Stroke & Vascular Disorders
Cerebellar infarction and cerebellar hemorrhage
Aug. 16, 2022
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Cardioembolic stroke is one of the more devastating causes of stroke. Significant progress has been made in identifying patients at high risk for cardioembolic stroke. With the aging of the population, an increasing number of patients are at risk for cardioembolism. In this article, the author provides an update on cardioembolic stroke prevention. Data from trials on stroke prevention, including information on novel oral anticoagulants in atrial fibrillation patients, are provided. In addition, studies on closure devices for patent foramen ovale are reviewed. New insights regarding endocarditis and stroke are highlighted. Finally, information is provided regarding antithrombotic therapy for patients with reduced cardiac ejection fraction.
• Cardioembolic strokes are more severe clinically than other forms of stroke.
• Atrial fibrillation is the leading source of cardioembolic stroke.
• The proportion of cardioembolic strokes will increase with the aging of the population.
• Trials have shown a modest reduction in stroke with patent foramen ovale closure but questions remain on appropriate patient selection.
What is now called "stroke" was referred to as "apoplexy" in the writings of Hippocrates (460 BCE to 370 BCE). Apoplexy was defined as "to be struck down by violence or paralysis." It was probably formed from the Greek words apo ("from"), plesso ("thunderstruck"), and ia ("condition"). The term "apoplexy" was applied to myriad conditions, from illnesses affecting the level of consciousness to disorders causing a change in sensation. Apoplexy was differentiated from other conditions by its sudden onset, resulting in loss of consciousness and paralysis. During the period of the Roman Empire, Aurelius Celsus (25 BCE to 50 AD) differentiated apoplexy from paralysis. He noted that during apoplexy the entire body is paralyzed, including sensation, understanding, and movement, whereas with paralysis the effects are localized (30; 26).
There was little progress in the understanding of stroke during the Middle Ages and Renaissance. During the 18th century, Hermann Boerhaave (1668 to 1738) and his followers returned to a more methodical and analytical approach to medicine. Van Swieten's commentaries on Boerhaave are generally believed to be the first suggestion that cerebral embolism could cause apoplexy:
It has been established by many observations that these polyps occasionally attach themselves as excrescences to the columnae carnae of the heart, and perhaps then separate from it and are propelled, along with the blood, into the pulmonary artery or the aorta, and its branches.... were they thrown into the carotid or vertebral arteries, could disturb—or if they completely blocked all approach of arterial blood to the brain—utterly abolish the functions of the brain (30).
During the 19th century, advances were made in understanding the pathophysiology of cerebral embolism and thrombosis. Julius Cohnhien, trained by Virchow, demonstrated the effects of embolization by producing ischemic and hemorrhagic lesions when wax globules were injected into a frog's tongue arteries (35).
The heart was established as an important source for the development of emboli when Gowers, in 1875, described a case of left middle cerebral artery and retinal artery emboli (35). The auricular appendage associated with mitral stenosis was identified as the likely origin of the emboli.
Embolic material usually originates from the heart or great vessels such as the aortic arch or carotid bifurcation. There is considerable overlap in the clinical presentation of cerebral ischemia resulting from embolic disease, large-vessel atherothrombotic disease, and small-vessel disease. The Cerebral Embolism Task Force set forth the following criteria for the diagnosis of cardiogenic cerebral embolism: (1) neurologic symptoms of abrupt onset with maximal severity at onset, (2) evidence of a potential cardiac source, (3) branch occlusions on cerebral angiography, (4) evidence of emboli to limbs or other organs, and (5) multiple infarctions involving more than one territory (15). Hemorrhagic infarction also suggests embolism. Hemorrhagic infarction is often due to reperfusion of infarcted tissue, reflecting the high (50%) spontaneous recanalization rate of cardiac emboli. If recanalization occurs early after occlusion, the neurologic deficit may clear in "spectacular" fashion (56).
The clinical manifestations of cerebral embolism depend on the arterial territory affected and the eloquence of the ischemic tissue. A large embolism may occlude the distal internal carotid artery or the stem of the middle cerebral artery, producing findings such as contralateral hemiparesis or hemisensory deficits, a gaze preference, and, depending on the involved hemisphere, cognitive findings such as aphasia or neglect. Branch occlusions within the anterior intracranial circulation are highly suggestive of cerebral embolism. These occlusions typically manifest as restricted deficits such as fluent aphasia or monoplegia. Embolic syndromes of the posterior circulation occur less frequently. The sites most commonly obstructed are at the union of the vertebral arteries to form the basilar artery and the upper bifurcation of the basilar artery into the posterior cerebral arteries. Occlusion of a vertebral artery as it joins to form the basilar artery can produce Wallenberg syndrome or related variants. Caplan described the "top of the basilar" syndrome and its manifestations when embolism occludes the distal basilar artery. Infarction in this region may produce coma, quadriplegia, visual loss, and various behavioral syndromes (13). A unilateral posterior cerebral artery occlusion leading to an isolated hemianopsia is often embolic in origin.
An early complication of embolic infarction is cerebral edema, which peaks between 24 and 96 hours after an ischemic insult. Treatment with intravenous mannitol and hypertonic saline should be considered.
Seizures complicate up to 10% of strokes. Seizures following stroke are often focal but may become generalized. Persons with seizures in the acute phase of cerebral embolism may have periodic lateralized epileptiform discharges detected by EEG, but these seizures are usually self-limited and do not require treatment. Seizures that recur can be controlled with anticonvulsant monotherapy.
Skin care, nutrition, and prevention of vascular complications take priority when a patient enters convalescence. A hemiparetic patient is prone to developing skin pressure ulcers. The patient's position should be rotated regularly and the skin examined for early signs of breakdown. Venous thromboembolism is a common complication in stroke patients secondary to immobility. It is estimated that without prophylactic measures, deep venous thrombosis develops in up to 75% of hemiplegic patients, and lethal pulmonary embolism occurs in approximately 3%. Undoubtedly, the incidence of nonfatal pulmonary embolism is much higher. Prophylactic measures to prevent venous thromboembolism include subcutaneous administration of heparin, pneumatic compression stockings, pressure-gradient stockings, aspirin, and low-dose warfarin (78).
A 78-year-old woman was admitted at an outside hospital with left-sided weakness of mild degree. A carotid ultrasound and 2D echocardiogram were normal, and she was placed on aspirin. Two weeks later, she presented with expressive speech difficulty that lasted 60 minutes. There was no definite right-sided weakness. Neurologic exam revealed mild right nasolabial flattening but was otherwise normal. An MRA of the brain and neck was normal. MRI of the brain showed a small perisylvian infarct on the diffusion-weighted images and an old right middle cerebral artery infarct. Transesophageal echocardiogram was ordered and this showed decreased contraction in the left atrial appendage and protuberant plaques in the ascending aorta. Cardiac monitoring did not show definite atrial fibrillation. The patient was placed on warfarin for presumed cardioembolic strokes and has done well for the ensuing 5 years.
Often, despite an extensive evaluation, an embolic fragment is not documented, and the diagnosis of cerebral embolism is made on circumstantial evidence. The most commonly recognized source for cerebral embolism is the heart. However, identification of a potential cardiac source does not prove embolism, especially if there is coexistent atherosclerosis or if the cardiac lesion is of uncertain clinical significance (45). Atheroembolism from the great vessels such as the aortic arch or carotid bifurcation is also a common cause of cerebral ischemia. Cardiac conditions predisposing to cerebral embolism include atrial fibrillation, valvular disorders, and the cardiomyopathies. Embolic stroke also occurs as a complication of cardiac catheterization, cardiac surgery, and cardiac transplant (27).
Atrial fibrillation is found in up to 20% of all persons with ischemic stroke and in approximately 50% of all cardioembolic strokes. The risk of embolism in patients with atrial fibrillation is highest during the first months after the initial diagnosis. Longitudinal studies (eg, Framingham) reveal that certain causes of atrial fibrillation or underlying heart disease increase the risk of cerebral embolism. For example, the combination of atrial fibrillation with mitral stenosis increases the risk of cerebral embolism by a factor of 17, whereas atrial fibrillation not associated with rheumatic heart disease is associated with a 6-fold increased risk. The Stroke Prevention in Atrial Fibrillation trials identified hypertension, recent congestive heart failure, and prior embolism as factors associated with increased stroke risk in atrial fibrillation (75). The annual rate of embolism was 2.5% in patients with atrial fibrillation and none of these factors, 7.2% with one factor, and 17.6% with more than one factor. Lone atrial fibrillation in young patients without any other detectable cardiac disorder has a substantially lower rate of cerebral embolism, ranging between 0.4% and 1% per year (82). Atrial fibrillation may coexist with other conditions such as congestive heart failure and obstructive sleep apnea (51).
There has been increased research on genetic aspects of atrial fibrillation. Several genetic loci have been linked with atrial fibrillation (77). These loci are related to ionic channels, calcium handling proteins, conduction, and fibrosis. Another report described 11 members of a family with atrial fibrillation in which a frameshift mutation was detected in the gene encoding atrial natriuretic peptide (37). Larger genome-wide studies will likely be done in the future.
Myocardial infarction frequently is the source of emboli to the brain. The period of highest risk of cerebral embolism is within the first 4 weeks of acute myocardial infarction (55). Embolism most frequently complicates transmural anterior wall infarcts; a secondary left ventricular thrombus is the usual substrate responsible for cerebral embolism (08; 46; 80). Intracavitary stasis occurring during left ventricular dysfunction provides the milieu for the formation of left ventricular thrombus (28). The majority of strokes occur within the first 2 weeks following an acute myocardial infarction, possibly reflecting the mobile nature of early thrombus formation. The rate of in-hospital stroke following MI was less than 1% in a large study from a myocardial infarction registry (79). There was a lower rate of stroke in patients who received early cardiac revascularization procedures. The risk of cerebral embolism may persist at approximately 10% for patients with left ventricular thrombus followed for 2 years (74).
Another cardiac condition that predisposes to cerebral embolism is dilated cardiomyopathy. The dilated cardiomyopathies are characterized by global ventricular dysfunction and are highly associated with arrhythmias. It is this combination that leads to chronic intracavitary stasis and is responsible for the conditions conducive to cerebral embolism.
Mitral valve stenosis is usually a sequela of rheumatic fever, which afflicts approximately 1.5 million Americans. Mitral stenosis causes the left atrium to dilate and is a frequent cause of atrial fibrillation. A left atrial thrombus forms in a large number of affected patients and provides the substrate for cerebral embolism. Embolism may also occur in mixed lesions of the mitral valve (stenosis-regurgitation), but isolated mitral regurgitation is not a common cause of cerebral embolism. Mitral valve prolapse is pathologically characterized by fibromyxomatous degeneration of the leaflets and the chordae tendinea. Mitral valve prolapse is a common finding in young adults and is typically associated with a benign course. Overall, the stroke risk for patients with mitral valve prolapse is low, with an estimated yearly incidence of 0.02%. It should be considered a potential cause of stroke or transient ischemic attack when all other causes have been excluded. Mitral annular calcification also is linked with embolic stroke, especially when there is associated atrial fibrillation. However, mitral annular calcification is prevalent in elderly people and may be a marker of concomitant atherosclerosis in most patients rather than a source of embolism.
Aortic stenosis is a rare cause of cerebral emboli, which are usually calcific.
Cerebral embolism is a major cause of morbidity and mortality associated with prosthetic cardiac valves. Rates of embolism vary depending on the position of the valve and whether the valve is mechanical or bioprosthetic. The rate of embolism in patients with mechanical mitral valves who are not treated with anticoagulants averages 3% to 4% per patient year. In the aortic position for patients not receiving anticoagulants, the rate of embolism averages 2% to 4% per year (48). Oral anticoagulants cut the risk of embolism by one half. The embolism rate in patients with bioprosthetic valves is similar to the rate in patients with mechanical valves who are on anticoagulation.
In a significant proportion of embolic strokes, the source is cryptic (58). Transesophageal echocardiography can reveal previously unrecognized potential mechanisms of cardioembolic strokes (47). The most common occult cardiac source of embolism is patent foramen ovale, which is present in approximately 20% of the normal population. Because it is so prevalent in the normal population, caution should be exercised before attributing a stroke to a patent foramen ovale. The mechanism of stroke is presumably paradoxical embolism of venous thrombi across the patent foramen ovale via a right-to-left shunt when the pressure in the right heart exceeds that in the left heart. A single center review of 1689 patients with stroke or transient ischemic attack identified several factors associated with patent foramen ovale (62). These included a history of deep venous thrombosis or pulmonary embolism, prolonged travel, migraine, preceding Valsalva maneuver, and waking up with stroke.
The Risk of Paradoxical Embolism (ROPE) score has been suggested as a tool to identify patients with a patent foramen ovale that plays a causal role in stroke (43). Factors included in the ROPE score include lack of conventional stroke risk factors and presence of a cortical infarct on neuroimaging.
Transesophageal echocardiography has also provided evidence that the aortic arch is a common source of embolic material. The risk of cerebral embolism appears to be directly related to the size of atherosclerotic plaques visualized (06).
Cerebral embolism is a common complication of infectious endocarditis but accounted for less than 1% of all causes of cerebral embolism in the Cerebral Embolism Stroke Registry (15; 16). Infectious emboli from valvular vegetations, usually mitral, occur in 30% to 40% of endocarditis cases. The manifestations of septic cerebral emboli vary from subtle protean symptomatology, such as encephalopathy and headache, to catastrophic intracranial hemorrhage and death. Intracranial hemorrhage in endocarditis is due to either mycotic aneurysm rupture or septic arteritis (69). The clinical presentation depends on the size and number of emboli. Large emboli may lead to obstruction of major vessels producing cerebral ischemia or suppuration leading to abscess formation (59). Multiple microemboli often lead to an encephalopathic clinical presentation. It is not uncommon to have a clinical picture involving both mechanisms. In a 15-year review of 707 endocarditis cases from an academic medical center, stroke occurred in 68 patients (9.6%) (07). Stroke was more common with mitral (17%) compared to aortic valve (9%) endocarditis. The risk of embolization is highest during the first week of antimicrobial therapy and in patients with mobile vegetations or vegetations greater than 10 mm on the anterior mitral leaflet (21). A metaanalysis of 21 studies confirmed that vegetation size of greater than 10 mm was associated with an increased stroke risk (57). Endocarditis appears to be more common as a cause of stroke in patients undergoing hemodialysis. In a single center review, 12% of strokes in patients undergoing hemodialysis were linked with endocarditis (41). The 1-year death rate for patients with stroke and endocarditis was 52%. Cerebral embolization is rare in right-sided infectious endocarditis but can occur via paradoxical embolization through a patent foramen ovale.
The underlying mechanism of cerebral infarction from embolism is occlusion of cerebral vessels with debris from a proximal source. An embolus may consist of platelet aggregates, thrombus, platelet-thrombi, cholesterol, calcium, bacteria, neoplastic cells, air, or any other foreign substance.
Most embolic debris contains platelet aggregates (09). Red thrombus may be more likely in conditions causing blood stasis, eg, atrial fibrillation and myocardial infarction. Thrombus may also form on an ulcerated internal carotid artery plaque or occur with intraplaque hemorrhage and rupture leading to distal embolism.
Cerebral embolism accounts for approximately 20% of the 730,000 strokes that occur in the United States each year. Risk factors associated with an increased risk of cerebral embolism include atrial fibrillation, myocardial infarction, and valvular heart disease (82; 11). The prevalence of atrial fibrillation increases with age, and approximately half of atrial fibrillation-related strokes occur in patients over 75 years of age. It is estimated that chronic atrial fibrillation affects more than 2 million Americans. The number of patients with chronic atrial fibrillation is estimated to increase to over 5 million by 2050. Population-based studies have associated atrial fibrillation with a 5-fold increase in stroke risk. Atrial fibrillation is associated with a stroke recurrence rate of 15% in the first year and 5% yearly thereafter. The risk of recurrence is strongly linked to the presence and type of underlying structural cardiac disorders. A statement from the American College of Cardiology, American Heart Association, and European Society of Cardiology identified the following risk factors for stroke with atrial fibrillation: (1) previous stroke or transient ischemic attack, (2) hypertension, (3) congestive heart failure, (4) advanced age, (5) diabetes, and (6) coronary artery disease (29).
Over 1 million Americans have a myocardial infarction each year. Acute myocardial infarction is complicated by stroke within 2 to 4 weeks of onset in 2.5% of patients. Factors that increase the risk of cerebral embolism in this population include transmural anterior wall infarcts, left ventricular thrombus, and advanced age.
Congestive heart failure affects 5.1 million people in the United States (33). The number of people who have had congestive heart failure is increasing due to the aging of the population.
When one considers the mortality according to stroke subtype, it is clear that cardioembolic strokes carry a high mortality. In a study following 998 patients with a first cerebral infarct, the 30-day mortality was 2% for lacunar strokes, 10% for atherothrombotic strokes, and 23% for cardioembolic strokes (20). Patients with cardioembolic stroke have a lower rate of recurrent stroke at 1 month compared to patients with large vessel atherosclerosis (49).
The 1990s produced several clinical trials devoted to the prevention of stroke due to cerebral embolism. These trials were largely aimed at the greatest cause of cerebral embolism, nonvalvular atrial fibrillation, and involved regimens of aspirin, warfarin, or a combination of both.
Studies from the 1990s emphasized the importance of patient selection in guiding therapy in atrial fibrillation. Overall, warfarin is more effective than aspirin for the prevention of cerebral embolism in patients with atrial fibrillation. In a pooled analysis from the major primary prevention studies, warfarin was associated with a 65% risk reduction, whereas aspirin had only a 20% risk reduction (36). However, subsets of patients may derive just as much benefit from aspirin and avoid the risks of anticoagulation. For example, aspirin is effective in patients with nonvalvular atrial fibrillation who are younger than 75 years and have no associated cardiac comorbidity. Approximately 30% of patients in this age group do have additional cardiac risk factors (left ventricular dysfunction, systolic hypertension, previous transient ischemic attack or stroke) and are more likely to benefit from warfarin. These statistics are reversed for patients aged greater than 75 years because only 30% are free of cardiac comorbidity, but the risks of anticoagulant therapy also increase. Similarly, aspirin may be just as effective as warfarin in atrial fibrillation patients who present with a lacunar stroke syndrome (24). Current recommendations encourage risk stratification of patients according to age and clinical and echocardiographic variables (36; 29). Risk factors for stroke in patients with atrial fibrillation cited by the American Heart Association include age 75 or greater, HTN, ejection fraction of less than 35%, heart failure, and diabetes. Use of warfarin is recommended for patients with more than one of these risk factors (29). In general, higher risk patients are likely to derive greater benefit from anticoagulation than low-risk patients. Use of a stroke risk stratification tool such as the CHADS or CHADS-VASC score is recommended in an updated guideline from the American Academy of Neurology (19).
After a patient has had a transient ischemic attack or stroke in the setting of atrial fibrillation, warfarin has been shown to be clearly beneficial, whereas aspirin is minimally effective. In the European Atrial Fibrillation Trial, patients with atrial fibrillation were enrolled after a transient ischemic attack or minor stroke. Subsequent follow-up revealed that with placebo, there was an annual risk of stroke of 12%. With aspirin, the annual stroke rate decreased slightly to 10%, whereas the stroke rate was lowered to 4% per year with warfarin (23). Therefore, for secondary prevention, warfarin is strongly preferred if the patient is a safe candidate for anticoagulation.
Despite its proven efficacy, warfarin is suboptimally used in atrial fibrillation patients. Analysis of patients from the Cardiovascular Health Study found that only 52.6% of atrial fibrillation patients were placed on warfarin (42). In patients older than 65 with atrial fibrillation, many have contraindications to warfarin use and in a hospital-based study, only 51% were judged to be warfarin candidates (40). In a study analyzing data on more than 13,000 patients in the Kaiser health system, the rate of intracranial hemorrhage with warfarin was fairly low (< 0.5% per year) until the age of 80 and older (25). However, even patients not receiving warfarin had an increase in intracranial hemorrhage rates at the age of 80 and above.
There have been concerns in the past about using warfarin in elderly patients with atrial fibrillation. The Birmingham Atrial Fibrillation Treatment of the Aged study randomly assigned 974 patients aged 75 and above (mean age 81 years) to warfarin (INR 2.0 to 3.0) or 75 mg aspirin per day. Treatment with warfarin was associated with a decrease in annual stroke risk from 3.8% per year to 1.8% per year (p=0.003) without an increase in major extracranial hemorrhage (50).
An alternative to warfarin is the use of novel oral anticoagulant medications. The oral direct thrombin inhibitor dabigatran is given in a fixed dose and does not require international normalized ratio monitoring. In the RE-LY study, over 18,000 patients were assigned to treatment with two doses of dabigatran (110 or 150 mg twice daily) or warfarin adjusted to an international normalized ratio of 2 to 3. Patients were followed for an average of 2 years (18). The rate of the primary endpoint (stroke or systemic embolism) was similar between the lower dose of dabigatran (1.53%) and warfarin (1.69%), with a lower rate of major bleeding with dabigatran. The 150-mg dose of dabigatran had a lower rate of embolism (1.11%) compared to warfarin (p< 0.001). Bleeding events were similar in the two groups. There were no major concerns about liver toxicity with dabigatran. Dosage of dabigatran requires adjustment for patients with impaired renal function (creatinine clearance less than 30 mg/dl).
Other novel oral anticoagulants have been approved by the FDA. Rivaroxaban is an oral factor Xa inhibitor that was compared to warfarin in the ROCKET study (63). Over 14,000 patients were randomly assigned to receive warfarin (INR 2 to 3) or rivaroxaban 20 mg per day. Stroke or systemic embolism occurred at a rate of 1.7% per year in the rivaroxaban group and 2.2% per year in the warfarin group (p< 0.001 for noninferiority). There was no difference in the rates of major bleeding.
A third oral anticoagulant is apixaban, which is also a factor Xa inhibitor. Over 18,000 patients were enrolled in the ARISTOTLE study comparing warfarin (INR 2 to 3) and apixaban 5 mg twice per day (34). The endpoint of stroke or systemic embolism occurred at a rate of 1.3% per year in the apixaban group and 1.6% per year in the warfarin group (p=0.01 for superiority). Major bleeding was reduced with apixaban (hazard ratio 0.69, p< 0.001). Finally, mortality was also lower with apixaban compared to warfarin (hazard ratio 0.89, p=0.047).
A fourth option for a direct-acting oral anticoagulant is edoxaban. Edoxaban is also a factor Xa inhibitor. Over 21,000 patients were enrolled in the ENGAGE-AF study comparing warfarin (INR 2-3) and edoxaban (2 different once-daily regimens) (31). The primary endpoint was stroke or systemic embolism, which occurred at an annual rate of 1.50% in the warfarin group, compared with 1.18% in the higher dose edoxaban patients (hazard ratio 0.79, p< 0.001 for noninferiority). The corresponding rate for the primary endpoint in the low-dose edoxaban group was 1.61%. The annual rates of major bleeding were 3.43% with warfarin, 2.75% with high-dose edoxaban, and 1.61% with low-dose edoxaban.
There has never been a direct comparison of the newer agents. A few observations are relevant, however. Dabigatran is the only agent proven superior to warfarin for prevention of ischemic stroke. Apixaban is the only agent to reduce all-cause mortality. All agents are associated with a reduction in the rate of intracerebral hemorrhage relative to warfarin (19).
An alternative strategy to warfarin prophylaxis in patients with atrial fibrillation is dual antiplatelet treatment with aspirin and clopidogrel. The ACTIVE-W trial randomly assigned 6706 patients with atrial fibrillation and one additional risk factor for stroke to warfarin (INR 2-3) or aspirin (75 mg gd to 100 mg qd) plus clopidogrel (75 mg qd) (03). The primary study endpoint was the composite outcome of stroke, systemic embolus, myocardial infarction, or vascular death. The study was stopped prematurely because of the increased event rate with dual antiplatelet treatment (5.6% per year) compared to warfarin (3.9% per year). Interestingly, rates of major hemorrhage were not that different in the two groups (2.4% per year with antiplatelet treatment and 2.2% with warfarin). Therefore, warfarin is still preferred prophylaxis in patients with atrial fibrillation.
For atrial fibrillation patients who are not optimal candidates for warfarin, aspirin plus clopidogrel has been associated with a decreased rate of stroke compared to aspirin alone. In the ACTIVE A study, 7554 patients who were considered unsuitable for warfarin were assigned to aspirin alone (75 to 100 mg daily) or aspirin plus clopidogrel (75 mg per day)(02). The rate of major vascular events (stroke, myocardial infarction, vascular death) was lower in the dual therapy group compared to aspirin monotherapy (6.8% per year versus 7.6% per year, p=0.01). Major bleeding occurred in 2.0% of the dual therapy patients compared to 1.3% of aspirin monotherapy patients (p< 0.001). Therefore, clinicians may consider dual antiplatelet therapy if the patient is judged to be at low risk for major bleeding.
For patients with atrial fibrillation who are not candidates for anticoagulation, left atrial appendage closure is a potential treatment option. A randomized trial compared the WATCHMAN left atrial appendage closure device to warfarin (INR 2-3) (66). After a mean follow-up of 3.8 years, the primary endpoint (stroke or systemic embolism or cardiovascular death) occurred at a rate of 2.3 events per 100 patient-years in the device group compared to 3.8 events per 100 patient-years in the warfarin group (rate ratio 0.60). Left atrial appendage closure can be associated with serious side effects, however, including pericardial tamponade. Further, studies are needed to assess the safety and effectiveness of these devices compared with direct-acting oral anticoagulants.
The AFFIRM trial investigated rate versus rhythm control in patients with atrial fibrillation and did not find a difference between the two groups (71). A 69% decrease in stroke with warfarin was found once again. A study comparing rate control versus rhythm control in patients with atrial fibrillation and heart failure showed no difference in stroke with the two treatment strategies (68).
With the increasing availability of prolonged cardiac monitoring, it has been noted that some patients with a stroke of unknown cause (cryptogenic stroke) have intermittent atrial fibrillation during follow-up. Two studies, CRYSTAL-AF and EMBRACE, have found that prolonged monitoring can detect a 5- or 6-fold higher rate of intermittent atrial fibrillation, compared to usual care (32; 70). The studies differed in the length of follow-up (90 days vs. 12 months) and the method for cardiac monitoring (external monitoring vs. an implanted device). In EMBRACE, there was a nearly 2-fold higher rate of anticoagulant use in patients who underwent prolonged monitoring. Therefore, if a patient with a cryptogenic stroke is a potential candidate for anticoagulation, prolonged cardiac monitoring should be considered.
Screening for atrial fibrillation has also been investigated in patients in whom the index stroke is either lacunar or due to large vessel atherosclerosis. In a multicenter study with stroke due to these mechanisms and in which an implanted loop recorder was placed within 10 days of the index stroke, atrial fibrillation was detected in 12.1% of patients, compared to 1.8% in the usual care group (10). In another trial, an implantable loop recorder was compared to an external 4-week loop recorder (12). The implanted device detected atrial fibrillation in 15.4% of patients, compared to 4.7% with the 4-week recording. Although these results might push some clinicians to utilize the implantable loop recorder more frequently, at present it has not been shown that atrial fibrillation monitoring decreases stroke. A trial from Europe enrolled over 6000 individuals with atrial fibrillation risk factors and compared implantable loop recorder placement with usual care (76). The implantable loop recorder device detected more atrial fibrillation than usual care (31.8% vs. 12.2%), but there was no difference in the stroke rates over 64.5 months of follow-up. This raised questions about whether all atrial fibrillation detected with monitors is of clinical significance.
Long-term oral anticoagulation is also recommended for the following conditions: (1) rheumatic mitral stenosis and coexistent atrial fibrillation and (2) mechanical valves (67). Shorter courses (3 to 6 months) of oral anticoagulation are recommended to prevent cerebral embolism after acute myocardial infarction if left ventricular thrombus or dyskinetic wall abnormalities are detected. Most patients with bioprosthetic valves do not require long-term anticoagulation after the first three postoperative months unless other risk factors (left atrial thrombus, previous emboli, or multiple valves replaced) are present.
For patients with a patent foramen ovale, treatment options include (1) antiplatelet agents, (2) warfarin, (3) percutaneous closure, and (4) open surgical closure. A French multicenter study found that the rate of recurrent stroke in patients with a patent foramen ovale as the sole abnormality who were treated with aspirin was low (less than 1% per year) (52). Only if the patent foramen ovale was associated with an atrial septal aneurysm was there a markedly higher rate of recurrent stroke. Most studies have shown that patent foramen ovale is not a major risk factor for stroke in the general population, when one includes subjects above the age of 50 (64).
Patent foramen ovale closure studies utilized a device known as the Amplatzer occluder. The RESPECT trial enrolled 980 patients between the ages of 18 and 60 with a cryptogenic stroke and evidence of a patent foramen ovale by transesophageal echocardiogram (14). Patients were randomly assigned to patent foramen ovale closure or antithrombotic therapy. After a mean follow-up period of 2.6 years, the closure group had a stroke rate of 1.8% (9 events), and the medical therapy group had a rate of 3.3% (16 events). In the intention-to-treat analysis, the hazard ratio was 0.49 (p=0.08). There was a 4.2% risk of serious adverse events with the closure device, including two cases of pericardial tamponade. There was no difference in major bleeding. Atrial fibrillation rates were 3.0% in the closure group and 1.5% in the medical therapy group (p=0.13).
The PC Trial Investigators enrolled 414 patients and followed them for an average of 4 years (54). Nonfatal stroke occurred in one patient in the closure group and in five patients in the medical therapy group (hazard ratio 0.20, 0.02 to 1.72, p=0.14).
Publications such as the CLOSE and REDUCE trials did identify a small stroke reduction with patent foramen ovale closure. In the CLOSE trial, 663 patients with a recent stroke and patent foramen ovale were enrolled if they also had an atrial septal aneurysm or large interatrial shunt (53). After a mean follow-up of 5.3 years, there were no strokes in the patent foramen ovale closure group compared to 14 with antiplatelet therapy (p < 0.001). The incidence of atrial fibrillation was higher in the patent foramen ovale closure group compared to medical therapy (4.6% vs. 0.9%, p = 0.02). Similar results were seen in the REDUCE trial (72). In 664 randomized patients, the stroke risk was lower with patent foramen ovale closure compared to antiplatelet therapy (1.4% vs. 5.4%, p = 0.002). Atrial fibrillation was higher in the device-treated patients, with a rate of 6.6%. An updated metaanalysis found that the number needed to treat with patent foramen ovale closure to prevent one stroke is 46.5 for 3.7 years. This analysis also found an increase in atrial fibrillation with device closure and no difference in all-cause mortality or transient ischemic attack (61). In addition to the RoPE score, the PASCAL classification system may also be useful in decision making. This system looks for the coexistence of a RoPE score of 7 or more along with either a large shunt or atrial septal aneurysm. If both a high score and high-risk anatomic feature are present, then the patent foramen ovale relation to the stroke is considered “probable”, whereas it is considered “possible” if either a high score or anatomic feature is present. A pooled analysis with close to 5 years follow-up found that the absolute risk reduction with patent foramen ovale closure was 2.1% if the patent foramen ovale relation was probable or possible, but there was no benefit if the patent foramen ovale relation was judged as unlikely (44).
These studies show that the recurrent stroke rate for patients with a patent foramen ovale treated medically is quite low, approximately 1% per year. Further, recurrent events are not always due to the patent foramen ovale. There may be a slight stroke risk reduction in individual patients but patients should be selected carefully and they must be carefully evaluated for other stroke mechanisms (intermittent atrial fibrillation, arterial dissection, etc.) before patent foramen ovale closure is considered.
As the population ages and cardiac care improves, there is a growing number of patients living with reduced cardiac ejection fraction.
The Warfarin Aspirin Reduced Cardiac Ejection Fraction (WARCEF) trial enrolled 2305 patients with ejection fraction less than 35% who were in sinus rhythm (38). Patients were randomly assigned to warfarin (INR 2.0 to 3.5) or aspirin 325 mg per day. Patients were followed for an average of 3.5 years. The primary endpoint was stroke or death from any cause. There was no difference between the warfarin and aspirin groups with respect to the primary endpoint. During follow-up, the rate of stroke was reduced with warfarin (0.72 events per 100 patient-years vs. 1.36, hazard ratio 0.52, p=0.005). However, major bleeding was also increased with warfarin (1.78 per 100 patient-years vs. 0.87, p< 0.001). There was no difference in the two groups with respect to intracranial hemorrhage. The authors concluded that the choice between warfarin and aspirin should be individualized, with consideration of stroke and bleeding risks. There may be a benefit with anticoagulation in patients below age 60 years but this requires further study (39).
Long-term anticoagulant therapy (warfarin) is best monitored with the international normalization ratio time. The international normalization ratio takes into account the differing sensitivities of the thromboplastin reagent used in the standard prothrombin time test and minimizes fluctuations in test results with subsequent dosing changes. In most patients with atrial fibrillation, the international normalization ratio is kept between 2.0 and 3.0.
The differential diagnosis of cerebral embolism is that for any acute focal neurologic deficit. Transient focal ischemia must be distinguished from focal seizures and migraine. In the acute phase of a stroke, an intracerebral hemorrhage must be excluded by CT. Headache and depressed level of consciousness also should suggest intracranial hemorrhage. Embolism may be clinically difficult to distinguish from any other mechanism of stroke. Pure sensory or pure motor syndromes involving one half of the body point to small-vessel occlusive disease but can be caused by emboli, and the clinical syndromes are of limited diagnostic specificity without corroborating laboratory studies.
The causes of focal brain ischemia are myriad. The vast majority of infarctions, however, are related either to atherosclerosis of extracranial or intracranial arteries, or to common cardiac sources of embolism. Inflammatory causes of stroke include the antiphospholipid antibody syndrome, Takayasu disease, granulomatous arteritis, aortoarteritis, infective arteritis, and systemic arteritis (Wegener granulomatosis, rheumatoid arthritis, sarcoidosis, polyarteritis nodosa, and Behçet disease). Nonatherosclerotic causes of stroke include arterial dissection, fibromuscular dysplasia, moyamoya syndrome, and vasospasm in subarachnoid hemorrhage.
Less common types of embolism include fat after long bone fractures, fibrocartilaginous, air in Caisson disease (in divers), amniotic fluid, tumor, and iatrogenic foreign particle.
One of the first diagnostic tests when evaluating a patient suspected of stroke is nonenhanced CT of the head, which distinguishes nonhemorrhagic from hemorrhagic stroke. CT findings suggestive of cerebral embolism include "wedge-shaped" low-attenuation defects at the gray-white cortical junction, multiple strokes crossing arterial territories, a hyperdense middle cerebral artery sign, and early conversion of a "bland" infarct to a hemorrhagic infarct. At least 40% of embolic infarctions eventually have CT evidence of hemorrhage that is usually of no clinical significance.
Prompt evaluation of the cervical carotid arteries with ultrasound or MRA helps identify occlusive arterial disease, potential candidates for endarterectomy, and patients with intracranial atherosclerosis. Transcranial Doppler may also identify middle cerebral artery occlusion, which often suggests embolism. An electrocardiogram may reveal potential sources of the stroke such as atrial fibrillation or myocardial infarction. Transthoracic echocardiography can confirm the presence of an akinetic or dyskinetic left ventricular wall, mural thrombus, valvular disorders, and other intracardiac masses. It is of limited use for viewing the left atrium and left atrial appendage, which are often the sites of a thrombus. In an echocardiographic study of 846 patients with ischemic stroke, among patients in sinus rhythm, 37.2% had findings that potentially might lead to a beneficial response from anticoagulation such as dilated cardiomyopathy, previous anterior wall myocardial infarction, or depressed ejection fraction (01). Transesophageal echocardiography is superior to transthoracic echocardiography for imaging these structures. A number of potential sources of emboli, such as patent foramen ovale, atrial septal aneurysm, atrial "smoke," aortic atherosclerosis, and congenital anomalies, may be identified by transesophageal echocardiography. Routine use of transthoracic echocardiography is unlikely to be useful in elderly patients (81). In patients with a stroke and patent foramen ovale, it may be worthwhile to check for conditions associated with an increased risk of venous thrombosis, such as the factor V Leiden mutation and anticardiolipin antibodies (17).
Transesophageal echocardiography is also potentially useful in risk stratification for patients with atrial fibrillation. In the SPAF III trial, transesophageal echocardiography was carried out in 786 patients. Dense, spontaneous echo contrast and left atrial appendage thrombus were present in 20% and 15% of patients, respectively, and each was associated with a 3-fold increased risk of stroke (36). Left atrial thrombus documentation has also been associated with an increased risk of transient ischemic attack (73).
Once the diagnosis of cerebral embolism has been established, thrombolytic therapy with intravenous tissue plasminogen activator can improve the long-term prognosis, if treatment can be initiated within 3 hours (NINDS Study group 1995). New guidelines from the American Heart Association/American Stroke Association also indicate that select patients with cardioembolic stroke can benefit from mechanical thrombectomy (65). Heparin anticoagulation is sometimes initiated in the acute setting to lower the risk of recurrence if a nonseptic cardiac source of embolism persists, although the benefits are unproven (05). Decisions regarding choice of long-term antithrombotic therapy need to be based on the clinical status of the patient, comorbidities, and echocardiographic variables (04).
The baseline laboratory evaluation should include a complete blood count with differential, platelet count, prothrombin time, partial thromboplastin time, erythrocyte sedimentation rate, serum glucose, electrolytes, lipids, and a VDRL test. Urinalysis, 12-lead ECG, and plain chest radiograph should also be performed.
Some patients require supplemental oxygen or intravascular volume expansion with colloid solutions if dehydration is suspected. Fever should be carefully monitored and aggressively evaluated and treated. There is experimental evidence to suggest that hyperthermia may increase infarct size. Fever may be the clue to another complication such as aspiration pneumonia, endocarditis, or deep venous thrombosis. Both hyperglycemia and hypoglycemia can exacerbate ischemic brain damage. Blood glucose levels that exceed 200 mg/dL should be treated with insulin and glucose levels below 60 mg/dL should be avoided.
Rehabilitation plans should begin on the first day of hospitalization and should include a physiatrist, physical and occupational therapists, a social worker, a dietitian, and, if indicated, a speech pathologist.
Pregnancy increases the likelihood of cerebral infarction to approximately 10 times that of the expected incidence in nonpregnant young women (22). Cardioemboli are responsible for the majority of ischemic infarctions of arterial origin during pregnancy. Most strokes during pregnancy affect the anterior circulation, especially the middle cerebral artery. Cardiac conditions frequently associated with cerebral embolism during pregnancy include atrial arrhythmias, congenital disorders (eg, atrial septal defects), and acquired disorders (eg, peripartum cardiomyopathy).
Venous infarction also occurs in the peripartum period (22).
The consequences of atrial fibrillation during pregnancy are potentially life-threatening. Atrial fibrillation may be chronic as a consequence of rheumatic mitral stenosis or it may develop de novo during the course of the pregnancy. Congestive heart failure occurs more frequently with de novo atrial fibrillation during pregnancy than with chronic atrial fibrillation (22). Women with chronic atrial fibrillation who are treated with warfarin should take contraceptive precautions to avoid exposing the fetus to the potential teratogenic effect of warfarin. If pregnancy is desired, alternative anticoagulation methods such as subcutaneous heparin should be implemented prior to conception and continued through the first trimester.
Patients with a history of cerebral embolism often are treated with oral anticoagulants. Prior to any surgical procedure, these patients require conversion from oral anticoagulants to intravenous anticoagulants. The risk of cerebral embolism increases if there is a definite source of embolism during the period of time when anticoagulation is reversed. However, in most patients warfarin can be safely withheld for 1 or 2 weeks to permit elective or emergent surgery.
Seemant Chaturvedi MD
Dr. Chaturvedi of University of Maryland received a consulting fee from Astra Zeneca.See Profile
Steven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.See Profile
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