Online newspaper of professor Yasser Metwally

Cardioembolic stroke

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

Background: Cardiogenic embolism is recognized increasingly as an important cause of stroke. The availability of new diagnostic techniques (especially transesophageal echocardiography) has allowed clinicians to better characterize well-established sources of embolism and to discover other potential etiologies of cardioembolic stroke. Cardioembolic stroke is largely preventable, making measures of primary prevention valuable. Once stroke secondary to cardiac embolism has occurred, the likelihood of recurrence is high; thus secondary prevention is equally important.

Pathophysiology: No single mechanism is responsible for the development of cardiac emboli. The underlying cardiac disease determines the pathophysiology. Emboli secondary to chamber abnormalities (eg, atrial fibrillation, acute myocardial infarction) are induced mainly by stasis, while those secondary to valve involvement are the result of endothelial abnormalities with attachment of material (eg, platelets, bacteria) to their free borders. The nature of the embolus differs depending on the source (eg, calcified particles from calcific valves, neoplastic cells from myxomas). This issue has to be considered when choosing specific therapies. Prothrombotic states have been proposed, although not confirmed convincingly, to contribute to most cardioemboli, although marantic or nonbacterial thrombotic endocarditis is an exception.

Emboli from the heart are distributed evenly throughout the body according to cardiac output, but more than 80% of symptomatic or clinically recognized emboli involve the brain. Of emboli to the brain, approximately 80% involve the anterior circulation, proportional to the distribution of cerebral blood flow.

Once emboli have reached the cerebral circulation, they obstruct brain-supplying arteries, causing ischemia to the neurons and to the blood vessels within the area of ischemia. In contrast to thrombi, emboli are attached loosely to the vascular walls and thus commonly migrate distally. When this occurs, reperfusion of the damaged capillaries and arterioles allows blood to leak into the surrounding infarcted tissue. This explains in part the more frequent association of hemorrhagic infarctions with embolism than with other causes of ischemic stroke. In the great majority of patients with hemorrhagic infarcts, the hemorrhagic transformation does not cause clinical worsening, since the bleeding involves necrotic tissue.

In short, cardioembolic stroke is not one disease with a single natural history. Many different types of cardiac disorders lead to cardioembolic stroke, each with unique clinical features, risks of initial and recurrent stroke, and optimal therapy.

Frequency:

• In the US: Approximately 20% of ischemic strokes are considered cardioembolic. The annual incidence is estimated at approximately 125,000 cases.

• Internationally: Estimated frequency varies from 14% to 31% of ischemic strokes depending on criteria applied for definition, extent of evaluation, and study design (see Table 1). Large or consistent geographic variation is not apparent. The risk of cardioembolic event rises with age. The older the cohort, the higher the estimated frequency of cardioembolic stroke.

Table 1. Frequency of Cardioembolic Stroke/Neurovascular Diseases

*Frequency of presumed cardioembolic stroke as a percentage of consecutive ischemic strokes, using each author’s criteria. Criteria, design, and extent of evaluation varied substantially among studies.

† 20% had a major embolic source.

†† This study included transient ischemic attacks (TIAs).

Mortality/Morbidity: In general, cardioembolic strokes have a worse prognosis and produce larger and more disabling strokes than other ischemic stroke subtypes. This general observation is derived from emboli originating in cardiac chambers, which are on average of large size (eg, atrial appendage, ventricular thrombi).

Race: African Americans and Hispanic Americans reportedly have a lower frequency of cardioembolic strokes than whites, possibly reflecting a lower prevalence of atrial fibrillation in these ethnic groups, who tend to experience stroke at younger mean ages.

Sex: The female-to-male ratio of cardioembolic stroke increases with age, reflecting the increased prevalence of atrial fibrillation among elderly women.

Age: The relative frequency of cardioembolic stroke as a proportion of all strokes is bimodal, higher in young (75 y) individuals. The incidence increases steadily with age.

CLINICAL PICTURE

History: Although not sufficiently sensitive or specific to establish the diagnosis, several clinical features help to distinguish cardiogenic embolism from other mechanisms of cerebral ischemia.

• Clinical features of cardioembolic stroke include the following:

  • Decreased level of consciousness at onset of stroke

  • Sudden onset of symptoms and signs that are maximal at onset

  • Rapid recovery from major hemispheric deficits (“spectacular shrinking deficit”) due to reperfusion of brain with early lysis of the embolus

  • Onset of symptoms after a Valsalva maneuver (patent foramen ovale)

  • Symptoms reflecting involvement of different vascular territories of the brain

  • Cortical deficit (eg, aphasia-visual field defect) involving mainly the middle cerebral arteries and the posterior cerebral arteries and their branches

• Neither seizures nor headache at the onset is a useful predictor of cardioembolism.

• Cardiogenic emboli (especially from valvular sources) do not often affect the deep penetrating arteries or present as a lacunar syndrome.

Physical:

• Evidence of cardiac dysrhythmias (eg, atrial fibrillation, sick sinus syndrome)

• Presence of cardiac murmurs (eg, mitral stenosis, calcific aortic stenosis)

• Signs of congestive heart failure (eg, after acute myocardial infarction, nonischemic cardiomyopathies)

• Concomitant diseases (eg, systemic lupus erythematosus and Libman-Sachs endocarditis, neoplasia, marantic endocarditis)

• Concomitant signs of systemic embolism

  • The probability of finding such signs in patients with suspected cardioembolic stroke is low (approximately 1%) for most cardioembolic sources.

  • Diagnosis is based on the triad of (1) identification of a potential cardioembolic source, (2) absence of other likely causes of stroke, and (3) support of specific clinical features described above.

Causes:

More than 20 specific cardiac disorders have been implicated in leading to embolism. Dividing cardiac sources of emboli into major and minor risk categories is clinically useful (see below). Major risk sources carry a relatively high risk of initial and recurrent stroke, convincingly linked to a cardioembolic mechanism. When one of these causes is present, efforts at primary prevention of stroke usually are indicated; stroke in patients with any of these causes is most often cardioembolic. Minor risk sources are frequent in the general population, and the associated risk of initial and recurrent stroke with any of these conditions is either low or uncertain. When any of these is present in a patient with cerebral ischemia, the etiologic role must be viewed with skepticism and considered in the context of other diagnostic information.

Sources of cardioembolic embolism include the following. Asterisk (*) indicates a major risk source; dagger (†) indicates emboli originating in the venous circulation or right heart that cause ischemic stroke via abnormal cardiac or pulmonary shunting around the pulmonary capillary bed.

• Valvular disease*

  • Rheumatic mitral stenosis*

  • Prosthetic valves*

  • Calcific aortic stenosis

  • Bicuspid aortic valves

  • Mitral annulus calcification

  • Nonbacterial thrombotic (marantic) endocarditis* – Malignancies and other prothrombic states

  • Myxomatous mitral valvulopathy with prolapse

  • Infective endocarditis*

  • Inflammatory valvulitis – Libman-Sacks endocarditis, Behçet disease, syphilis

  • Lambl excrescences and/or strands

• Left ventricular thrombi

  • Ischemic heart disease*

  • Acute myocardial infarction*

  • Left ventricular akinesis or aneurysm*

  • Nonischemic dilating cardiomyopathies*

  • Hypertrophy

  • Contusion

  • Amyloid deposition

  • Hypereosinophilia

  • Rheumatic myocarditis

  • Sarcoidosis

  • Neuromuscular disorders

  • Alcoholic sequela

  • Catecholamine induced

  • Chagas disease

  • Doxorubicin

  • Crack cocaine use

  • Idiopathic

  • Oxalosis

  • Viral infection

  • Echinococcosis

  • Peripartum effect

  • Noncompaction

  • Prothrombotic states

  • Antiphospholipid antibodies

  • Diffuse intravascular coagulation

  • Polycystic disease

  • Essential thrombocythemia and myeloproliferative diseases

• Left atrial thrombi

  • Arrhythmias

  • Atrial fibrillation*

  • Sick sinus syndrome/atrial asystole

  • Atrial flutter

  • Other structural disease

  • Atrial septal aneurysms

  • Chiari network and patent foramen ovale

• Cardiac tumors

  • Atrial myxoma*
     

  • Cardiac sarcoma

  • Endocardial fibroelastoma

  • Metastatic disease

• Paradoxical emboli †

  • Atrial septal defects

  • Patient foramen ovale

  • Ventricular septal defects

  • Pulmonary arteriovenous fistulas

• Miscellaneous

  • Postcardiac catheterization

  • Postvalvuloplasty
  • Esophageal-atrial fistula

• Major risk sources

  • Atrial fibrillation: The leading cause of cardioembolic stroke, especially in elderly individuals, atrial fibrillation is present in approximately 1% of the US population and in approximately 5% of those older than 70 years.

    • Formerly associated with rheumatic valvular disease, it now is related most frequently to hypertension and ischemic heart disease (ie, nonvalvular atrial fibrillation).

    • Both paroxysmal and chronic atrial fibrillation are associated with increased risk of stroke.

    • Stasis secondary to decreased contractility of the left atrium leading to thrombus formation in its appendage is the postulated mechanism.

    • Transesophageal echocardiography is more sensitive than transthoracic echocardiography for the visualization of the left atrium and its appendage.

    • Not all atrial fibrillation–associated strokes are cardioembolic; in individual cases excluding other potential causes of stroke, such as intrinsic cerebrovascular disease or aortic atheroma, is important.

    • The annual rate of stroke in atrial fibrillation varies widely from 0.5% per year to 12% per year depending on prevalence and combination of risk factors; thus risk stratification is the first necessary step in choosing the best preventive therapy. Results from randomized trials have allowed identification of different risk subgroups of patients (see Table 2). The risk stratification criteria of the American College of Chest Physicians Consensus Conference (2001) are recommended most often; the authors’ Stroke Prevention in Atrial Fibrillation (SPAF) criteria (1995) have been validated independently as predictive.

    • Adjusted-dose warfarin (international normalized ratio [INR] 2-3) is associated with a 60% reduction in stroke incidence, while the efficacy of aspirin is modest (20%). Low-dose warfarin (INR <1.5), either alone or combined with aspirin, was not effective, highlighting the marginal benefit of warfarin when it is used inappropriately. Incidence of intracerebral hemorrhage, the most dreaded complication of warfarin therapy, is estimated to be 0.5% per year in this population.>

    • Recommendations for primary and secondary prevention based on risk factor stratification are presented in Table 3.

    • In acute stroke secondary to atrial fibrillation, anticoagulation with heparin has not demonstrated more benefit than early treatment with aspirin. Initiate aspirin early, followed by warfarin as soon as the patient is medically stable; discontinue aspirin after therapeutic anticoagulation is achieved.

    • In short, warfarin has demonstrated high efficacy in stroke prevention in patients with this common arrhythmia. Disadvantages include the increased risk of hemorrhagic complications and the need for close INR monitoring in these patients; thus consider patient preferences along with risk stratification and absolute risk reduction offered by this therapy. Alternative approaches (eg, cardioversion, surgical ablation of atrial appendage) are the subjects of ongoing clinical trials.

Table 2. Risk Stratification Schemes for Prevention of Stroke in Nonvalvular Atrial Fibrillation* (Click to download table 2 in PDF format)

Table 3. Prevention of Stroke in Nonvalvular Atrial Fibrillation – Recommendations

AF = Atrial fibrillation

* See Table 2 for current risk stratification schemes

† Lower doses of aspirin probably equally efficacious

•  

  • Rheumatic mitral stenosis: The incidence of this valvulopathy has decreased dramatically in the last decades. No good estimates are available of absolute stroke rates or randomized comparison of different therapies, but as it generally is associated closely with atrial fibrillation, anticoagulation with warfarin (INR 2-3) usually is recommended.

• Sick sinus syndrome: Also known as brady-tachy syndrome, this arrhythmia usually occurs in very elderly (70 y) individuals. Annual risk of stroke is 5-10%. Atrial and dual chamber pacing may reduce the stroke rate somewhat, but anticoagulation (INR 2-3) still is recommended; a lower target INR (eg, 1.6-2.5) may be tolerated better in these elderly patients.

• Atrial flutter (sustained): This is an uncommon arrhythmia. Because of the close association with atrial fibrillation with appendage stasis, anticoagulation (INR 2-3) is advocated.

• Prosthetic valves: Mechanical prosthetic valves carry an annual risk of stroke between 2-4% even in patients receiving anticoagulation. Permanent anticoagulation (INR 2.5-3.5) is mandatory. Bioprosthetic valves carry a lower annual risk rate (0.2-2.9%), and aspirin usually is recommended unless the patient has atrial fibrillation or evidence of atrial stasis.

• Infective endocarditis: Of patients with infective endocarditis, 20% suffer an embolic stroke. Staphylococcus aureus is the agent producing the highest stroke rate. Mitral valve endocarditis is the most common source of emboli. Antibiotic therapy reduces the embolic potential when administrated in the acute phase. Anticoagulation is contraindicated because of unacceptable rates of hemorrhagic stroke. In patients with prosthetic valve endocarditis, the risk of thromboembolism is greater than the risk of intracranial hemorrhage, thus anticoagulation usually is recommended if no evidence of hemorrhage is found on CT scan 24-48 hours after the stroke. Consensus is to start anticoagulation 7 days after the stroke. The role of antiplatelet therapy has not been established.

• Nonbacterial thrombotic endocarditis: Associated with a variety of malignancies, nonbacterial thrombotic endocarditis also has been reported in patients with severe diseases such as septicemia and extensive burns. Mitral and aortic valves are affected most commonly, and embolic stroke is frequent. A prothrombotic state has been postulated as the precursor of emboli development. Treatment is directed toward control of the underlying disease, and heparin (intravenous in the acute stage, subcutaneous in the outpatient setting) is advocated for stroke prevention. Warfarin failed to show any benefit.

• Atrial myxomas: This is the most common cardiac tumor, and it usually is located on the fossa ovalis. It is believed to cause 1% of strokes in young individuals. Surgical excision is the treatment of choice. Most can be detected by transthoracic echocardiography; rarely, they are detected only by transesophageal echocardiogram.

• Acute myocardial infarction: The incidence of stroke after acute myocardial infarction is approximately 2% in the first 3 months. Anterior myocardial infarctions with mural thrombus on transthoracic echocardiography have been recognized as predictive of stroke. Anticoagulation (INR 2-3) is recommended in these patients in the first 3 months, while antiplatelet therapy is advocated in the chronic phase. The presence of congestive heart failure after myocardial infarction usually dictates treatment with warfarin indefinitely, although randomized comparisons with other therapies are ongoing. Low-output cardiac failure (ejection fraction)

• Minor risk sources

  • Patent foramen ovale: Persistent connection between the right and left atrium has a prevalence of 25% in the general population. It is present by chance association in patients with stroke at least one half of the time. The rate of stroke recurrence is 1-2% per year. Larger size, spontaneous right-to-left shunting, and associated atrial septal aneurysm are postulated to identify subgroups at high risk for recurrence. Antiplatelet therapy is advocated initially, and warfarin is recommended empirically if stroke recurs during antiplatelet therapy. Elucidation of the role of other therapeutic approaches such as surgical closure (transthoracic, percutaneous) awaits better characterization of the natural history. At present, patent foramen ovale should not be considered the cause of stroke until other etiologies have been excluded thoroughly.

• Atrial septal aneurysms: These aneurysms are areas of redundant atrial septal tissue that bulge alternatively into the right or left atrium. They have a high degree of association with other sources of embolism (mainly atrial fibrillation and patent foramen ovale). Insufficient data are available at present to consider atrial septal aneurysm as an independent risk factor for stroke. When atrial septal aneurysms coexist with other sources of embolism, anticoagulation usually is recommended.

• Mitral valve prolapse: Mitral valve prolapse is the most common valve disease in adults. The role of mitral valve prolapse as an independent risk factor for stroke is controversial and evolving. The estimated prevalence is not greater in patients who have had a stroke than in the general population in recent population-based studies. Long-term aspirin therapy is recommended, although this has not been confirmed by randomized trials. Anticoagulation is reserved for whenever antiplatelet therapy fails.

• Calcific aortic stenosis and bicuspid aortic valves: Systemic embolism is uncommon in isolated aortic valve disease. Calcific microemboli can be detected in the retinal artery in asymptomatic patients, possibly reflecting the fact that most cerebral emboli are asymptomatic. Clinical embolism often follows invasive cardiac procedures (ie, catheterization). Because of the calcific nature of the emboli, anticoagulation is not recommended, and antiplatelet therapy remains an empiric approach.

• Fibroelastomas and Lambl excrescences: Fibroelastomas are rare benign tumors located on the valves. Antiplatelet therapy is indicated, and surgical repair is reserved for patients who have stroke recurrence. Lambl excrescences are filiform outgrowths from the free borders of the cardiac valves and have been implicated as sources of embolism when they attain large size. Antiplatelet therapy is initiated followed by surgery if aspirin fails.

• Mitral annular calcification: This is associated with advancing age, hypertension, and atherosclerosis, and it is rarely an embolic source.

MEDICAL WORK-UP

Lab Studies:

• Protein C, protein S, antithrombin III, and factor V may be ordered to exclude hematologic abnormalities in cases of stroke associated with intracardiac shunts. (These factors are associated primarily with venous thrombosis rather than arterial emboli.)

Imaging Studies:

• Echocardiography: Transesophageal echocardiography provides more information about the atria than transthoracic echocardiography (see Table 4).

• Radiologic studies: Several radiologic findings, when associated with clinical features, are suggestive of cardioembolic stroke, including the following:

  • Hemorrhagic infarct on CT scan or MRI

  • Multiple arterial infarcts on CT scan or MRI (not lacunar)

  • Embolus “in transit” on angiography

Table 4. Transesophageal vs Transthoracic Echocardiography for Cardiac Sources of Embolism

* Possible predictor of intracardiac thrombosis but not an embolic source per se

Other Tests:

• ECG – Atrial arrhythmias, myocardial infarction

• Ambulatory ECG – Indicated for elderly patients in whom paroxysmal atrial fibrillation is suspected (eg, history of palpitations, enlarged left atrium on echocardiography)

• Transcranial Doppler – May become a valuable tool in the future once standardized and correlated with clinical outcomes

MANAGEMENT

Medical Care:

• Antiplatelet and anticoagulant therapies are mainstays in the prevention of cardioembolic stroke. Consider the absolute rate of stroke of each source, the risk-benefit relationship of each therapy, and each patient’s preferences. Warfarin is first-line anticoagulant treatment of most causes of cardioembolic stoke. Among antiplatelet agents, aspirin has been proved in clinical trials to reduce risk of cardioembolic stroke. The role of other antiplatelet agents (eg, dipyridamole, clopidogrel, ticlopidine) is inconclusive at the present time.

• Randomized trials have demonstrated that the efficacy of anticoagulation is related directly to how it is used. Inadequate anticoagulation produces minimal or no protection, while supratherapeutic anticoagulation may increase the risk of serious hemorrhagic complications. To optimize the level of anticoagulation, interactions with concomitant medications known to potentiate or inhibit the anticoagulant effect should be considered.

• Monitor INRs at least monthly.

Consultations:

• Cardiology – To evaluate the management of arrhythmias and structural abnormalities of the heart

• Hematology – When the possibility of a prothrombotic state is suspected

Diet:

• Provide patients treated with warfarin with a list of vitamin K–containing foods (eg, broccoli, avocado, other green vegetables) that inhibit its anticoagulant effects.

• Most physicians severely limit or proscribe consumption of alcoholic beverages in patients taking warfarin.

Activity: Review limitations on physical activities (eg, contact sports) in patients on warfarin.

MEDICATION

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

References

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