no, 0 points Infratentorial origin: Yes, 1 point; no, 0 points Intracerebral hemorrhage volume 30 cm3: 1 point Intracerebral hemorrhage volume < 30 cm3: 0 points Intraventricular hemorrhage: Yes, 1 point; no, 0 points

In a study by Hemphill et al, all patients with an Intracerebral Hemorrhage Score of 0

survived, and all of those with a score of 5 died; 30-day mortality increased steadily with the

Score.[27]

Other prognostic factors include the following:

Nonaneurysmal perimesencephalic stroke has a less severe clinical course and, in general, abetter prognosis

The presence of blood in the ventricles is associated with a higher mortality rate; in onestudy, the presence of intraventricular blood at presentation was associated with a mortality

increase of more than 2-fold

Patients with oral anticoagulation-associated intracerebral hemorrhage have highermortality rates and poorer functional outcomes

In studies, withdrawal of medical support or issuance of Do Not Resuscitate (DNR) orders

within the first day of hospitalization predict poor outcome independent of clinical factors.

Because limiting care may adversely impact outcome, American Heart Association/American

Stroke Association (AHA/ASA) guidelines suggest that new DNR orders should probably be

postponed until at least the second full day of hospitalization. Patients with DNRs should be

given all other medical and surgical treatment, unless the DNR explicitly says otherwise.

History

Obtaining an adequate history includes determining the onset and progression of symptoms,

as well as assessing for risk factors and possible causative events. Such risk factors includethe following:

Previous transient ischemic attack (TIA) and stroke Hypertension Diabetes Smoking Arrhythmia and valvular disease Illicit drug use Use of anticoagulants Risk factors for thrombosis

A history of trauma, even if minor, may be important, as extracranial arterial dissections canresult in ischemic stroke.


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Hemorrhagic versus ischemic stroke

Symptoms alone are not specific enough to distinguish ischemic from hemorrhagic stroke.

However, generalized symptoms, including nausea, vomiting, and headache, as well as an

altered level of consciousness, may indicate increased intracranial pressure and are more

common with hemorrhagic strokes and large ischemic strokes.

Seizures are more common in hemorrhagic stroke than in the ischemic kind. Seizures occur

in up to 28% of hemorrhagic strokes, generally at the onset of the intracerebral hemorrhage or

within the first 24 hours.

Focal neurologic deficits

The neurologic deficits reflect the area of the brain typically involved, and stroke syndromes

for specific vascular lesions have been described. Focal symptoms of stroke include the

following:

Weakness or paresis that may affect a single extremity, one half of the body, or all 4extremities

Facial droop Monocular or binocular blindness Blurred vision or visual field deficits Dysarthria and trouble understanding speech Vertigo or ataxia Aphasia

Subarachnoid hemorrhage

Symptoms of subarachnoid hemorrhage may include the following:

Sudden onset of severe headache Signs of meningismus with nuchal rigidity Photophobia and pain with eye movements Nausea and vomiting Syncope - Prolonged or atypical

The most common clinical scoring systems for grading aneurysmal subarachnoid hemorrhage

are the Hunt and Hess grading scheme and the World Federation of Neurosurgeons (WFNS)

grading scheme, which incorporates the Glasgow Coma Scale. The Fisher Scale incorporates

findings from noncontrast computed tomography (NCCT) scans.

Physical Examination

The assessment in patients with possible hemorrhagic stroke includes vital signs; a generalphysical examination that focuses on the head, heart, lungs, abdomen, and extremities; and a

thorough but expeditious neurologic examination.[28]However, intracerebral hemorrhage may

be clinically indistinguishable from ischemic stroke. (Though stroke is less common in

children, the clinical presentation is similar.)

Hypertension (particularly systolic blood pressure [BP] greater than 220 mm Hg) is

commonly a prominent finding in hemorrhagic stroke. Higher initial BP is associated with

early neurologic deterioration, as is fever.[28]

An acute onset of neurologic deficit, altered level of consciousness/mental status, or coma is

more common with hemorrhagic stroke than with ischemic stroke. Often, this is caused by

increased intracranial pressure. Meningismus may result from blood in the subarachnoidspace.


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Examination results can be quantified using various scoring systems. These include the

Glasgow Coma Scale (GCS), the Intracerebral Hemorrhage Score (which incorporates the

GCS; see Prognosis), and theNational Institutes of Health Stroke Scale.

Focal neurologic deficits

The type of deficit depends upon the area of brain involved. If the dominant hemisphere(usually the left) is involved, a syndrome consisting of the following may result:

Right hemiparesis Right hemisensory loss Left gaze preference Right visual field cut Aphasia Neglect (atypical)

If the nondominant (usually the right) hemisphere is involved, a syndrome consisting of the

following may result:

Left hemiparesis Left hemisensory loss Right gaze preference Left visual field cut

Nondominant hemisphere syndrome may also result in neglect when the patient has left-sided

hemi-inattention and ignores the left side.

If the cerebellum is involved, the patient is at high risk for herniation and brainstem

compression. Herniation may cause a rapid decrease in the level of consciousness and may

result in apnea or death.

Specific brain sites and associated deficits involved in hemorrhagic stroke include thefollowing:

Putamen - Contralateral hemiparesis, contralateral sensory loss, contralateral conjugate gazeparesis, homonymous hemianopia, aphasia, neglect, or apraxia

Thalamus - Contralateral sensory loss, contralateral hemiparesis, gaze paresis, homonymoushemianopia, miosis, aphasia, or confusion

Lobar - Contralateral hemiparesis or sensory loss, contralateral conjugate gaze paresis,homonymous hemianopia, abulia, aphasia, neglect, or apraxia

Caudate nucleus - Contralateral hemiparesis, contralateral conjugate gaze paresis, orconfusion

Brainstem - Quadriparesis, facial weakness, decreased level of consciousness, gaze paresis,ocular bobbing, miosis, or autonomic instability

CerebellumIpsilateral ataxia, facial weakness, sensory loss; gaze paresis, skew deviation,miosis, or decreased level of consciousness

Other signs of cerebellar or brainstem involvement include the following:

Gait or limb ataxia Vertigo or tinnitus Nausea and vomiting Hemiparesis or quadriparesis Hemisensory loss or sensory loss of all 4 limbs Eye movement abnormalities resulting in diplopia or nystagmus Oropharyngeal weakness or dysphagia
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Crossed signs (ipsilateral face and contralateral body)Many other stroke syndromes are associated with intracerebral hemorrhage, ranging from

mild headache to neurologic devastation. At times, a cerebral hemorrhage may present as a

new-onset seizure.

TreatmentThe treatment and management of patients with acute intracerebral hemorrhage depends on

the cause and severity of the bleeding. Basic life support, as well as control of bleeding,

seizures, blood pressure (BP), and intracranial pressure, are critical. Medications used in the

treatment of acute stroke include the following:

Anticonvulsants - To prevent seizure recurrence Antihypertensive agents - To reduce BP and other risk factors of heart disease Osmotic diuretics - To decrease intracranial pressure in the subarachnoid space

Management begins with stabilization of vital signs. Perform endotracheal intubation for

patients with a decreased level of consciousness and poor airway protection. Intubate and

hyperventilate if intracranial pressure is elevated, and initiate administration of mannitol forfurther control. Rapidly stabilize vital signs, and simultaneously acquire an emergent

computed tomography (CT) scan. Glucose levels should be monitored, with normoglycemia

recommended.[28]Antacids are used to prevent associated gastric ulcers.

Currently, no effective targeted therapy for hemorrhagic stroke exists. Studies of recombinant

factor VIIa (rFVIIa) have yielded disappointing results. Evacuation of hematoma, either via

open craniotomy or endoscopy, may be a promising ultra-early-stage treatment for

intracerebral hemorrhage that may improve long-term prognosis.

Management of Seizures

Early seizure activity occurs in 4-28% of patients with intracerebral hemorrhage; theseseizures are often nonconvulsive.[30, 31] According to American Heart Association/American

Stroke Association (AHA/ASA) 2010 guidelines for the management of spontaneous

intracerebral hemorrhage, patients with clinical seizures or electroencephalographic (EEG)

seizure activity accompanied by a change in mental status should be treated with antiepileptic

drugs.[28]

Patients for whom treatment is indicated should immediately receive a benzodiazepine, such

as lorazepam or diazepam, for rapid seizure control. This should be accompanied by

phenytoin or fosphenytoin loading for longer-term control.

Prophylaxis

The utility of prophylactic anticonvulsant medication remains uncertain. In prospective and

population-based studies, clinical seizures have not been associated with worse neurologic

outcome or mortality. Indeed, 2 studies have reported worse outcomes in patients who did not

have a documented seizure but who received antiepileptic drugs (primarily phenytoin).[28]

The 2010 AHA/ASA guidelines do not offer recommendations on prophylactic

anticonvulsants, but suggest that continuous EEG monitoring is probably indicated in patients

with intracranial hemorrhage whose mental status is depressed out of proportion to the degree

of brain injury

Prophylactic anticonvulsant therapy has been recommended in patients with lobar

hemorrhages to reduce the risk of early seizures. One large, single-center study showed that


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prophylactic antiepileptic drugs significantly reduced the number of clinical seizures in these

patients.[30]

In addition, AHA/ASA guidelines from 2012 suggest that prophylactic anticonvulsants may

be considered for patients with aneurysmal subarachnoid hemorrhage. In such cases,

however, anticonvulsant u

stroke emed

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