3338 PART 13 Neurologic Disorders

Endovascular mechanical thrombectomy has been studied as

an alternative or adjunctive treatment of acute stroke in patients

who are ineligible for, or have contraindications to, thrombolytics

or in those who failed to achieve vascular recanalization with IV

thrombolytics (see Fig. 426-12). In 2015, the results of six randomized trials were published, all demonstrating that endovascular

therapy improved clinical outcomes for internal carotid and MCA

occlusions proven by CT angiography (CTA), under 6 h from stroke

onset, with or without pretreatment with IV tissue plasminogen

activator (tPA). One study concluded that patients were home

nearly 2 months earlier if they received endovascular therapy. A

combined meta-analysis of all patients in these trials confirmed

a large benefit with endovascular therapy (odds ratio [OR], 2.49;

95% confidence interval [CI], 1.76–3.53; p <.001). The percentage

of patients who achieved modified Rankin scores of 0–2 (normal

or symptomatic but independent) was 46% in the endovascular

group and 26.5% in the medical arm. A more recent meta-analysis

reveals a mortality benefit as well with thrombectomy. As with IV

rtPA treatment, clinical outcome is dependent on time to effective

therapy. The odds of a good outcome exceed 3 if groin puncture

occurs within 2 h of symptom onset but is only 2 if 8 h elapse. Over

80% of patients who had vessel opening within 1 h of arrival to the

emergency department had a good outcome, whereas only onethird had a good outcome if 6 h elapsed.

The outcomes from endovascular therapy are likely improved

with IV rtPA treatment prior to thrombectomy if the patient is

eligible for rtPA and it is safe to administer. Recent data support

replacing IV rtPA with IV tenecteplase because its simple bolus

administration makes transporting the patient to an endovascular

center less cumbersome.

Extending the time window beyond 6 h appears to be effective

if the patient has specific imaging findings demonstrating good

vascular collaterals (CT perfusion or magnetic resonance [MR] perfusion techniques, see Chap. 426) and can be treated within 24 h.

The Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (DAWN)

trial reported good outcomes more frequently with endovascular

therapy than with medical care alone (47 vs 13%, p <.0001). The

Endovascular Therapy Following Imaging Evaluation for Ischemic

Stroke 3 (DEFUSE-3) trial confirmed these results (45 vs 17%,

p <.001) if treated up to 16 h from stroke onset. Nonrandomized

data of thrombectomy for basilar occlusion have found this treatment to be safe up to 24 h from symptom onset and associated with

lower 3-month Rankin scores.

Now that endovascular stroke therapy is proven to be effective,

the creation of comprehensive stroke centers designed to rapidly

identify and treat patients with large-vessel cerebral ischemia is a

major focus internationally. Creating geographic systems of care

whereby stroke patients are first evaluated at primary stroke centers

(which can administer IV rtPA or tenecteplase) then transferred to

comprehensive centers if needed, or directly triaged to comprehensive centers based on field assessment, appears to be an effective

strategy to improve outcomes.

ANTITHROMBOTIC TREATMENT

Platelet Inhibition Aspirin is the only antiplatelet agent that has

been proven to be effective for the acute treatment of ischemic

stroke; there are several antiplatelet agents proven for the secondary

prevention of stroke (see below). Two large trials, the International

Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST),

found that the use of aspirin within 48 h of stroke onset reduced

both stroke recurrence risk and mortality minimally. Among

19,435 patients in IST, those allocated to aspirin, 300 mg/d, had

slightly fewer deaths within 14 days (9.0 vs 9.4%), significantly

fewer recurrent ischemic strokes (2.8 vs 3.9%), no excess of hemorrhagic strokes (0.9 vs 0.8%), and a trend toward a reduction in

death or dependence at 6 months (61.2 vs 63.5%). In CAST, 21,106

patients with ischemic stroke received 160 mg/d of aspirin or a

placebo for up to 4 weeks. There were very small reductions in the

aspirin group in early mortality (3.3 vs 3.9%), recurrent ischemic

strokes (1.6 vs 2.1%), and dependency at discharge or death (30.5

vs 31.6%). These trials demonstrate that the use of aspirin in the

treatment of AIS is safe and produces a small net benefit. For every

1000 acute strokes treated with aspirin, ~9 deaths or nonfatal stroke

recurrences will be prevented in the first few weeks and ~13 fewer

patients will be dead or dependent at 6 months. Combining aspirin

with clopidogrel or with ticagrelor following minor stroke or TIA is

effective at preventing second stroke (see below).

Anticoagulation Numerous clinical trials have failed to demonstrate any benefit of routine anticoagulation in the primary treatment of atherothrombotic cerebral ischemia and have also shown

an increase in the risk of brain and systemic hemorrhage. Therefore,

the routine use of heparin or other anticoagulants for patients

with atherothrombotic stroke is not warranted. Heparin and oral

anticoagulation are likely no more effective than aspirin for stroke

associated with arterial dissection. However, there may be benefit of

anticoagulation for halting progression of dural sinus thrombosis.

NEUROPROTECTION

Neuroprotection is the concept of providing a treatment that prolongs the brain’s tolerance to ischemia. Drugs that block the excitatory amino acid pathways have been shown to protect neurons and

glia in animals, but despite multiple human trials, they have not yet

been proven to be beneficial. Hypothermia is a powerful neuroprotective treatment in patients with cardiac arrest (Chap. 307) and is

neuroprotective in animal models of stroke, but it has not been adequately studied in patients with ischemic stroke and is associated

with an increase in pneumonia rates that could adversely impact

stroke outcomes. Hypothermia combined with hemicraniectomy is

no more effective than hemicraniectomy with euthermia.

STROKE CENTERS AND REHABILITATION

Patient care in stroke units followed by rehabilitation services

improves neurologic outcomes and reduces mortality. Use of clinical

pathways and staff dedicated to the stroke patient can improve care.

This includes use of standardized stroke order sets. Stroke teams

TABLE 427-1 Administration of Intravenous Recombinant Tissue

Plasminogen Activator (rtPA) for Acute Ischemic Stroke (AIS)a

INDICATION CONTRAINDICATION

Clinical diagnosis of stroke

Onset of symptoms to time of drug

administration ≤4.5 hb

CT scan showing no hemorrhage or

edema of >1/3 of the MCA territory

Age ≥18 years

Sustained BP >185/110 mmHg despite

treatment

Bleeding diathesis

Recent head injury or intracerebral

hemorrhage

Major surgery in preceding 14 days

Gastrointestinal bleeding in preceding

21 days

Recent myocardial infarction

Administration of rtPA

IV access with two peripheral IV lines (avoid arterial or central line placement)

Review eligibility for rtPA

Administer 0.9 mg/kg IV (maximum 90 mg) IV as 10% of total dose by bolus,

followed by remainder of total dose over 1 hc

Frequent cuff BP monitoring

No other antithrombotic treatment for 24 h

For decline in neurologic status or uncontrolled BP, stop infusion, give

cryoprecipitate, and reimage brain emergently

Avoid urethral catheterization for ≥2 h

a

See Activase (tissue plasminogen activator) package insert for complete list of

contraindications and dosing. b

Depending on the country, IV rtPA may be approved

for up to 4.5 h with additional restrictions. c

A dose of 0.6 mg/kg is commonly used in

Asia (Japan and China) based on randomized data indicating less hemorrhage and

similar efficacy using this lower dose.

Abbreviations: BP, blood pressure; CT, computed tomography; MCA, middle cerebral

artery.

3339 Ischemic Stroke CHAPTER 427

that provide emergency 24-h evaluation of acute stroke patients for

acute medical management and consideration of thrombolysis or

endovascular treatments are essential components of primary and

comprehensive stroke centers, respectively.

Proper rehabilitation of the stroke patient includes early physical,

occupational, and speech therapy. It is directed toward educating

the patient and family about the patient’s neurologic deficit, preventing the complications of immobility (e.g., pneumonia, DVT

and pulmonary embolism, pressure sores of the skin, and muscle

contractures), and providing encouragement and instruction in

overcoming the deficit. Use of pneumatic compression stockings is

of proven benefit in reducing risk of DVT and is a safe alternative

to heparin. The goal of rehabilitation is to return the patient home

and to maximize recovery by providing a safe, progressive regimen

suited to the individual patient. Additionally, the use of constrained

movement therapy (immobilizing the unaffected side) has been

shown to improve hemiparesis following stroke, even years after

the stroke, suggesting that physical therapy can recruit unused

neural pathways. Controversy exists regarding whether selective

serotonin uptake inhibitors improve motor recovery but they may

be helpful in preventing poststroke depression. Newer robotic therapies appear promising as well. The human nervous system is more

adaptable than previously thought, and developing physical and

pharmacologic strategies to enhance long-term neural recovery is

an active area of research.

■ ETIOLOGY OF ISCHEMIC STROKE

(Fig. 427-3 and Table 427-2) Although the initial management of

AIS often does not depend on the etiology, establishing a cause is

essential to reduce the risk of recurrence. Focus should be on atrial

fibrillation and carotid atherosclerosis, because these etiologies have

proven secondary prevention strategies. The clinical presentation and

examination findings often establish the cause of stroke or narrow the

possibilities to a few. Judicious use of laboratory testing and imaging

studies completes the initial evaluation. Nevertheless, nearly 30% of

strokes remain unexplained despite extensive evaluation.

Clinical examination should focus on the peripheral and cervical

vascular system (measuring blood pressure), the heart (dysrhythmia,

murmurs), extremities (peripheral emboli), and retina (effects of

hypertension and cholesterol emboli [Hollenhorst plaques]). A complete neurologic examination is performed to localize the anatomic

site of stroke (Chap. 426). An imaging study of the brain is nearly

always indicated and is required for patients being considered for

thrombolysis; it may be combined with CT- or MRI-based angiography to visualize the vasculature of the neck and intracranial vessels

(see “Imaging Studies,” Chap. 426). A chest x-ray, electrocardiogram

(ECG), urinalysis, complete blood count, erythrocyte sedimentation

rate (ESR), serum electrolytes, blood urea nitrogen (BUN), creatinine, blood glucose, serum lipid profile, prothrombin time (PT), and

partial thromboplastin time (PTT) are often useful and should be

considered in all patients. An ECG, and subsequent cardiac telemetry,

may demonstrate arrhythmias or reveal evidence of recent myocardial

infarction (MI). Of all these studies, only brain imaging is necessary

prior to IV rtPA; the results of other studies should not delay the rapid

administration of IV rtPA if the patient is eligible.

Cardioembolic Stroke Cardioembolism is responsible for ~20%

of all ischemic strokes. Stroke caused by heart disease is primarily

due to embolism of thrombotic material forming on the atrial or

ventricular wall or the left heart valves. These thrombi then detach

and embolize into the arterial circulation. The thrombus may fragment or lyse quickly, producing only a TIA. Alternatively, the arterial

occlusion may last longer, producing stroke. Embolic strokes tend to

occur suddenly with maximum neurologic deficit present at onset.

With reperfusion following more prolonged ischemia, petechial hemorrhages can occur within the ischemic territory. These are usually

of no clinical significance and should be distinguished from frank

intracranial hemorrhage into a region of ischemic stroke where the

mass effect from the hemorrhage can cause a significant decline in

neurologic function.

Emboli from the heart most often lodge in the intracranial internal

carotid artery, the MCA, the posterior cerebral artery (PCA), or one

of their branches; infrequently, the anterior cerebral artery (ACA) is

Left ventricular

thrombi

Valve disease

Atrial fibrillation

Flowreducing

carotid

stenosis

External

carotid

Common

carotid

Internal

carotid

Cardiogenic

emboli

Carotid

plaque with

arteriogenic

emboli

Intracranial

atherosclerosis

Penetrating

artery disease

A B C

FIGURE 427-3 Pathophysiology of ischemic stroke. A. Diagram illustrating the three major mechanisms that underlie ischemic stroke: (1) occlusion of an intracranial vessel

by an embolus (e.g., cardiogenic sources such as atrial fibrillation or artery-to-artery emboli from carotid atherosclerotic plaque), often affecting the large intracranial

vessels; (2) in situ thrombosis of an intracranial vessel, typically affecting the small penetrating arteries that arise from the major intracranial arteries; (3) hypoperfusion

caused by flow-limiting stenosis of a major extracranial (e.g., internal carotid) or intracranial vessel, often producing “watershed” ischemia. B. and C. Diagram and

reformatted computed tomography angiogram of the common, internal, and external carotid arteries. High-grade stenosis of the internal carotid artery, which may be

associated with either cerebral emboli or flow-limiting ischemia, was identified in this patient.

3340 PART 13 Neurologic Disorders

involved. Emboli large enough to occlude the stem of the MCA (3–4

mm) or internal carotid terminus lead to large infarcts that involve

both deep gray and white matter and some portions of the cortical surface and its underlying white matter. A smaller embolus may occlude

a small cortical or penetrating arterial branch. The location and size

of an infarct within a vascular territory depend on the extent of the

collateral circulation.

The most significant cause of cardioembolic stroke in most of the

world is nonrheumatic (often called nonvalvular) atrial fibrillation. MI,

prosthetic valves, rheumatic heart disease, and ischemic cardiomyopathy are other considerations (Table 427-2). Cardiac disorders causing

brain embolism are discussed in the chapters on heart diseases, but a

few pertinent aspects are highlighted here.

Nonrheumatic atrial fibrillation is the most common cause of cerebral embolism overall. The presumed stroke mechanism is thrombus

formation in the fibrillating atrium or atrial appendage, with subsequent embolization. Patients with atrial fibrillation have an average

annual risk of stroke of ~5%. The risk of stroke can be estimated

by calculating the CHA2

DS2

-VASc score (Table 427-3). Left atrial

enlargement is an additional risk factor for formation of atrial thrombi.

Rheumatic heart disease usually causes ischemic stroke when there

is prominent mitral stenosis or atrial fibrillation. Recent MI may be

a source of emboli, especially when transmural and involving the

anteroapical ventricular wall, and prophylactic anticoagulation following MI with left ventricular thrombus has been shown to reduce

ischemic stroke risk. Mitral valve prolapse is not usually a source of

emboli unless the prolapse is severe.

Paradoxical embolization occurs when venous thrombi migrate to

the arterial circulation, usually via a patent foramen ovale (PFO) or

atrial septal defect. Bubble-contrast echocardiography (IV injection

of agitated saline coupled with either transthoracic or transesophageal echocardiography) can demonstrate a right-to-left cardiac shunt,

revealing the conduit for paradoxical embolization. Alternatively, a

right-to-left shunt is implied if immediately following IV injection of

agitated saline, the ultrasound signature of bubbles is observed during

transcranial Doppler insonation of the MCA; pulmonary arteriovenous malformations should be considered if this test is positive yet

an echocardiogram fails to reveal an intracardiac shunt. Both techniques are highly sensitive for detection of right-to-left shunts. Besides

venous clot, fat and tumor emboli, bacterial endocarditis, IV air, and

amniotic fluid emboli at childbirth may occasionally be responsible

for paradoxical embolization. The importance of a PFO as a cause

of stroke is debated, particularly because they are present in ~15% of

the general population. The presence of a venous source of embolus,

most commonly a deep-venous thrombus, may provide confirmation

of the importance of a PFO with an accompanying right-to-left shunt

in a particular case. Meta-analysis of three recent randomized trials

reported a hazard ratio of 0.41 for recurrent stroke (about a 1% per year

absolute reduction) using percutaneous occlusion devices in patients

with no other explanation for their stroke. Guidelines now endorse

PFO closure with percutaneous devices after consultation with a neurologist and a cardiologist. This is the practice followed by the authors.

Bacterial endocarditis can be a source of valvular vegetations that

give rise to septic emboli. The appearance of multifocal symptoms

and signs in a patient with stroke makes bacterial endocarditis more

likely. Infarcts of microscopic size occur, and large septic infarcts may

evolve into brain abscesses or cause hemorrhage into the infarct, which

generally precludes use of anticoagulation or thrombolytics. Mycotic

aneurysms caused by septic emboli may also present as subarachnoid

hemorrhage (SAH) or intracerebral hemorrhage.

Artery-to-Artery Embolic Stroke Thrombus formation on atherosclerotic plaques may embolize to intracranial arteries producing

an artery-to-artery embolic stroke. Less commonly, a diseased vessel

may acutely thrombose. Unlike the myocardial vessels, artery-to-artery

embolism, rather than local thrombosis, appears to be the dominant

vascular mechanism causing large-vessel brain ischemia. Any diseased

vessel may be an embolic source, including the aortic arch, common

carotid, internal carotid, vertebral, and basilar arteries.

CAROTID ATHEROSCLEROSIS Atherosclerosis within the carotid

artery occurs most frequently within the common carotid bifurcation

and proximal internal carotid artery; the carotid siphon (portion

within the cavernous sinus) is also vulnerable to atherosclerosis. Male

gender, older age, smoking, hypertension, diabetes, and hypercholesterolemia are risk factors for carotid disease, as they are for stroke in

general (Table 427-4). Carotid atherosclerosis produces an estimated

10% of ischemic stroke. For further discussion of the pathogenesis of

atherosclerosis, see Chap. 237.

Carotid disease can be classified by whether the stenosis is symptomatic or asymptomatic and by the degree of stenosis (percent narrowing of the narrowest segment compared to a nondiseased segment).

Symptomatic carotid disease implies that the patient has experienced

TABLE 427-2 Causes of Ischemic Stroke

COMMON CAUSES UNCOMMON CAUSES

Thrombosis

Lacunar stroke (small vessel)

Large-vessel thrombosis

Dehydration

Embolic occlusion

Artery-to-artery

 Carotid bifurcation

 Aortic arch

 Arterial dissection

Cardioembolic

 Atrial fibrillation

 Mural thrombus

 Myocardial infarction

 Dilated cardiomyopathy

 Valvular lesions

 Mitral stenosis

 Mechanical valve

 Bacterial endocarditis

Paradoxical embolus

 Atrial septal defect

 Patent foramen ovale

Atrial septal aneurysm

Spontaneous echo contrast

 Stimulant drugs: cocaine,

amphetamine

Hypercoagulable disorders

Protein C deficiencya

Protein S deficiencya

Antithrombin III deficiencya

Antiphospholipid syndrome

Factor V Leiden mutationa

Prothrombin G20210 mutationa

Systemic malignancy

Sickle cell anemia

β Thalassemia

Polycythemia vera

Systemic lupus erythematosus

Homocysteinemia

Thrombotic thrombocytopenic

purpura

Disseminated intravascular

coagulation

Dysproteinemiasa

Nephrotic syndromea

Inflammatory bowel diseasea

Oral contraceptives

COVID-19 infection

Venous sinus thrombosisb

Fibromuscular dysplasia

Vasculitis

 Systemic vasculitis (PAN,

 granulomatosis with polyangiitis

[Wegener’s], Takayasu’s, giant cell

arteritis)

Primary CNS vasculitis

Meningitis (syphilis, tuberculosis,

fungal, bacterial, zoster)

Noninflammatory vasculopathy

Reversible vasoconstriction

syndrome

Fabry’s disease

Angiocentric lymphoma

Cardiogenic

Mitral valve calcification

Atrial myxoma

Intracardiac tumor

Marantic endocarditis

Libman-Sacks endocarditis

Subarachnoid hemorrhage vasospasm

Moyamoya disease

Eclampsia

a

Chiefly cause venous sinus thrombosis. b

May be associated with any

hypercoagulable disorder.

Abbreviations: CNS, central nervous system; PAN, polyarteritis nodosa.

3341 Ischemic Stroke CHAPTER 427

TABLE 427-3 Recommendations on Chronic Use of Antithrombotics

for Various Cardiac Conditions

CONDITION RECOMMENDATION

Nonvalvular atrial fibrillation Calculate CHA2

DS2

-VASc scorea

• CHA2

DS2

-VASc score of 0 Aspirin or no antithrombotic

• CHA2

DS2

-VASc score of 1 Aspirin or OAC

• CHA2

DS2

-VASc score of ≥2 OAC

Rheumatic mitral valve disease

• With atrial fibrillation, previous

embolization, or atrial appendage thrombus,

or left atrial diameter >55 mm

OAC

• Embolization or appendage clot despite OAC OAC plus aspirin

Mitral valve prolapse

• Asymptomatic No therapy

• With otherwise cryptogenic stroke or TIA Aspirin

• Atrial fibrillation OAC

Mitral annular calcification

• Without atrial fibrillation but systemic

embolization, or otherwise cryptogenic

stroke or TIA

Aspirin

• Recurrent embolization despite aspirin OAC

• With atrial fibrillation OAC

Aortic valve calcification

• Asymptomatic No therapy

• Otherwise cryptogenic stroke or TIA Aspirin

Aortic arch mobile atheroma

• Otherwise cryptogenic stroke or TIA Aspirin or OAC

Patent foramen ovale

• Otherwise cryptogenic ischemic stroke

or TIA

Aspirin or closure with device

• Indication for OAC (deep-venous

thrombosis or hypercoagulable state)

OAC

Mechanical heart value

• Aortic position, bileaflet or Medtronic Hall

tilting disk with normal left atrial size and

sinus rhythm

VKA INR 2.5, range 2–3

• Mitral position tilting disk or bileaflet valve VKA INR 3.0, range 2.5–3.5

• Mitral or aortic position, anterior-apical

myocardial infarct or left atrial enlargement

VKA INR 3.0, range 2.5–3.5

• Mitral or aortic position, with atrial

fibrillation, or hypercoagulable state, or

low ejection fraction, or atherosclerotic

vascular disease

Aspirin plus VKA INR 3.0,

range 2.5–3.5

• Systemic embolization despite target INR Add aspirin and/or increase

INR: prior target was 2.5,

increase to 3.0, range 2.5–3.5;

prior target was 3.0, increase to

3.5, range 3–4

Bioprosthetic valve

• No other indication for VKA therapy Aspirin

Infective endocarditis Avoid antithrombotic agents

Nonbacterial thrombotic endocarditis

• With systemic embolization Full-dose, unfractionated

heparin or SC LMWH, or Xa

inhibitor

a

CHA2

DS2

-VASc score is calculated as follows: 1 point for congestive heart failure,

1 point for hypertension, 2 points for age ≥75 years, 1 point for diabetes mellitus,

2 points for stroke or TIA, 1 point for vascular disease (prior myocardial infarction,

peripheral vascular disease, or aortic plaque), 1 point for age 65–74 years, 1 point

for female sex category; sum of points is the total CHA2

DS2

-VASc score.

Note: Dose of aspirin is 50–325 mg/d; target INR for VKA is between 2 and 3 unless

otherwise specified.

Abbreviations: INR, international normalized ratio; LMWH, low-molecular-weight

heparin; OAC, oral anticoagulant (VKA, thrombin inhibitor, or oral factor Xa

inhibitors); TIA, transient ischemic attack; VKA, vitamin K antagonist.

Sources: Data from DE Singer et al: Chest 133:546S, 2008; DN Salem et al: Chest

133:593S, 2008; CT January et al: JACC 64:2246, 2014.

a stroke or TIA within the vascular distribution of the artery, and it is

associated with a greater risk of subsequent stroke than asymptomatic stenosis, in which the patient is symptom free and the stenosis is

detected through screening. Greater degrees of arterial narrowing are

generally associated with a higher risk of stroke, except that those with

near occlusions are at lower risk of stroke.

OTHER CAUSES OF ARTERY-TO-ARTERY EMBOLIC STROKE Intracranial

atherosclerosis produces stroke either by an embolic mechanism or by

in situ thrombosis of a diseased vessel. It is more common in patients

of Asian and African-American descent. Recurrent stroke risk is ~15%

per year, similar to untreated symptomatic carotid atherosclerosis.

Dissection of the internal carotid or vertebral arteries or even vessels

beyond the circle of Willis is a common source of embolic stroke in

young (age <60 years) patients. The dissection is usually painful and

precedes the stroke by several hours or days. Extracranial dissections

do not cause hemorrhage, presumably because of the tough adventitia

of these vessels. Intracranial dissections, conversely, may produce

SAH because the adventitia of intracranial vessels is thin and pseudoaneurysms may form, requiring urgent treatment to prevent rerupture. Treating asymptomatic pseudoaneurysms following extracranial

dissection is likely not necessary. The cause of dissection is usually

unknown, and recurrence is rare. Ehlers-Danlos type IV, Marfan’s

disease, cystic medial necrosis, and fibromuscular dysplasia are associated with dissections. Trauma (usually a motor vehicle accident or a

sports injury) can cause carotid and vertebral artery dissections. Spinal

manipulative therapy is associated with vertebral artery dissection

and stroke. Most dissections heal spontaneously, and stroke or TIA is

uncommon beyond 2 weeks. One trial showed no difference in stroke

prevention with aspirin compared to anticoagulation, with a low recurrent stroke rate of 2%.

■ SMALL-VESSEL STROKE

The term lacunar infarction refers to infarction following atherothrombotic or lipohyalinotic occlusion of a small artery in the brain. The

term small-vessel stroke denotes occlusion of such a small penetrating

artery and is now the preferred term. Small-vessel strokes account for

~20% of all strokes.

Pathophysiology The MCA stem, the arteries comprising the

circle of Willis (A1 segment, anterior and posterior communicating

arteries, and P1 segment), and the basilar and vertebral arteries all give

rise to 30- to 300-μm branches that penetrate the deep gray and white

matter of the cerebrum or brainstem (Fig. 427-4). Each of these small

branches can occlude either by atherothrombotic disease at its origin or

by the development of lipohyalinotic thickening. Thrombosis of these

vessels causes small infarcts that are referred to as lacunes (Latin for

“lake” of fluid noted at autopsy). These infarcts range in size from 3 mm

to 2 cm in diameter. Hypertension and age are the principal risk factors.

Clinical Manifestations The most common small-vessel stroke

syndromes are the following: (1) pure motor hemiparesis from an

infarct in the posterior limb of the internal capsule or the pons; the

face, arm, and leg are almost always involved; (2) pure sensory stroke

from an infarct in the ventral thalamus; (3) ataxic hemiparesis from an

infarct in the ventral pons or internal capsule; (4) and dysarthria and a

clumsy hand or arm due to infarction in the ventral pons or in the genu

of the internal capsule.

Transient symptoms (small-vessel TIAs) may herald a small-vessel

infarct; they may occur several times a day and last only a few minutes.

Recovery from small-vessel strokes tends to be more rapid and complete than recovery from large-vessel strokes; in some cases, however,

there is severe permanent disability.

A large-vessel source (either thrombosis or embolism) may manifest

initially as a small-vessel infarction. Therefore, the search for embolic

sources (carotid and heart) should not be completely abandoned in

the evaluation of these patients. Secondary prevention of small-vessel

stroke involves risk factor modification, specifically reduction in blood

pressure (see “Treatment: Primary and Secondary Prevention of Stroke

and TIA,” below).

3342 PART 13 Neurologic Disorders

TABLE 427-4 Risk Factors for Stroke

RISK FACTOR RELATIVE RISK RELATIVE RISK REDUCTION WITH TREATMENT

NUMBER NEEDED TO TREATa

PRIMARY PREVENTION SECONDARY PREVENTION

Hypertension 2–5 38% 100–300 50–100

Atrial fibrillation 1.8–2.9 68% warfarin, 21% aspirin 20–83 13

Diabetes 1.8–6 No proven effect

Smoking 1.8 50% at 1 year, baseline risk at 5 years

postcessation

Hyperlipidemia 1.8–2.6 16–30% 560 230

Asymptomatic carotid stenosis 2.0 53% 85 N/A

Symptomatic carotid stenosis

(70–99%)

65% at 2 years N/A 12

Symptomatic carotid stenosis

(50–69%)

29% at 5 years N/A 77

a

Number needed to treat to prevent one stroke annually. Prevention of other cardiovascular outcomes is not considered here.

Abbreviation: N/A, not applicable.

Anterior cerebral a.

Anterior cerebral a.

Internal carotid a.

Basilar a.

Basilar a.

Vertebral a.

Vertebral a.

Internal

carotid a.

Middle cerebral a.

Deep branches

of the basilar a.

Middle cerebral a.

Deep branches of the

middle cerebral a.

FIGURE 427-4 Diagrams and reformatted computed tomography (CT) angiograms in the coronal section illustrating

the deep penetrating arteries involved in small-vessel strokes. In the anterior circulation, small penetrating

arteries called lenticulostriates arise from the proximal portion of the anterior and middle cerebral arteries and

supply deep subcortical structures (upper panels). In the posterior circulation, similar arteries arise directly from

the vertebral and basilar arteries to supply the brainstem (lower panels). Occlusion of a single penetrating artery

gives rise to a discrete area of infarct (pathologically termed a “lacune,” or lake). Note that these vessels are too

small to be visualized on CT angiography.

■ LESS COMMON CAUSES OF STROKE

(Table 427-2) Hypercoagulable disorders (Chap. 65) primarily increase

the risk of cortical vein or cerebral venous sinus thrombosis. Systemic

lupus erythematosus with Libman-Sacks endocarditis can be a cause

of embolic stroke. These conditions overlap with the antiphospholipid

syndrome (Chap. 357), which probably requires long-term anticoagulation to prevent further stroke. Homocysteinemia may cause arterial

thromboses as well; this disorder is caused by various mutations in the

homocysteine pathways and responds to different forms of cobalamin depending on the

mutation. Disseminated intravascular coagulopathy can cause both venous and arterial

occlusive events; COVID-19 infection may

predispose for acute ischemic stroke due to

large-vessel occlusion.

Venous sinus thrombosis of the lateral or

sagittal sinus or of small cortical veins (cortical vein thrombosis) occurs as a complication

of oral contraceptive use, pregnancy and the

postpartum period, inflammatory bowel disease, intracranial infections (meningitis), and

dehydration. It is also seen in patients with

laboratory-confirmed thrombophilia including antiphospholipid syndrome, polycythemia, sickle cell anemia, deficiencies of proteins

C and S, factor V Leiden mutation (resistance to activated protein C), antithrombin III

deficiency, homocysteinemia, and the prothrombin G20210 mutation. Women who take

oral contraceptives and have the prothrombin

G20210 mutation may be at particularly high

risk for sinus thrombosis. Patients present

with headache and may also have focal neurologic signs (especially paraparesis) and seizures. Often, CT imaging is normal unless an

intracranial venous hemorrhage has occurred,

but the venous sinus occlusion is readily visualized using MR or CT venography or conventional x-ray angiography. With greater degrees

of sinus thrombosis, the patient may develop

signs of increased ICP and coma. Intravenous

heparin, regardless of the presence of intracranial hemorrhage, reduces morbidity and

mortality, and the long-term outcome is generally good. Heparin prevents further thrombosis and reduces venous hypertension and

ischemia. If an underlying hypercoagulable

state is not found, many physicians treat with

oral anticoagulants for 3–6 months and then

convert to aspirin, depending on the degree

of resolution of the venous sinus thrombus.

Anticoagulation is often continued indefinitely if thrombophilia is diagnosed.

3343 Ischemic Stroke CHAPTER 427

Sickle cell anemia (SS disease) is a common cause of stroke in children. A subset of homozygous carriers of this hemoglobin mutation

develop stroke in childhood, and this may be predicted by documenting high-velocity blood flow within the MCAs using transcranial

Doppler ultrasonography. In children who are identified to have high

velocities, treatment with aggressive exchange transfusion dramatically

reduces risk of stroke, and if exchange transfusion is ceased, their

stroke rate increases again along with MCA velocities.

Fibromuscular dysplasia (Chap. 281) affects the cervical arteries

and occurs mainly in women. The carotid or vertebral arteries show

multiple rings of segmental narrowing alternating with dilatation.

Vascular occlusion is usually incomplete. The process is often asymptomatic but occasionally is associated with an audible bruit, TIAs, or

stroke. Involvement of the renal arteries is common and may cause

hypertension. The cause and natural history of fibromuscular dysplasia

are unknown. TIA or stroke generally occurs only when the artery is

severely narrowed or dissects. Anticoagulation or antiplatelet therapy

may be helpful.

Temporal (giant cell) arteritis (Chap. 363) is a relatively common

affliction of elderly individuals in which the external carotid system,

particularly the temporal arteries, undergoes subacute granulomatous

inflammation with giant cells. Occlusion of posterior ciliary arteries

derived from the ophthalmic artery results in blindness in one or both

eyes and can be prevented with glucocorticoids. It rarely causes stroke

because the internal carotid artery is usually not inflamed. Idiopathic

giant cell arteritis involving the great vessels arising from the aortic

arch (Takayasu’s arteritis) may cause carotid or vertebral thrombosis; it

is rare in the Western Hemisphere.

Necrotizing (or granulomatous) arteritis (Chap. 363), occurring

alone or in association with generalized polyarteritis nodosa or granulomatosis with polyangiitis (Wegener’s), involves the distal small

branches (<2 mm diameter) of the main intracranial arteries and

produces small ischemic infarcts in the brain, optic nerve, and spinal

cord. The CSF often shows pleocytosis, and the protein level is elevated.

Primary central nervous system vasculitis is rare; small or mediumsized vessels are usually affected, without apparent systemic vasculitis.

The differential diagnosis includes other inflammatory vasculopathies

including infection (tuberculous, fungal), sarcoidosis, angiocentric

lymphoma, carcinomatous meningitis, and noninflammatory causes

such as atherosclerosis, emboli, connective tissue disease, vasospasm,

migraine-associated vasculopathy, and drug-associated causes. Some

cases develop in the postpartum period and are self-limited.

Patients with any form of vasculopathy may present with insidious

progression of combined white and gray matter infarctions, prominent

headache, and cognitive decline. Brain biopsy or high-resolution conventional x-ray angiography is usually required to make the diagnosis

(Fig. 427-5). A lumbar puncture (elevated white blood cells, elevated

IgG index, bands on electrophoresis) can provide support for an

inflammatory etiology of a neurovascular problem. When inflammation is confirmed, aggressive immunosuppression with glucocorticoids,

and often cyclophosphamide, is usually necessary to prevent progression; a diligent investigation for infectious causes such as tuberculosis

is essential prior to immunosuppression. With prompt recognition and

treatment, many patients can make an excellent recovery.

Drugs, in particular amphetamines and perhaps cocaine, may cause

stroke on the basis of acute hypertension or drug-induced vasculopathy. This vasculopathy is commonly due to vasospasm or atherosclerosis, but cases of inflammatory vasculitis have also been reported. No

data exist on the value of any treatment, but cessation of stimulants

is prudent. Phenylpropanolamine has been linked with intracranial

hemorrhage, as has cocaine and methamphetamine, perhaps related

to a drug-induced vasculopathy. Moyamoya disease is a poorly understood occlusive disease involving large intracranial arteries, especially

the distal internal carotid artery and the stem of the MCA and ACA.

Vascular inflammation is absent. The lenticulostriate arteries develop

a rich collateral circulation around the occlusive lesion, which gives

the impression of a “puff of smoke” (moyamoya in Japanese) on

conventional x-ray angiography. Other collaterals include transdural

anastomoses between the cortical surface branches of the meningeal

and scalp arteries. The disease occurs mainly in Asian children or

young adults, but the appearance may be identical in adults who have

atherosclerosis, particularly in association with diabetes. Intracranial

hemorrhage may result from rupture of the moyamoya collaterals;

thus, anticoagulation is risky. Progressive occlusion of large surface

arteries can occur, producing large-artery distribution strokes. Surgical

bypass of extracranial carotid arteries to the dura or MCAs may prevent stroke and hemorrhage.

Posterior reversible encephalopathy syndrome (PRES) can occur

with head injury, seizure, migraine, sympathomimetic drug use,

and eclampsia and in the postpartum period. The pathophysiology

is uncertain but likely involves a hyperperfusion state where blood

pressure exceeds the upper limit of cerebral autoregulation resulting

in cerebral edema (Chap. 307). Patients complain of headache and

manifest fluctuating neurologic symptoms and signs, especially visual

symptoms. Sometimes cerebral infarction ensues, but typically, the

clinical and imaging findings reverse completely. MRI findings are

characteristic with the edema present within the occipital lobes but

can be generalized and do not respect any single vascular territory. A

closely related reversible cerebral vasoconstriction syndrome (RCVS)

typically presents with sudden, severe headache closely mimicking

SAH. Patients may experience ischemic infarction and intracerebral

hemorrhage and typically have new-onset, severe hypertension. Conventional x-ray angiography reveals changes in the vascular caliber

throughout the hemispheres resembling vasculitis, but the process is

noninflammatory. Oral calcium channel blockers may be effective in

producing remission, and recurrence is rare.

Leukoaraiosis, or periventricular white matter disease, is the result

of multiple small-vessel infarcts within the subcortical white matter.

It is readily seen on CT or MRI scans as areas of white matter injury

surrounding the ventricles and within the corona radiata. The pathophysiologic basis of the disease is lipohyalinosis of small penetrating

arteries within the white matter, likely produced by chronic hypertension. Patients with periventricular white matter disease may develop

a subcortical dementia syndrome, and it is likely that this common

form of dementia may be delayed or prevented with antihypertensive

medications (Chap. 433).

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited disorder that

presents as small-vessel strokes, progressive dementia, and extensive

symmetric white matter changes often including the anterior temporal

lobes visualized by MRI. Approximately 40% of patients have migraine

with aura, often manifest as transient motor or sensory deficits. Onset

is usually in the fourth or fifth decade of life. This autosomal dominant

condition is caused by one of several mutations in Notch-3, a member

of a highly conserved gene family characterized by epidermal growth

factor repeats in its extracellular domain. Other monogenic ischemic

FIGURE 427-5 Cerebral angiogram from a 32-year-old male with central nervous

system vasculopathy. Dramatic beading (arrows) typical of vasculopathy is seen.

3344 PART 13 Neurologic Disorders

stroke syndromes include cerebral autosomal recessive arteriopathy

with subcortical infarcts and leukoencephalopathy (CARASIL) and

hereditary endotheliopathy, retinopathy, nephropathy, and stroke

(HERNS). Fabry’s disease also produces both a large-vessel arteriopathy and small-vessel infarctions. The COL4A1 mutation is associated

with multiple small-vessel strokes with hemorrhagic transformation.

■ TRANSIENT ISCHEMIC ATTACKS

TIAs are episodes of stroke symptoms that last only briefly; the standard definition of duration is <24 h, but most TIAs last <1 h. If a relevant brain infarction is identified on brain imaging, the clinical entity is

now classified as stroke regardless of the duration of symptoms. A normal brain imaging study following a TIA does not rule out TIA; rather,

the clinical syndrome is diagnostic. The causes of TIA are similar to

the causes of ischemic stroke, but because TIAs may herald stroke,

they are an important risk factor that should be considered separately

and urgently. TIAs may arise from emboli to the brain or from in situ

thrombosis of an intracranial vessel. With a TIA, the occluded blood

vessel reopens and neurologic function is restored.

The risk of stroke after a TIA is ~10–15% in the first 3 months, with

most events occurring in the first 2 days. This risk can be directly estimated using the well-validated ABCD2

 score (Table 427-5). Therefore,

urgent evaluation and treatment are justified. Because etiologies for

stroke and TIA are identical, evaluation for TIA should parallel that

of stroke.

TREATMENT

Transient Ischemic Attack

The improvement characteristic of TIA is a contraindication to

thrombolysis. However, because the risk of subsequent stroke in

the first few hours and days following TIA is high, some physicians

admit the patient to the hospital so a plasminogen activator can

be rapidly administered if symptoms return. The combination of

aspirin and clopidogrel was found to prevent stroke following TIA

better than aspirin alone in a large Chinese randomized trial and

the National Institutes of Health (NIH)–sponsored trial (POINT

study). Failure to respond to the combination of aspirin and clopidogrel is linked to carriage of a common CYP2C19 polymorphism

that leads to poor metabolism of clopidogrel into its active form.

This mutation is common, particularly in Asians. Recently, ticagrelor, 180-mg loading dose and then 90 mg twice daily, was tested in

combination with aspirin compared to aspirin alone, and this also

showed benefit in preventing stroke; this dual antiplatelet regimen

may be favored because of the lack of genetic heterogeneity in

platelet inhibition.

Primary and Secondary Prevention of

Stroke and TIA

GENERAL PRINCIPLES

Many medical and surgical interventions, as well as lifestyle modifications, are available for preventing stroke. Some of these can be

widely applied because of their low cost and minimal risk; others

are expensive and carry substantial risk but may be valuable for

selected high-risk patients. Identification and control of modifiable

risk factors, and especially hypertension, is the best strategy to

reduce the burden of stroke, and the total number of strokes could

be reduced substantially by these means (Table 427-4).

ATHEROSCLEROSIS RISK FACTORS

The relationship of various factors to the risk of atherosclerosis

is described in Chaps. 237 and 238. Older age, diabetes mellitus, hypertension, tobacco smoking, abnormal blood cholesterol

(particularly, low high-density lipoprotein [HDL] and/or elevated

low-density lipoprotein [LDL]), lipoprotein (a) excess, and other

factors are either proven or probable risk factors for ischemic

stroke, largely by their link to atherosclerosis. Risk of stroke is much

greater in those with prior stroke or TIA. Many cardiac conditions

predispose to stroke, including atrial fibrillation and recent MI.

Oral contraceptives and hormone replacement therapy increase

stroke risk, and although rare, certain inherited and acquired

hypercoagulable states predispose to stroke.

Hypertension is the most significant of the risk factors; in general,

all hypertension should be treated to a target of <130/80 mmHg.

Recent data (the Systolic Blood Pressure Intervention Trial—

SPRINT) suggest that lowering systolic blood pressure <120 mmHg

reduces stroke and heart attack by 43% compared to systolic blood

pressure <140 mmHg, without an increased risk of syncope or falls.

The presence of known cerebrovascular disease is not a contraindication to treatment aimed at achieving normotension. Data are

particularly strong in support of thiazide diuretics and angiotensinconverting enzyme inhibitors.

Several trials have confirmed that statin drugs reduce the risk

of stroke even in patients without elevated LDL or low HDL. The

Stroke Prevention by Aggressive Reduction in Cholesterol Levels

(SPARCL) trial showed benefit in secondary stroke reduction for

patients with recent stroke or TIA who were prescribed atorvastatin,

80 mg/d. The primary prevention trial, Justification for the Use of

Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), found that patients with low LDL (<130 mg/dL)

caused by elevated C-reactive protein benefitted by daily use of

this statin. Primary stroke occurrence was reduced by 51% (hazard

ratio, 0.49; p = .004), and there was no increase in the rates of intracranial hemorrhage. Meta-analysis has also supported a primary

treatment effect for statins given acutely for ischemic stroke. A

serum LDL <70 mg/dL lowers recurrent stroke risk better than an

LDL of 90–110 mg/dL. Therefore, a statin should be considered in

all patients with prior ischemic stroke. Tobacco smoking should

be discouraged in all patients (Chap. 454). The use of pioglitazone

(an agonist of peroxisome proliferator-activated receptor gamma)

in patients with type 2 diabetes and previous stroke does not lower

stroke, MI, or vascular death rates but is effective in lowering vascular events in patients with stroke and prediabetes or insulin resistance alone. Diabetes prevention is likely the most effective strategy

for primary and secondary stroke prevention.

TABLE 427-5 Risk of Stroke Following Transient Ischemic Attack:

The ABCD2

 Score

CLINICAL FACTOR SCORE

A: Age ≥60 years 1

B: SBP >140 mmHg or DBP >90 mmHg 1

C: Clinical symptoms

Unilateral weakness 2

Speech disturbance without weakness 1

D: Duration

>60 min 2

10–59 min 1

D: Diabetes (oral medications or insulin) 1

TOTAL SCORE SUM EACH CATEGORY

ABCD2

 Score Total 3-Month Rate of Stroke (%)a

0 0

1 2

2 3

3 3

4 8

5 12

6 17

7 22

a

Data ranges are from five cohorts.

Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

Source: Data from SC Johnston et al: Validation and refinement of scores to predict

very early stroke risk after transient ischaemic attack. Lancet 369:283, 2007.

3345 Ischemic Stroke CHAPTER 427

ANTIPLATELET AGENTS FOR STROKE PREVENTION

Platelet antiaggregation agents can prevent atherothrombotic events,

including TIA and stroke, by inhibiting the formation of intraarterial platelet aggregates. These can form on diseased arteries,

induce thrombus formation, and occlude or embolize into the distal

circulation. Aspirin, clopidogrel, the combination of aspirin plus

extended-release dipyridamole, and recently ticagrelor are the antiplatelet agents most commonly used for this purpose. Ticagrelor

has not been found to be better than aspirin for stroke prevention

except in combination with aspirin following TIA.

Aspirin is the most widely studied antiplatelet agent. Aspirin

acetylates platelet cyclooxygenase, which irreversibly inhibits the

formation in platelets of thromboxane A2

, a platelet aggregating and

vasoconstricting prostaglandin. This effect is permanent and lasts

for the usual 8-day life of the platelet. Paradoxically, aspirin also

inhibits the formation in endothelial cells of prostacyclin, an antiaggregating and vasodilating prostaglandin. This effect is transient. As

soon as aspirin is cleared from the blood, the nucleated endothelial

cells again produce prostacyclin. Aspirin in low doses given once

daily inhibits the production of thromboxane A2

 in platelets without substantially inhibiting prostacyclin formation. Higher doses of

aspirin have not been proven to be more effective than lower doses.

Clopidogrel and ticagrelor block the adenosine diphosphate

(ADP) receptor on platelets and thus prevent the cascade resulting in activation of the glycoprotein IIb/IIIa receptor that leads to

fibrinogen binding to the platelet and consequent platelet aggregation. Clopidogrel can cause rash and, in rare instances, thrombotic

thrombocytopenic purpura. The Clopidogrel versus Aspirin in

Patients at Risk of Ischemic Events (CAPRIE) trial, which led to

U.S. Food and Drug Administration (FDA) approval, found that

it was only marginally more effective than aspirin in reducing risk

of stroke. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) trial was a large multicenter, randomized, double-blind study that compared clopidogrel in

combination with aspirin to clopidogrel alone in the secondary

prevention of TIA or stroke. The MATCH trial found no difference

in TIA or stroke prevention with this combination but did show

a small but significant increase in major bleeding complications

(3 vs 1%). In the Clopidogrel for High Atherothrombotic Risk and

Ischemic Stabilization, Management, and Avoidance (CHARISMA)

trial, which included a subgroup of patients with prior stroke or

TIA along with other groups at high risk of cardiovascular events,

there was no benefit of clopidogrel combined with aspirin compared to aspirin alone. Lastly, the SPS3 trial looked at the long-term

combination of clopidogrel and aspirin versus clopidogrel alone in

small-vessel stroke and found no improvement in stroke prevention

and a significant increase in both hemorrhage and death. Thus, the

long-term use of clopidogrel in combination with aspirin is not

recommended for stroke prevention.

The short-term combination of clopidogrel with aspirin may

be effective in preventing second stroke, however. A large trial of

Chinese patients enrolled within 24 h of TIA or minor ischemic

stroke found that a clopidogrel-aspirin regimen (clopidogrel

300 mg load then 75 mg/d with aspirin 75 mg for the first 21 days)

was superior to aspirin (75 mg/d) alone, with 90-day stroke risk

decreased from 11.7 to 8.2% (p <.001) and no increase in major

hemorrhage. This benefit was limited to those not carrying the

CYP2C19 polymorphism associated with clopidogrel hypometabolism. An international NIH-sponsored trial demonstrated similar

results; therefore, the combination of aspirin and clopidogrel should

be administered for TIA or minor ischemic stroke for the first

21–90 days before switching to monotherapy.

A recent study of oral ticagrelor plus aspirin versus aspirin alone

has shown similar benefits in secondary stroke reduction and carries the likely advantage that ticagrelor’s antiplatelet effect is not

genetically variable, as is the case with clopidogrel.

Dipyridamole is an antiplatelet agent that inhibits the uptake

of adenosine by a variety of cells, including those of the vascular endothelium. The accumulated adenosine is an inhibitor of

aggregation. At least in part through its effects on platelet and

vessel wall phosphodiesterases, dipyridamole also potentiates the

antiaggregatory effects of prostacyclin and nitric oxide produced

by the endothelium and acts by inhibiting platelet phosphodiesterase, which is responsible for the breakdown of cyclic AMP.

The resulting elevation in cyclic AMP inhibits aggregation of platelets. Dipyridamole is erratically absorbed depending on stomach

pH, but a newer formulation combines timed-release dipyridamole,

200 mg, with aspirin, 25 mg, and has better oral bioavailability.

This combination drug was studied in three trials. The European

Stroke Prevention Study (ESPS) II showed efficacy of both

50 mg/d of aspirin and extended-release dipyridamole in preventing stroke and a significantly better risk reduction when the

two agents were combined. The open-label ESPRIT (European/

Australasian Stroke Prevention in Reversible Ischaemia Trial) trial

confirmed the ESPS-II results. After 3.5 years of follow-up, 13%

of patients on aspirin and dipyridamole and 16% on aspirin alone

(hazard ratio, 0.80; 95% CI, 0.66–0.98) met the primary outcome of

death from all vascular causes. In the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, the combination of

extended-release dipyridamole and aspirin was compared directly

with clopidogrel with and without the angiotensin receptor blocker

telmisartan; there were no differences in the rates of second stroke

(9% each) or degree of disability in patients with median follow-up

of 2.4 years. Telmisartan also had no effect on these outcomes. This

suggests that these antiplatelet regimens are similar and raises questions about default prescription of agents to block the angiotensin

pathway in all stroke patients. The principal side effect of dipyridamole is headache. The combination capsule of extended-release

dipyridamole and aspirin is approved for prevention of stroke.

Many large clinical trials have demonstrated clearly that most

antiplatelet agents reduce the risk of all important vascular atherothrombotic events (i.e., ischemic stroke, MI, and death due to all vascular causes) in patients at risk for these events. The overall relative

reduction in risk of nonfatal stroke is ~25–30% and of all vascular

events is ~25%. The absolute reduction varies considerably, depending on the patient’s risk. Individuals at very low risk for stroke seem

to experience the same relative reduction, but their risks may be so

low that the “benefit” is meaningless. Conversely, individuals with

a 10–15% risk of vascular events per year experience a reduction

to ~7.5–11%.

Aspirin is inexpensive, can be given in low doses, and could

be recommended for all adults to prevent both stroke and MI.

However, it causes epigastric discomfort, gastric ulceration, and

gastrointestinal hemorrhage, which may be asymptomatic or life

threatening. Consequently, not every 40- or 50-year-old should

be advised to take aspirin regularly because the risk of atherothrombotic stroke is extremely low and is outweighed by the risk of

adverse side effects. Conversely, every patient who has experienced

an atherothrombotic stroke or TIA and has no contraindication to

antiplatelet therapy (or indication for anticoagulation) should be

taking an antiplatelet agent regularly because the average annual

risk of another stroke is 8–10%; another few percent will experience

an MI or vascular death. Clearly, the likelihood of benefit far outweighs the risks of treatment.

The choice of antiplatelet agent and dose must balance the risk of

stroke, the expected benefit, and the risk and cost of treatment. However, there are no definitive data, and opinions vary. Many authorities believe low-dose (30–75 mg/d) and high-dose (650–1300 mg/d)

aspirin are about equally effective. Some advocate very low doses to

avoid adverse effects, and still others advocate very high doses to

be sure the benefit is maximal. Most physicians in North America

recommend 81–325 mg/d, whereas most Europeans recommend

50–100 mg. Clopidogrel and extended-release dipyridamole plus

aspirin are being increasingly recommended as first-line drugs for

secondary prevention. Similarly, the choice of aspirin, clopidogrel,

or dipyridamole plus aspirin must balance the fact that the latter are

more effective than aspirin but the cost is higher, and this is likely to

affect long-term patient adherence. The use of platelet aggregation