Stroke: Cleveland Clinic

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/ischemic-stroke/
Published September 2013

Definition and Etiology

A stroke is defined as an acute loss of neurological function due to an abnormal perfusion of brain tissue. Most
strokes are ischemic (87%) in nature and commonly result from an arterial obstruction by a thrombus or
embolus. Hemorrhagic strokes (13%) are caused by rupture or leak of a blood vessel either within the primary
brain tissue or subarachnoid space. This chapter provides a clinical approach to the evaluation and management
of stroke, with a focus on ischemic stroke.

Prevalence and Risk Factors

Because stroke is the leading cause of morbidity and the fourth-leading cause of death in the United States
today, optimal reduction of risk factors is paramount in preventing and managing stroke. Modifiable and
nonmodifiable stroke risk factors are listed in Table 1. In 2005, the prevalence of stroke in noninstitutionalized
adults was 5.8 million in the United States alone. Based on American Stroke Association data, the estimated
direct and indirect cost of stroke for 2008 was $65.5 billion, with an estimated lifetime cost of $140,000 per
patient.
Table 1: Cerebrovascular Disease Risk Factors

Disease

Modifiable

Not Modifiable

Ischemic stroke

Hypertension
Diabetes
Atrial fibrillation
Smoking
Hyperlipidemia
Carotid stenosis
Lack of physical activity

Age >55
Male gender
Black race
Family history of stroke
Personal history of stroke
Sickle Cell Disease

Intraparenchymal
hemorrhage

Hypertension
Antithrombotic use
Thrombolytic use
Coagulopathy
Illicit Drug Use

Vascular malformation
Amyloid angiopathy
Neoplasm
Trauma
Acute ischemic stroke

Aneurysm
Family history of aneurysm or connective tissue
disease
Black or Hispanic Race
Other vascular malformation
Trauma
Female gender

Subarachnoid hemorrhage

Hypertension
Smoking
Alcohol Abuse

Pathophysiology and Natural History

Ischemic Stroke
The mechanism of stroke is an important characteristic of ischemic strokes and help predict outcomes after
stroke and assess risk of stroke recurrence. Based on prior clinical trials, a subclassification scheme of five
etioloiges of ischemic stroke has become widely accepted. They are large-artery atherosclerosis, embolism,
small-vessel disease, stroke of other determined etiology, and stroke of undetermined etiology.
Large-Artery Atherosclerosis

High-grade stenosis or occlusion of the major intra- and extra-cranial arteries, which include the internal carotid
artery, the vertebral artery, the basilar artery, and other major branches of the circle of Willis, occur due to
deposition of plaque and may lead to a flow-dependent state of perfusion. With interruption of flow due to acute
plaque rupture or a prolonged low-flow state due to relative hypotension, a loss of adequate cerebral perfusion
results in ischemia and focal neurologic deficit. A more common cause of stroke in the setting of large-artery
atherosclerosis is the formation of thrombus that can block flow directly or dislodge to form an atheroembolism
that obstructs a distal vessel.
Cardiac Embolism

Turbulent or stagnant flow states in the heart can result in formation of thrombi. These thrombi can dislodge
and occlude blood vessels in the intracranial circulation farther downstream. The most common cause of
cardioembolic stroke is atrial fibrillation. Other causes include severe left ventricular dysfunction resulting in a
low ejection fraction, paradoxical embolus from the venous system due to a shunt through a septal defect such
as an aneurysm or patent foramen ovale, or vessel-to-vessel atheroembolism due to atherosclerotic disease in
the vertebral arteries, carotid arteries, and aortic arch.
Small-Vessel Disease

Changes in the arterial vasculature of small perforating arteries can result in narrowing of the vessel lumen and
eventual occlusion. Chronic hypertension is one state that leads to vessel damage secondary to lipohyalinosis
and endothelial damage. Hyperlipidemia, smoking, and diabetes also lead to changes in the vessel wall that
result in decreased compliance and intraluminal stenosis. These changes often result in lacunar infarcts, which
are small infarcts defined by their size (<15 mm3) and are typically located in deep structures such as the
internal capsule, basal ganglia, thalamus, and pons.
Stroke of Other Determined Etiology

The majority of ischemic strokes are classified in one of the previous categories. Rarely, other causes must be
investigated, particularly in patients who are young and have no risk factors for stroke. Among these causes are
coagulopathies, vasculopathies, genetic disorders, and metabolic disorders.
Stroke of Undetermined Etiology

In a significant number of cases (40%), no clear explanation can be found for an ischemic stroke despite an
extensive diagnostic evaluation. These strokes are classified as strokes of undetermined etiology, or cryptogenic
strokes. This is a diagnosis of exclusion, however, and should only be made once a thorough search for both
common and uncommon causes of stroke has been completed.
Transient Ischemic Attack

A transient ischemic attack (TIA) is a brief episode of neurological dysfunction caused by focal brain or retinal
ischemic, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction.
It is important to note that many patients with transient symptoms lasting less than 24 hours actually have
associated infarction on imaging and should be classified as a stroke. Patients with TIA or mild stroke are at risk
for developing stroke in the near future: 10% to 15% of patients will have a stroke within 3 months, with half
occurring within 48 hours.
Intracerebral Hemorrhage
Intracerebral hemorrhage occurs when a blood vessel within the brain parenchyma ruptures and causes
accumulation of blood within the brain tissue. Weakening of the blood vessel wall is often a result of chronic
uncontrolled hypertension or a problem intrinsic to the blood vessel such as amyloid angiopathy or other
vascular malformation. In hypertension, microaneurysms in perforating vessels, known as Charcot-Bouchard
aneurysms, can rupture and cause bleeding. The thalamus, basal ganglia, pons, and cerebellum are the most
common sites for these hypertensive bleeds. Lobar hemorrhages more commonly result from amyloid
angiopathy, which is typically seen in older patients. This should be suspected when there is evidence of prior
areas of hemorrhage manifested as hemosiderin deposits on magnetic resonance imaging (MRI). Other causes
of intracerebral hemorrhage include the use of anticoagulants, thrombolytics, and antiplatelet agents,
particularly when levels are supratherapeutic. They may also be caused by an underlying primary or metastatic
brain tumor, especially when there are focal areas of necrosis within the tumor bed.
Subarachnoid Hemorrhage
Subarachnoid hemorrhage is most commonly due to trauma and typically occurs adjacent to areas of bony
prominence, such as the temporal poles and the frontal poles. Subarachnoid hemorrhage can also result from
rupture of a cerebral aneurysm. Aneurysms are usually located at vulnerable branch points in the circle of Willis
due to weakening of the vessel wall. The most common sites of aneurysm formation and rupture are in the
distribution of the anterior communicating artery and the posterior communicating artery. Uncontrolled chronic
hypertension, smoking, and a family history of aneurysms are risk factors for formation and rupture of
aneurysms. In 10% to 20% of cases of spontaneous, nontraumatic subarachnoid hemorrhage, no cause is found
despite serial angiography. The prognosis for these patients is typically favorable.

Signs and Symptoms

An acute stroke is signified by a sudden onset of focal neurologic deficit and is variable depending on the area
of tissue ischemia. Localization can often be made by the pattern of clinical findings. Common stroke
syndromes are listed in Table 2 according to vascular distribution. Although headache might accompany an
ischemic stroke, an acute and severe headache that is maximal at onset more commonly represents a
subarachnoid or intraparenchymal hemorrhage, especially if this is followed by somnolence or decreased mental
status. Seizures can also occur at the onset of ischemic or hemorrhagic strokes.
Table 2: Overview of Selected Stroke Syndromes

Vascular Territory

Area Affected

Signs and Symptoms

Anterior cerebral
artery

Frontal pole and mesial

frontal lobe

Contralateral: leg > face and arm weakness

Frontal signs such as abulia

Middle cerebral
artery

Posterior frontal,
temporal, parietal lobes

Contralateral: face and arm > leg weakness, sensory loss to all
modalities, visual field cut, visual-spatial neglect
Ipsilateral: gaze preference

Posterior cerebral
Occipital lobe
artery
Anterior inferior
cerebellar artery

Lateral pontine
syndrome

Posterior inferior
cerbellar artery

Lateral medulla
(Wallenberg syndrome)

Basilar artery

Pons (locked-in
syndrome)

Vertebral artery

Medial medulla

Vertebral artery

Lateral medulla

Dominant hemisphere affected: aphasia, alexia, agraphia, acalculia

Contralateral: homonymous hemianopia

With thalamic involvement: Sensory loss to all modalities or pain

Contralateral: hemiparesis and hemisensory loss of pain and

temperature
Ipsilateral: ataxia

Contralateral: hemibody pain and temperature loss

Ipsilateral: facial pain, hemifacial pain and temperature loss, ataxia,
nystagmus, nausea/vomiting, vertigo, Horner's syndrome, dysphagia
Hiccups

Bilateral: progressive quadriplegia, facial weakness

Lateral gaze weakness with sparing of vertical gaze

Contralateral: hemibody weakness, loss of vibration and

proprioception
Ipsilateral: tongue weakness and/or atrophy

Wallenberg syndrome

Motor symptoms consist of facial droop, hemiparesis, or isolated weakness of the arm or leg. Dizziness, slurred
speech, problems with coordination, or difficulty with gait and balance may also be reported and may be due to
involvement of cerebellar fibers. Sensory symptoms include numbness or altered sensation, with tingling
paresthesias of one side of the body or face, or both. Vision loss in one eye or both eyes as in a homonymous
hemianopsia can also occur.
Patients with an acute stroke might also present with confusion or are sometimes perceived as being confused when
there is an expressive or receptive aphasia or a visuospatial neglect phenomenon.

One of the most urgent and potentially devastating stroke syndromes is thrombosis of the basilar artery, which
can manifest with acute quadriparesis, loss of consciousness, and respiratory failure.

Diagnosis
The first step in correctly identifying a stroke is a rapid, thorough neurologic assessment consisting of a focused
history and neurologic examination. A differential diagnosis is listed in Box 1. It is of utmost importance to
establish a time of symptom onset when eliciting the history from the patient or witnesses. If the patient woke
with symptoms, treatment is based on the time the patient was last seen normal, which for many would be when
they went to bed the night before.

Box 1: Differential Diagnosis of Stroke

Complex or atypical migraine
Conversion disorder
Electrolyte disturbance
Hypoglycemia or hyperglycemia
Intracranial neoplasm
Meningitis, encephalitis, or systemic infection
Multiple sclerosis exacerbation
Seizure
Subdural hemorrhage

Vital signs should be assessed frequently, with particular attention to blood pressure and heart rate. It is also
necessary to obtain a blood glucose level immediately because both hypo- and hyperglycemia can manifest
clinically with acute neurologic deficits, mimicking a stroke.
Regarding the physical examination, a variety of tools in the form of validated scales are available for
evaluation of the patient at presentation. The NIH Stroke Scale is a widely accepted and useful tool that is
recommended in the acute phase for the purpose of quickly identifying focal neurologic deficits and their
severity (Class I, Level B recommendation).

Treatment
Acute Management and Interventions
The first step in the appropriate management of acute stroke is early identification at symptom onset. Early
notification of emergency medical services with use of stroke-identification algorithms, management in the field
with stroke protocols, and emergent transport to the nearest center capable of treating acute stroke is
recommended (Class I, Level B evidence). Airway, breathing, and circulation should be stabilized, with airway
support and ventilatory assistance in the appropriate patients (Class I, Level C evidence). Initial laboratory
testing and CT brain scan should be performed as detailed earlier.
In patients who present with stroke symptoms within 3 hours of 'last known well' and who meet eligibility
criteria (Box 2), treatment with IV recombinant tissue plasminogen activator (rtPA) is recommended at a dose
of 0.9 mg/kg (maximum dose, 90 mg) over 1 hour, with the first 10% given as a bolus over 1 minute (Class I,
Level A evidence). Studies have demonstrated that 31% to 50% of patients treated with rtPA within 3 hours
experienced improved recovery at 3 months as compared to 20% to 38% of patients in the placebo arm.
However, strict adherence to national guidelines in the administration of rtPA and postlysis management is
critical, given the 6% risk of intracranial hemorrhage. The time window for IV rtPA has been expanded more
recently out to 4.5 hours from time last known well. (Class I, Level B evidence) based upon a European study
The European Cooperative Acute Study III (ECASS III). In this study, 52.4% of subjects receiving IV rtPA
within 3 to 4.5 hours had favorable outcome compared to 45.2% of subjects that received placebo. The

eligibility criteria for treatment in the 3- to 4.5-hour time period are similar to those for persons treated at earlier
time periods, but with the additional exclusion criteria (See Box 2). Although the 3- to 4.5-hour time period has
been endorsed by the American Stroke Association, it has not yet been approved by the Food and Drug
Administration (FDA).
Box 2: Exclusion Criteria for Treatment of Acute Ischemic Stroke with rtPA within 3 Hours of Last Known Well
Onset of symptoms >3 hours
CT with acute hemorrhage or hypodensity involving >1/3 of the hemisphere
Systolic blood pressure >185 mm Hg and diastolic blood pressure >110 mm Hg
Evidence of active bleeding or acute trauma on exam
Anticoagulant therapy with INR >1.7 (or elevated PTT if receiving heparin)
Platelet count <100,000 mm3
Blood glucose <50 mg/dL
Seizure at symptom onset
History of prior intracranial hemorrhage, neoplasm, or vascular malformation
Head trauma or stroke in past 3 months
Myocardial infarction in past 3 months
Gastrointestinal or urinary tract hemorrhage in past 3 weeks
Major surgery in past 14 days
Arterial puncture at a noncompressible site in past 7 days
Rapid, spontaneous improvement of neurologic signs
Symptoms suggesting subarachnoid hemorrhage
Mild neurologic deficit
Additional Exclusion Criteria for Treatment within 3 to 4.5 Hours of Last Known Well
Age >80 years
Taking oral anticoagulants regardless of INR level Baseline NIHSS >25
History of both stroke and diabetes

CT, computed tomography; INR, international normalized ratio; PTT, partial thromboplastin time; rtPA,
recombinant tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scale.
In selected patients who are not candidates for IV rtPA therapy, intra-arterial thrombolysis by a qualified neurointerventionalist may be considered in stroke patients who present within 6 hours of onset (Class I, Level B
recommendation). However, the availability of intra-arterial thrombolysis should not preclude the
administration of IV rtPA in eligible patients (Class III, Level C evidence). Endovascular intervention,
including angioplasty and disruption or removal of the clot, is another option available at some specialized
stroke centers for patients within 8 hours of last known well. Several devices have been approved by the FDA to
recanalize occluded vessels, but guideline recommendations for mechanical revascularization are generally
lacking.
Urgent anticoagulation in acute ischemic stroke is no longer recommended and should not be used to replace IV
rtPA therapy in eligible patients (Class III, Level A evidence). Oral aspirin therapy at a dose of 325 mg daily is
recommended 24 to 48 hours after stroke onset in most patients (Class I, Level A evidence), but it should not be
given within 24 hours following rtPA therapy (Class III, Level A and B).
In patients who are eligible for rtPA, treatment of arterial hypertension is recommended (Class I, Level C
evidence) with a goal blood pressure of less than 185/110 mm Hg before rTPA is administered. Close post-lysis
monitoring, with antihypertensive treatment given according to the rtPA protocol, is also crucial to prevent
hemorrhage (Class I, Level B evidence). In patients who are not candidates for rtPA, blood pressure
management in the acute setting is still controversial, but the consensus is that antihypertensive medications
should be withheld unless systolic blood pressure is higher than 220 or diastolic blood pressure is higher than
120 (Class I, Level C evidence). After 24 hours, initiation of antihypertensive agents is considered relatively
safe for patients with pre-existing hypertension.
Hypoxemia should be treated with supplemental oxygen, and fever should be treated with antipyretic agents
(Class I, Level C evidence). Euglycemia should be targeted, because persistent hyperglycemia has been
associated with poor outcomes (Class IIa, Level C evidence).
Patients should be admitted to specialized stroke care units incorporating rehabilitation when possible (Class I,
Level A evidence). Close monitoring during the first 72 to 96 hours of acute ischemic stroke is important to
assess for signs of hemorrhagic transformation or brain edema (Class I, Level B evidence). Decompressive
surgery in the setting of malignant edema may be life-saving, but the morbidity is unknown in the setting of
major cerebral hemispheric infarctions (Class IIa, Level B evidence).
Treatment of concomitant medical illnesses, pneumonia, and urinary tract infections is recommended (Class I,
Level B and C evidence). Screening swallow evaluations should be performed to assess the patients risk for
aspiration pneumonia (Class I, Level B evidence). Subcutaneous anticoagulation or sequential compression
devices should be instituted to prevent formation of deep venous thrombosis, especially in patients with
decreased mobility (Class I, Level A evidence). Additional early and late complications are listed in Box 3.
Box 3: Early and Late Complications of Stroke
Early Complications (within 7 days)

Cerebral edema and herniation (within 96 hr)

Expansion of the infarct/recurrent infarction
Hemorrhagic transformation of the infarcted area
Seizure
Aspiration pneumonitis
Gastrointestinal ulcers and/or bleeding

Deep vein thrombosis and pulmonary embolism

Myocardial infarction
Late Complications (>7 days later)

Recurrent stroke
Seizure
Aspiration pneumonitis
Deep vein thrombosis and pulmonary embolism
Decubitus ulcer
Persistent cognitive or language dysfunction
Persistent loss of mobility
Spasticity

Primary Prevention
The American Heart Association and American Stroke Association issued a guideline for the primary
prevention of stroke in 2010 and one focused on the management of patients with extracranial carotid stenoses
in 2011, which are summarized here.

Each patient should undergo formal assessment of his or her stroke risk (Class I, Level A evidence).
Hypertension has been well documented to increase the risk of stroke, and current recommendations are to
perform regular screening for hypertension a (Class I, Level A evidence). Diet and lifestyle should be modified
and pharmacologic treatment should be prescribed according to the JNC 7 recommendations. Currently,
guidelines emphasize individualization of therapy, with the overall goal being blood pressure reduction to at
least less than 140/90 mm Hg.
In patients with diabetes, stricter blood pressure control to less than 130/80 mm Hg with use of angiotensinconverting enzyme inhibitors or angiotensin receptor blockers is recommended (Class I, Level A evidence). In
these patients, a statin to lower the risk of first stroke is also recommended (Class I, Level A evidence). Tight
glycemic control is encouraged to reduce microvascular complications, but evidence showing a reduction in
stroke risk is lacking.
In patients with dyslipidemia, recommendations state that those with known coronary disease and patients at
high-risk for coronary disease be treated with lifestyle measures and a statin, even in the presence of a normal
LDL (Class I, Level A evidence). In patients with atrial fibrillation, warfarin therapy with a target international
normalized ratio of 2.0 to 3.0 is recommended in those without contraindications to oral anticoagulants (Class I,
Level A evidence).
Smoking doubles the risk of ischemic stroke and doubles or quadruples the risk of subarachnoid hemorrhage.
Smoking cessation is recommended (Class I, Level B evidence) and the use of counseling, nicotine replacement,
and oral medications should be considered (Class IIa, Level B evidence). In addition, it is reasonable to avoid
exposure to environmental smoke (Class IIa, Level C evidence).
Physical activity is recommended to reduce the risk of stroke (Class I, Level B evidence). Adults should engage in
2 hours and 30 minutes of moderate intensity activity each week or one hour and 15 minutes of vigorous
intensity aerobic activity each week (Class I, Evidence B evidence).
Currently, aspirin therapy is not recommended for primary stroke prevention in people at low risk for a
cardiovascular event (Class III, Level A evidence), but it may be helpful in primary stroke prevention for people
whose risk is sufficiently high for the benefits to outweigh the risks (a 10-year risk of cardiovascular events of 6%
to 10%) (Class I, Level A evidence).
In patients with asymptomatic carotid artery stenosis, screening for other treatable causes of stroke and
aggressive control of all risk factors is recommended (Class I, Level C evidence). Aspirin therapy is recommended
in the absence of contraindications (Class I, Level A evidence). Selection of asymptomatic patients for carotid
revascularization should be guided by an assessment of multiple different factors and discussion of risk and
benefits of the procedure (Class I, Level C evidence). Prophylactic carotid endarterectomy is reasonable in

selected patients with high-grade asymptomatic carotid stenosis if the risk of perioperative complications is low
(Class IIa, Level A evidence). Carotid artery angioplasty and stenting may be considered in asymptomatic
patients, but its effectiveness compared with medical therapy has not been well established (Class IIb, Level B
evidence). For both symptomatic and asymptomatic patients with high-grade carotid stenosis who are at high
risk of complications with revascularization, the effectiveness of revascularization over medical management is
also not established (Class IIb, Level B evidence).

Secondary Prevention
Following a stroke, lifestyle changes should be made, with particular attention to reducing risk factors for stroke
as outlined earlier. In patients with atrial fibrillation, warfarin therapy is recommended for preventing recurrent
stroke in the absence of contraindications. In patients with a history of noncardioembolic ischemic stroke,
antiplatelet therapy is recommended. Aspirin, clopidogrel, and dipyridamole in combination with low-dose
aspirin have all been shown to be beneficial in reducing the risk of recurrent stroke in multiple clinical trials.
The most recently published study, the PRoFESS trial from 2008, directly compared clopidogrel alone and
dipyridamole in combination with low-dose aspirin for preventing recurrent stroke. Although the results did not
meet the predefined statistical criteria for noninferiority, there was no statistically significant difference between
the groups in the primary outcome of recurrent stroke. However, there was an increase in the rate of intracranial
hemorrhage with the dipyridamole and aspirin arm, which was not seen in prior studies evaluating this
combination. Currently there is no clear uniform recommendation of one agent over another, and therapy must
be tailored to individual patients based on availability, cost, and side-effect profile.
For patients with symptomatic high-grade carotid artery stenosis, carotid endarterectomy is recommended for
patients within 6 months of the stroke event if they are at average or low risk (Class I, Level A evidence).
Carotid stenting is an alternative to CEA for symptomatic patients at average or low risk (Class I, Level B
evidence) based upon the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), which
demonstrated no significant difference in the primary outcome of stroke, death, or myocardial infarction, in
symptomatic or asymptomatic patients randomized to CEA or stenting.
Considerations in Special Populations
In patients with known medical conditions that increase the risk of stroke, such as sickle cell disease, vasculitis,
or cardiomyopathy, the approach to stroke prevention should be a coordinated effort among the patient, the
primary care physician, and involved specialists. Often, it is important to aggressively manage the underlying
disease state. The risk of ischemic stroke or intracerebral hemorrhage is 2.4 times greater during pregnancy and
the first 6 weeks following delivery. Focal neurologic signs in this population merits prompt evaluation by a
neurologist. Other special considerations include children or young adults with stroke and patients in whom no
clear etiology of stroke is determined. Further workup may include referral to a geneticist for evaluation of
potential genetic or metabolic causes of stroke in these populations.

Outcomes
During the hospitalization for an acute stroke, intensive speech, physical, and occupational therapy should be
initiated as soon as the patient is stable enough to participate. Most functional recovery occurs within the first 3
months. After this, further recovery is possible, but it is generally limited. The 1-year mortality in first-time
stroke sufferers is 14% to 24% in persons aged 40 to 69 years, and the 1-year mortality increases to 22% to 27%
in patients aged 70 years and older. Following a first stroke, the mean survival for persons aged 60 to 79 years
ranges from 5.4 to 7.4 years. After age 80 years, the mean survival decreases to 1.8 years for men and 3.1 years
for women.

Summary

A stroke is defined as a sudden focal loss of neurologic function due to decreased perfusion of brain tissue.
In patients who present with stroke symptoms, a rapid, focused neurologic history and physical examination
should be performed, making every attempt to establish a specific time of onset because this helps to guide
further therapy.
Patients presenting within a 4.5-hour time window of last known well should receive IV rtPA at a dose of 0.9
mg/kg (maximum dose 90 mg) after a CT brain excludes the presence of an intracranial hemorrhage and there
are no other contraindications to therapy. The dose is administered over 60 minutes, with 10% of the total dose
being given initially as a bolus.
The remaining hospital course is focused on evaluating potential etiologies of stroke, preventing early
complications, and performing intensive rehabilitation.
Anticoagulation should be considered for patients with a history of cardioembolic stroke, and antiplatelet
therapy should be considered for ischemic strokes of noncardiac etiology.
Optimization of stroke risk factor reduction is critical in both primary and secondary prevention.

The recommendations on early management of adults with ischemic stroke and prevention are based on
guidelines from the American Heart Association and American Stroke Association. Data regarding clinical
trials in ischemic stroke are available at strokecenter.org.