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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Morphology of perforated atrial septal aneurysm suitable for closure by transcatheter device placement. Heart 2000; 84:327. 29. Djaiani G, Phillips-Bute B, Podgoreanu M, et al. The association of patent foramen ovale and atrial fibrillation after coronary artery bypass graft surgery. Anesth Analg 2004; 98:585. 30. Ilercil A, Meisner JS, Vijayaraman P, et al. Clinical significance of fossa ovalis membrane aneurysm in adults with cardioembolic cerebral ischemia. Am J Cardiol 1997; 80:96. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 15/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 31. Hobbes B, Akseer S, Pikula A, et al. Risk of Perioperative Stroke in Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis. Can J Cardiol 2022; 38:1189. 32. Ng PY, Ng AK, Subramaniam B, et al. Association of Preoperatively Diagnosed Patent Foramen Ovale With Perioperative Ischemic Stroke. JAMA 2018; 319:452. 33. Rais G, Vassallo P, Schorer R, et al. Patent foramen ovale and perioperative stroke in noncardiac surgery: a systematic review and meta-analysis. Br J Anaesth 2022; 129:898. 34. Elgendy AY, Saver JL, Amin Z, et al. Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke. JAMA Neurol 2020; 77:878. 35. Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2:11. 36. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148. 37. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992; 117:461. 38. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. 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Bogousslavsky J, Garazi S, Jeanrenaud X, et al. Stroke recurrence in patients with patent foramen ovale: the Lausanne Study. Lausanne Stroke with Paradoxal Embolism Study Group. Neurology 1996; 46:1301. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 16/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 45. Pezzini A, Grassi M, Zotto ED, et al. Do common prothrombotic mutations influence the risk of cerebral ischaemia in patients with patent foramen ovale? Systematic review and meta- analysis. Thromb Haemost 2009; 101:813. 46. Kitsios GD, Lasker A, Singh J, Thaler DE. Recurrent stroke on imaging and presumed paradoxical embolism: a cross-sectional analysis. Neurology 2012; 78:993. 47. Schuchlenz HW, Weihs W, Horner S, Quehenberger F. The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events. 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Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study. Catheter Cardiovasc Interv 2008; 72:973. 53. Turc G, Lee JY, Brochet E, et al. Atrial Septal Aneurysm, Shunt Size, and Recurrent Stroke Risk in Patients With Patent Foramen Ovale. J Am Coll Cardiol 2020; 75:2312. 54. Serena J, Marti-F bregas J, Santamarina E, et al. Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. Stroke 2008; 39:3131. 55. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 56. Di Tullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol 2007; 49:797. 57. Petty GW, Khandheria BK, Meissner I, et al. 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Topic 1092 Version 30.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 18/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate GRAPHICS Risk of Paradoxical Embolism (RoPE) score RoPE score Characteristic Points No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 19/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal aneurysm or (2) a large-shunt PFO Possible Probable Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 20/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 21/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Naser M Ammash, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 22/22