Patent Foramen Ovale in Young Adults with Unexplained Stroke
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《新英格兰医药杂志》
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
A 38-year-old man notes abrupt loss of vision in his right visual field while reading. He has no significant medical history and reports that he neither smokes nor uses alcohol or illicit drugs. Physical examination reveals right homonymous hemianopia but no other abnormalities. Magnetic resonance imaging reveals acute left occipital infarction and normal head and neck vessels. Transesophageal echocardiography shows a patent foramen ovale without atrial septal aneurysm. What are the implications of this finding, and what therapy should be recommended?
The Clinical Problem
Stroke is a leading cause of death and long-term disability worldwide. Eighty-five percent of strokes are ischemic, and most ischemic strokes occur in persons older than 65 years of age in tandem with the development of atherosclerosis. Although a minority of ischemic strokes in the community affect younger adults,1 as many as half the patients referred to tertiary care centers are younger than 65 years of age, and up to 12 percent are younger than 45 years.2 Young patients with ischemic stroke often have few, if any, risk factors for atherosclerosis.3 Initial evaluation of the cerebral arteries is essential but frequently unrevealing, and thus in many cases the focus must shift to the detection of potential cardiac sources of embolism that are commonly associated with, and that may cause, unexplained stroke in young persons.4
In as many as 43 percent of affected young adults, strokes are cryptogenic (i.e., they do not have a definite cause despite extensive evaluation).1 The most prevalent potential source of cardioembolism in young adults with cryptogenic stroke is patent foramen ovale, which is detected in more than half of such persons undergoing evaluation.5 This discussion focuses principally on patent foramen ovale occurring in young patients (those younger than 45 years old) or middle-aged patients (those 45 to 64 years old) who have minimal risk factors for atherosclerosis and in whom evaluations for vascular disease or systemic illnesses are negative. Other potential sources of cardioembolism in these patients are described in Table 1.
Table 1. Overview of Potential Cardiac Sources of Embolism Other Than Patent Foramen Ovale.
Patent Foramen Ovale and the Risk of Stroke
Patent foramen ovale, which is present in 27 percent of unselected adults,16 is a vestige of the fetal circulation and results from failure of the primum and secundum septa to fuse postnatally.17 Persistence of the one-way flap valve overlying the fossa ovalis allows right-to-left blood flow when right atrial pressure exceeds left atrial pressure (Figure 1).17
Figure 1. Transesophageal Echocardiograms of a Patent Foramen Ovale.
In Panel A, a transesophageal echocardiogram in the longitudinal plane shows a separation (arrow) between the primum septum (arrowhead) and the secundum septum — a finding consistent with the presence of patent foramen ovale. Panel B shows a transesophageal echocardiogram, also in the longitudinal plane, obtained during the injection of agitated-saline contrast material through an antecubital vein with use of the Valsalva maneuver. There is complete opacification of the right atrium, and passage of a cloud of bubbles (arrow) between the primum and secundum septa into the left atrium is visible.
In support of the proposition that patent foramen ovale can serve as a gateway to the arterial circulation for venous thromboemboli, various studies have documented thrombus straddling the foramen in patients with deep-vein thrombosis and systemic embolism.17 Such "thrombus-in-transit," however, is rarely detected in patients with stroke and patent foramen ovale, and the clinical diagnosis of paradoxical embolism instead depends on the concurrence of arterial embolism, venous thrombosis, interatrial communication, and a gradient favoring right-to-left shunting.18
An important role for patent foramen ovale in the pathogenesis of ischemic stroke was first suggested by a case–control study that showed a markedly higher frequency of patent foramen ovale (detected by transthoracic echocardiography) in patients with cryptogenic stroke who were younger than 55 years of age than in controls (54 percent vs. 10 percent).5 A meta-analysis of case–control studies subsequently confirmed an increased prevalence of patent foramen ovale among patients 55 years of age or younger with cryptogenic stroke as compared with stroke-free controls (odds ratio, 5.01; 95 percent confidence interval, 3.24 to 7.75)19 but not among persons 55 years of age or older (odds ratio, 1.20; 95 percent confidence interval, 0.56 to 2.56).19
Many of these studies, however, lacked blinded interpretation of echocardiograms — a limitation that may have led to ascertainment bias. Furthermore, the studies compared patients and controls who had been referred for echocardiography for different indications and hence were susceptible to biases related to varying thoroughness in the assessment of patent foramen ovale or associated anatomical features. Nevertheless, a significant association between patent foramen ovale and cryptogenic stroke has since been documented in a prospective clinical trial in which ascertainment of patent foramen ovale was made without knowledge of the participants' clinical history.20
Despite this association, the etiologic role of patent foramen ovale in cryptogenic stroke has been questioned.21 Paradoxical embolism, the presumptive mechanism, requires a favorable pressure gradient for right-to-left shunting, but such a gradient normally occurs only transiently, in early systole.22 Moreover, conditions that promote right-to-left shunting, such as pulmonary hypertension or Valsalva-inducing activities, are rarely documented in patients with stroke who have patent foramen ovale.21
In addition, evaluation of patients with cryptogenic stroke and patent foramen ovale rarely reveals a venous source of thrombus.21 The reportedly low rate of detection of deep-vein thrombosis, however, may reflect delays in imaging, which often was performed after the initiation of anticoagulation.23 Furthermore, the absence of a detectable venous thrombus is not unique to patients with stroke and patent foramen ovale. In 20 to 30 percent of patients with pulmonary embolism, deep-vein thrombi are not identified.24 Failure to detect a thrombus in such patients may be attributable to complete thrombus migration, inability to detect residual thrombus, or undetected thrombosis in a calf or pelvic vein. In a venographic study involving 42 patients with arterial embolism and patent foramen ovale, deep-vein thrombosis was documented in 24 of the patients; in 13, thrombosis was identified only in calf veins.23 This finding raises the possibility that calf-vein thrombi, which must generally extend proximally before causing clinically important pulmonary embolism,24 may be able to discharge small embolic fragments (1 mm in diameter) that are sufficient to cause a clinical stroke should they gain access to the arterial circulation.25 In another study, pelvic-vein thrombi were documented by magnetic resonance venography in 20 percent of patients with cryptogenic stroke who had patent foramen ovale.26
Nevertheless, the difficulty of confirming the occurrence of paradoxical embolism has led to the consideration of alternative explanations, such as in situ thrombosis or atrial tachyarrhythmia. The former, however, is very rarely found by transesophageal echocardiography or at autopsy.27 Moreover, although patients with interatrial septal abnormalities and stroke have lower thresholds for the induction of atrial fibrillation,28 this arrhythmia is almost never documented in patients with cryptogenic stroke and patent foramen ovale.21
Adding to the mechanistic uncertainty, population-wide figures suggest that the yearly risk of cryptogenic stroke in healthy persons with patent foramen ovale may be as low as 0.1 percent.29 This observation suggests that additional factors may be necessary to increase the associated risk of stroke. Features of the patent foramen ovale may be important. A large anatomical separation (4 mm or more) between the primum and secundum septa,30 increased right-to-left shunting31 or shunting at rest,32 increased septal mobility,32 and the presence of an atrial septal aneurysm33 have been linked to an increased risk of stroke, but ascertainment bias remains possible. Moreover, the clinical relevance of patent foramen ovale is influenced by concurrent risk factors for venous thromboembolism, such as trauma, recent surgery, use of oral contraceptives, and hypercoagulable states.18
Atrial Septal Aneurysm
The prevalence at autopsy of atrial septal aneurysm, caused by redundancy of the interatrial septum (Figure 2), is 1 percent.34 A relation between atrial septal aneurysm and stroke has been documented,19 with one study reporting a greater prevalence among persons with stroke (7.9 percent) than among population-based controls (2.2 percent) on transesophageal echocardiography.35 Detection of thrombi in situ on the interatrial septum led to the notion that the redundant membrane promotes thrombogenesis,36 but in situ thrombosis is seen only rarely.37 Alternative explanations for the increased risk of stroke in patients with atrial septal aneurysms are the high prevalence (50 to 90 percent) of coexisting patent foramen ovale, especially larger foramina, or of an atrial septal defect35,36,37 (as shown in Video Clip 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). Moreover, atrial septal aneurysms are associated with prominent eustachian valves or Chiari networks, right atrial membranes that facilitate right-to-left shunting by directing flow from the inferior vena cava toward the fossa ovalis,38 and with tachyarrhythmias predisposing to thromboembolism.28
Figure 2. Transesophageal Echocardiograms of an Atrial Septal Aneurysm.
In Panel A, a transesophageal echocardiogram (in the horizontal plane) shows an atrial septal aneurysm protruding into the right atrium (arrow). Atrial septal aneurysm is defined as either sustained bowing of a 15-mm segment of interatrial septal membrane in the fossa ovalis of at least 11 mm (or at least 15 mm by a more conservative definition) beyond the plane of the interatrial septum or as phasic excursion to either side totaling the same distance. Panel B shows a transesophageal echocardiogram showing the same atrial septal aneurysm (arrow) viewed in the longitudinal plane.
Strategies and Evidence
Evaluation
Transesophageal echocardiography is superior to transthoracic echocardiography for the detection of potential sources of cardioembolism.4 Although transthoracic echocardiography identifies such sources in about 25 percent of patients with clinically apparent cardiac disease, its yield in patients without cardiac signs or symptoms is less than 10 percent.39 By contrast, transesophageal echocardiography detects potential sources of cardioembolism in as many as 57 percent of patients with unexplained stroke.39 Intravenous injection of saline mixed with air greatly enhances the diagnosis of right-to-left shunts by transthoracic or transesophageal echocardiography by permitting visualization of microbubbles in the chambers of the left side of the heart that would otherwise be filtered by the lung capillaries.17 The sensitivities of traditional transthoracic echocardiography with agitated-saline contrast agent for right-to-left shunts40 and atrial septal aneurysm are at most half those of contrast-based transesophageal echocardiography,37 but recent refinements (for example, a contrast-based transmitral Doppler technique) have improved its diagnostic accuracy.17 Another alternative, contrast transcranial Doppler sonography, in which imaging of the middle cerebral arteries is used to detect right-to-left shunting of microbubbles, offers accuracy similar to that of transesophageal echocardiography.17 Its utility, however, is limited by its inability to assess interatrial septal morphologic features or other cardiac structures. Although transesophageal echocardiography is semi-invasive, it is associated with a low risk of serious complications (0.2 percent), which may include bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, or bleeding.41
Formal analyses of the optimal use of echocardiography in young patients with cryptogenic stroke are lacking. Nevertheless, the increased diagnostic yield of transesophageal echocardiography as compared with that of transthoracic echocardiography or transcranial Doppler sonography supports the use of the transesophageal technique in this population, pending further evidence regarding the benefits of treating specific lesions found on echocardiography.
Treatment
The available evidence on pharmacologic approaches (involving the use of antiplatelet or anticoagulant agents) and mechanical approaches to secondary prevention in patients with cryptogenic stroke who have patent foramen ovale is inadequate for assessment of their relative merits. To date, no study has randomly assigned patients with cryptogenic stroke and patent foramen ovale to different therapies. Studies thus far have been observational, with disparate definitions of the qualifying or recurrent cerebrovascular event, nonuniform criteria for interatrial septal abnormalities, absence of blinding during examination of echocardiograms or ascertainment of end points, and incomplete accounting of associated risk factors or the use of adjunctive therapies.
The risk of stroke recurrence in patients 60 years of age or younger who have unexplained cerebral ischemia and patent foramen ovale appears to be low, regardless of the therapy used. In a prospective study of 140 such patients treated medically or surgically at their physicians' discretion, the annual rate of stroke recurrence was 1.9 percent, and the type of treatment had no detectable influence.42 Similarly, a longitudinal study of 581 persons 55 years of age or younger who had cryptogenic stroke treated with aspirin found similarly low rates of recurrence at four years among those who had a patent foramen ovale (2.3 percent) and those who did not (4.2 percent).33 Patients who had both patent foramen ovale and atrial septal aneurysm, however, had a 15.2 percent rate of recurrence despite the use of aspirin therapy — a rate nearly fourfold that among patients who did not have either abnormality. Unlike prior investigations, this study found that a greater shunt magnitude was not associated with increased risk, but the study had limited power to assess the relative effects of foraminal size and atrial septal aneurysm.33
By contrast, in a randomized trial in which aspirin therapy and warfarin therapy were compared in older patients with stroke, the two-year rate of recurrent stroke or death in the subgroup with cryptogenic stroke was not significantly higher among those who had a patent foramen ovale and atrial septal aneurysm than among those with neither abnormality.38 However, the study was underpowered for this comparison, and patients without interatrial septal abnormalities had more risk factors20 for subclinical atherosclerotic disease than did those with those abnormalities. Post hoc analyses43 of data from this study indicated that there was no significant association between patent foramen ovale and the risk of recurrent stroke or death among patients younger than 65 years of age but an association was observed in older patients. These findings, however, are limited by the small numbers of events in each subgroup and by the performance of multiple comparisons that were not prespecified.
Medical Therapy
In a retrospective study of 90 patients younger than 60 years of age with cerebral ischemia, 52 of whom had patent foramen ovale, those receiving aspirin or no therapy had a rate of recurrence almost threefold that of patients treated with warfarin.44 (The numbers were too small to allow comparison between the group that received aspirin and the group that did not receive therapy.) The results are inconclusive, however, for several reasons: treatment assignments were at the discretion of the consulting neurologist; treatment crossover was frequent; and ascertainment of end points, which included multiple events, was not blinded. For similar reasons, it is impossible to draw firm conclusions from a meta-analysis that found that warfarin (as compared with antiplatelet therapy) lowered the risk of recurrence (odds ratio, 0.37; 95 percent confidence interval, 0.23 to 0.60) among patients with cerebral ischemia and patent foramen ovale.45 In a randomized trial, subgroup analysis of 98 patients with cryptogenic stroke and patent foramen ovale revealed a nonsignificant reduction in the two-year incidence of recurrent stroke or death with warfarin therapy as compared with aspirin therapy (9.5 percent vs. 17.9 percent; hazard ratio, 0.52; 95 percent confidence interval, 0.16 to 1.67), but the power of the analysis was limited.20 Although the incidence of major hemorrhage did not differ between warfarin and aspirin (1.78 vs. 1.91 events per 100 patient-years, P=1.0), warfarin did increase the rate of minor hemorrhage (22.9 vs. 8.66 events per 100 patient-years, P<0.001).20
Mechanical Closure
The traditional approach to foraminal closure involves open thoracotomy. Reported case series are small, but the rate of postoperative stroke ranges from 0 to 3.5 percent46 47,48 at two years. The mortality associated with closure of an uncomplicated atrial septal defect is less than 1.5 percent.49 Perioperative risks also include atrial fibrillation, pericardial sequelae, and the need for reexploration because of bleeding.46,47,48 Minimally invasive surgery50 is an alternative approach, but percutaneous-closure techniques hold greater appeal (Figure 3). A systematic review found that among 1355 patients undergoing percutaneous closure, the rate of recurrent stroke or transient ischemic attack was 0 to 4.9 percent at one year.51 Although these values appeared favorable next to one-year recurrence rates among 895 patients receiving medical therapy (3.8 to 12.0 percent),51 several considerations — the nonrandomized treatment assignment, differences in the clinical characteristics of the patients treated by the various techniques, and inconsistent criteria for ascertainment of outcomes — preclude meaningful comparison. Serious complications of percutaneous closure (major hemorrhage, cardiac tamponade, the need for surgery, pulmonary embolism, and death) were reported in 1.5 percent of the patients, and minor complications (arrhythmia, device fracture or embolization, air embolism, femoral hematoma, and fistula) in 7.9 percent.51
Figure 3. Percutaneous Closure of a Patent Foramen Ovale.
With use of a femoral approach, a transvenous sheath is advanced across the foramen into the left atrium, where a folded disk is expanded and pulled back, apposing the primum and secundum septa closed. This step is followed by deployment of a right-sided disk, at which time the two-disk device is released. Clopidogrel and aspirin are recommended for a period of three months to prevent thrombus formation on the device, with aspirin therapy continued for an additional three months, when endothelialization is complete. Antibiotic prophylaxis for six months is recommended. Complete late closure of the foramen has been reported in 80 to 95 percent of patients.
In one follow-up study of young patients with cryptogenic stroke and patent foramen ovale, surgical closure was performed if at least two of four purported "high-risk" features for paradoxical embolism (major shunt , atrial septal aneurysm, infarcts in multiple territories, and Valsalva-provoking activity preceding the onset of stroke42) were present. There were no recurrences after 23 months, but the study did not include a control group.46 A decision analysis modeling different therapeutic approaches in a 55-year-old patient with patent foramen ovale concluded that, for a yearly risk of stroke recurrence of 0.8 percent, surgical closure or warfarin were the best options.49 (Percutaneous closure was not considered.) Surgery became preferable when the annual risk of recurrence reached 1.4 percent. These conclusions, however, rest on the questionable assumptions that paradoxical embolism underlies the risk of stroke and that anticoagulation lowers the risk of recurrence to the same degree as it does in persons with venous thromboembolism or atrial fibrillation. Currently, the Food and Drug Administration allows the use of transcatheter-closure devices under a humanitarian device exemption only in cases of recurrence of stroke during therapeutic oral anticoagulation.52
Areas of Uncertainty
The pathogenesis of cryptogenic stroke in patients with interatrial septal abnormalities is not well understood. Features of the interatrial septum that best predict the risk of thromboembolism and the role of hypercoagulable disorders in determining risk also remain unclear. Data from ongoing randomized trials that evaluate warfarin, aspirin, or both as compared with transcatheter closure are needed. Pending completion of such studies, which have been hampered by slow recruitment,52 the relative safety and efficacy of these approaches remain uncertain.
Guidelines
Current guidelines from professional societies (Table 2) do not include specific recommendations regarding the optimal diagnostic strategy for transthoracic and transesophageal echocardiography.53 Moreover, they deem the available evidence insufficient to permit firm recommendations for the management of interatrial septal abnormalities.54,55
Table 2. Guidelines from Professional Societies.
Conclusions and Recommendations
In patients with cryptogenic stroke, assessment for patent foramen ovale and other potential cardiac sources of embolism is recommended; transesophageal echocardiography is more sensitive for detecting these abnormalities than is transthoracic echocardiography. Because the presumed pathophysiology of cryptogenic stroke in younger patients with patent foramen ovale is paradoxical embolism of fibrin-rich thrombus, and because observational data suggest a benefit with warfarin relative to aspirin, we would consider the use of warfarin anticoagulation for three to six months in patients such as the man described in the vignette. Available data are not sufficient for confirmation that this approach is preferable to aspirin therapy, however, and current guidelines do not specifically recommend one over the other.54,55 Appropriate investigation for deep-vein thrombosis and thrombophilia is essential. We recommend switching most patients' therapy to aspirin after they have received a course of warfarin. However, we favor long-term anticoagulation in patients with associated venous thromboembolism or selected hypercoagulable states and probably in patients with high-risk features (atrial septal aneurysm, major shunt, infarcts in multiple territories, or antecedent Valsalva-provoking activity).
Decisions must take into account coexisting conditions and the patients' preferences. Patients should be encouraged to participate in ongoing randomized trials comparing percutaneous closure and medical therapy. Otherwise, percutaneous closure is currently indicated in the United States only for patients with recurrence despite therapeutic anticoagulation. Surgical closure may be considered for high-risk patients when warfarin is contraindicated.
Supported in part by a Career Development Award (K23 HL070854, to Dr. Kizer) from the National Heart, Lung, and Blood Institute.
Source Information
From the Departments of Medicine (J.R.K., R.B.D.) and Public Health (J.R.K.), Weill Medical College of Cornell University, New York.
Address reprint requests to Dr. Kizer at Box 222, New York–Presbyterian Hospital, 525 E. 68th St., New York, NY 10021, or at jok2007@med.cornell.edu.
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A 38-year-old man notes abrupt loss of vision in his right visual field while reading. He has no significant medical history and reports that he neither smokes nor uses alcohol or illicit drugs. Physical examination reveals right homonymous hemianopia but no other abnormalities. Magnetic resonance imaging reveals acute left occipital infarction and normal head and neck vessels. Transesophageal echocardiography shows a patent foramen ovale without atrial septal aneurysm. What are the implications of this finding, and what therapy should be recommended?
The Clinical Problem
Stroke is a leading cause of death and long-term disability worldwide. Eighty-five percent of strokes are ischemic, and most ischemic strokes occur in persons older than 65 years of age in tandem with the development of atherosclerosis. Although a minority of ischemic strokes in the community affect younger adults,1 as many as half the patients referred to tertiary care centers are younger than 65 years of age, and up to 12 percent are younger than 45 years.2 Young patients with ischemic stroke often have few, if any, risk factors for atherosclerosis.3 Initial evaluation of the cerebral arteries is essential but frequently unrevealing, and thus in many cases the focus must shift to the detection of potential cardiac sources of embolism that are commonly associated with, and that may cause, unexplained stroke in young persons.4
In as many as 43 percent of affected young adults, strokes are cryptogenic (i.e., they do not have a definite cause despite extensive evaluation).1 The most prevalent potential source of cardioembolism in young adults with cryptogenic stroke is patent foramen ovale, which is detected in more than half of such persons undergoing evaluation.5 This discussion focuses principally on patent foramen ovale occurring in young patients (those younger than 45 years old) or middle-aged patients (those 45 to 64 years old) who have minimal risk factors for atherosclerosis and in whom evaluations for vascular disease or systemic illnesses are negative. Other potential sources of cardioembolism in these patients are described in Table 1.
Table 1. Overview of Potential Cardiac Sources of Embolism Other Than Patent Foramen Ovale.
Patent Foramen Ovale and the Risk of Stroke
Patent foramen ovale, which is present in 27 percent of unselected adults,16 is a vestige of the fetal circulation and results from failure of the primum and secundum septa to fuse postnatally.17 Persistence of the one-way flap valve overlying the fossa ovalis allows right-to-left blood flow when right atrial pressure exceeds left atrial pressure (Figure 1).17
Figure 1. Transesophageal Echocardiograms of a Patent Foramen Ovale.
In Panel A, a transesophageal echocardiogram in the longitudinal plane shows a separation (arrow) between the primum septum (arrowhead) and the secundum septum — a finding consistent with the presence of patent foramen ovale. Panel B shows a transesophageal echocardiogram, also in the longitudinal plane, obtained during the injection of agitated-saline contrast material through an antecubital vein with use of the Valsalva maneuver. There is complete opacification of the right atrium, and passage of a cloud of bubbles (arrow) between the primum and secundum septa into the left atrium is visible.
In support of the proposition that patent foramen ovale can serve as a gateway to the arterial circulation for venous thromboemboli, various studies have documented thrombus straddling the foramen in patients with deep-vein thrombosis and systemic embolism.17 Such "thrombus-in-transit," however, is rarely detected in patients with stroke and patent foramen ovale, and the clinical diagnosis of paradoxical embolism instead depends on the concurrence of arterial embolism, venous thrombosis, interatrial communication, and a gradient favoring right-to-left shunting.18
An important role for patent foramen ovale in the pathogenesis of ischemic stroke was first suggested by a case–control study that showed a markedly higher frequency of patent foramen ovale (detected by transthoracic echocardiography) in patients with cryptogenic stroke who were younger than 55 years of age than in controls (54 percent vs. 10 percent).5 A meta-analysis of case–control studies subsequently confirmed an increased prevalence of patent foramen ovale among patients 55 years of age or younger with cryptogenic stroke as compared with stroke-free controls (odds ratio, 5.01; 95 percent confidence interval, 3.24 to 7.75)19 but not among persons 55 years of age or older (odds ratio, 1.20; 95 percent confidence interval, 0.56 to 2.56).19
Many of these studies, however, lacked blinded interpretation of echocardiograms — a limitation that may have led to ascertainment bias. Furthermore, the studies compared patients and controls who had been referred for echocardiography for different indications and hence were susceptible to biases related to varying thoroughness in the assessment of patent foramen ovale or associated anatomical features. Nevertheless, a significant association between patent foramen ovale and cryptogenic stroke has since been documented in a prospective clinical trial in which ascertainment of patent foramen ovale was made without knowledge of the participants' clinical history.20
Despite this association, the etiologic role of patent foramen ovale in cryptogenic stroke has been questioned.21 Paradoxical embolism, the presumptive mechanism, requires a favorable pressure gradient for right-to-left shunting, but such a gradient normally occurs only transiently, in early systole.22 Moreover, conditions that promote right-to-left shunting, such as pulmonary hypertension or Valsalva-inducing activities, are rarely documented in patients with stroke who have patent foramen ovale.21
In addition, evaluation of patients with cryptogenic stroke and patent foramen ovale rarely reveals a venous source of thrombus.21 The reportedly low rate of detection of deep-vein thrombosis, however, may reflect delays in imaging, which often was performed after the initiation of anticoagulation.23 Furthermore, the absence of a detectable venous thrombus is not unique to patients with stroke and patent foramen ovale. In 20 to 30 percent of patients with pulmonary embolism, deep-vein thrombi are not identified.24 Failure to detect a thrombus in such patients may be attributable to complete thrombus migration, inability to detect residual thrombus, or undetected thrombosis in a calf or pelvic vein. In a venographic study involving 42 patients with arterial embolism and patent foramen ovale, deep-vein thrombosis was documented in 24 of the patients; in 13, thrombosis was identified only in calf veins.23 This finding raises the possibility that calf-vein thrombi, which must generally extend proximally before causing clinically important pulmonary embolism,24 may be able to discharge small embolic fragments (1 mm in diameter) that are sufficient to cause a clinical stroke should they gain access to the arterial circulation.25 In another study, pelvic-vein thrombi were documented by magnetic resonance venography in 20 percent of patients with cryptogenic stroke who had patent foramen ovale.26
Nevertheless, the difficulty of confirming the occurrence of paradoxical embolism has led to the consideration of alternative explanations, such as in situ thrombosis or atrial tachyarrhythmia. The former, however, is very rarely found by transesophageal echocardiography or at autopsy.27 Moreover, although patients with interatrial septal abnormalities and stroke have lower thresholds for the induction of atrial fibrillation,28 this arrhythmia is almost never documented in patients with cryptogenic stroke and patent foramen ovale.21
Adding to the mechanistic uncertainty, population-wide figures suggest that the yearly risk of cryptogenic stroke in healthy persons with patent foramen ovale may be as low as 0.1 percent.29 This observation suggests that additional factors may be necessary to increase the associated risk of stroke. Features of the patent foramen ovale may be important. A large anatomical separation (4 mm or more) between the primum and secundum septa,30 increased right-to-left shunting31 or shunting at rest,32 increased septal mobility,32 and the presence of an atrial septal aneurysm33 have been linked to an increased risk of stroke, but ascertainment bias remains possible. Moreover, the clinical relevance of patent foramen ovale is influenced by concurrent risk factors for venous thromboembolism, such as trauma, recent surgery, use of oral contraceptives, and hypercoagulable states.18
Atrial Septal Aneurysm
The prevalence at autopsy of atrial septal aneurysm, caused by redundancy of the interatrial septum (Figure 2), is 1 percent.34 A relation between atrial septal aneurysm and stroke has been documented,19 with one study reporting a greater prevalence among persons with stroke (7.9 percent) than among population-based controls (2.2 percent) on transesophageal echocardiography.35 Detection of thrombi in situ on the interatrial septum led to the notion that the redundant membrane promotes thrombogenesis,36 but in situ thrombosis is seen only rarely.37 Alternative explanations for the increased risk of stroke in patients with atrial septal aneurysms are the high prevalence (50 to 90 percent) of coexisting patent foramen ovale, especially larger foramina, or of an atrial septal defect35,36,37 (as shown in Video Clip 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). Moreover, atrial septal aneurysms are associated with prominent eustachian valves or Chiari networks, right atrial membranes that facilitate right-to-left shunting by directing flow from the inferior vena cava toward the fossa ovalis,38 and with tachyarrhythmias predisposing to thromboembolism.28
Figure 2. Transesophageal Echocardiograms of an Atrial Septal Aneurysm.
In Panel A, a transesophageal echocardiogram (in the horizontal plane) shows an atrial septal aneurysm protruding into the right atrium (arrow). Atrial septal aneurysm is defined as either sustained bowing of a 15-mm segment of interatrial septal membrane in the fossa ovalis of at least 11 mm (or at least 15 mm by a more conservative definition) beyond the plane of the interatrial septum or as phasic excursion to either side totaling the same distance. Panel B shows a transesophageal echocardiogram showing the same atrial septal aneurysm (arrow) viewed in the longitudinal plane.
Strategies and Evidence
Evaluation
Transesophageal echocardiography is superior to transthoracic echocardiography for the detection of potential sources of cardioembolism.4 Although transthoracic echocardiography identifies such sources in about 25 percent of patients with clinically apparent cardiac disease, its yield in patients without cardiac signs or symptoms is less than 10 percent.39 By contrast, transesophageal echocardiography detects potential sources of cardioembolism in as many as 57 percent of patients with unexplained stroke.39 Intravenous injection of saline mixed with air greatly enhances the diagnosis of right-to-left shunts by transthoracic or transesophageal echocardiography by permitting visualization of microbubbles in the chambers of the left side of the heart that would otherwise be filtered by the lung capillaries.17 The sensitivities of traditional transthoracic echocardiography with agitated-saline contrast agent for right-to-left shunts40 and atrial septal aneurysm are at most half those of contrast-based transesophageal echocardiography,37 but recent refinements (for example, a contrast-based transmitral Doppler technique) have improved its diagnostic accuracy.17 Another alternative, contrast transcranial Doppler sonography, in which imaging of the middle cerebral arteries is used to detect right-to-left shunting of microbubbles, offers accuracy similar to that of transesophageal echocardiography.17 Its utility, however, is limited by its inability to assess interatrial septal morphologic features or other cardiac structures. Although transesophageal echocardiography is semi-invasive, it is associated with a low risk of serious complications (0.2 percent), which may include bronchospasm, hypoxia, arrhythmias, upper gastrointestinal trauma, or bleeding.41
Formal analyses of the optimal use of echocardiography in young patients with cryptogenic stroke are lacking. Nevertheless, the increased diagnostic yield of transesophageal echocardiography as compared with that of transthoracic echocardiography or transcranial Doppler sonography supports the use of the transesophageal technique in this population, pending further evidence regarding the benefits of treating specific lesions found on echocardiography.
Treatment
The available evidence on pharmacologic approaches (involving the use of antiplatelet or anticoagulant agents) and mechanical approaches to secondary prevention in patients with cryptogenic stroke who have patent foramen ovale is inadequate for assessment of their relative merits. To date, no study has randomly assigned patients with cryptogenic stroke and patent foramen ovale to different therapies. Studies thus far have been observational, with disparate definitions of the qualifying or recurrent cerebrovascular event, nonuniform criteria for interatrial septal abnormalities, absence of blinding during examination of echocardiograms or ascertainment of end points, and incomplete accounting of associated risk factors or the use of adjunctive therapies.
The risk of stroke recurrence in patients 60 years of age or younger who have unexplained cerebral ischemia and patent foramen ovale appears to be low, regardless of the therapy used. In a prospective study of 140 such patients treated medically or surgically at their physicians' discretion, the annual rate of stroke recurrence was 1.9 percent, and the type of treatment had no detectable influence.42 Similarly, a longitudinal study of 581 persons 55 years of age or younger who had cryptogenic stroke treated with aspirin found similarly low rates of recurrence at four years among those who had a patent foramen ovale (2.3 percent) and those who did not (4.2 percent).33 Patients who had both patent foramen ovale and atrial septal aneurysm, however, had a 15.2 percent rate of recurrence despite the use of aspirin therapy — a rate nearly fourfold that among patients who did not have either abnormality. Unlike prior investigations, this study found that a greater shunt magnitude was not associated with increased risk, but the study had limited power to assess the relative effects of foraminal size and atrial septal aneurysm.33
By contrast, in a randomized trial in which aspirin therapy and warfarin therapy were compared in older patients with stroke, the two-year rate of recurrent stroke or death in the subgroup with cryptogenic stroke was not significantly higher among those who had a patent foramen ovale and atrial septal aneurysm than among those with neither abnormality.38 However, the study was underpowered for this comparison, and patients without interatrial septal abnormalities had more risk factors20 for subclinical atherosclerotic disease than did those with those abnormalities. Post hoc analyses43 of data from this study indicated that there was no significant association between patent foramen ovale and the risk of recurrent stroke or death among patients younger than 65 years of age but an association was observed in older patients. These findings, however, are limited by the small numbers of events in each subgroup and by the performance of multiple comparisons that were not prespecified.
Medical Therapy
In a retrospective study of 90 patients younger than 60 years of age with cerebral ischemia, 52 of whom had patent foramen ovale, those receiving aspirin or no therapy had a rate of recurrence almost threefold that of patients treated with warfarin.44 (The numbers were too small to allow comparison between the group that received aspirin and the group that did not receive therapy.) The results are inconclusive, however, for several reasons: treatment assignments were at the discretion of the consulting neurologist; treatment crossover was frequent; and ascertainment of end points, which included multiple events, was not blinded. For similar reasons, it is impossible to draw firm conclusions from a meta-analysis that found that warfarin (as compared with antiplatelet therapy) lowered the risk of recurrence (odds ratio, 0.37; 95 percent confidence interval, 0.23 to 0.60) among patients with cerebral ischemia and patent foramen ovale.45 In a randomized trial, subgroup analysis of 98 patients with cryptogenic stroke and patent foramen ovale revealed a nonsignificant reduction in the two-year incidence of recurrent stroke or death with warfarin therapy as compared with aspirin therapy (9.5 percent vs. 17.9 percent; hazard ratio, 0.52; 95 percent confidence interval, 0.16 to 1.67), but the power of the analysis was limited.20 Although the incidence of major hemorrhage did not differ between warfarin and aspirin (1.78 vs. 1.91 events per 100 patient-years, P=1.0), warfarin did increase the rate of minor hemorrhage (22.9 vs. 8.66 events per 100 patient-years, P<0.001).20
Mechanical Closure
The traditional approach to foraminal closure involves open thoracotomy. Reported case series are small, but the rate of postoperative stroke ranges from 0 to 3.5 percent46 47,48 at two years. The mortality associated with closure of an uncomplicated atrial septal defect is less than 1.5 percent.49 Perioperative risks also include atrial fibrillation, pericardial sequelae, and the need for reexploration because of bleeding.46,47,48 Minimally invasive surgery50 is an alternative approach, but percutaneous-closure techniques hold greater appeal (Figure 3). A systematic review found that among 1355 patients undergoing percutaneous closure, the rate of recurrent stroke or transient ischemic attack was 0 to 4.9 percent at one year.51 Although these values appeared favorable next to one-year recurrence rates among 895 patients receiving medical therapy (3.8 to 12.0 percent),51 several considerations — the nonrandomized treatment assignment, differences in the clinical characteristics of the patients treated by the various techniques, and inconsistent criteria for ascertainment of outcomes — preclude meaningful comparison. Serious complications of percutaneous closure (major hemorrhage, cardiac tamponade, the need for surgery, pulmonary embolism, and death) were reported in 1.5 percent of the patients, and minor complications (arrhythmia, device fracture or embolization, air embolism, femoral hematoma, and fistula) in 7.9 percent.51
Figure 3. Percutaneous Closure of a Patent Foramen Ovale.
With use of a femoral approach, a transvenous sheath is advanced across the foramen into the left atrium, where a folded disk is expanded and pulled back, apposing the primum and secundum septa closed. This step is followed by deployment of a right-sided disk, at which time the two-disk device is released. Clopidogrel and aspirin are recommended for a period of three months to prevent thrombus formation on the device, with aspirin therapy continued for an additional three months, when endothelialization is complete. Antibiotic prophylaxis for six months is recommended. Complete late closure of the foramen has been reported in 80 to 95 percent of patients.
In one follow-up study of young patients with cryptogenic stroke and patent foramen ovale, surgical closure was performed if at least two of four purported "high-risk" features for paradoxical embolism (major shunt , atrial septal aneurysm, infarcts in multiple territories, and Valsalva-provoking activity preceding the onset of stroke42) were present. There were no recurrences after 23 months, but the study did not include a control group.46 A decision analysis modeling different therapeutic approaches in a 55-year-old patient with patent foramen ovale concluded that, for a yearly risk of stroke recurrence of 0.8 percent, surgical closure or warfarin were the best options.49 (Percutaneous closure was not considered.) Surgery became preferable when the annual risk of recurrence reached 1.4 percent. These conclusions, however, rest on the questionable assumptions that paradoxical embolism underlies the risk of stroke and that anticoagulation lowers the risk of recurrence to the same degree as it does in persons with venous thromboembolism or atrial fibrillation. Currently, the Food and Drug Administration allows the use of transcatheter-closure devices under a humanitarian device exemption only in cases of recurrence of stroke during therapeutic oral anticoagulation.52
Areas of Uncertainty
The pathogenesis of cryptogenic stroke in patients with interatrial septal abnormalities is not well understood. Features of the interatrial septum that best predict the risk of thromboembolism and the role of hypercoagulable disorders in determining risk also remain unclear. Data from ongoing randomized trials that evaluate warfarin, aspirin, or both as compared with transcatheter closure are needed. Pending completion of such studies, which have been hampered by slow recruitment,52 the relative safety and efficacy of these approaches remain uncertain.
Guidelines
Current guidelines from professional societies (Table 2) do not include specific recommendations regarding the optimal diagnostic strategy for transthoracic and transesophageal echocardiography.53 Moreover, they deem the available evidence insufficient to permit firm recommendations for the management of interatrial septal abnormalities.54,55
Table 2. Guidelines from Professional Societies.
Conclusions and Recommendations
In patients with cryptogenic stroke, assessment for patent foramen ovale and other potential cardiac sources of embolism is recommended; transesophageal echocardiography is more sensitive for detecting these abnormalities than is transthoracic echocardiography. Because the presumed pathophysiology of cryptogenic stroke in younger patients with patent foramen ovale is paradoxical embolism of fibrin-rich thrombus, and because observational data suggest a benefit with warfarin relative to aspirin, we would consider the use of warfarin anticoagulation for three to six months in patients such as the man described in the vignette. Available data are not sufficient for confirmation that this approach is preferable to aspirin therapy, however, and current guidelines do not specifically recommend one over the other.54,55 Appropriate investigation for deep-vein thrombosis and thrombophilia is essential. We recommend switching most patients' therapy to aspirin after they have received a course of warfarin. However, we favor long-term anticoagulation in patients with associated venous thromboembolism or selected hypercoagulable states and probably in patients with high-risk features (atrial septal aneurysm, major shunt, infarcts in multiple territories, or antecedent Valsalva-provoking activity).
Decisions must take into account coexisting conditions and the patients' preferences. Patients should be encouraged to participate in ongoing randomized trials comparing percutaneous closure and medical therapy. Otherwise, percutaneous closure is currently indicated in the United States only for patients with recurrence despite therapeutic anticoagulation. Surgical closure may be considered for high-risk patients when warfarin is contraindicated.
Supported in part by a Career Development Award (K23 HL070854, to Dr. Kizer) from the National Heart, Lung, and Blood Institute.
Source Information
From the Departments of Medicine (J.R.K., R.B.D.) and Public Health (J.R.K.), Weill Medical College of Cornell University, New York.
Address reprint requests to Dr. Kizer at Box 222, New York–Presbyterian Hospital, 525 E. 68th St., New York, NY 10021, or at jok2007@med.cornell.edu.
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