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Practice Essentials

Ischemic stroke (see the image below) 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.

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.

See Acute Stroke, a Critical Images slideshow, for more information on incidence, presentation, intervention,
and additional resources.

Essential update: Study indicates intra-arterial treatment improves functional recovery in acute
ischemic stroke
A randomized clinical trial from the Netherlands indicates that endovascular intervention benefits functional
outcomes in patients with acute ischemic stroke resulting from a proximal intracranial arterial occlusion. In the
study, by Berkhemer et al, 500 patients were randomized to receive intra-arterial treatment (within 6 hours of
symptom onset) or usual treatment alone. Although 89% of the patients were treated with tissue-type
plasminogen activator (t-PA) prior to randomization, only those who were found on computed tomography (CT)
angiography to still have a proximal arterial occlusion were entered into the study. In most of the patients who
received intra-arterial treatment, the procedure was performed with latest-generation stent retrievers. [1, 2]
The investigators found that at 90 days, the rate of functional independence (modified Rankin scale score of 02) in the intra-arterial treatment group was 32.6%, compared with 19.1% in the usual-treatment-only group,
while after 5-7 days, the National Institutes of Health Stroke Scale (NIHSS) score was an average of 2.9 points
lower in the intra-arterial treatment patients than it was in the other group. The two groups did not differ
significantly with regard to the rate of morality or symptomatic intracerebral hemorrhage.

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
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 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.
See Clinical Presentation for more detail.

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 angiography
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
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 or anticoagulants are
to be used
Cardiac biomarkers: Important because of the association of cerebral vascular disease and coronary
artery disease

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

Pregnancy testing: A urine pregnancy test should be obtained for all women of childbearing age 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 gas defines
the severity of hypoxemia and may be used to detect acid-base disturbances
See Workup 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
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
See Treatment and Medication for more detail.

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.

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 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 also Hemorrhagic 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.
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 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:

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

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

Anterior Inferior Cerebellar Artery

Anterolateral cerebellum

Superior Cerebellar Artery

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 membrane and 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 iontransport systems fail. Disruption of cellular metabolism also impairs normal sodium-potassium plasma
membrane pumps, producing an intracellular increase in sodium, 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 activates N -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.)

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 emboli.
Vascular distributions: Posterior cerebral artery (PCA) infarction.
The noncontrast computed tomography (CT) images demonstrate PCA distribution infarction involving the right occipital and
inferomedial temporal lobes. The image on the right demonstrates additional involvement of the thalamus, also part of the

PCA territory.
Vascular distributions: Anterior choroidal artery infarction. The diffusionweighted 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 cerebral artery (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 evacuation or 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 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 common causes 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. 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 (although there are likely many others):

Age
Race
Sex
Ethnicity
History of migraine headaches [21]
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.[22]
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[23] :

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 [24]
Obesity
Oral contraceptive use/postmenopausal hormone use
Sickle cell disease
In 2014, the American Heart Association and the American Stroke Association issued guidelines for the
reduction of stroke risk specifically in women. These gender-specific recommendations include the following [25,
26]
:
A stroke risk score should be developed specifically for women
Women with a history of high blood pressure before pregnancy should be considered for low-dose
aspirin and/or calcium supplement treatment to reduce the risk of preeclampsia
Blood pressure medication may be considered for pregnant women with moderately high blood
pressure (150-159 mmHg/100-109 mmHg), and pregnant women with severe high blood pressure (160/110
mmHg or above) should be treated
Women should be screened for high blood pressure before they start using birth control pills because
of an increased risk of stroke
Women with migraine headaches with aura should be encouraged to quit smoking to reduce the risk of
stroke
Women over age 75 should be screened for atrial fibrillation

Genetic and inflammatory mechanisms


Evidence continues to accumulate that inflammation and genetic factors have important roles in the
development of atherosclerosis 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 disorders with 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 the F2 and F5 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 [27]


ALOX5AP: Involved in the metabolism of arachidonic acid [28]
PRKCH: Involved in major signal transduction systems [29]
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
for MTHFR mutation, 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 recessive manner.
Symptoms usually manifest early in life. Patients have a marfanoid habitus, ectopia lentis, and myopia and
generally have intellectual disability.[30]
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.[31] 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 CST3 gene 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. [32]
CADASIL
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy (CADASIL), is
caused by mutations in the NOTCH3 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. [33]
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. [34]
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.[35]
Large-vessel stroke has been associated with variations in HDAC9, PITX2, andZFHX3.[36] HDAC9 is located
on7p21.1, while PITX2 and ZFHX3 are 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.[37] An additional study suggested an association between ischemic stroke and a locus on
12p13.[38]
For more information, see Genetic 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.)

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 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
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.[39] Sources of cardiogenic emboli include the following:

Valvular thrombi (eg, in mitral stenosis or endocarditis or from use of a prosthetic valve)
Mural thrombi (eg, in myocardial infarction, atrial fibrillation, dilated cardiomyopathy, or severe
congestive heart failure)

Atrial myxoma
Acute myocardial infarction is associated with a 2-3% incidence of embolic strokes, of which 85% occur in the
first month after the infarction.[40] 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.) [41, 42]

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 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, see Cardioembolic 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, 43] :

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


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.) [44, 45, 46]

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, see Blood
Dyscrasias and Stroke.

Epidemiology
Stroke is the leading cause of disability and the fourth leading cause of death in the United States. [47, 48] 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. [49]

Race-, sex-, and age-related demographics


In the United States, blacks have an age-adjusted risk of death from stroke that is 1.49 times that of whites.
[50]
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.[48] 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. [51] 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, 52, 53] Hemorrhagic transformation 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.
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.[54, 55, 56]
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 article Motor 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 acronym FAST to
teach the warning signs of stroke and the importance of calling 911, as follows:
F: Face drooping
A: Arm weakness
S: Speech difficulty

T: Time to call 911


For patient education information, see the Stroke Health Center and the Brain and Nervous System Health
Center, as well as Stroke, Transient Ischemic Attack (TIA, Mini-stroke),and Stroke-Related Dementia.

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 from hemorrhagic 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
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, 57]

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)
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.
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 Stroke Scale (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.
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 in assessing 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). [58]
Table 2. National Institutes of Health Stroke Scale (Open Table in a new window)

1a

Category

Description

Score

level of consciousness (LOC)

Alert

Drowsy

Stuporous

Coma

1b

1c

LOC questions (month, age)

Answers both correctly

Answers 1 correctly

Incorrect on both

LOC commands (open and close eyes,

Obeys both correctly

grip and release nonparetic hand)

Obeys 1 correctly

Incorrect on both

Normal

Partial gaze palsy

Forced deviation

No visual loss

Partial hemianopia

Complete hemianopia

Bilateral hemianopia

Facial palsy (show teeth, raise brows,

Normal

squeeze eyes shut)

Minor

Partial

Complete

No drift

Best gaze (follow finger)

Best visual (visual fields)

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

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

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

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

Drift

Cannot resist gravity

No effort against gravity

No movement

No drift

Drift

Cannot resist gravity

No effort against gravity

No movement

No drift

Drift

Cannot resist gravity

No effort against gravity

No movement

No drift

Drift

Cannot resist gravity

No effort against gravity

10

11

12

13

No movement

Absent

Present in 1 limb

Present in 2 limbs

Normal

Partial loss

Severe loss

No neglect

Partial neglect

Complete neglect

Dysarthria (speech clarity to "mama,

Normal articulation

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

Mild to moderate dysarthria

Near to unintelligible or worse

Best language** (name items,

No aphasia

describe pictures)

Mild to moderate aphasia

Severe aphasia

Mute

Limb ataxia (finger-nose, heel-shin)

Sensory (pinprick to face, arm, leg)

Extinction/neglect (double simultaneous testing)

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
Neglect, inattention, and extinction of double simultaneous stimulation, with some nondominant
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
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.

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 noncerebrovascular 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. [59, 60] 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 metaanalysis found that the following clinical findings increase the probability of hemorrhagic stroke [61] :

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
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.[62] 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.
[63, 64]

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.
[62]

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.[51]
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
Syncope
Transient Global Amnesia

Approach Considerations
Imaging studies
Emergent brain imaging is essential for confirming the diagnosis of ischemic stroke. Noncontrast CT scanning
is the most commonly used form of neuroimaging in the acute evaluation of patients with apparent acute
stroke. A lumbar puncture is required to rule out meningitis or subarachnoid hemorrhage when the CT scan is
negative but the clinical suspicion remains high.
MRI with magnetic resonance angiography (MRA) has been a major advance in the neuroimaging of stroke.
MRI not only provides great structural detail but also can demonstrate early cerebral edema. In addition, MRI
has proved to be sensitive for detection of acute intracranial hemorrhage. However, MRI is not as available as
CT scanning is in emergencies, many patients have contraindications to MRI imaging (eg, pacemakers,
implants), and interpretation of MRI scans may be more difficult.
Carotid duplex scanning is one of the most useful tests in evaluating patients with stroke. Increasingly, it is
being performed earlier in the evaluation, not only to define the cause of the stroke but also to stratify patients
for either medical management or carotid intervention if they have carotid stenoses.
Digital subtraction angiography is considered the definitive method for demonstrating vascular lesions,
including occlusions, stenoses, dissections, and aneurysms.
For more information, see Cerebral Revascularization Imaging.

Laboratory studies
Extensive laboratory testing is not routinely required before decisions are made regarding fibrinolysis. Testing
can often be limited to blood glucose, plus coagulation studies if the patient is on warfarin, heparin, or one of
the newer antithrombotic agents (eg, dabigatran, rivaroxaban). A complete blood count (CBC) and basic
chemistry panel can be useful baseline studies.
Additional laboratory tests are tailored to the individual patient and may include the following:

Cardiac biomarkers
Toxicology screen
Fasting lipid profile
Erythrocyte sedimentation rate
Pregnancy test

Antinuclear antibody (ANA)


Rheumatoid factor
Homocysteine level
Rapid plasma reagent (RPR)
A urine pregnancy test should be obtained for all women of childbearing age with stroke symptoms. The safety
of the fibrinolytic agent recombinant tissue-type plasminogen activator (rt-PA) in pregnancy has not been
studied in humans (ie, the agent is in the FDA pregnancy category C).

Brain Imaging With CT Scanning and MRI


CT scanning
Imaging with CT scanning has multiple logistic advantages for patients with acute stroke. Image acquisition is
faster with CT scanning than with MRI, allowing for assessment with an examination that includes noncontrast
CT scanning, CT angiography (CTA), and CT perfusion scanning in a short amount of time. Expedient
acquisition is of the utmost importance in acute stroke imaging because of the narrow window of time available
for definitive ischemic stroke treatment with pharmacologic agents and mechanical devices.
CT scanning can also be performed in patients who are unable to tolerate an MR examination or who have
contraindications to MRI, including implantable pacemakers, some aneurysm clips, or other ferromagnetic
materials in their bodies. Additionally, CT scanning is more easily accessible for patients who require special
equipment for monitoring and life support. [65, 66]

MRI
Conventional (spin echo) MRI may take hours to produce discernible findings in acute ischemic stroke.
Diffusion-weighted imaging (DWI) is highly sensitive to early cellular edema, which correlates well with the
presence of cerebral ischemia. For this reason, many centers include DWI in their standard brain MRI protocol.
DWI MRI can detect ischemia much earlier than standard CT scanning or spin echo MRI can and provides
useful data in patients with stroke or transient ischemic attack (TIA). (See the image below.) [3, 67, 68, 69]

Magnetic resonance imaging (MRI) scan in a 70-year-old woman with a history of


left-sided weakness for several hours. An axial T2 fluid-attenuated inversion recovery (FLAIR) image (left) demonstrates
high signal in the lentiform nucleus with mass effect. The axial diffusion-weighted image (middle) demonstrates high signal in
the same area, with corresponding low signal on the apparent diffusion coefficient (ADC) maps, consistent with true
restricted diffusion and an acute infarction. Maximum intensity projection from a 3-dimensional (3-D) time-of-flight magnetic
resonance angiogram (MRA, right) demonstrates occlusion of the distal middle cerebral artery (MCA) trunk (red circle).

The most commonly used technique for perfusion MRI is dynamic susceptibility, which involves generating
maps of brain perfusion by monitoring the first pass of a rapid bolus injection of contrast through the cerebral
vasculature. Susceptibility-related T2 effects create signal loss in capillary blood vessels and parenchyma
perfused by contrast.
For more information on MRI and MRA in this setting, see Magnetic Resonance Imaging in Acute Stroke.
Based on the central volume principle, dynamic brain perfusion data can be obtained. Cerebral blood volume
(CBV), cerebral blood flow (CBF), and mean transit time (MTT) can be calculated using either perfusion MRI or
CT scanning. (See the image below.)

Regions of interest are selected for arterial and venous input (image on left) for
dynamic susceptibility-weighted perfusion magnetic resonance imaging (MRI). Signal-time curves (image on right) obtained
from these regions of interest demonstrate transient signal drop following the administration of intravenous contrast. The

information obtained from the dynamic parenchymal signal changes postcontrast is used to generate maps of different
perfusion parameters.

An evidence-based guideline from the American Academy of Neurology advises that DWI is more useful than
noncontrast CT scanning for the diagnosis of acute ischemic stroke within 12 hours of symptom onset and
should be performed for the most accurate diagnosis of acute ischemic stroke (level A). No recommendations
were made regarding the use of perfusion-weighted imaging (PWI) in diagnosing acute ischemic stroke, as
evidence to support or refute its value in this setting is insufficient. [70]
Intra-arterial contrast enhancement may be seen secondary to slow flow during the first or second day after
onset of infarction. This finding has been correlated with increased infarct volume size. [71]

Other Imaging Studies in Ischemic Stroke


Transcranial Doppler ultrasonography is useful for evaluating more proximal vascular anatomyincluding the
middle cerebral artery (MCA), intracranial carotid artery, and vertebrobasilar arterythrough the infratemporal
fossa.[72]Echocardiography is obtained in all patients with acute ischemic stroke in whom cardiogenic embolism
is suspected.
Chest radiography has potential utility for patients with acute stroke. However, obtaining a chest radiograph
should not delay the administration of rt-PA, as radiographs have not been shown to alter the clinical course or
decision-making in most cases.[73]
The use of single-photon emission CT (SPECT) scanning in stroke is still experimental and is available only at
select institutions. Theoretically, it can define areas of altered regional blood flow.[74]
Conventional angiography is the gold standard in evaluating for cerebrovascular disease as well as for disease
involving the aortic arch and great vessels in the neck. Conventional angiography can be performed to clarify
equivocal findings or to confirm and treat disease seen on MRA, CTA, transcranial Doppler, or ultrasonography
of the neck. (See the images below.)

A 48-year-old man presented with acute left-sided hemiplegia, facial palsy, and right-sided gaze
preference. Angiogram with selective injection of the right internal carotid artery demonstrates occlusion of the M1 segment
of the right middle cerebral artery (MCA) and A2 segment of the right anterior cerebral artery (ACA; images courtesy of

Concentric Medical).
Follow-up imaging after mechanical embolectomy in 48-year-old
man with acute left-sided hemiplegia, facial palsy, and right-sided gaze preference demonstrates complete recanalization of

the right middle cerebral artery (MCA) and partial recanalization of the right A2 segment (images courtesy of Concentric

Medical).
Cerebral angiogram performed approximately 4.5 hours after symptom
onset in a 31-year-old man demonstrates an occlusion of the distal basilar artery (images courtesy of Concentric Medical).

Image on the left demonstrates deployment of a clot retrieval device in a 31-year-old


man. Followup angiogram after embolectomy demonstrates recanalization of the distal basilar artery with filling of the
superior cerebellar arteries and posterior cerebral arteries. The patient had complete resolution of symptoms following
embolectomy (images courtesy of Concentric Medical).

Blood Studies
A CBC serves as a baseline study and may reveal a cause for the stroke (eg, polycythemia, thrombocytosis,
thrombocytopenia, leukemia) or provide evidence of concurrent illness (eg, anemia). The basic chemistry panel
serves as a baseline study and 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 or anticoagulants are to be
used. In patients who are not taking anticoagulants or antithrombotics and in whom there is no suspicion for
coagulation abnormality, administration of rt-PA should not be delayed while awaiting laboratory results.
Cardiac biomarkers are important because of the association of cerebral vascular disease and coronary artery
disease. Additionally, several studies have indicated a link between elevations of cardiac enzyme levels and
poor outcome in ischemic stroke.
Toxicology screening may be useful in selected patients in order to assist in identifying intoxicated patients with
symptoms/behavior mimicking stroke syndromes. In patients with suspected hypoxemia, arterial blood gas
studies define the severity of hypoxemia and may detect acid-base disturbances. However, arterial punctures
should be avoided unless absolutely necessary in patients being considered for fibrinolytic therapy.

Approach Considerations
The central goal of therapy in acute ischemic stroke is to preserve tissue in the ischemic penumbra, where
perfusion is decreased but sufficient to stave off infarction. Tissue in this area of oligemia can be preserved by
restoring blood flow to the compromised area and optimizing collateral flow.
Recanalization strategies, including the administration of intravenous (IV) recombinant tissue-type plasminogen
activator (rt-PA) and intra-arterial approaches, attempt to establish revascularization so that cells in the
penumbra can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of
ischemia only if performed quickly.
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 acutely in ischemic stroke.
In addition to limiting the duration of ischemia, an alternative strategy is to limit the severity of ischemic injury
(ie, neuronal protection). Neuroprotective strategies are intended to preserve the penumbral tissues and to
extend the time window for revascularization techniques. At the present time, however, no neuroprotective
agents have been shown to impact outcomes in ischemic stroke.

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 their comfort is the most humane and appropriate
therapeutic concern. Some patients have advance directives providing instructions for medical providers in the
event of severe medical illness or injury.

Clinical education
Prehospital care providers are essential to timely stroke care. Course curricula for prehospital care providers
are beginning to include more information on stroke than ever before. Through certification and Acute Cardiac
Life Support (ACLS) instruction, as well as continuing medical education classes, prehospital care providers
can remain current on stroke warning signs, prehospital stroke tools, and triage protocols in their region, and
can promote stroke awareness in their own communities.
Physician and nursing staff involved in the care of stroke patients, in the emergency department (ED) and in
the hospital, should participate in scheduled stroke education. This will help them to maintain the skills required
to treat stroke patients effectively and to remain current on medical advances for all stroke types.

Emergency Response and Transport


Recognition that a stroke may have occurred, activation of 911, and rapid transport to the appropriate receiving
facility are necessary to provide stroke patients with the best chance for acute interventions. Of patients with
signs or symptoms of stroke, 29-65% utilize some facet of the emergency medical services (EMS) system. [75, 76]
Most of the patients who call EMS are those who present within 3 hours of symptom onset. Calls to 911 and the
use of EMS are associated with shorter time periods from symptom onset to hospital arrival. [77, 78]
Stroke should be a priority dispatch with prompt EMS response. EMS responders should provide advance
notice to their ED destination in as timely a manner as possible so as to allow preparation and marshaling of
personnel and resources. With the development of stroke center designation, which is currently in progress,
such centers would then become the preferred destination for patients with acute stroke symptoms who utilize
EMS.
Data supporting the use of emergency air transport for patients with acute stroke symptoms are limited. Further
evaluation of this transportation modality is necessary to minimize the potentially high number of stroke mimics
and to maximize the appropriate use of transport resources. Telemedicine is also a technology that has the
potential to provide timely expert advice to rural and underserved clinics and hospitals. [3]

Acute Management of Stroke


The goal for the emergent management of stroke is to assess the patients airway, breathing, and circulation
(ABCs); stabilize the patient as necessary; and complete initial evaluation and assessment, including imaging
and laboratory studies, within 60 minutes of patient arrival. [3] A Finnish study demonstrated that time to
treatment with fibrinolytics can be decreased with changes in EMS and ED coordination and in ED procedures
for treating acute stroke patients.[79]
A US study in which a multidisciplinary team used value stream analysis to assess the steps required to treat
acute ischemic stroke with IV rt-PA found several inefficiencies in the protocol (eg, in patient routing) that were
slowing treatment. Use of a revised protocol that targeted those inefficiencies reduced door-to-needle times
from 60 to 39 minutes and increased the percentage of patients treated in 60 minutes or less after hospital
arrival from 52% to 78%, with no change in symptomatic hemorrhage rate.[80]
Critical decisions focus on the need for airway management, establishment of optimal blood pressure control,
and identification of potential reperfusion therapies (IV 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.

Comorbidities
Comorbid medical conditions also need to be addressed. Hyperthermia is infrequently associated with stroke
but can increase morbidity. Administration of acetaminophen, by mouth or per rectum, is indicated in the
presence of fever (temperature >100.4F).

Oxygen supplementation
Supplemental oxygen is recommended when the patient has a documented oxygen requirement (ie, oxygen
saturation < 95%). In the small proportion of patients with stroke who are relatively hypotensive, administration
of IV fluid, vasopressor therapy, or both may improve flow through critical stenoses.

Hypoglycemia and hyperglycemia


Hypoglycemia needs to be identified and treated early in the evaluation. In contrast, the management of
hyperglycemia in acute stroke remains an area of uncertainty.[81]
Hyperglycemia is common after acute ischemic stroke, even in patients without diabetes. A Cochrane review
found that the use of IV insulin to maintain serum glucose in the range of 4-7.5 mmol/L (72-135 mg/dL) in the
first 24 hours of ischemic stroke did not improve functional outcome, death rates, or final neurologic deficit and
significantly increased the risk of hypoglycemia. [82]

Fibrinolytic Therapy

The only fibrinolytic agent that has been shown to benefit selected patients with acute ischemic stroke is rt-PA.
While streptokinase may benefit patients with acute MI, in patients with acute ischemic stroke it has been
shown to increase the risk of intracranial hemorrhage and death.
Fibrinolytics (ie, rt-PA) restore cerebral blood flow in some patients with acute ischemic stroke and may lead to
improvement or resolution of neurologic deficits. Unfortunately, fibrinolytics may also cause symptomatic
intracranial hemorrhage. Other complications include potentially hemodynamically significant hemorrhage and
angioedema or allergic reactions.[3]

Inclusion/exclusion criteria
Therefore, if the patient is a candidate for fibrinolytic therapy, a thorough review of the inclusion and exclusion
criteria must be performed. The exclusion criteria largely focus on identifying risk of hemorrhagic complications
associated with fibrinolytic use. The American Heart Association/American Stroke Association (AHA/ASA)
inclusion guidelines for the administration of rt-PA are as follows [3] :

Diagnosis of ischemic stroke causing measurable neurologic deficit


Neurologic signs not clearing spontaneously to baseline
Neurologic signs not minor and isolated
Symptoms not suggestive of subarachnoid hemorrhage
No head trauma or prior stroke in past 3 months
No myocardial infarction (MI) in past 3 months
No gastrointestinal/genitourinary hemorrhage in previous 21 days
No arterial puncture in a noncompressible site during the past 7 days
No major surgery in past 14 days
No history of prior intracranial bleeding
Systolic blood pressure under 185 mm Hg, diastolic blood pressure under 110 mm Hg
No evidence of acute trauma or bleeding
Not taking an oral anticoagulant, or if so, international normalized ratio (INR) under 1.7
If taking heparin within 48 hours, a normal activated prothrombin time (aPT)
Platelet count of more than 100,000/L
Blood glucose greater than 50 mg/dL (2.7 mmol)
No seizure with residual postictal impairments
CT scan does not show evidence of multilobar infarction (hypodensity over one third hemisphere) or
intracerebral hemorrhage

The patient and family understand the potential risks and benefits of therapy
Whereas these inclusion/exclusion criteria are from the original FDA approval, subsequent data and experience
have allowed some patients with what were previously considered relative contraindications to be safely
treated. Involvement of a physician with stroke expertise is critical for assessing the risk/benefit consideration
for these groups of patients.

Time to therapy
An rt-PA stroke study group from the National Institute of Neurologic Disorders and Stroke (NINDS) first
reported that the early administration of rt-PA benefited carefully selected patients with acute ischemic stroke.
[5]
The FDA subsequently approved the use of rt-PA in patients who met NINDS criteria. In particular, rt-PA had
to be given within 3 hours of stroke onset and only after CT scanning had ruled out hemorrhagic stroke.
Subsequently, fibrinolytic therapy administered 3-4.5 hours after symptom onset was found to improve
neurologic outcomes in the European Cooperative Acute Stroke Study III (ECASS III), suggesting a wider time
window for fibrinolysis.[83] On the basis of these and other data, in May 2009 the AHA/ASA revised the guidelines
for the administration of rt-PA after acute stroke, expanding the window of treatment from 3 hours to 4.5 hours
to provide more patients with an opportunity to benefit from this therapy.[83, 84, 85, 86]
Eligibility criteria for treatment during this later period are similar to those for earlier treatment but are more
stringent, with any 1 of the following serving as an additional exclusion criterion:

Age older than 80 years

Use of oral anticoagulants, regardless of the INR


Baseline score on the National Institutes of Health Stroke Scale (NIHSS) greater than 25
History of stroke and diabetes
In a meta-analysis of nine major trials of thrombolysis treatment involving a total of 6756 patients with acute
ischemic stroke, researchers found that administration of alteplase within 4.5 hours of stroke onset significantly
improved outcomes, irrespective of age or stroke severity, with earlier treatment providing the greatest benefit.
Good outcome was defined as modified Rankin score of 0 or 1, which indicates little or no residual disability at
3-6 months. The odds of a good stroke outcome were 75% higher for patients who received alteplase within 3
hours of symptom onset compared with those who did not. Patients given alteplase 3 to 4.5 hours after
symptom onset had a 26% increased chance of a good outcome, and patients with a delay of more than 4.5
hours in receiving alteplase treatment had a nonsignificant 15% increase in the chance of a good recovery.[87, 88]
A 10-center European study of nearly 6900 patients found IV rt-PA to be most effective when given within 90
minutes of the onset of stroke symptoms.[89, 90]Patients scoring in the 7-12 range on the NIHSS had better
outcomes when thrombolytic therapy was provided within 90 minutes of symptom onset than when it was
provided 90-270 minutes after onset. For patients with minor stroke or moderate-to-severe stroke, however,
treatment within the initial 90-minute window provided no additional advantage.

Hemorrhage risk
Although antiplatelet therapy may increase the risk for symptomatic intracerebral hemorrhage with fibrinolysis,
a study by Diedler et al that included 3782 patients who had received 1 or 2 antiplatelet drugs found that the
risk of intracerebral hemorrhage was small compared with the documented benefit of fibrinolysis. [91]These
researchers concluded that antiplatelet treatment should not be considered a contraindication to fibrinolysis,
although caution is warranted in patients receiving the combination of aspirin and clopidogrel.
Data regarding the safety of fibrinolytic therapy in patients taking dabigatran, rivaroxaban, or apixaban are not
available. Extreme caution should be used when considering fibrinolytic therapy in such patients.
Caution should also be exercised in the administration of rt-PA to patients with evidence of low attenuation
(edema or ischemia) involving more than a third of the distribution of the middle cerebral artery (MCA) on their
initial noncontrast CT scan; such patients are less likely to have a favorable outcome after fibrinolytic therapy
and are at higher risk for hemorrhagic transformation of their ischemic stroke. [52]

Ultrasound therapy
Researchers have studied the use of transcranial ultrasound as a means of assisting rt-PA in fibrinolysis. [92, 93] By
delivering mechanical pressure waves to the thrombus, ultrasound can theoretically expose more of the
thrombuss surface to the circulating fibrinolytic agent. Further research is necessary to determine the exact
role of transcranial Doppler ultrasound in assisting fibrinolytics in acute ischemic stroke.
For more information, see Thrombolytic Therapy in Stroke and Reperfusion Injury in Stroke.

Intra-arterial Reperfusion
There have been no completed human trials comparing intravenous versus intra-arterial administration of
fibrinolytics. Theoretically, intra-arterial delivery may produce higher local concentrations of the fibrinolytic agent
at lower total doses (and thus possibly lower the risk of a systemic bleed) and allow a longer therapeutic
window. However, the longer time for initiating intra-arterial administration may mitigate some of this advantage.
[3]

The Interventional Management of Acute Stroke Study (IMS-III) was halted for futility after showing no
additional benefit from intra-arterial therapies (rt-PA, mechanical thrombectomy, or both) compared with
intravenous rt-PA in patients with large-vessel occlusions. Additional analyses of the IMS III data are under way
to better understand the results and potentially identity subsets of patients who may benefit from the combined
approach.[94]
Intra-arterial fibrinolysis has been the traditional approach for patients with stroke from basilar artery occlusion.
However, results of the Basilar Artery International Cooperation Study (BASICS), a prospective registry study in
592 patients, did not support unequivocal superiority of intra-arterial fibrinolysis over intravenous fibrinolysis. [95]

A meta-analysis of case studies involving a total of 420 patients with basilar artery occlusion did indicate that
recanalization was achieved more frequently with intra-arterial fibrinolysis than with intravenous fibrinolysis
(65% vs 53%), but the report also found that death and long-term disability were equally common with the 2
techniques.[96] These researchers concluded that intravenous fibrinolysis represents probably the best treatment
that can be offered to these patients in hospitals without a 24-hour interventional neuroradiologic service. [96]

Antiplatelet Agents
AHA/ASA guidelines recommend giving aspirin, 325 mg orally, within 24-48 hours of ischemic stroke onset. The
benefit of aspirin is modest but statistically significant and appears principally to involve the reduction of
recurrent stroke.[86]
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 19,435
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
stroke recurrence within 14 days (2.8% vs 3.9%), with no significant excess of hemorrhagic strokes. [97, 98]
In CAST, which included 21,106 patients, aspirin treatment (160 mg/day) that was started within 48 hours of the
onset of suspected acute ischemic stroke and was continued in hospital for up to 4 weeks reduced mortality to
3.3%, compared with 3.9% with placebo. A separate study also found that the combination of aspirin and low
molecular-weight heparin did not significantly improve outcomes. [97]
Other antiplatelet agents have also been under evaluation for use in the acute presentation of ischemic stroke.
In a preliminary pilot study, abciximab given within 6 hours showed a trend toward improved outcome at 3
months.[99] However, the phase 3 Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II) was terminated
prematurely after 808 patients because of lack of efficacy and an increased rate of symptomatic or fatal
intracranial hemorrhage in patients receiving abciximab.[100]

Blood Pressure Control


Although hypertension is common in acute ischemic stroke and is associated with poor outcome, studies of
antihypertensive treatment in this setting have produced conflicting results. A theoretical drawback of blood
pressure reduction is that elevated blood pressure may counteract dysfunctional cerebral autoregulation from
stroke, but limited evidence suggests that antihypertensive treatment in acute stroke does not change cerebral
perfusion.[101]
Calcium channel blockers did not alter outcome after ischemic stroke in some trials. Possible adverse effects of
antihypertensive treatment have been reported in certain trials, especially those using intravenous calcium
channel blockers or oral beta blockers. In the Controlling Hypertension and Hypotension Immediately PostStroke (CHHIPS) trial, early lowering of blood pressure with labetalol and lisinopril slightly improved outcome
and did not increase serious adverse events. However, CHHIPS had a small sample size. [102]
A study in 339 patients with ischemic stroke found that oral candesartan reduced combined vascular events but
had no effect on disability.[101] However, the Scandinavian Candesartan Acute Stroke Trial (SCAST), a
randomized, placebo-controlled, double-blind study involving 2029 patients, found no indication of benefit from
candesartan but did find some suggestion of harm.[103]
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. [104, 105]
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.[104, 105]
For patients who are not candidates for fibrinolytic therapy, current guidelines recommend permitting moderate
hypertension in most patients with acute ischemic stroke. Most patients will experience spontaneous reduction

in blood pressure over the first 24 hours without treatment. [86] The exceptions would be patients who have
comorbidities (eg, aortic dissection, acute myocardial infarction [MI], decompensated heart failure, hypertensive
emergency) that require emergent blood pressure management.
Thresholds for antihypertensive treatment in acute ischemic stroke patients who are not fibrinolysis candidates,
according to the 2013 ASA guidelines, are systolic blood pressure higher than 220 mm Hg or diastolic blood
pressure above 120 mm Hg.[86]In those patients, a reasonable goal is to lower blood pressure by 15% during
the first 24 hours after onset of stroke. Care must be taken to not lower blood pressure too quickly or
aggressively, since this could worsen perfusion in the penumbra.

Mechanical Thrombectomy
Mechanical clot disruption is an alternative for patients in whom fibrinolysis is ineffective or contraindicated.
Currently, 4 devices are approved by the FDA for the endovascular treatment of acute ischemic stroke, as
follows:

Merci Retriever (Concentric Medical, Mountain View, CA): Corkscrew-shaped device that captures and
engages clots

Penumbra System (Penumbra, Alameda, CA): Employs both aspiration and extraction

Solitaire FR Revascularization Device (Covidien, Dublin, Ireland): Stent-retriever system; combines the
ability to restore blood flow and retrieve clot

Trevo (Concentric Medical, Mountain View, CA): Stent-retriever system


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.[106] In a second MERCI study,
recanalization was achieved in 48% of patients in whom the device was deployed. Clot was successfully
retrieved from all major cerebral arteries; however, the recanalization rate for the MCA was lowest. [107]
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 to whom t-PA was
given. Seventy-three percent of patients who failed intravenous t-PA therapy had recanalization following
mechanical embolectomy.[108] On the basis of these results, the FDA cleared the use of the MERCI device in
patients who are either ineligible for or who have failed intravenous fibrinolytics.
In a trial of the Penumbra System in 23 patients who presented within 8 hours of symptom onset,
revascularization to a Thrombolysis in Myocardial Infarction (TIMI) grade of 2 or 3 was accomplished in all 21
treated vessels. Vessel tortuosity prevented access by the device in 3 patients. [109]
More recent trials of the stent-retriever systems demonstrated superiority in reperfusion over the original Merci
systems. In the Solitaire Flow Restoration Device Versus the Merci Retriever in Patients with Acute Ischaemic
Stroke (SWIFT) study, which enrolled 113 subjects with moderate or severe strokes within 8 hours after
symptom onset, the Solitaire FR system demonstrated successful revascularization (TIMI 2-3 flow) in 61% of
patients, compared with 24% of patients treated with the Merci system. Patients in the Solitaire FR group also
had a higher rate of good 90-day clinical outcomes than did those in the Merci group (58% versus 33%,
respectively).[110]
A similar study, the Trevo Versus Merci Retrievers for Thrombectomy Revascularisation of Large Vessel
Occlusions in Acute Ischaemic Stroke (TREVO 2) trial, reported successful reperfusion (TIMI 2-3 flow) in 86%
of patients using the Trevor stent retriever, compared with 60% in the Merci group. The rate of good clinical
outcomes at 90 days was also higher in the Trevo group than in the Merci group (40% vs 22%, respectively).
[111]
Ongoing studies will better define the role of intra-arterial therapies with and without intravenous fibrinolysis.
Long-term results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in
Intracranial Stenosis (SAMMPRIS) study confirm the superiority of aggressive medical management alone to
aggressive medical management with stenting in patients with a stroke or transient ischemic attack resulting
from stenosis of a major intracranial artery.[112, 113, 114] Long-term follow-up results were available for 227 patients in
the medical management group and 224 patients in the stenting group.
Occurrence rates for primary endpoint events (stroke or death within 30 days after enrollment or after either a
revascularization procedure for the qualifying lesion during follow-up or a stroke in the territory of the qualifying
artery beyond 30 days) in the medical group and the stenting group were 14.1% and 20.6%, respectively, at

year 2 and 14.9% and 23.9% at year 3.[113] Rates of any stroke and of any major hemorrhage were also
significantly lower in the medical group than in the stenting group.
For more information, see Mechanical Thrombolysis in Acute Stroke.

Fever Control
Antipyretics are indicated for febrile stroke patients, since hyperthermia accelerates ischemic neuronal injury.
Substantial experimental evidence suggests that mild brain hypothermia is neuroprotective. The use of induced
hypothermia is currently being evaluated in phase II clinical trials. [115, 116, 117]
High body temperature in the first 12-24 hours after stroke onset has been associated with poor functional
outcome. However, results from the Paracetamol (Acetaminophen) in Stroke (PAIS) trial did not support the
routine use of high-dose acetaminophen (6 g daily) in patients with acute stroke, although post-hoc analysis
suggested a possible beneficial effect on functional outcome in patients admitted with a body temperature of
37-39 C.[118]

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 noncontrast CT (NCCT) scans are independent indicators
of potential swelling and deterioration (see the image below). Mannitol and other therapies to reduce
intracranial pressure (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. [3]

Axial noncontrast computed tomography (NCCT) scan demonstrates diffuse hypodensity


in the right lentiform nucleus with mass effect upon the frontal horn of the right lateral ventricle in a 70-year-old woman with a
history of left-sided weakness for several hours.

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 been shown to decrease
mortality and disability among patients with large hemispheric infarctions associated with life-threatening
edema.[119, 120, 121, 122]
The American Heart Association and the American Stroke Association have released a guideline for the
management of cerebral and cerebellar infarction with brain swelling; recommendations include the following [123,
124]
:

Selected patients, including those able to handle an aggressive rehabilitation program, may benefit
from decompressive craniectomy; younger patients may benefit most, and surgery is not recommended for
patients older than 60 years
Clinical evidence of deterioration in swollen supratentorial hemispheric ischemic stroke includes new
or further impairment of consciousness, cerebral ptosis, and changes in pupillary size
In patients with swollen cerebellar infarction, level of consciousness decreases because of brainstem
compression; this decrease may include early loss of corneal reflexes and the development of miosis

Standardized definitions are needed to facilitate studies of incidence, prevalence, risk factors, and
outcomes
Identification of high-risk patients should include both clinical and neuroimaging data
Complex medical care of these patients includes airway management and mechanical ventilation,
blood pressure control, fluid management, and glucose and temperature control
In patients with swollen supratentorial hemispheric ischemic stroke, routine intracranial pressure
monitoring or cerebrospinal fluid diversion is not indicated, but in patients who continue to deteriorate
neurologically, decompressive craniectomy with dural expansion should be considered
In patients with swollen cerebellar stroke who deteriorate neurologically, suboccipital craniectomy with
dural expansion should be performed
After a cerebellar infarct, performance of ventriculostomy to relieve obstructive hydrocephalus should
be accompanied by decompressive suboccipital craniectomy to avoid deterioration from upward cerebellar
displacement
As many as one third of patients with swollen hemispheric supratentorial infarcts will be severely
disabled and fully dependent on care even after decompressive craniectomy, whereas most patients with
cerebellar infarct will have acceptable functional outcomes after surgery

Seizure Control
Seizures occur in 2-23% of patients within the first days after ischemic stroke. These seizures are usually focal,
but they may be generalized. Although primary prophylaxis for poststroke seizures is not indicated, secondary
prevention of subsequent seizures with standard antiepileptic therapy is recommended. [3]
A fraction of patients who have experienced stroke develop chronic seizure disorders. Seizure disorders
secondary to ischemic stroke should be managed in the same manner as other seizure disorders that arise as
a result of neurologic injury.[3]

Acute Decompensation
In the case of the rapidly decompensating patient or the patient with deteriorating neurologic status,
reassessment of the 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. Careful
observation for hemorrhagic transformation (especially in the first 24 hours postreperfusion) and cerebral
edema in patients with hemispheric or posterior fossa strokes in the first 24-36 hours is warranted.

Anticoagulation and Prophylaxis


Currently, data are inadequate to justify the routine use of heparin or other anticoagulants in the acute
management of ischemic stroke.[125] Patients with embolic stroke who have another indication for anticoagulation
(eg, atrial fibrillation) may be placed on anticoagulation therapy nonemergently, with the goal of preventing
further embolic disease; however, the potential benefits of that intervention must be weighed against the risk of
hemorrhagic transformation.[3] For more information, see Stroke Anticoagulation and Prophylaxis.
Immobilized stroke patients in particular are at increased risk of developing deep venous thrombosis (DVT) and
should receive early efforts to reduce the occurrence of DVT. The use of low-dose, subcutaneous
unfractionated or lowmolecular-weight heparin may be appropriate in these cases. [3] The CLOTS (Clots in Legs
Or sTockings after Stroke) trial demonstrated that intermittent pneumatic compression of the lower extremities,
started in the first 3 hospital days, reduced the risk of DVT in immobile patients with acute stroke. [126]

Neuroprotective Agents
The rationale for the use of neuroprotective agents is that reducing the release of excitatory neurotransmitters
by neurons in the ischemic penumbra may enhance the survival or these neurons. Despite very promising
results in several animal studies, however, no single neuroprotective agent in ischemic stroke has as yet been
supported by randomized, placebo-controlled human studies. Nevertheless, substantial research is under way
evaluating different neuroprotective strategies.
Hypothermia is fast becoming the standard of care for the ongoing treatment of patients surviving cardiac arrest
from ventricular tachycardia or ventricular fibrillation. However, no major clinical study has demonstrated a role
for hypothermia in the early treatment of ischemic stroke. [3]

For more information, see Neuroprotective Agents in Stroke.

Stroke Prevention
Primary prevention refers to the treatment of individuals with no history of stroke. Measures may include the
use of platelet antiaggregants, statins, and exercise. The 2011 AHA/ASA guidelines for the primary prevention
of stroke emphasize 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.[23]
Secondary prevention refers to the treatment of individuals who have already had a stroke. Measures may
include the use of platelet antiaggregants,[127]antihypertensives, statins,[128] and lifestyle interventions. A study by
the Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators concluded that in stroke patients who
have significant intracranial arterial stenosis, aspirin should be used in preference to warfarin for secondary
prevention.[129]
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. The 2011 AHA/ASA guidelines
recommend ED-based smoking cessation interventions, and consider it reasonable for EDs to screen patients
for hypertension and drug abuse.[23]
Written prescriptions for exercise and medications for smoking cessation (ie, nicotine patch, bupropion,
varenicline) increase the likelihood of success with these interventions. In addition, 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.

Aspirin for primary prevention


Overall, the value of aspirin in primary prevention appears uncertain, [130] and its use for this purpose is not
recommended for patients at low risk. Aspirin is recommended for primary prevention only in persons with at
least a 6-10% risk of cardiovascular events over 10 years. [23]
On the other hand, low-dose aspirin may be beneficial for primary prevention of stroke in women. A
randomized, placebo-controlled trial in 39,876 initially healthy women aged 45 years or older demonstrated that
100 mg of aspirin on alternate days resulted in a 24% reduction in the risk of ischemic stroke, with a
nonsignificant increase in the risk of hemorrhagic stroke.[131]

Secondary prevention guidelines


Guidelines issued in 2014 by the American Heart Association (AHA)/American Stroke Association (ASA) on the
secondary prevention of stroke emphasize nutrition and lifestyle and include a new section on aortic
atherosclerosis. New recommendations include the following [132, 133] :

Patients who have had a stroke or transient ischemic attack (TIA) should be screened for diabetes and
obesity
Patients should possibly be screened for sleep apnea
Patients should possibly undergo a nutritional assessment and be advised to follow a Mediterraneantype diet
Patients who have had a stroke of unknown cause should undergo long-term monitoring for atrial
fibrillation (AF)
The new oral anticoagulants dabigatran (class I, level of evidence [LOE] A), apixaban (class I, LOE B),
and rivaroxaban (class IIa, LOE B) are among the drugs recommended for patients with nonvalvular AF
Based on research results, the guidelines also recommend that, in patients without deep venous thrombosis
(DVT), a patent foramen ovale not be closed. In addition, because there is little data to suggest that niacin or
fibrate drugs, as a means to raise high-density lipoprotein (HDL) cholesterol, reduce secondary stroke risk, the
guidelines no longer recommend their use.

Dual antiplatelet therapy for secondary prevention


A systematic review and meta-analysis of 12 randomized trials involving 3766 patients concluded that,
compared with aspirin alone, dual antiplatelet therapy with aspirin plus either dipyridamole or clopidogrel

appears to be safe and effective in reducing stroke recurrence and other vascular events (ie, transient ischemic
attack [TIA], acute coronary syndrome, MI), in patients with acute ischemic stroke or TIA. [134] Dual therapy was
also associated with a nonsignificant trend toward increased major bleeding.
The European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) showed that the
combination of aspirin and dipyridamole was preferable to aspirin alone as antithrombotic therapy for cerebral
ischemia of arterial origin.[135]In ESPRIT, secondary prevention was started within 6 months of a TIA or minor
stroke of presumed arterial origin.
The addition of extended-release dipyridamole to aspirin therapy appears to be equally safe and effective
whether started early or late after stroke. A German study in 543 patients found no significant difference in
disability at 90 days, regardless of whether dipyridamole was started within 24 hours of stroke or TIA onset or
after 7 days of aspirin monotherapy.[136]
In contrast, the Management of AtheroThrombosis with Clopidogrel in High-risk patients with recent transient
ischaemic attack or ischaemic stroke (MATCH) trial, which included 7599 patients, found that adding aspirin to
clopidogrel did not significantly reduce major vascular events. However, the risk of life-threatening or major
bleeding was increased by the addition of aspirin. [137]

Carotid artery stenosis


For patients at risk for stroke from 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 because of improvements in medical therapies. Therefore, individual patient
comorbidities, life expectancy, and preferences should determine whether medical treatment alone or carotid
revascularization is selected.[23]

Atrial fibrillation
Atrial fibrillation (AF) is a major risk factor for stroke. The 2011 AHA/ASA primary stroke prevention guideline
recommends that EDs screen for AF and assess patients for anticoagulation therapy if AF is found. [23]
In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W), oral
anticoagulation with warfarin proved superior to clopidogrel plus aspirin for prevention of vascular events in
patients with AF who were at high risk of stroke. [138] The study was stopped early because of clear evidence of
superiority of oral anticoagulation therapy.
Interestingly, in ACTIVE W, the rate of vascular events was significantly higher in patients who switched from
warfarin to clopidogrel plus aspirin as a result of randomization than in patients who had been on warfarin
before study enrollment and remained on warfarin during the study. The benefit of anticoagulation therapy over
dual antiplatelet therapy was much more modest in patients who had not been on warfarin before study
initiation and were then randomized to warfarin.
The 2011 ACC Foundation (ACCF)/AHA/Heart Rhythm Society (HRS) AF guideline update states that the new
anticoagulant dabigatran is useful as an alternative to warfarin in patients with AF who do not have a prosthetic
heart valve or hemodynamically significant valve disease.[139] However, a 2012 meta-analysis found an
increased risk for MI or acute coronary syndrome with dabigatran. [140]
For patients with AF after stroke or TIA, the 2010 AHA/ASA secondary stroke prevention guidelines are 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 of warfarin after stroke or TIA in patients without AF has not been established. [141]

Specialized Stroke Centers


The concept of the specialized stroke center has evolved in response to the multitude of factors involved in the
care of patients with acute stroke. The Brain Attack Coalition provided recommendations for the establishment
of 2 tiers of stroke centers: primary stroke centers (PSCs) and comprehensive stroke centers (CSCs). [3] The
Joint Commission for the Accreditation of Hospital Organizations (JCAHO) now provides accreditation for PSCs
and CSCs. These centers are characterized as follows:

PSC: Designed to maximize the timely provision of stroke-specific therapy, including the administration
of rt-PA; the center is also capable of providing care to patients with uncomplicated stroke

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, as well as to all patients with stroke who
require emergent advanced imaging, intra-arterial therapies, neurosurgical interventions, and management in
a neurosurgical intensive care unit (NSICU)
PSCs and CSCs work most effectively when integrated into a regional stroke system of care so that patients
are treated at the most appropriate hospital based on factors such as severity, comorbidities, and timing.
Integrating regional prehospital services (911 and EMS) into this system of care ensures the most appropriate
triage from the field.
Additionally, stroke centers should have personnel versed in the monitoring of stroke vital signs, which include
the following:

Blood pressure
Glucose levels
Temperature
Oxygenation
Change in neurologic status
A further tier, acute stroke ready hospitals, is being defined as hospitals in which most of the necessary
resources are in place to emergently evaluate patients and potentially treat them with fibrinolytics, with the
assistance of remote stroke expertise, typically by telemedicine. Key to the optimal function of these stroke
centers is their interactions within a regional stroke system of care.

Coordination of care
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 for
the notification and involvement of neurologic consultants. These requirements have led to the development of
"code stroke" protocols for the ED. In addition, EMS personnel are trained to identify possible stroke patients
and arrange for their speedy, preferential transport to a PSC or CSC. [80]
Hospitals with specialized stroke teams have demonstrated significantly increased rates of fibrinolytic
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 intensive care unit (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, triage to the most appropriate hospital,
rapid transport, treatment, and rehabilitation of stroke patients. For more information, see Stroke Team Creation
and Primary Stroke Center Certification.

Consultations
A stroke team or an experienced professional who is sufficiently familiar with stroke should be available within
15 minutes of the patient's arrival in the ED. Other consultations are tailored to individual patient needs. Often,
occupational therapy, physical therapy, speech therapy, and physical medicine and rehabilitation experts are
consulted within the first day of hospitalization.
Consultation of cardiology, vascular surgery, 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

Medication Summary
While only 1 drug, recombinant tissue-type plasminogen activator (rt-PA), has demonstrated efficacy and
effectiveness in treating acute ischemic stroke and is approved by the FDA, other medications are equally
important. National consensus panels have included the use of antihypertensives, anticonvulsants, and osmotic
agents in their recommendations. Additional agents may be required for comorbid illnesses in many patients
with stroke.
Medications for the management of ischemic stroke can be distributed into the following categories:

Anticoagulation
Reperfusion
Antiplatelet
Neuroprotective

Thrombolytics
Class Summary
Thrombolyticmore accurately, fibrinolyticagents convert entrapped plasminogen to plasmin and initiate
local fibrinolysis by binding to fibrin in a clot.
View full drug information

Alteplase (Activase)
Alteplase is a t-PA used in management of acute myocardial infarction (MI), acute ischemic stroke, and
pulmonary embolism. Safety and efficacy with concomitant administration of heparin or aspirin during the first
24 hours after symptom onset have not been investigated.

Anticonvulsants, Other
Class Summary
While seizures associated with stroke are relatively uncommon, recurrent seizures may be life threatening.
Generally, agents used for treating recurrent convulsive seizures are also used in patients with seizures after
stroke. Benzodiazepines, typically diazepam and lorazepam, are the first-line drugs for ongoing seizures.
View full drug information

Diazepam (Valium)

Diazepam acts on the gamma-aminobutyric acid (GABA) receptor complex in the limbic system and thalamus,
producing a calming effect. The drug is useful in controlling active seizures and should be augmented by
longer-acting anticonvulsants, such as phenytoin or phenobarbital.
View full drug information

Lorazepam (Ativan)
Lorazepam is a short-acting benzodiazepine with a moderately long half-life. It has become the drug of choice
in many centers for treating active seizures.

Antiplatelet Agents
Class Summary
Although antiplatelet agents have proved useful for preventing recurrent stroke or stroke after transient
ischemic attacks (TIAs), efficacy in the treatment of acute ischemic stroke has not been demonstrated. Early
aspirin therapy is recommended within 48 hours of the onset of symptoms but should be delayed for at least 24
hours after rt-PA administration. Aspirin should not be considered as an alternative to intravenous fibrinolysis or
other therapies aimed at improving outcomes after stroke.
View full drug information

Aspirin (ASA)
Aspirin blocks prostaglandin synthetase action, which in turn inhibits prostaglandin synthesis and prevents the
formation of platelet-aggregating thromboxane A2. It also acts on the hypothalamic heat-regulating center to
reduce fever.
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Dipyridamole and aspirin (Aggrenox)


The combination of extended-release dipyridamole and aspirin reduces the relative risk of stroke, death, and
myocardial infarction (MI). It is used for the secondary prevention of ischemic stroke and TIAs.
View full drug information

Clopidogrel (Plavix)
Clopidogrel inhibits platelet aggregation and is used for secondary stroke prevention. It is indicated for the
reduction of atherothrombotic events following a recent stroke.

Anticoagulants, Hematologic
Class Summary
Anticoagulants such as warfarin are used for secondary stroke prevention.
View full drug information

Warfarin (Coumadin, Jantoven)


Warfarin is an anticoagulant used to reduce the risk of death, recurrent MI, and thromboembolic events such as
stroke or systemic embolization after MI.
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Dabigatran (Pradaxa)
Dabigatran is a competitive, direct inhibitor of thrombin that can prevent thrombus development. This agent
inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It may be used as an
alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal
to permanent atrial fibrillation and risk factors for stroke or systemic embolization.
View full drug information

Rivaroxaban (Xarelto)
Rivaroxaban is a Factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in patients
with nonvalvular atrial fibrillation. The dose is adjusted according to estimated creatinine clearance.

View full drug information

Apixaban (Eliquis)
Apixaban is a factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking the active
site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It inhibits free and clot-bound
factor Xa and prothrombinase activity. Although this agent has no direct effect on platelet aggregation, it does
indirectly inhibit platelet aggregation induced by thrombin. Apixaban is indicated to reduce risk of stroke and
systemic embolism associated with nonvalvular atrial fibrillation.
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Edoxaban (Savaysa)
Edoxaban is a Factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with
nonvalvular atrial fibrillation. A lower dose is needed with CrCl < 50 mL/min. Do not use with CrCL >95 mL/min.
In the ENGAGE AF-TIMI 48 study, patients with NVAF with CrCL >95 mL/min had an increased rate of ischemic
stroke with edoxaban 60 mg/day compared with patients treated with warfarin.

Analgesics, Other
Class Summary
Hyperthermia in acute stroke is potentially harmful and should be treated. Agents with potential bleeding risk
should be avoided, if possible.
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Acetaminophen (Tylenol, Feverall, Aspirin Free Anacin)


Acetaminophen reduces fever by acting directly on hypothalamic heat-regulating centers, which increases the
dissipation of body heat via vasodilation and sweating.

Beta Blockers, Alpha Activity


Class Summary
Optimal blood pressure management in acute stroke remains subject to some debate. Treatment parameters
depend largely on whether the patient is a candidate for fibrinolytic therapy. While the target blood pressures
may differ, the therapeutic agents are primarily the same.
View full drug information

Labetalol (Normodyne, Trandate)


Labetalol is an adrenergic receptor-blocking agent with nonselective beta-adrenergic and selective alpha1
competitive receptor-blocking actions. It produces dose-related decreases in blood pressure without inducing
reflex tachycardia.

ACE Inhibitors
Class Summary
Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II, a
potent vasoconstrictor, resulting in lower aldosterone secretion.
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Enalapril (Vasotec)
An ACE inhibitor, enalapril decreases circulating angiotensin II levels and suppresses the renin-angiotensinaldosterone system, lowering overall blood pressure.

Calcium Channel Blockers


Class Summary

Optimal blood pressure management in acute stroke remains subject to some debate. Treatment parameters
depend largely on whether the patient is a candidate for fibrinolytic therapy. While the target blood pressures
may differ, the therapeutic agents are largely the same.
View full drug information

Nicardipine (Cardene)
A calcium channel blocker, nicardipine inhibits calcium ion influx into vascular smooth muscle and myocardium.
[92]

Vasodilators
Class Summary
Vasodilators lower blood pressure through direct vasodilation and relaxation of the vascular smooth muscle.
They are used more for blood pressure lowering in severe or refractory situations and should be used with
caution.
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Nitroprusside sodium (Nipride, Nitropress, Sodium Nitroprusside)


Nitroprusside sodium is a vasodilator that decreases peripheral vascular resistance by relaxing arteriolar
smooth muscle. It also decreases venous return through venous dilation.