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1. OVERVIEW

Practice Essentials

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

resulting in a corresponding loss of neurologic function. Acute ischemic stroke is caused by

thrombotic or embolic occlusion of a cerebral artery and is more common than hemorrhagic

stroke.

Essential update: Antihypertensive treatment found not beneficial in acute ischemic stroke

In the single-blind, randomized China Antihypertensive Trial in Acute Ischemic Stroke (CATIS)

study, which included 4,071 patients with acute ischemic stroke and elevated blood pressure,

immediate blood pressure reduction with antihypertensive medication within 48 hours of

symptom onset did not reduce the risk for death or major disability. CATIS excluded patients

who received thrombolytic therapy. Mean systolic blood pressure was reduced from 166.7 to

144.7 mm Hg within 24 hours in the antihypertensive treatment group.[1, 2]

Among the 2,038 patients who received antihypertensive treatment, 683 reached the primary

endpoint of death or major disability at 14 days or hospital discharge, compared with 681 of the

2,033 patients who received no antihypertensive treatment. At 3-month follow-up, 500 patients

in the antihypertensive treatment group and 502 patients in the control group reached the

secondary endpoint of death or major disability.[1, 2]

Signs and symptoms

Consider stroke in any patient presenting with acute neurologic deficit or any alteration in level

of consciousness. Common stroke signs and symptoms include the following:

Abrupt onset of hemiparesis, monoparesis, or (rarely) quadriparesis Hemisensory deficits Monocular or binocular visual loss Visual field deficits Diplopia


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Dysarthria Facial droop Ataxia Vertigo (rarely in isolation) Nystagmus Aphasia Sudden decrease in level of consciousness

Although such symptoms can occur alone, they are more likely to occur in combination. No

historical feature distinguishes ischemic from hemorrhagic stroke, although nausea, vomiting,

headache, and sudden change in level of consciousness are more common in hemorrhagic

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

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

With the availability of fibrinolytic 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 Distinguishing stroke from stroke mimics Establishing a neurologic baseline, should the patient's condition improve or deteriorate Establishing stroke severity, using a structured neurologic exam and score (National Institutes

of Health Stroke Scale [NIHSS]) to assist in prognosis and therapeutic selectionEssential

components of the neurologic examination include the following evaluations:

Cranial nerves Motor function Sensory function Cerebellar function Gait Deep tendon reflexes Language (expressive and receptive capabilities) Mental status and level of consciousness


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The skull and spine also should be examined, and signs of meningismus should be sought.

Diagnosis

Emergent brain imaging is essential for confirming the diagnosis of ischemic stroke. Noncontrast

computed tomography (CT) scanning is the most commonly used form of neuroimaging in the

acute evaluation of patients with apparent acute stroke. The following neuroimaging techniques

are also used:

CT angiography and CT perfusion scanning Magnetic resonance imaging (MRI) Carotid duplex scanning Digital subtraction angiographyLumbar 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

Laboratory studies

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

following:

Complete blood count (CBC): A baseline study that may reveal a cause for the stroke (eg,polycythemia, thrombocytosis, thrombocytopenia, leukemia) or provide evidence of

concurrent illness (eg, anemia)

Basic chemistry panel: A baseline study that may reveal a stroke mimic (eg, hypoglycemia,hyponatremia) or provide evidence of concurrent illness (eg, diabetes, renal insufficiency)

Coagulation studies: May reveal a coagulopathy and are useful when fibrinolytics oranticoagulants are to be used

Cardiac biomarkers: Important because of the association of cerebral vascular disease andcoronary artery disease

Toxicology screening: May assist in identifying intoxicated patients with symptoms/behaviormimicking stroke syndromes


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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: In selected patients with suspected hypoxemia, arterial blood gasdefines the severity of hypoxemia and may be used to detect acid-base disturbances

SeeWorkup for more detail.

Management

The goal for the emergent management of stroke is to complete the following within 60 minutes

of patient arrival[3] :

Assess airway, breathing, and circulation (ABCs) and stabilize the patient as necessary Complete the initial evaluation and assessment, including imaging and laboratory studies Initiate reperfusion therapy, if appropriate

Critical treatment decisions focus on the following:

The need for airway management

Optimal blood pressure control Identifying potential reperfusion therapies (eg, intravenous fibrinolysis with rt-PA or intra-

arterial approaches)

Involvement of a physician with a special interest in stroke is ideal. Stroke care units with

specially trained personnel exist and improve outcomes.

Ischemic stroke therapies include the following:

Fibrinolytic therapy Antiplatelet agents[4, 5] Mechanical thrombectomy

Treatment of comorbid conditions may include the following:

Reduce fever
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Correct hypotension/significant hypertension Correct hypoxia Correct hypoglycemia Manage cardiac arrhythmias Manage myocardial ischemia

Stroke prevention

Primary stroke prevention refers to the treatment of individuals with no previous history of

stroke. Measures may include use of the following:

Platelet antiaggregants Statins Exercise Lifestyle interventions (eg, smoking cessation, alcohol moderation)

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

Measures may include use of the following:

Platelet antiaggregants Antihypertensives Statins Lifestyle interventions

SeeTreatment andMedication for more detail.

Image library
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Maximum intensity projection (MIP) image from a computed

tomography angiogram (CTA) demonstrates a filling defect or high-grade stenosis at the

branching point of the right middle cerebral artery (MCA) trunk (red circle), suspicious for

thrombus or embolus. CTA is highly accurate in detecting large- vessel stenosis and occlusions,

which account for approximately one third of ischemic strokes.Background

Acute ischemic stroke (AIS) is characterized by the sudden loss of blood circulation to an area of

the brain, typically in a vascular territory, resulting in a corresponding loss of neurologic

function. Also previously called cerebrovascular accident (CVA) or stroke syndrome, stroke is a

nonspecific state of brain injury with neuronal dysfunction that has several pathophysiologic

causes. Strokes can be divided into 2 types: hemorrhagic or ischemic. Acute ischemic stroke is

caused by thrombotic or embolic occlusion of a cerebral artery. (See the image below.)

Maximum intensity projection (MIP) image from a computed

tomography angiogram (CTA) demonstrates a filling defect or high-grade stenosis at the

branching point of the right middle cerebral artery (MCA) trunk (red circle), suspicious for

thrombus or embolus. CTA is highly accurate in detecting large- vessel stenosis and occlusions,

which account for approximately one third of ischemic strokes.
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Nearly 800,000 people suffer strokes each year in the United States; 82-92% of these strokes are

ischemic. Stroke is the fourth leading cause of adult death and disability, resulting in over $72

billion in annual cost.[6]

Ischemic and hemorrhagic stroke cannot be reliably differentiated on the basis of clinical

examination findings alone. Further evaluation, especially with brain imaging tests (ie, computed

tomography [CT] scanning or magnetic resonance imaging [MRI]), is required. (See Workup.)

Stroke categories

The system of categorizing stroke developed in the multicenter Trial of ORG 10172 in Acute

Stroke Treatment (TOAST) divides ischemic strokes into the following 3 major subtypes[4] :

Large-artery Small-vessel, or lacunar Cardioembolic infarction

Large-artery infarctions often involve thrombotic in situ occlusions on atherosclerotic lesions in

the carotid, vertebrobasilar, and cerebral arteries, typically proximal to major branches; however,

large-artery infarctions may also be cardioembolic.

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.[7] (See

Pathophysiology.)

Treatment

Recanalization strategies, including intravenous recombinant tissue-type plasminogen activator

(rt-PA) and intra-arterial approaches, attempt to establish revascularization so that cells in the

ischemic penumbra (a metabolically active region, peripheral to the ischemic area, where blood

flow is reduced) can be rescued before irreversible injury occurs. Restoring blood flow can

mitigate the effects of ischemia only if performed quickly.

The US Food and Drug Administration (FDA) has approved the use of rt-PA in patients who

meet criteria set forth by the National Institute of Neurologic Disorders and Stroke (NINDS). In


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particular, rt-PA must be given within 3 hours of stroke onset and only after CT scanning has

ruled out hemorrhagic stroke.

On the basis of recent European data, the American Heart Association and American Stroke

Association recommended expanding the window of treatment from 3 hours to 4.5 hours, with

more stringent exclusion criteria for the later period (see Treatment). The FDA has not yet

approved rt-PA for this expanded indication, but this has become the community standard in

many institutions.

Other aspects of treatment for acute ischemic stroke include the following:

Treatment of neurologic complications

Supplemental oxygen as required Antiplatelet therapy Glycemic control Optimal blood pressure control Prevention of hyperthermia

See alsoHemorrhagic Stroke.

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.

Knowledge of cerebrovascular arterial anatomy and the territories supplied by the cerebral

arteries is useful in determining which vessels are involved in acute stroke. Atypical patterns of

brain ischemia that do not conform to specific vascular distributions may indicate a diagnosis

other than ischemic stroke, such as venous infarction.

Arterial distributions

In a simplified model, the cerebral hemispheres are supplied by 3 paired major arteries,

specifically, the anterior, middle, and posterior cerebral arteries.
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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. (See the image below.)

Lateral view of a cerebral angiogram illustrates the branches of

the anterior cerebral artery (ACA) and Sylvian triangle. The pericallosal artery has been

described to arise distal to the anterior communicating artery or distal to the origin of the

callosomarginal branch of the ACA. The segmental anatomy of the ACA has been described as

follows: the A1 segment extends from the internal carotid artery (ICA) bifurcation to the anterior

communicating artery; A2 extends to the junction of the rostrum and genu of the corpus

callosum; A3 extends into the bend of the genu of the corpus callosum; A4 and A5 extend

posteriorly above the callosal body and superior portion of the splenium. The Sylvian triangle

overlies the opercular branches of the middle cerebral artery (MCA), with the apex representing

the Sylvian point.

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 MCA is the dominant source

of vascular supply to the hemispheres. (See the images below.)

The supratentorial vascular territories of the major cerebral

arteries are demonstrated superimposed on axial (left) and coronal (right) T2-weighted images

through the level of the basal ganglia and thalami. The middle cerebral artery (MCA; red)

supplies the lateral aspects of the hemispheres, including the lateral frontal, parietal, and anterior


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temporal lobes; insula; and basal ganglia. The anterior cerebral artery (ACA; blue) supplies the

medial frontal and parietal lobes. The posterior cerebral artery (PCA; green) supplies the thalami

and occipital and inferior temporal lobes. The anterior choroidal artery (yellow) supplies the

posterior limb of the internal capsule and part of the hippocampus extending to the anterior and

superior surface of the occipital horn of the lateral ventricle. Frontal view of

a cerebral angiogram with selective injection of the left internal carotid artery (ICA) illustrates

the anterior circulation. The anterior cerebral artery (ACA) consists of the A1 segment proximal

to the anterior communicating artery, with the A2 segment distal to it. The middle cerebral artery

(MCA) can be divided into 4 segments: the M1 (horizontal segment) extends to the anterior basal

portion of the insular cortex (the limen insulae) and gives off lateral lenticulostriate branches, the

M2 (insular segment), M3 (opercular branches), and M4 (distal cortical branches on the lateral

hemispheric convexities).

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. (See Table 1, below.)

The cerebellar hemispheres are supplied as follows:
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Inferiorly by the posterior inferior cerebellar artery (PICA), arising from the vertebral artery

(see the image below) Frontal projection from a right vertebral

artery angiogram illustrates the posterior circulation. The vertebral arteries join to form the

basilar artery. The posterior inferior cerebellar arteries (PICAs) arise from the distal vertebral

arteries. The anterior inferior cerebellar arteries (AICAs) arise from the proximal basilar

artery. The superior cerebellar arteries (SICAs) arise distally from the basilar artery prior to its

bifurcation into the posterior cerebral arteries (PCAs).

Superiorly by the superior cerebellar artery Anterolaterally by the anterior inferior cerebellar artery (AICA), from the basilar artery

Table 1. Vascular Supply to the Brain(Open Table in a new window)

VASCULAR

TERRITORY

Structures Supplied

Anterior Circulation (Carotid)

Anterior Cerebral Artery Cortical branches:medial frontal and parietal lobe

Medial lenticulostriate branches: caudate head, globus pallidus,

anterior limb of internal capsule


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Middle Cerebral Artery Cortical branches:lateral frontal and parietal lobes lateral and

anterior temporal lobe

Lateral lenticulostriate branches: globus pallidus and putamen,

internal capsule

Anterior Choroidal

Artery

Optic tracts, medial temporal lobe, ventrolateral thalamus, corona

radiata, posterior limb of the internal capsule

Posterior Circulation (Vertebrobasilar)

Posterior Cerebral

Artery

Cortical branches:occipital lobes, medial and posterior temporal

and parietal lobes

Perforating branches:brainstem, posterior thalamus and

midbrain

Posterior Inferior

Cerebellar Artery

Inferior vermis; posterior and inferior cerebellar hemispheres


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Anterior Inferior

Cerebellar Artery

Anterolateral cerebellum

Superior CerebellarArtery

Superior vermis; superior cerebellum

Pathophysiology

Acute ischemic strokes result from vascular occlusion secondary to thromboembolic disease (see

Etiology). Ischemia causes cell hypoxia and depletion of cellular adenosine triphosphate (ATP).

Without ATP, there is no longer the energy to maintain ionic gradients across the cell membraneand cell depolarization. Influx of sodium and calcium ions and passive inflow of water into the

cell lead to cytotoxic edema.[8, 9, 10]

Ischemic core and penumbra

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

territory. Local blood flow is limited to any residual flow in the major arterial source plus the

collateral supply, if any.

Affected regions with cerebral blood flow of lower than 10 mL/100 g of tissue/min are referred

to collectively as the core. These cells are presumed to die within minutes of stroke onset.[11]

Zones of decreased or marginal perfusion (cerebral blood flow < 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.[11]

Ischemic cascade

On the cellular level, the ischemic neuron becomes depolarized as ATP is depleted and

membrane ion-transport systems fail. Disruption of cellular metabolism also impairs normal

sodium-potassium plasma membrane pumps, producing an intracellular increase in sodium,


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which in turns increases intracellular water content. This cellular swelling is referred to as

cytotoxic edema and occurs very early in cerebral ischemia.

Cerebral ischemia impairs the normal sodium-calcium exchange protein also found on cell

plasma membranes. 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.[12] 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 of the

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.

This produces greater levels of brain swelling and mass effect that peak at 3-5 days and resolve

over the next several weeks with resorption of water and proteins.[13, 14]

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.[12] 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 oligodendroglial and

microglial 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, resulting from encephalomalacia and cystic

change, is eventually seen. The evolution of these chronic changes may be seen in the weeks to

months following the infarction. (See the images below.)


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Vascular distributions: Middle cerebral artery (MCA) infarction. Noncontrast computed

tomography (CT) scanning demonstrates a large acute infarction in the MCA territory involving

the lateral surfaces of the left frontal, parietal, and temporal lobes, as well as the left insular and

subinsular regions, with mass effect and rightward midline shift. There is sparing of the caudate

head and at least part of the lentiform nucleus and internal capsule, which receive blood supply

from the lateral lenticulostriate branches of the M1 segment of the MCA. Note the lack of

involvement of the medial frontal lobe (anterior cerebral artery [ACA] territory), thalami, and

paramedian occipital lobe (posterior cerebral artery [PCA] territory).

Vascular distributions: Anterior cerebral artery (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 middle cerebral artery

[MCA] distributions), greater on the left indicating multivessel involvement and suggesting
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emboli.The supratentorial vascular territories of the major cerebral arteries are demonstrated

superimposed on axial (left) and coronal (right) T2-weighted images through the level of the

basal ganglia and thalami. The middle cerebral artery (MCA; red) supplies the lateral aspects of

the hemispheres, including the lateral frontal, parietal, and anterior temporal lobes; insula; and

basal ganglia. The anterior cerebral artery (ACA; blue) supplies the medial frontal and parietal

lobes. The posterior cerebral artery (PCA; green) supplies the thalami and occipital and inferior

temporal lobes. The anterior choroidal artery (yellow) supplies the posterior limb of the internal

capsule and part of the hippocampus extending to the anterior and

superior surface of the occipital horn of the lateral ventricle.Vascular distributions: Anterior

choroidal artery infarction. The diffusion-weighted image (left) demonstrates high signal with

associated signal dropout on the apparent diffusion coefficient (ADC) map involving the

posterior limb of the internal capsule. This is the typical distribution of the anterior choroidal

artery, the last branch of the internal carotid artery (ICA) before bifurcating into the anterior and

middle cerebral arteries. The anterior choroidal artery may also arise from the middle cerebralartery (MCA).

Hemorrhagic transformation of ischemic stroke

Hemorrhagic transformation represents the conversion of an ischemic infarction into an area of

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

of fibrinolytic treatment. Hemorrhagic transformation is not always associated with neurologic

decline, with the conversion ranging from the development of small petechial hemorrhages to the

formation of hematomas that produce neurologic decline and may necessitate surgical evacuationor decompressive hemicraniectomy.

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


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barrier, red blood cells extravasate from the weakened capillary bed, producing petechial

hemorrhage or more frank intraparenchymal hematoma.[8, 15, 16]

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 to occur with larger infarct volumes.[5, 8, 17] Hemorrhagic transformation is also more likely

following administration of rt-PA in patients whose noncontrast CT (NCCT) scans demonstrate

areas of hypodensity.[18, 19, 20]

Poststroke cerebral edema and seizures

Although clinically significant cerebral edema can occur after anterior circulation ischemic

stroke, it is thought to be somewhat rare (10-20%).[3]

Edema and herniation are the most commoncauses of early death in patients with hemispheric stroke.

Seizures occur in 2-23% of patients within the first days after ischemic stroke.[3] 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 thrombotic embolism, thrombosis in situ, or relative hypoperfusion. As blood flow

decreases, neurons cease functioning. Although a range of thresholds has been described,

irreversible neuronal ischemia and injury is generally thought to begin at blood flow rates of less

than 18 mL/100 g of tissue/min, with cell death occurring rapidly at rates below 10 mL/100 g of

tissue/min

Risk factors

Risk factors for ischemic stroke include modifiable and nonmodifiable conditions. Identificationof 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 (although there are likely many others):

Age


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Race Sex Ethnicity History of migraine headaches Fibromuscular dysplasia Heredity: Family history of stroke or transient ischemic attacks (TIAs)

In a prospective study of 27,860 women aged 45 years or older who were participating in the

Women's Health Study, Kurth et al found that migraine with aura was a strong risk factor for any

type of stroke. The adjusted incidence of this risk factor per 1000 women per year was similar to

those of other known risk factors, including systolic blood pressure 180 mm Hg or higher, body

mass index 35 kg/m2 or greater, history of diabetes, family history of myocardial infarction, and

smoking.[21]

For migraine with aura, the total incidence of stroke in the study was 4.3 per 1000 women per

year, the incidence of ischemic stroke was 3.4 per 1000 per year, and the incidence of

hemorrhagic stroke was 0.8 per 1000 per year.

Modifiable risk factors include the following[22] :

Hypertension (the most important) Diabetes mellitus Cardiac disease: Atrial fibrillation, valvular disease, heart failure, mitral stenosis, structural

anomalies allowing right-to-left shunting (eg, patent foramen ovale), and atrial and ventricular

enlargement

Hypercholesterolemia TIAs Carotid stenosis Hyperhomocystinemia Lifestyle issues: Excessive alcohol intake, tobacco use, illicit drug use, physical inactivity[23] Obesity Oral contraceptive use/postmenopausal hormone use Sickle cell disease


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Genetic and inflammatory mechanisms

Evidence continues to accumulate that inflammation and genetic factors have important roles in

the development ofatherosclerosis and, specifically, in stroke. According to the current

paradigm, 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) cholesterol 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 disorderswith stroke as a component of the phenotype demonstrate the potency of genetics in determining

stroke risk.

A number of genes are known to increase susceptibility to ischemic stroke. Mutations to

theF2andF5 genes are relatively common in the general population and increase the risk of

thrombosis. Mutations in the following genes also are known to increase the risk of stroke:

NOS3: A nitric oxide synthetase gene; involved in vascular relaxation

[24]

ALOX5AP: Involved in the metabolism of arachidonic acid[25] PRKCH: Involved in major signal transduction systems[26]Hyperhomocysteinemia and homocystinuria

Hyperhomocysteinemia is implicated in the pathogenesis of ischemic stroke. The most common

concern is mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. In many

populations, the mutant allele frequency reaches polymorphic proportions, and the risk factor for

cerebrovascular disease is related to the serum level of homocysteine. Furthermore, in persons

who are compound heterozygotes forMTHFRmutation, if elevated homocysteine is found it can

be lowered with oral folic acid therapy.

In addition, hyperhomocysteinemia can be seen in cystathione beta synthetase (CBS) deficiency,

which is generally referred to as homocystinuria. This disorder is inherited in an autosomal


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recessive manner. Symptoms usually manifest early in life. Patients have a marfanoid habitus,

ectopia lentis, and myopia and generally have intellectual disability.[27]

Thromboembolic events are the most common cause of death for patients with homocystinuria

and may be of any type, including myocardial infarction. The risk of having a vascular event in

homocystinuria is 50% by age 30.[28] It was previously suggested that persons who are

heterozygous for mutations in the CBS gene may have an increased risk of cerebrovascular

disease as well, but several more recent studies on this subject failed to replicate this finding.

Amyloid angiopathies

Amyloid angiopathies are also known to increase risk for stroke and dementia. Mutations in

the CST3gene are causative and are inherited in an autosomal dominant manner. Sufferers will

have diffuse deposition of amyloid, including in the brain. The onset of symptoms is typically in

the third or fourth decade of life, with death occurring before age 60 years. These angiopathies

appear to be most common in the Icelandic population.[29]

CADASIL

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy

(CADASIL), is caused by mutations in theNOTCH3 gene. It affects the small arteries of the

brain. Strokelike episodes typically occur at a mean age of 46 years, with an age range of 19-67

years. White-matter changes in the brain are typically evident by young adulthood and progress

over time.[30]

Migraine headaches occur in 30-40% of people with CADASIL. Approximately 60% of

symptomatic individuals have cognitive deficits, which can start as early as age 35 years, and

many develop multi-infarct dementia.[31]

Other mutations

Genome-wide association studies have revealed additional loci that are commonly associated

with ischemic stroke. Early onset ischemic stroke has been found to be associated with 2 single-

nucleotide polymorphisms on 2q23.3.[32]


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Large-vessel stroke has been associated with variations inHDAC9,PITX2,

andZFHX3.[33]HDAC9is located on7p21.1, whilePITX2andZFHX3are located on 9p21. It is of

note that the 9p21 locus has also been associated with cardiovascular disease.

A polymorphism at 2q36.3 was found in which adenosine substitution conferred a lower risk of

ischemic stroke in an additive fashion.[34] An additional study suggested an association between

ischemic stroke and a locus on 12p13.[35]

For more information, seeGenetic and Inflammatory Mechanisms in Stroke. In addition,

complete information on the following metabolic diseases and stroke can be found in the

following main articles:

Methylmalonic Acidemia Homocystinuria/Homocysteinemia Fabry Disease MELAS Syndrome Hyperglycemia and Hypoglycemia in Stroke

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. (See the images below.)
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Noncontrast computed tomography (CT) scan in a 52-year-old man

with a history of worsening right-sided weakness and aphasia demonstrates diffuse hypodensity

and sulcal effacement with mass effect involving the left anterior and middle cerebral artery

territories consistent with acute infarction. There are scattered curvilinear areas of hyperdensity

noted suggestive of developing petechial hemorrhage in this large area of infarction.

Magnetic resonance angiogram (MRA) in a 52-year-old man

demonstrates occlusion of the left precavernous supraclinoid internal carotid artery (ICA, red

circle), occlusion or high-grade stenosis of the distal middle cerebral artery (MCA) trunk and

attenuation of multiple M2 branches. The diffusion-weighted image (right) demonstrates high

signal confirmed to be true restricted diffusion on the apparent diffusion coefficient (ADC) map


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consistent with acute infarction. Maximum intensity projection (MIP)

image from a computed tomography angiogram (CTA) demonstrates a filling defect or high-

grade stenosis at the branching point of the right middle cerebral artery (MCA) trunk (red circle),

suspicious for thrombus or embolus. CTA is highly accurate in detecting large- vessel stenosis

and occlusions, which account for approximately one third of ischemic strokes.Lacunar strokes

Lacunar strokes represent 13-20% of all ischemic strokes. They result from occlusion of the

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

circle of Willis, vertebral artery, or basilar artery. The great majority of lacunar strokes are

related to hypertension. (See the image below.)

Axial noncontrast computed tomography (CT) scan demonstrates

a focal area of hypodensity in the left posterior limb of the internal capsule in a 60-year-old man

with acute onset of right-sided weakness. The lesion demonstrates high signal on the fluid-

attenuated inversion recovery (FLAIR) sequence (middle image) and diffusion-weighted

magnetic resonance imaging (MRI) scan (right image), with low signal on the apparent diffusion

coefficient (ADC) maps indicating an acute lacunar infarction. Lacunar infarcts are typically no

more than 1.5 cm in size and can occur in the deep gray matter structures, corona radiata,

brainstem, and cerebellum.

Causes of lacunar infarcts include the following:

Microatheroma Lipohyalinosis


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

Embolic strokes

Cardiogenic emboli may account for up to 20% of acute strokes. Emboli may arise from the

heart, the extracranial arteries, including the aortic arch or, rarely, the right-sided circulation

(paradoxical emboli) with subsequent passage through a patent foramen ovale.[36] Sources of

cardiogenic emboli include the following:

Valvular thrombi (eg, inmitral stenosis orendocarditis or from use of a prosthetic valve) Mural thrombi (eg, inmyocardial infarction,atrial fibrillation, dilated cardiomyopathy, or

severe congestive heart failure)

Atrial myxomaAcute myocardial infarction is associated with a 2-3% incidence of embolic strokes, of which

85% occur in the first month after the infarction.[37] Embolic strokes tend to have a sudden onset,

and neuroimaging may demonstrate previous infarcts in several vascular territories or may show

calcific emboli.

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. (See the image below.)[38, 39]

Cardioembolic stroke: Axial diffusion-weighted images demonstrate scattered foci of high signal

in the subcortical and deep white matter bilaterally in a patient with a known cardiac source for
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embolization. An area of low signal in the left gangliocapsular region may be secondary to prior

hemorrhage or subacute to chronic lacunar infarct. Recurrent strokes are most commonly

secondary to cardioembolic phenomenon.

For more information, seeCardioembolic Stroke.

Thrombotic strokes

Thrombogenic factors may include injury to and loss of endothelial cells; this loss exposes the

subendothelium and results in 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 promote 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 of thrombotic stroke in patients with widespread

atherosclerosis. In other patients, especially younger patients, other causes should be considered,

including the following[8, 40] :

Hypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein Sdeficiency, pregnancy)

Sickle cell disease Fibromuscular dysplasia Arterial dissections Vasoconstriction associated with substance abuse (eg, cocaine, amphetamines)

Watershed infarcts

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 to severe

hypoperfusion, as occurs, for example, in carotid occlusion or prolonged hypotension. (See the

image below.)[41, 42, 43]


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Magnetic resonance imaging (MRI) scan was obtained in a 62-

year-old man with hypertension and diabetes and a history of transient episodes of right-sided

weakness and aphasia. The fluid-attenuated inversion recovery (FLAIR) image (left)

demonstrates patchy areas of high signal arranged in a linear fashion in the deep white matter,

bilaterally. This configuration is typical for deep border-zone, or watershed, infarction, in this

case the anterior and posterior middle cerebral artery (MCA) watershed areas. The left-sided

infarcts have corresponding low signal on the apparent diffusion coefficient (ADC) map (right),signifying acuity. An old left posterior parietal infarct is noted as well.

Flow disturbances

Stroke symptoms can result from inadequate cerebral blood flow because of decreased blood

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

hyperviscosity from 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. For more information, seeBlood Dyscrasias and Stroke.

Epidemiology

Stroke is the leading cause of disability and the fourth leading cause of death in the United

States.[44, 45] Each year, approximately 795,000 people in the United States experience new

(610,000 people) or recurrent (185,000 people) stroke.[6]Epidemiologic studies indicate that 82-

92% of strokes in the United States are ischemic.

According to the World Health Organization (WHO), 15 million people suffer stroke worldwide

each year. Of these, 5 million die, and another 5 million are left permanently disabled.[46]

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

of whites.[47] 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 men 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%.

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

persons younger than 65 years.[45] Risk of stroke increases with age, especially in patients older

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

Prognosis

In the Framingham and Rochester stroke studies, the overall mortality rate at 30 days after stroke

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%. However, the prognosis after acute ischemic

stroke varies greatly in individual patients, depending on the stroke severity and on the patients

premorbid condition, age, and poststroke complications.[4]

A study utilizing the large national Get With The Guidelines - Stroke registry found that the

baseline National Institutes of Health Stroke Scale (NIHSS) score was the strongest predictor of

early mortality risk, even more so than currently used mortality prediction models incorporating

multiple clinical data.[48] Cardiogenic emboli are associated with the highest 1-month mortality in

patients with acute stroke.

The presence of computed tomography (CT) scan evidence of infarction early in presentation has

been associated with poor outcome and with an increased propensity for hemorrhagic

transformation after fibrinolytic therapy (see Pathophysiology).

[5, 49, 50]

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

fibrinolytic therapy, although it is not always associated with neurologic decline. Indeed,

hemorrhagic transformation ranges from the development of small petechial hemorrhages to the

formation of hematomas requiring evacuation.


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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

fibrinolysis, as well as extension of the infarcted territory.[51, 52, 53]

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. For more information, see the Medscape Reference articleMotor Recovery in Stroke.

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 could include local churches, employers,

and senior organizations to promote stroke awareness.

The American Stroke Association (ASA) advises the public to be aware of the symptoms of

stroke that are easily recognized, including the sudden onset of any of the following, and to call

911 immediately:

Numbness or weakness of face, arm, or leg, especially on 1 side of the body

Confusion Difficulty in speaking or understanding Deterioration of vision in 1 or both eyes Difficulty in walking, dizziness, and loss of balance or coordination Severe headache with no known cause

In the spring of 2013, the ASA launched a stroke public education campaign that uses the

acronymFAST to teach the warning signs of stroke and the importance of calling 911, asfollows:

F: Face drooping A: Arm weakness S: Speech difficulty
http://emedicine.medscape.com/article/324386-overviewhttp://strokeassociation.org/STROKEORG/WarningSigns/Stroke-Warning-Signs-and-Symptoms_UCM_308528_SubHomePage.jsphttp://strokeassociation.org/STROKEORG/WarningSigns/Stroke-Warning-Signs-and-Symptoms_UCM_308528_SubHomePage.jsphttp://emedicine.medscape.com/article/324386-overview


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T: Time to call 911


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BAB II PRESENTATION

History

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

atherosclerotic and cardiac disease, including the following (see Etiology):

Hypertension Diabetes mellitus Tobacco use High cholesterol History of coronary artery disease, coronary artery bypass, or atrial fibrillation

In younger patients, elicit a history of the following:

Recent trauma Coagulopathies Illicit drug use (especially cocaine) Migraines Oral contraceptive use

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 fromhemorrhagic stroke, although nausea, vomiting, headache, and a sudden change in the patients

level of consciousness are more common in hemorrhagic strokes.

Consider stroke in any patient presenting with acute neurologic deficit or any alteration in level

of consciousness. Common signs and symptoms of stroke include the abrupt onset of any of the

following:

Hemiparesis, monoparesis, or (rarely) quadriparesis Hemisensory deficits Monocular or binocular visual loss Visual field deficits Diplopia Dysarthria


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Facial droop Ataxia Vertigo (rarely in isolation) Aphasia Sudden decrease in the level of consciousness

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

Establishing the time at which the patient was last without stroke symptoms, or last known to be

normal, is especially critical when fibrinolytic therapy is an option. Unfortunately, the median

time from symptom onset to emergency department (ED) presentation ranges from 4-24 hours in

the United States.[3]

Multiple factors contribute to delays in seeking care for symptoms of stroke. Many strokes occur

while patients are sleeping and are not discovered until the patient wakes (this phenomenon is

also known as "wake-up" stroke). Stroke can leave some patients too incapacitated to call for

help. Occasionally, a stroke goes unrecognized by patients or their caregivers.[6, 54]

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. Input from family members, coworkers, and

bystanders may be required to help establish the exact time of onset, especially in right

hemispheric strokes accompanied by neglect or left hemispheric strokes with aphasia.

Physical Examination

The goals of the physical examination are as follows:

Detect extracranial causes of stroke symptoms Distinguish stroke from stroke mimics

Determine and document for future comparison the degree of deficit Localize the lesion Identify comorbidities Identify conditions that may influence treatment decisions (eg, trauma, active bleeding, active

infection)


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

trauma, infection, and meningeal irritation. A careful search for the cardiovascular causes of

stroke requires examination of the following:

Ocular fundi (retinopathy, emboli, hemorrhage) Heart (irregular rhythm, murmur, gallop) Peripheral vasculature (palpation of carotid, radial, and femoral pulses; auscultation for carotid

bruit)

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

breathing, and circulation (ABCs) and the vital signs. Patients with a decreased level of

consciousness should be assessed to ensure that they are able to protect their airway. Patients

with stroke, especially hemorrhagic stroke, can suffer quick clinical deterioration; therefore,constant reassessment is critical.

Ischemic strokes, unless large or involving the brainstem, do not tend to cause immediate

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

with intracerebral or subarachnoid hemorrhage frequently require intervention for 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.

Head and neck, cardiac, and extremities 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 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 heart failure; thus, auscultation for murmurs and gallops is

recommended.


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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 fibrinolytic 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 with cranial CT scanning) Distinguishing stroke from stroke mimics Establishing a neurologic baseline should the patient's condition improve or deteriorate Establishing stroke severity to assist in prognosis and therapeutic selection

Essential components of the neurologic examination include the following evaluations:

Cranial nerves Motor function Sensory function Cerebellar function Gait Deep tendon reflexes Language (expressive and receptive capabilities) Mental status and level of consciousness

The skull and spine also should be examined, and signs of meningismus should be sought.

National Institutes of Health Stroke Scale

A useful tool in quantifying neurologic impairment is the National Institutes of Health StrokeScale (NIHSS) (see Table 2, below). The NIHSS enables the healthcare provider to rapidly

determine the severity and possible location of the stroke. NIHSS scores are strongly associated

with outcome and can help to identify those patients who are likely to benefit from fibrinolytic

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

use.


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The NIHSS is easily performed; it focuses on the following 6 major areas of the neurologic

examination:

level of consciousness Visual function Motor function Sensation and neglect Cerebellar function Language

The NIHSS is a 42-point scale. Patients with minor strokes usually have a score of less than 5.

An NIHSS score of greater than 10 correlates with an 80% likelihood of proximal vessel

occlusions (as identified on CT or standard angiograms). However, discretion must be used inassessing the magnitude of the clinical deficit and resulting disability; for instance, if a patient's

only deficit is mutism, the NIHSS score will be 3. Additionally, the scale does not measure some

deficits associated with posterior circulation strokes (ie, vertigo, ataxia).[55]

Table 2. National Institutes of Health Stroke Scale(Open Table in a new window)

Category Description Score

1a level of consciousness (LOC) Alert

Drowsy

Stuporous

0

1

2


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Coma 3

1b LOC questions (month, age) Answers both correctly

Answers 1 correctly

Incorrect on both

0

1

2

1c LOC commands (open and close eyes,

grip and release nonparetic hand)

Obeys both correctly

Obeys 1 correctly

Incorrect on both

0

1

2


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2 Best gaze (follow finger) Normal

Partial gaze palsy

Forced deviation

0

1

2

3 Best visual (visual fields) No visual loss

Partial hemianopia

Complete hemianopia

Bilateral hemianopia

0

1

2

3

4 Facial palsy (show teeth, raise brows, Normal 0


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squeeze eyes shut) Minor

Partial

Complete

1

2

3

5 Motor arm left* (raise 90, hold 10 seconds) No drift

Drift

Cannot resist gravity

No effort against gravity

0

1

2

3


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No movement 4

6 Motor arm right* (raise 90, hold 10 seconds) No drift

Drift



No movement

0

1

2

3

4

7 Motor leg left* (raise 30, hold 5 seconds) No drift

Drift

0

1


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No movement

2

3

4

8 Motor leg right* (raise 30, hold 5 seconds) No drift

Drift



0

1

2

3


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No movement 4

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

Present in 1 limb

Present in 2 limbs

0

1

2

10 Sensory (pinprick to face, arm, leg) Normal

Partial loss

Severe loss

0

1

2

11 Extinction/neglect (double simultaneous No neglect 0


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testing)

Partial neglect

Complete neglect

1

2

12 Dysarthria (speech clarity to "mama,

baseball, huckleberry, tip-top, fifty-fifty")

Normal articulation

Mild to moderate dysarthria

Near to unintelligible or worse

0

1

2

13 Best language** (name items,

describe pictures)

No aphasia

Mild to moderate aphasia

0

1


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Severe aphasia

Mute

2

3

Total - 0-42

* For limbs with amputation, joint fusion, etc, score 9 and explain.

** For intubation or other physical barriers to speech, score 9 and explain. Do not add 9 to the

total score.NIH Stroke Scale (PDF)

Middle cerebral artery stroke

Middle cerebral artery (MCA) occlusions commonly produce the following:

Contralateral hemiparesis Contralateral hypesthesia Ipsilateral hemianopsia Gaze preference toward the side of the lesion Agnosia Receptive or expressive aphasia, if the lesion occurs in the dominant hemisphere
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Neglect, inattention, and extinction of double simultaneous stimulation, with somenondominant hemisphere lesions

The MCA supplies the upper extremity motor strip. Consequently, weakness of the arm and face

is usually worse than that of the lower limb.

Anterior cerebral artery stroke

Anterior cerebral artery (ACA) occlusions primarily affect frontal lobe function. Findings in

ACA stroke may include the following:

Disinhibition and speech perseveration Primitive reflexes (eg, grasping, sucking reflexes) Altered mental status Impaired judgment Contralateral weakness (greater in legs than arms) Contralateral cortical sensory deficits Gait apraxia Urinary incontinence

Posterior cerebral artery stroke

Posterior cerebral artery (PCA) occlusions affect vision and thought. Manifestations include the

following:

Contralateral homonymous hemianopsia Cortical blindness Visual agnosia Altered mental status Impaired memory

Vertebrobasilar artery occlusions are particularly difficult to localize, because they may cause a

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

Vertigo Nystagmus Diplopia


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Visual field deficits Dysphagia Dysarthria Facial hypesthesia Syncope Ataxia

A hallmark of posterior circulation stroke is the presence of crossed findings: ipsilateral cranial

nerve deficits and contralateral motor deficits. This contrasts with 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 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.


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BAB III

Diagnostic Considerations

Stroke mimics commonly confound the clinical diagnosis of stroke. One study reported that 19%

of patients diagnosed with acute ischemic stroke by neurologists before cranial CT scanning

actually had non-cerebrovascular causes for their symptoms.

The most frequent stroke mimics include the following:

Seizure (17%) Systemic infection (17%) Brain tumor (15%) Toxic-metabolic disorders, such as hyponatremia and hypoglycemia (13%) Positional vertigo (6%) Conversion disorder

In the prehospital and emergency department (ED) settings, hypoglycemia is a common stroke

mimic and is particularly important to consider, since it can be readily detected and corrected.[56,

57] For more information, seeHyperglycemia and Hypoglycemia in Stroke.

Ischemic versus hemorrhagic stroke

Although the definitive distinction of ischemic stroke from hemorrhagic stroke requires

neuroimaging, a meta-analysis found that the following clinical findings increase the probability

of hemorrhagic stroke[58] :

Coma (likelihood ratio [LR] 6.2) Neck stiffness (LR 5.0) Seizures accompanying the neurologic deficit (LR, 4.7) Diastolic blood pressure >110 mm Hg (LR, 4.3) Vomiting (LR, 3.0)

Findings that decrease the probability of hemorrhage include cervical bruit (LR 0.12) and prior

transient ischemic attack (LR, 0.34).

Transient ischemic attack


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Transient ischemic attack (TIA) is an acute episode of temporary neurologic dysfunction that

results from focal cerebral, spinal cord, or retinal ischemia and is not associated with acute tissue

infarction. Roughly 80% of TIAs resolve within 60 minutes.[59] TIA can result from the same

mechanisms as ischemic stroke. Data suggest that roughly 10% of patients with TIA suffer

stroke within 90 days and of those, half suffer stroke within 2 days.[60, 61]

The classic definition of TIA included symptoms lasting as long as 24 hours. With advances in

neuroimaging, however, it now appears that many such cases represent minor strokes with

resolved symptoms rather than true TIAs. Thus, the current definition of TIA is based on tissue

pathophysiology rather than symptom duration.[59]

Cerebral venous thrombosis

Diagnosis and management of a rare form of stroke,cerebral venous thrombosis (CVT), was the

subject of a 2011 American Heart Association/American Stroke Association (AHA/ASA)

statement for healthcare professionals. According to the statement, diagnosing CVT requires a

high degree of clinical suspicion. Most people diagnosed with CVT present with headache, often

of increasing severity and usually accompanied by focal neurologic signs.[48]

Differentials

Bell Palsy

Brain Neoplasms

Conversion Disorder in Emergency Medicine

Hemorrhagic Stroke

Hypoglycemia

Migraine Headache

Seizure Assessment in the Emergency Department

Emergent Management of Subarachnoid Hemorrhage
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Syncope

Transient Global Amnesia

Bells palsy

Practice Essentials

Bell palsy, also termed idiopathic facial paralysis (IFP), is the most common cause of unilateral

facial paralysis and the most common cause of facial paralysis worldwide. It is one of the most

common neurologic disorders of the cranial nerves. In the great majority of cases, Bell palsy

gradually resolves over time, and its cause is unknown.

Essential update: New Bell palsy guidelines issued by the The American Academy of

OtolaryngologyHead and Neck Surgery Foundation

The American Academy of OtolaryngologyHead and Neck Surgery Foundation has issued

updated guidelines for the diagnosis and management of Bell palsy that recommend the use of

corticosteroids within 72 hours after the onset of symptoms in patients 16 years of age and older.
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Antiviral agents (eg, acyclovir, valacyclovir) may be considered if a viral etiology is suspected,

but only in combination with corticosteroids.[1]

Additional recommendations include the following[1] :

Patients with acute-onset unilateral facial paralysis should be assessed to exclude otherpossible identifiable causes (eg, herpes zoster, Lyme disease, sarcoidosis)

Diagnostic imaging and routine lab testing are not recommended for patients with new-onsetdisease

Electrodiagnostic testing is not recommended in patients with incomplete facial paralysis;however, it may be offered to those patients with complete facial paralysis

If there is impaired eye closure, appropriate eye protection should be implemented Referral to a facial nerve specialist should occur in cases of new or worsening neurologic

symptoms, developing ocular symptoms, or incomplete facial recovery after 3 months

These guidelines concur with the American Academy of Neurology guidelines issued in 2012.[2]

Signs and symptoms

Signs and symptoms of Bell palsy include the following:

Acute onset of unilateral upper and lower facial paralysis (over a 48-hr period)

Posterior auricular pain Decreased tearing Hyperacusis Taste disturbances Otalgia Weakness of the facial muscles Poor eyelid closure Aching of the ear or mastoid Tingling or numbness of the cheek/mouth Epiphora Ocular pain Blurred vision Flattening of forehead and nasolabial fold on the side affected by palsy


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When patient raises eyebrows, palsy-affected side of forehead remains flat When patient smiles, face becomes distorted and lateralizes to side opposite the palsySeeClinical Presentation for more specific information on the signs and symptoms of Bell palsy.

Diagnosis

Examination for Bell palsy includes the following:

Otologic examination: Pneumatic otoscopy and tuning fork examination, particularly ifevidence of acute or chronic otitis media

Ocular examination: Patient often unable to completely close eye on affected side Oral examination: Taste and salivation often affected Neurologic examination: All cranial nerves, sensory and motor testing, cerebellar testingGrading

The grading system developed by House and Brackmann categorizes Bell palsy on a scale of I to

VI,[3, 4, 5] as follows:

Grade I: normal facial function

Grade II: mild dysfunction

Grade III: moderate dysfunction

Grade IV: moderately severe dysfunction

Grade V: severe dysfunction

Grade VI: total paralysis

SeeClinical Presentation for more specific information on patient history and physical

examination for Bell palsy.

Testing

Although there are no specific diagnostic tests for Bell palsy, the following may be useful for

identifying or excluding other disorders:
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Rapid plasma reagin and/or venereal disease research laboratory test or fluorescenttreponemal antibody absorption test

HIV screening by enzyme-linked immunosorbent assay and/or Western blot Complete blood count Erythrocyte sedimentation rate Thyroid function Serum glucose CSF analysis Blood glucose Hemoglobin A1c Antineutrophil cytoplasmic antibody levels Salivary flow Schirmer blotting test Nerve excitability test Computed tomography Magnetic resonance imagingSeeWorkup for more specific information on testing and imaging modalities for Bell palsy.

Management

Goals of treatment: (1) improve facial nerve (seventh cranial nerve) function; (2) reduce

neuronal damage; (3) prevent complications from corneal exposure

Treatment includes the following:

Corticosteroid therapy (prednisone)[6, 7] Antiviral agents[6, 8] Eye care: Topical ocular lubrication is usually sufficient in most cases to prevent corneal

drying, abrasion, and ulcers[9]

Surgical options

Surgical treatment options include the following:

Facial nerve decompression Subocularis oculi fat lift
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Implantable devices (eg, gold weights) placed into the eyelid Tarsorrhaphy Transposition of the temporalis muscle Facial nerve grafting Direct brow liftSeeTreatment andMedication for more specific information regarding pharmacologic and other

therapies for Bell palsy.

Image library

Left-sided Bell palsy.

Background

Bell palsy, more appropriately termed idiopathic facial paralysis (IFP), is the most common

cause of unilateral facial paralysis. Bell palsy is an acute, unilateral, peripheral, lower-motor-

neuronfacial nerve paralysis that gradually resolves over time in 80-90% of cases.

Controversy surrounds the etiology and treatment of Bell palsy. The cause of Bell palsy remains

unknown, though the disorder appears to be a polyneuritis with possible viral, inflammatory,

autoimmune, and ischemic etiologies. Increasing evidence implicates herpes simplex type I and

herpes zoster virus reactivation from cranial-nerve ganglia.[10] (See Etiology.)
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Bell palsy is one of the most common neurologic disorders affecting the cranial nerves, and it is

the most common cause of facial paralysis worldwide. It is thought to account for approximately

60-75% of cases of acute unilateral facial paralysis. Bell palsy is more common in adults, in

people with diabetes, and in pregnant women. (See Epidemiology.)

Diagnosis

Determining whether facial nerve paralysis is peripheral or central is a key step in the diagnosis.

A lesion involving the central motor neurons above the level of the facial nucleus in the pons

causes weakness of the lower face alone. Thorough history taking and examination, including the

ears, nose, throat, and cranial nerves, must be performed. (See Presentation.)

The minimum diagnostic criteria include paralysis or paresis of all muscle groups on one side of

the face, sudden onset, and absence of central nervous system (CNS) disease. Note that the

diagnosis of IFP can be made only after other causes of acute peripheral palsy have been

excluded. (See DDx.)

If the clinical findings are doubtful or if paralysis lasts longer than 6-8 weeks, further

investigations, including gadolinium-enhanced magnetic resonance imaging (MRI) of the

temporal bones and pons, should be considered.[11] Electrodiagnostic tests (eg, stapedius reflex

test, evokedfacial nerve electromyography [EMG], audiography) may help to improve the

accuracy of prognosis in difficult cases. (See Workup.)

Treatment

Treatment of Bell palsy should be conservative and guided by the severity and probable

prognosis in each particular case. Studies have shown the benefit of high-dose corticosteroids for

acute cases.[12, 13] Although antiviral treatment has also come into use, evidence is now available

indicating that it may not be beneficial.[12] (See Treatment and Medication.)

Topical ocular therapy is useful in most cases, with the exception of those in which the condition

is severe or prolonged. In these cases, surgical management is best. Several procedures are aimed

at protecting the cornea from exposure and achieving facial symmetry. These procedures reduce


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the need for constant use of lubrication drops or ointments, may improve cosmesis, and may be

needed to preserve vision on the affected side. (See Treatment.)

Patient education

To prevent corneal abrasions, patients should be instructed about eye care. They also should be

encouraged to do facial muscle exercises using passive range of motion, as well as actively close

their eyes and smile.

For patient education information, see theBrain and Nervous System Center,as well asBells

Palsy.

Anatomy

In 1550, Fallopius noted the narrow foramen in the temporal bone through which a part of theseventh cranial nerve (facial nerve) passes; this feature is now sometimes called the fallopian

canal or the facial canal. In 1828, Charles Bell made the distinction between the fifth and seventh

cranial nerves; he noted that the seventh nerve was involved mainly in the motor function of the

face and that the fifth nerve primarily conducted sensation from the face.

The facial nerve contains parasympathetic fibers to the nose, palate, and lacrimal glands. Its

course is tortuous, both centrally and peripherally. The facial nerve travels a 30-mm intraosseous

course through the internal auditory canal (with the eighth cranial nerve) and through the internal

fallopian canal in the petrous temporal bone. This bony confinement limits the amount that the

nerve can swell before it becomes compressed.

The nucleus of the facial nerve lies within the reticular formation of the pons, adjacent to the

fourth ventricle. The facial nerve roots include fibers from the motor, solitary, and salivatory

nuclei. The preganglionic parasympathetic fibers that originate in the salivatory nucleus join the

fibers from nucleus solitarius to form the nervus intermedius.

The nervus intermedius is composed of sensory fibers from the tongue, mucosa, and

postauricular skin, as well as parasympathetic fibers to the salivary and lacrimal glands. These

fibers then synapse with the submandibular ganglion, which has fibers that supply the sublingual

and submandibular glands. The fibers from the nervus intermedius also supply the
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pterygopalatine ganglion, which has parasympathetic fibers that supply the nose, palate, and

lacrimal glands.

The fibers of the facial nerve then course around the sixth cranial nerve nucleus and exit the pons

at the cerebellopontine angle. The fibers go through the internal auditory canal along with thevestibular portion of the eighth cranial nerve.

The facial nerve passes through the stylomastoid foramen in the skull and terminates into the

zygomatic, buccal, mandibular, and cervical branches. These nerves serve the muscles of facial

expression, which include the frontalis, orbicularis oculi, orbicularis oris, buccinator, and

platysma muscles. Other muscles innervated by the facial nerve include the stapedius,

stylohyoid, posterior belly of the digastric, occipitalis, and anterior and posterior auricular

muscles. All muscles innervated by the facial nerve are derived from the second branchial arch.

See the images below.

The facial nerve.

Pathophysiology

The precise pathophysiology of Bell palsy remains an area of debate. The facial nerve courses

through a portion of the temporal bone commonly referred to as the facial canal. A populartheory proposes that edema and ischemia result in compression of the facial nerve within this

bony canal. The cause of the edema and ischemia has not yet been established. This compression

has been seen in MRI scans with facial nerve enhancement.[14]


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The first portion of the facial canal, the labyrinthine segment, is the narrowest; the meatal

foramen in this segment has a diameter of only about 0.66 mm. This is the location that is

thought to be the most common site of compression of the facial nerve in Bell palsy. Given the

tight confines of the facial canal, it seems logical that inflammatory, demyelinating, ischemic, or

compressive processes may impair neural conduction at this site.

Injury to the facial nerve in Bell palsy is peripheral to the nerves nucleus. The injury is thought

to occur near, or at, the geniculate ganglion. If the lesion is proximal to the geniculate ganglion,

the motor paralysis is accompanied by gustatory and autonomic abnormalities. Lesions between

the geniculate ganglion and the origin of the chorda tympani produce the same effect, except that

they spare lacrimation. If the lesion is at the stylomastoid foramen, it may result in facial

paralysis only.

Etiology

Herpes simplex virus

In the past, situations that produced cold exposure (eg, chilly wind, cold air conditioning, or

driving with the car window down) were considered to be the only triggers for Bell palsy.

Several authors now believe, however, that the herpes simplex virus (HSV) is a common cause

of Bell palsy, though a definitive causal relationship of HSV to Bell palsy may be difficult to

prove because of the ubiquitous nature of HSV.

The hypothesis that HSV is the etiologic agent in Bell palsy holds that after causing primary

infection on the lips (ie, cold sores), the virus travels up the axons of the sensory nerves and

resides in the geniculate ganglion. At times of stress, the virus reactivates and causes local

damage to the myelin.

This hypothesis was first suggested in 1972 by McCormick.[15] Autopsy studies have since

shown HSV in the geniculate ganglion of patients with Bell palsy. Murakami et al performed

polymerase chain reaction (PCR) assay testing on the endoneural fluid of the facial nerve in

patients who underwentsurgery for Bell palsy and found HSV in 11 of 14 cases.[16]

Additional support for a viral etiology was seen when intranasal, inactivated influenza vaccine

was strongly linked to the development of Bell palsy.[17, 18] With those cases, however, it is not


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clear whether another component of the vaccine caused the paresis, which was then accompanied

by a reactivation of HSV infection.

Additional causes

Besides HSV infection, possible etiologies for Bell palsy include other infections (eg, herpes

zoster, Lyme disease, syphilis, Epstein-Barr viral infection, cytomegalovirus, human

immunodeficiency virus [HIV], mycoplasma); inflammation alone; and microvascular disease

(diabetes mellitus and hypertension). Bell palsy has also been known to follow recent upper

respiratory infection (URI).[19, 20, 21, 22, 23, 24]

Bell palsy may be secondary to viral and/or autoimmune reactions that cause the facial nerve to

demyelinate, resulting in unilateral facial paralysis.

A family history of Bell palsy has been reported in approximately 4% of cases. Inheritance in

such cases may be autosomal dominant with low penetration; however, which predisposing

factors are inherited is unclear.[25] The family history may also be positive for other nerve, nerve

root, or plexus disorders (eg, trigeminal neuralgia) in siblings.[26] In addition, there are isolated

reports of familial Bell palsy with neurologic deficits, including ophthalmoplegia[27] and essential

tremor.[28] A rare form of familial Bell palsy has a predilection for juvenile females.[29]

Because there is a strong environmental predisposition to Bell palsy, due to the common viraletiology, a positive family history may or may not indicate a true genetic etiology.

Epidemiology

In the United States, the annual incidence of Bell palsy is approximately 23 cases per 100,000

persons.[7] Very few cases are observed during the summer months. Internationally, the highest

incidence was found in a study in Seckori, Japan, in 1986, and the lowest incidence was found in

Sweden in 1971. Most population studies generally show an annual incidence of 15-30 cases per

100,000 population.

Bell palsy is thought to account for approximately 60-75% of cases of acute unilateral facial

paralysis, with the right side affected 63% of the time. It can also be recurrent, with a reported

recurrence range of 4-14%.[20]


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Though bilateral simultaneous Bell palsy can develop, it is rare. It accounts for only 23% of

bilateral facial paralysis and has an occurrence rate that is less than 1% of that for unilateral

facial nerve palsy.[30, 31] The majority of patients with bilateral facial palsy have Guillain-Barr

syndrome, sarcoidosis, Lyme disease, meningitis (neoplastic or infectious), or bilateral

neurofibromas (in patients with neurofibromatosis type 2).

Persons with diabetes have a 29% higher risk of being affected by Bell palsy than do persons

without diabetes. Thus, measuring blood glucose levels at the time of diagnosis of Bell palsy

may detect undiagnosed diabetes. Diabetic patients are 30% more likely than nondiabetic

patients to have only partial recovery; recurrence of Bell palsy is also more common among

diabetic patients.[32]

Bell palsy is also more common in people who are immunocompromised or in women with

preeclampsia.[33]

Sex- and age-related demographics

Bell palsy appears to affect the sexes equally. However, young women aged 10-19 years are

more likely to be affected than are men in the same age group. Pregnant w

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