7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults : Steven R Mess , MD, Naser M Ammash, MD : Scott E Kasner, MD, Heidi M Connolly, MD, FACC, FASE : John F Dashe, MD, PhD, Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 10, 2023. INTRODUCTION Stroke can be associated with abnormalities of the atrial septum, specifically patent foramen ovale (PFO), atrial septal defect (ASD), and atrial septal aneurysm (ASA). The relationship between PFO, ASD, or ASA and ischemic neurologic complications will be reviewed here. Treatment is reviewed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) PFO AND ASD The foramen ovale and its flap-like valve between the right and left atrium are important components of the fetal circulation. In the developing fetus, oxygenated blood from the umbilical vein enters the right atrium via the inferior vena cava and is shunted into the left atrium, circumventing the noninflated lungs. After birth, a relative increase in left atrial pressure closes the flap, and adhesions frequently result in a structurally intact atrial septum. However, in approximately 25 percent of adults, the foramen ovale remains patent and acts as a potential interatrial shunt ( movie 1 and movie 2). (See "Patent foramen ovale".) Less commonly, an open communication called an ASD persists between the atria after septation. The majority of these are secundum ASD defects caused by deficiency in the septum https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 1/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate primum. This may be visualized on transthoracic ( movie 3 and movie 4) or transesophageal echocardiography ( movie 5). The pathophysiology and clinical features of PFOs and ASDs are discussed in detail separately. (See "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Embryology and classification'.) SOURCES OF EMBOLI Some patients with ischemic stroke and no other evident source cause for stroke have a PFO, ASD, or an ASA that can be identified by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). Alternatively, a right-to-left shunt (RLS; most of which are caused by PFO) can be identified by contrast-enhanced transcranial Doppler (TCD). (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) These structures have been implicated in the pathogenesis of embolic events, primarily by causing paradoxical embolization from the systemic venous circulation. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other, more common, sources or conduits of embolism may also be present. Paradoxical emboli A paradoxical embolus originates in the systemic venous circulation and enters the systemic arterial circulation through a PFO, ASD, ventricular septal defect, or extracardiac communication such as a pulmonary arteriovenous malformation [1-6]. Paradoxical embolism is a potential cause of embolic stroke of undetermined source (ESUS), which is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic source. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) Case reports have described patients with an "impending" paradoxical embolus due to a trapped embolus in a PFO [7-9]. Increased risk of decompression sickness complicating SCUBA diving in individuals at risk for paradoxical emboli (including those with PFO or ASD) is discussed separately. (See "Complications of SCUBA diving", section on 'Right-to-left shunt'.) Right-sided sources Thromboemboli can originate from lower extremity or pelvic veins, right-sided valve (tricuspid) vegetations, a papillary fibroelastoma or other cardiac tumor, an https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 2/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ASA, or thrombi (in transit or in situ) within the PFO [10,11]. Air emboli can arise from intravenous lines. Fat emboli can complicate trauma or orthopedic procedures. Thromboembolism from a right-sided source can result in concurrent pulmonary embolism and stroke. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Early'.) Transvenous cardiac device (pacemaker or defibrillator) leads, which are most commonly placed in right-sided heart chambers, are another potential nidus for the formation of mobile thrombi that can be a source of pulmonary emboli [12] or, via paradoxical embolization, can result in cerebral or other systemic emboli [13,14]. Small mobile thrombi are frequently observed by echocardiography attached to the right atrial segments of these leads. Although data are limited, a retrospective study of patients with transvenous cardiac device leads in the right atrium or right ventricle found that the presence of PFO was associated with a significantly increased risk of cardioembolic stroke [15]. Further data are needed to confirm this finding and determine how this compares with the risk of cardioembolic stroke in patients with PFO who do not have intracardiac device leads. Right-to-left shunting Right-to-left shunting through a PFO or an ASD can result in a paradoxical embolus (see 'Paradoxical emboli' above). Since a transient right-to-left atrial pressure gradient is sufficient to induce right-to-left shunting across a PFO (or ASD), such shunts commonly occur in individuals with no significant net right- to-left shunting between the atria (ie, those with no net intracardiac shunt or with a net left-to- right shunt). Chronic elevation in right heart pressures (eg, Eisenmenger syndrome) is not required for paradoxical embolism to occur. Transient right-to-left shunting across a PFO is a dynamic phenomenon given the significant variability of both right and left atrial pressures. Transient increases in right atrial pressure occur in normal individuals during early ventricular systole ( movie 1 and movie 2), during the Valsalva maneuver, and with repetitive cough [16]. In addition, a persistent, large Eustachian valve or a Chiari network may direct inferior vena caval blood toward the atrial septum where a PFO or ASD is located and potentially into the left atrium and systemic circulation. (See "Patent foramen ovale", section on 'Eustachian valve and Chiari network'.) With the Valsalva maneuver, transient right-to-left shunting in patients with a PFO or an ASD can be induced particularly during Valsalva release. During the straining phase, the right atrial pressure rises disproportionately, and during release there is a sudden increase in systemic venous return into the right atrium. Physiologic conditions associated with a Valsalva maneuver include straining to defecate, lifting or pushing heavy objects, and vigorous repetitive cough. In https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 3/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate one series of 148 patients with a PFO, 84 (57 percent) had right-to-left shunting at rest, and 136 (92 percent) had right-to-left shunting with straining or coughing [17]. (See "Contrast echocardiography: Clinical applications", section on 'Shunt detection' and "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Agitated saline contrast'.) An uncommon consequence of intermittent right-to-left shunting is the platypnea-orthodeoxia syndrome [5]. This disorder is defined as an orthostatic right-to-left shunt across an ASD or PFO resulting in decreases in oxygen saturation when changing position from prone to upright, leading to significant positional dyspnea. (See "Patent foramen ovale", section on 'Platypnea- orthodeoxia syndrome'.) ASA An ASA is defined as redundant and mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm during the cardiorespiratory cycle. ASAs have been classified according to their oscillation (intrusion) into the left or right atrium and according to their motion during the respiratory cycle [18]. Most investigators have defined an ASA as an excursion of at least 10 or 15 mm. The aneurysm may either bulge persistently into the right or left atrium or exhibit striking oscillations from right atrium to left atrium during respiration, in response to fluctuating pressure gradients between the atria [18-20]. ASA is most commonly an incidental finding. However, some patients with ASA present with systemic thromboembolism and some present with symptoms and signs of significant intracardiac shunting via one or more associated ASDs. (See "Clinical manifestations and diagnosis of atrial septal defects in adults".) The diagnosis of ASA can sometimes be established by TTE7 ( movie 6), but TEE is more sensitive since the interatrial septum is visualized more consistently ( movie 7). In the review of 195 cases cited above, 47 percent were missed with TTE [21]. The prevalence of ASA varies with the method of identification and the population studied. ASAs have been found in 1 percent of necropsies [22] and 0.2 to 2 percent of patients undergoing TTE [23,24]. With TEE, ASAs were detected in 2.2 percent of population controls [25], 4 percent of patients referred for TEE for a reason other than detection of a source of embolic stroke [18], and 4.9 percent of patients undergoing cardiac surgery [26]. There is an increased prevalence of ASAs among patients with cerebral ischemic events [18,25,27]. As an example, ASA was observed in 7.9 to 15 percent of patients with a possible embolic stroke [18,25] and 28 percent of those with a cerebral ischemic event and normal carotid arteries [27]. Two mechanisms have been proposed to explain the association between ASA and cryptogenic stroke. Since ASA is commonly associated with PFO and ASD, paradoxical https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 4/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate embolism may occur via the septal defect. In patients with ASA without an intracardiac shunt, it has been hypothesized that fibrin-platelet particles adhere to the left atrial side of the aneurysm and are dislodged by oscillations of the aneurysm, causing systemic embolism. An intracardiac shunt has been reported in up to 78 percent of patients with an ASA [18- 21,25,27]. Most patients (54 to 84 percent) with cerebral ischemic events and an ASA also have an interatrial shunt, usually via a PFO [3,21,25,27]. In a multicenter review of 195 cases in which ASA was detected by TEE, ASA was the only defect in 32 percent and was associated with an interatrial shunt in 54 percent, most often a PFO (33 percent) or ASD (19 percent) [21]. Some ASAs are associated with multiple atrial septal fenestrations (perforations) [28]. Left-sided sources A common source of cerebral emboli originating in the systemic arterial circulation in patients with atrial septal abnormalities is the left atrium (particularly left atrial appendage), especially in those with atrial fibrillation. Patients with a hemodynamically significant ASD causing volume overload of the atria and right ventricle are at risk for atrial fibrillation, especially after age 50 years. Although evidence is more limited, patients with PFO or ASA may also be predisposed to atrial fibrillation [23,29]. However, whereas ASD can cause volume overload of the right heart chambers, an isolated PFO is not associated with volume overload of any cardiac chamber. Other potential sources of emboli are left-sided tumors, such as atrial myxoma and papillary fibroelastoma, left-sided prosthetic valve thrombosis, and vegetations caused by infective endocarditis or other disorders. (See "Complications and outcome of infective endocarditis", section on 'Metastatic infection'.) RISK OF EMBOLIC STROKE Approximately 25 to 40 percent of ischemic strokes are cryptogenic, including embolic stroke of undetermined source (ESUS; defined as a brain infarct without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous with embolism a dominant etiology. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) There is an increased prevalence of PFO and ASA in patients who have an embolic-appearing ischemic stroke and no other evident source of stroke, suggesting that paradoxical embolism and/or other mechanisms related to PFO and ASA are the cause of some ischemic strokes. However, the detection of an atrial septal abnormality in a patient with an embolic stroke does not prove a cause-and-effect relationship given how common they are in the general population and the likelihood of other potential source when properly investigated. As an example, in a https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 5/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate report of 134 patients with cerebral embolic events, an ASA was found in 45, but 41 of these 45 patients had other potential sources for embolization [30]. PFO may be a risk factor for perioperative stroke, but the quality of the evidence is low [31]. One study found that a preoperative diagnosis of PFO was associated with an increased risk of perioperative ischemic stroke within 30 days after noncardiac surgery [32], and meta-analyses of observational studies have also found an association of PFO with an increased risk of stroke at 30 days after noncardiac surgery [31,33]. The strength of these findings is limited by the largely retrospective nature of the data, since patients with prior cardiac disease, including coronary artery disease and atrial fibrillation, were more likely to have a PFO identified. Nevertheless, patients, especially those 60 years of age, with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke despite a comprehensive evaluation are now recognized as most likely having a PFO-associated stroke [34]. Data on the risk of stroke in patients with PFO and pulmonary embolism is discussed separately. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Early'.) Prevalence of PFO in cryptogenic stroke A number of case-control and population-based studies have reported an increased prevalence of PFO and/or ASA in patients who have had a cryptogenic stroke [18,19,21,25,35-39]. A 2007 prospective case-control study examined 503 consecutive patients with ischemic stroke using transesophageal echocardiography (TEE), and compared 227 patients who had cryptogenic stroke (classified before TEE was performed) with 276 control patients who had stroke of known cause [38]. The prevalence of PFO was significantly higher among those with cryptogenic stroke compared with those with known cause of stroke in both the younger (<55 years of age; 43.9 versus 14.3 percent) and older ( 55 years of age; 28.3 versus 11.9 percent) groups. In multivariate analysis, the presence of a PFO was independently associated with cryptogenic stroke in both the younger (odds ratio [OR] 3.7, 95% CI 1.42-9.65) and older age groups (OR 3.0, 95% CI 1.73-5.23). Similarly, a 2018 prospective population-based study found that the prevalence of right-to-left shunt (RLS, which is known to be caused mainly by PFO) identified by contrast-enhanced transcranial Doppler (TCD) was significantly higher among patients with cryptogenic events (transient ischemic attack [TIA] or ischemic stroke) compared with those who had a known cause of stroke, both in the overall population (OR 1.93, 95% CI 1.32-2.82) and in those >60 years of age (OR 2.06, 95% CI 1.32-3.23) [39]. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 6/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate In a meta-analysis that included 9 studies (including both of the above prospective studies) of PFO prevalence (as assessed by TEE, transthoracic echocardiography [TTE], or TCD), a significant association between PFO and cryptogenic events was identified for all three screening modalities [39]. A significant association between PFO and cryptogenic events was also identified among older patients (patients greater than 40 to 60 years old in various studies) for each of the three screening modalities, although the results of the TEE studies were heterogeneous. Even in a patient with a cryptogenic stroke, the presence of an atrial septal abnormality does not establish the stroke etiology. A 2009 meta-analysis of case-control studies evaluating the prevalence of PFO in patients with cryptogenic stroke suggested that approximately one-third of PFOs detected in such patients are incidental findings [40]. In a 2021 meta-analysis of individual patient data from six randomized controlled trials of PFO closure for patients with PFO- associated stroke, the risk reduction for recurrent stroke with PFO closure varied among subgroups with different probabilities that the stroke was causally related to the PFO, as determined by the Risk of Paradoxical Embolism (RoPE) score ( table 1A) and a modified PFO- associated stroke causal likelihood (PASCAL) classification ( table 2) [41]. The RoPE score and PASCAL classification are discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) Risk factors In patients with PFO, some retrospective analyses have suggested that certain factors may increase the likelihood of initial and recurrent stroke [42]. These include a history of Valsalva maneuver (eg, straining) preceding the cerebral embolic event, a history of multiple strokes in different vascular distributions, and possibly a transient or chronic hypercoagulable state [17,43-45]. By contrast, one study found that these factors were not associated with radiologic markers of stroke recurrence [46]. The association of an ASD with cerebral embolic events has been less well studied [4,21]. In one series of 103 patients (mean age 52 years) with a presumed paradoxical embolism and an atrial septal abnormality undergoing percutaneous closure, a PFO alone was present in 81, an ASD alone in 12, and both a PFO and ASD in 10 [4]. PFO characteristics PFO characteristics possibly associated with an increased risk of recurrent stroke include large PFO, large right-to-left shunt, spontaneous right-to-left shunt, greater PFO flap mobility, prominent Eustachian valve or Chiari network, and the presence of an ASA [41,42,47-53]. However, characteristics such as concurrent ASA or shunt size were not associated with increased recurrent stroke risk in some studies [54-57]. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 7/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate An analysis of individual patient data on 898 patients with recent PFO-associated stroke from two prospective observational studies and the medical arms of two randomized trials (CLOSE and DEFENSE-PFO) assessed risk factors for recurrent stroke with medical therapy [53]. During a median follow-up of 3.8 years, 47 patients (5 percent) experienced a recurrent stroke. In a multivariate model incorporating age, hypertension, antithrombotic therapy and PFO anatomy, presence of an ASA was associated with recurrent stroke (adjusted HR 3.27; 95% CI 1.82-5.86), whereas large PFO was not (adjusted HR 1.43; 95% CI 0.50-4.03). Prospective studies Prospective observational and therapeutic studies of the risk of cryptogenic stroke with PFO and ASA have yielded variable results [3,26,38,49,54,55,58]. However, there is good evidence that PFO as a sole risk factor for stroke is associated with a low risk of recurrent stroke. The Risk of Paradoxical Embolism (RoPE) study performed a patient level meta-analysis of 12 cryptogenic stroke cohorts [59,60]. The following observations were noted: Among 3023 patients with cryptogenic stroke, the prevalence of PFO, and the likelihood that PFO was the cause of the stroke (the PFO-attributable fraction), correlated with the absence of vascular risk factors (ie, hypertension, diabetes, smoking, prior stroke or TIA, older age) and the presence of a cortical (as opposed to subcortical) cryptogenic infarct on imaging [59]. Using multivariate modeling, the investigators devised the RoPE score [( table 1A) and (calculator 1)], which estimates the probability that a PFO is incidental or pathogenic in a patient with cryptogenic stroke [59]. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic PFOs, while low RoPE scores, as found in older patients with vascular risk factors, suggest incidental PFOs. For each RoPE score stratum, the corresponding PFO prevalence was used to estimate the PFO-attributable fraction ( table 1B) (ie, the probability that the index event was related to the PFO). Patients with the highest PFO-attributable fraction (ie, those whose PFO was most likely to have caused the cryptogenic stroke) were at the lowest risk for stroke recurrence. As an example, a patient less than 30 years of age with none of the vascular risk factors noted above had a PFO-attributable fraction of 88 percent and an estimated two-year stroke recurrence rate of 1 percent (95% CI 0-2 percent), while a patient 70 years of age or older with all of the vascular risk factors noted above had a PFO-attributable fraction of 0 percent and an estimated two-year stroke recurrence rate of 16 percent (95% CI 9- 24 percent). https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 8/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate In a subsequent analysis, stroke recurrence was associated with the following three variables only in the high RoPE score group: a history of stroke or TIA (hazard ratio [HR] 3.79, 95% CI 1.43-10.09), a hypermobile interatrial septum (HR 2.31, 95% CI 1.05-5.05), and a small shunt (HR 3.26, 95% CI 1.59-6.67) [60]. In a meta-analysis of 14 prospective studies reporting recurrent cerebrovascular events in 4241 medically treated patients, patients with a PFO had no increased risk of recurrent cryptogenic stroke compared with those without a PFO (annual rate 2.0 versus 2.4 percent, risk ratio 0.85, 95% CI 0.59-1.22) [61]. Furthermore, PFO size was not associated with the risk of recurrent stroke or TIA. Among several of the cryptogenic stroke cohorts included in the RoPE analysis cited above, the presence of PFO together with an ASA was a significant predictor of an increased risk of recurrent stroke, but this was not the case in PICSS, the German Stroke Study, or CODICIA studies [54,55,62]. Population-based studies Two prospective population-based cohort studies [56,63] and one population-based case-control study [57] suggest that PFO and large PFO are not independent risk factors for ischemic stroke in patients without prior stroke. These results could be due to study populations composed largely of older adults and therefore a low average RoPE score (ie, a low PFO-attributable fraction of stroke). In the NOMAS study of 1100 stroke-free subjects 40 years of age or older (mean age 69 years), PFO was not associated with a statistically significant increase in stroke risk (HR 1.64, 95% CI 0.87-3.09), nor was the coexistence of PFO and ASA (HR 1.25, 95% CI 0.17-9.24) or the presence of an isolated ASA (HR 3.66, 95% CI 0.88-15.3), although the confidence intervals for these HRs do not exclude clinically important associations [56]. In the SPARC study of 585 randomly sampled subjects 45 years of age or older, PFO was not a significant independent predictor of cerebrovascular events after adjustment for age and comorbid conditions (HR 1.46; 95% CI 0.74-2.88) [63]. Furthermore, there was no association of large PFO size with risk of cerebrovascular events. ASA was associated with a nearly fourfold increase in the risk of cerebrovascular events, but this risk did not achieve statistical significance (HR 3.72; 95% CI 0.88-15.71), possibly because ASA was present in only 11 subjects, of whom only two had cerebrovascular events. In a population-based, case-control study, PFO and large PFO were not independent risk factors for cryptogenic stroke in the entire study population, which was generally older than age 65 [57]. The small number of patients younger than age 55 led to wide confidence intervals in the analysis of that subgroup, and the study does not refute the contention https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 9/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate that PFO is associated with an increased ischemic stroke risk in children or young adults [64]. Conclusions The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Prevalence of PFO in cryptogenic stroke' above and 'Prospective studies' above and 'Population-based studies' above): Multiple case-control trials have reported an increased prevalence of PFO in younger patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors. Differences in the PFO-attributable fraction of stroke likely explain, at least in part, the discrepant findings of the case-control and population-based studies. Subjects with cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. Additionally, it is possible that patients with PFO-associated stroke have other risk factors that may predispose to paradoxical embolism, such as a hypercoagulable condition [65]. For patients with cryptogenic stroke and PFO, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably risk factors for recurrent PFO-associated stroke. DIAGNOSIS The diagnosis of ischemic stroke or transient ischemic attack (TIA) due to paradoxical embolism through a PFO (ie, a PFO-associated stroke) or ASD is usually one of exclusion. A PFO or ASD should be considered as a potential cause of embolic stroke or TIA in patients with no other identifiable cause, particularly in younger patients (eg, 60 years of age). When evaluating whether an ischemic stroke is related to PFO or to another mechanism, the assessment should look for features that increase the probability that a PFO is the cause of the https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 10/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate stroke. These include [34]: Factors that increase right-to-left shunt flow (eg, large PFO size, chronic right atrial hypertension, or a Valsalva maneuver) Presence of embolic stroke Presence of associated ASA Risk for current or prior venous thrombosis Absence of atherosclerotic risk factors or other likely causes of ischemic stroke, including atrial fibrillation The diagnostic evaluation and treatment of PFO-associated stroke is discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) TREATMENT Therapeutic options for secondary prevention of PFO-associated stroke include medical therapy with antithrombotic agents or percutaneous closure of the defect. These options are discussed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) No specific treatment is needed for incidentally discovered PFO, small ASD and/or ASA in asymptomatic patients. The available evidence from population-based studies suggests that PFO and large PFO are not independent risk factors for ischemic stroke in otherwise asymptomatic individuals. However, given the potential risk of paradoxical embolism in patients with PFO or small ASD, it is reasonable to educate the patient on how to prevent deep venous thrombosis by avoiding prolonged period of immobilization and dehydration. (See 'Population-based studies' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 11/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY Embolic sources Emboli leading to stroke or to transient ischemic attack (TIA) can originate in either the systemic venous circulation (paradoxical emboli) or in the systemic arterial circulation. Some patients with an embolic-appearing ischemic stroke and no other evident source of stroke have a patent foramen ovale (PFO), an atrial septal defect (ASD), and/or an atrial septal aneurysm (ASA) that can be best identified by transesophageal echocardiography (TEE). These structures have been implicated in the pathogenesis of embolic events. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other sources or conduits of embolism may also be present. (See 'Sources of emboli' above.) Cryptogenic stroke Approximately 25 to 40 percent of ischemic strokes are cryptogenic (ie, without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous, with embolism a dominant etiology. (See 'Risk of embolic stroke' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) Risk of stroke from a PFO The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Conclusions' above): Multiple case-control trials have reported an increased prevalence of PFO in patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 12/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors, as shown in the table ( table 1A-B) and calculator (calculator 1) for the RoPE score. Differences in the PFO-attributable fraction of stroke probably explain the discrepant findings of the case-control and population-based studies. Subjects with an embolic-appearing cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. For patients with cryptogenic stroke, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably a risk factors for recurrent PFO-associated stroke. PFO-associated stroke Patients with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke or other risk factors for stroke despite a comprehensive evaluation are now recognized as having a PFO- associated stroke. Select patients with PFO-associated stroke may benefit from PFO closure. (See 'Risk of embolic stroke' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management".) ACKNOWLEDGMENTS The editorial staff at UpToDate, Inc. acknowledge Joseph K Perloff, MD (deceased), Thomas Graham Jr, MD and Robert S Schwartz, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Cardiogenic brain embolism. Cerebral Embolism Task Force. Arch Neurol 1986; 43:71. 2. CORRIN B. PARADOXICAL EMBOLISM. Br Heart J 1964; 26:549. 3. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. 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