Valve-related cerebral emboli may result from various conditions, including rheumatic heart disease, other aortic and mitral valvular diseases, prosthetic valves, cardiac procedures, and infective and noninfective endocarditis. Cerebral embolization in rheumatic heart disease may occur during the acute illness, when inflammatory vegetations on the heart valves may detach and embolize, or, more commonly, during the chronic phase of the disease, when valvular deformity, atrial enlargement, and abnormal cardiac rhythm have developed. The greatest risk of cerebral infarction from chronic rheumatic heart disease occurs within 1 year after the onset of atrial fibrillation. In clinical series, the brain is the site of emboli in roughly 30% of patients, but in autopsy series, nearly 50% of patients show cerebral infarction presumably related to emboli. Mitral stenosis has been present in most of these patients.

Anticoagulation treatment with intravenously administered heparin or subcutaneous low-molecular-weight heparin (LMWH) followed by warfarin anticoagulation or valve repair is recommended for all embolic cerebral events associated with rheumatic heart disease, particularly in patients with an audible murmur or those in whom surgical therapy is to be delayed or cannot be done.

Spontaneous calcium embolization uncommonly occurs with calcific aortic stenosis, but more commonly such embolization produces symptomatic retinal rather than cerebral ischemia. Cerebral ischemic events without some other clear cause have been rarely noted in patients with mitral valve prolapse. However, available data suggest that mitral valve prolapse plays a limited role in cerebral ischemia. Embolic material may uncommonly arise from the surface of the prolapsed, degenerated mitral valve. Mitral annulus calcification is another possible risk factor for cardioembolic events, but the overall association with cerebral ischemia is unproved.

Prosthetic and porcine heart valves are associated with an increased occurrence of cerebral and systemic emboli. The risk is higher with prosthetic valves, and chronic anticoagulation with warfarin is used in this setting. Even with therapeutic warfarin (international normalized ratio [INR], 3.0-4.5), the rate of stroke is 2%-4% per year, and the risk is higher with prosthetic mitral valves than with prosthetic aortic valves. In addition to warfarin, some advocate concurrent use of low-dose aspirin or extended-release dipyridamole because of some evidence suggesting a potential reduction in the risk of stroke. Direct oral anticoagulants (DOACs) should not be used in patients with a prosthetic heart valve because of inadequate effectiveness in preventing an embolic event.

Cardiac catheterization and arteriography, performed in nearly all patients before cardiac surgery, are associated with a low risk of cerebrovascular complications (˜0.2%). Such complications may occur from direct displacement of clot or atheromatous material or from trauma to the arterial intima, which causes subsequent embolization.

Cardiac operations of all types are associated with an increased risk of cerebral ischemia. This may be caused by manipulation that leads to clot formation and embolization; nonfocal encephalopathic syndromes caused by either hypotension or anoxia; or multifocal ischemic syndromes caused by embolization of air, fibrin, calcium, or fat globules. Focal ischemic deficits are observed more frequently after valve operations than they are after coronary bypass procedures. Late embolization is a complication of valve replacement and is more common with mitral valve replacement than it is with aortic valve prostheses.

Cerebral embolization occurs in approximately 20% of patients with infective endocarditis and may be the presenting symptom of the disorder. The probability of embolization is highest in patients with mitral valve involvement. Four distinct clinical and pathologic syndromes are observed: (1) focal cerebral infarction (the most common) that results from embolic occlusion of large arteries, (2) multiple small areas of cerebral infarction that produce a diffuse encephalopathy with or without alteration in consciousness, (3) meningitis from small infected emboli that lodge in meningeal arteries, and (4) mycotic aneurysm formation that results from septic embolization with subsequent aneurysmal rupture and intracranial hemorrhage.

Treatment of patients with infective endocarditis includes appropriate antimicrobial therapy for at least 4 weeks (blood culture analysis should be repeated 5-7 days after the treatment to confirm eradication of the infection), usually guided by culture results. Anticoagulants are generally not used, at least during
the period of active infection, because of the increased risk of hemorrhagic infarction. Ongoing use of chronic antiplatelet therapy is reasonable. Cerebrovascular imaging should be considered for all patients with infective endocarditis, even if no neurologic symptoms are present. If mycotic aneurysm is detected on initial imaging, then repeat imaging is necessary after antimicrobial therapy, and surgical or endovascular intervention may be necessary if an aneurysm persists.

Nonbacterial thrombotic endocarditis, also called marantic endocarditis, usually occurs in cachectic, debilitated elderly patients with some underlying systemic disease, most commonly carcinoma. Pathologically, nonbacterial thrombotic endocarditis vegetations consist of amorphous, acellular material composed of a mixture of fibrin and platelets. Fewer than half of the patients with this condition have heart murmurs. As with infective endocarditis, many patients show signs of diffuse cerebral dysfunction, either alone or in association with recognizable focal deficits.

Although the value of antithrombotic therapy is still undetermined in patients with marantic (nonbacterial thrombotic) endocarditis, anticoagulants followed by antiplatelet therapy are usually advised for patients with focal cerebral ischemic events. Disseminated intravascular coagulation, often associated with nonbacterial endocarditis, may independently produce multiple small areas of cerebral infarction.

Noninfectious valvular deposits called Libman-Sacks endocarditis may occur in patients with systemic lupus erythematosus (SLE). Patients with cerebral or systemic emboli in this context typically are treated with at least short-term warfarin anticoagulation. Therapy is often switched to an antiplatelet agent, especially when serial echocardiographic studies demonstrate lesion resolution.

A papillary fibroelastoma is an uncommon, histologically benign tumor, most commonly found on the cardiac valves and rarely seen on the endocardium. They can serve as a source of emboli, causing sudden death as a result of coronary artery occlusion, or cerebral infarction. When detected, they are usually treated with surgical resection, often performed without the need for valve replacement. If surgery cannot be performed, then antithrombotic therapy with warfarin or antiplatelet therapy should be initiated, but there is no medical therapy that is clearly effective in emboli prevention.

Atrial fibrillation is the cardiac arrhythmia most frequently associated with embolic brain infarction. In this condition, the atria do not contract effectively, and the resultant stagnation of blood predisposes to intraluminal thrombi. The risk of cerebral embolization increases with longer duration of the dysrhythmia and increasing patient age; an enlarged left atrium; previous systemic thromboembolism or cerebral ischemic events; history of hypertension, diabetes mellitus, or congestive heart failure; and associated valvular heart disease, especially mitral stenosis.

If atrial fibrillation is a new finding at the time of presentation with an ischemic event, conversion to normal sinus rhythm with either electrical or chemical cardioversion may be indicated. Conversion of atrial fibrillation to a normal rhythm is associated with a risk of embolization, which often occurs within 48 hours. Anticoagulant therapy should precede conversion, especially in high-risk patients (those with recent or recurrent embolization, cardiac enlargement, heart failure, or associated mitral valve disease) and patients in whom the absence of left atrium thrombus is not documented by transesophageal echocardiography (TEE).

In patients with chronic atrial fibrillation, the long-term stroke risk is usually determined by the CHA₂DS₂-VASc score (see Chapter 28 for details regarding the CHA₂DS₂-VASc score). Long-term oral anticoagulation is typically recommended either with warfarin (INR 2.0-3.0; a lower range of 1.8-2.5 may also be efficacious, particularly for patients older than 75 years and other patients at higher risk of bleeding) or with a DOAC (see later), except in patients who are younger than 60 years and have no associated cardiovascular disease, including hypertension, recent congestive heart failure, left atrial enlargement, left ventricular dysfunction, or previous thromboembolic events. The recommendation for anticoagulation becomes even stronger for patients who have had focal cerebrovascular ischemic events within the previous 2 years. The risk of major bleeding episodes with long-term warfarin anticoagulation ranges from approximately 1.2% to 7.4% per 100 patient-years and has been linked to several factors including uncontrolled hypertension, abnormal renal/liver function, prior bleeding or stroke history, concomitant drugs and alcohol consumption, age over 65 years, and labile INR (see Pisters et al. [2010] in Suggested Reading for Section IV).

In recent years, the US Food and Drug Administration has approved three new oral anticoagulants (dabigatran, rivaroxaban, and apixaban) for use in nonvalvular atrial fibrillation patients. In clinical trials, these agents have generally been associated with lower risks of stroke and systemic embolic events and lower rates of fatal bleeding and intracranial hemorrhage compared to warfarin and are typically considered as the initial anticoagulant strategy. There were initial concerns regarding the ability to reverse the anticoagulant effect of these newer agents in the setting of serious bleeding. However, andexanet alfa, a factor Xa decoy protein, has been approved for reversal of severe bleeding with apixaban and rivaroxaban, and idarucizumab has been approved for reversal of dabigatran-associated bleeding.

For those patients with atrial fibrillation and a significant contraindication to anticoagulation, left atrial appendage occlusion with one of several available devices may be considered. Aspirin or other antiplatelet drugs (e.g., clopidogrel) may also be used in patients with a contraindication to anticoagulation and device-based left atrial appendage occlusion, but the effectiveness in embolus prevention is less than that of anticoagulation.

Sick sinus syndrome is a common dysrhythmia among the elderly, occurring in 2% to 3% of people older than 75 years. The risk of cerebral ischemia in individuals with sick sinus syndrome is controversial. Although some investigators believe that this is a relatively benign condition, others have documented an increased risk of cerebral embolism, particularly among those with a bradycardia-tachycardia syndrome.

The most appropriate therapy for primary prevention of stroke in sick sinus syndrome is unknown. Some have advocated atrial or dual-chamber pacing, whereas others believe that long-term anticoagulation is necessary. Further study is necessary to define better the risk of stroke and clarify the most efficacious prophylactic treatment approach. In patients with cerebral ischemic events related to sick sinus syndrome, a pacemaker should generally be implanted with or without accompanying antithrombotic therapy.

Atrial flutter may also be associated with an increased risk of thromboembolic events. Population-based data have demonstrated that the risk is at least as high as in those with lone atrial fibrillation. They are also at increased risk for future atrial fibrillation. Although specific guidelines do not exist, these patients likely should be treated similarly to those with lone atrial fibrillation, including
the use of anticoagulation in all patients who have atrial flutter and are older than 65 years or among those with previous thromboembolic events.

Patients who experience transient loss of consciousness and syncopal events associated with other serious rhythm disorders, such as complete heart block or serious paroxysmal ventricular rhythm disturbances, usually do not require antithrombotic therapy because of the relatively low risk of thromboembolism.

Brain infarction occurs in approximately 10% of patients with myocardial infarction (MI), with a particularly increased risk in the first 30 days after MI. Although systemic hypotension may be responsible for some ischemic brain deficits, clinical and autopsy studies have shown that most focal brain lesions are caused by the formation of mural thrombus and subsequent embolization. Autopsy studies reveal that left ventricular thrombus may occur in up to 44% of patients after MI, especially in those with large areas of infarcted tissue and congestive heart failure. When cerebral embolization occurs, it is often within the first 30 days after acute MI and may be the presenting symptom. In addition, because a ventricular aneurysm develops as an additional source of thrombus formation in 5% to 20% of patients with MI, cerebral events that occur later should be evaluated carefully for a possible cardiac source. In this situation, long-term anticoagulant therapy should be instituted unless contraindications exist. After a patient has had MI, most patients receive dual antiplatelet therapy with aspirin and a P2Y₁₂ receptor blocker such as clopidogrel, prasugrel, or ticagrelor. For those on aspirin and clopidogrel, some have suggested the use of rivaroxaban for 1 year in combination with antiplatelet therapy. In the setting of an indication for short- or long-term anticoagulation, selected patients may require triple antithrombotic therapy (such as those with a coronary artery stent). However, dual therapy with aspirin and anticoagulation may be utilized in nonstented patients to reduce the risk of hemorrhagic complication associated with triple antithrombotic therapy. When anticoagulation is indicated, intravenously administered heparin (or subcutaneous LMWH) may be initiated followed by oral anticoagulant therapy (warfarin), and use of heparin may be discontinued when the INR is therapeutic (2.0-3.0; see Chapter 12). The specific indications for DOACs in this setting continue to be clarified.

Congestive heart failure is characterized by cardiac enlargement, poor myocardial contractility, and decreased cardiac output that predisposes to blood stagnation and intracardiac thrombi. Any pathologic condition that interferes with cardiac filling or emptying may be associated with congestive heart failure. Although occasionally congestive heart failure is the only identifiable cause of intracardiac or pulmonary venous thrombus formation, other identifiable cardiac disorders, such as MI, generalized cardiomyopathy, valvular disease, or arrhythmia, may also contribute to thrombus at these sites.

In patients who have focal cerebral ischemic events associated with cardiomyopathy and in whom the ejection fraction is less than 30% or if definite mural thrombi are seen on echocardiography, then anticoagulants are used. Among these patients, as well as in patients with various congenital heart diseases, decisions regarding long-term anticoagulant therapy should be considered on an individual basis.

The foramen ovale is anatomically patent in at least 15% of individuals and retains the functional capacity of patency in an additional 15%. In these situations, venous emboli can occasionally enter the cerebral circulation (paradoxical
embolism), especially after pulmonary embolization with an associated increase in pulmonary and right atrial pressures. The clinical syndrome is uncommon, but the diagnosis should be suspected in patients who have deep venous thrombosis, pulmonary embolism, or recent prolonged sedentary period and in whom acute focal cerebral deficit subsequently develops. Several recent studies have cast considerable doubt upon the importance of patent foramen ovale (PFO) as an underlying cause for stroke. Other cardiac deficits that produce right-to-left shunts may also potentially enable paradoxical emboli. Approximately 5% of children with cyanotic congenital heart disease have cerebral infarction. In most cases, these infarcts are embolic, occurring in the first 2 years of life. Associated hematologic deficits may also predispose these children to cerebral ischemia.

The optimal management of patients with PFO remains unclear. Current evidence suggests that individuals with cerebral infarction or TIA and PFO should be treated with antiplatelet agents. If there is evidence of pulmonary embolism, deep vein thrombosis, pulmonary vein thrombosis, or hypercoagulable state, long-term anticoagulation should be considered. A similar approach appears warranted for patients with cerebral infarction or TIA who have interatrial or interventricular septal defects. Three large recent randomized clinical trials have not provided support for the routine device closure of PFOs as a means of recurrent stroke prevention in those presenting with TIA or cerebral infarction. However, in those patients with moderate to large interatrial shunt, particularly in the setting of an atrial septal aneurysm, PFO closure followed by antiplatelet therapy should be considered in younger patients, under the age of 60 years, with cryptogenic stroke or recurrent cerebral ischemic events on antiplatelet agents or anticoagulation. Atrial fibrillation has been noted to be the most common complication following PFO device closure. A scale has been developed that assesses the potential for the PFO to be the etiology for a cryptogenic cerebral infarction. Factors include age, the detection of cortical infarction on brain imaging, and the absence of atherosclerotic risk factors (see Kent et al. [2013] in Suggested Reading for Section IV for further details).

Approximately 25% of patients who have stroke and have a cardioembolic source have another potential cause of the ischemic event. If one of the proven cardiac risks (Table 16-1) is identified in a patient with an ischemic cerebrovascular event, then long-term anticoagulation may be needed for prophylaxis even if another potential mechanism for the current ischemic event is identified. In nonhypertensive patients with small or moderate cardioembolic stroke, a DOAC or heparin (followed by warfarin) is typically given in the acute stage. In patients with a small cerebral infarct, a DOAC or heparin followed with warfarin usually is not delayed, but should be delayed in those with a moderate stroke until CT that is performed 24 to 48 hours after the event reveals no significant hemorrhagic transformation. Anticoagulant therapy may be postponed (a few days to 2 weeks) or not used if the stroke is large or if a patient is severely hypertensive.

The most commonly identified disease process that produces retinal or cerebral ischemia is atherosclerosis. Atherosclerosis may produce cerebral symptoms through a hemodynamic or thromboembolic mechanism or both (Fig. 16-2). The lumen of an involved artery may become progressively narrowed and eventually occluded by atherosclerotic deposits. Blood flow across the stenotic area becomes impaired when more than 75% of the luminal area becomes compromised.
This process usually progresses slowly during years or decades, often allowing time to establish collateral blood flow distal to the lesion. Consequently, not uncommonly, asymptomatic patients have occlusion of one or more major cranial cervical arteries. When collateral circulation distal to the lesion is insufficient, hemodynamic compromise occurs and produces symptoms of cerebral ischemia. The terminal branches (watershed areas) of the anterior, middle, and posterior cerebral arteries are most frequently involved.

Thromboembolism is another mechanism whereby atherosclerosis may produce cerebral ischemic symptoms. Atherosclerotic deposits in the process of evolution tend to ulcerate and form necrotic areas that are capable of attracting blood products, and clot formation results. This atherothrombotic material may either stenose or occlude the vessel lumen, or it may break off to embolize distally in the arterial tree. When either mechanism is combined with systemic factors such as hypotension, hypoxia, anemia, abnormal blood viscosity, and hypoglycemia, focal or multifocal cerebral ischemia may result.

Pathologic changes of atherosclerosis are characterized by focal proliferation of smooth muscle cells within the intima of medium-sized to large arteries and associated deposits of lipids (including cholesterol), blood products, calcium, and fibrous tissue. Although atherosclerosis is usually found diffusely in multiple areas of the body, the primary sources of cerebrovascular symptoms are atherosclerotic deposits, usually localized at cervical artery bifurcations. The most commonly affected areas (Fig. 16-3) in the neck are (1) the proximal portions of the internal carotid arteries and (2) the proximal portions of the vertebral arteries. Intracranially, the circle of Willis and the basilar artery are the areas of maximal involvement. With the increasing use of TEE, aortic arch atherosclerosis has become recognized as a frequent finding in association with cerebral ischemia. Although this finding is a marker for systemic atherosclerosis, the primary association with cerebral ischemia is unproven and still under study.

Epidemiologic studies have identified several factors that seem to contribute to the formation of atherosclerosis. Among these risk factors, cigarette smoking and hypertension are the most clearly implicated. Diabetes mellitus and elevated serum total cholesterol, low-density lipoprotein cholesterol, triglyceride levels,
and chronic inflammation have also been implicated. Atherosclerosis and its complications are especially likely to develop in patients with combinations of these risk factors (see Chapters 23 and 25, 26, 27).