Patent Foramen Ovale Management for Secondary Stroke Prevention: State-of-the-Art Appraisal of Current Evidence.

Patent foramen ovale (PFO) is frequently identified in young patients with ischemic stroke. Randomized controlled trials provide robust evidence supporting PFO closure in selected patients with cryptogenic ischemic stroke; however, several questions remain unanswered. This report summarizes current knowledge on the epidemiology of PFO-associated stroke, the role of PFO as a cause of stroke, and anatomic high-risk features. We also comment on breakthrough developments in patient selection algorithms for PFO closure in relation to the PFO-associated stroke causal likelihood risk stratification system. We further highlight areas for future research in PFO-associated stroke including the efficacy and safety of PFO closure in the elderly population, incidence, and long-term consequences of atrial fibrillation post-PFO closure, generalizability of the results of clinical trials in the real world, and the need for assessing the effect of neurocardiology teams on adherence to international recommendations. Other important knowledge gaps such as sex, race/ethnicity, and regional disparities in access to diagnostic technologies, PFO closure devices, and clinical outcomes in the real world are also discussed as priority research topics.

Study design and rationale of COMPETE: Comparison of the effect of medication therapy in alleviating migraine with patent foramen ovale.

BACKGROUND: Previous studies have examined the impact of antithrombotic agents on Patent Foramen Ovale (PFO) in relation to migraine. However, differences in effectiveness of different antithrombotic agents and traditional migraine medications are not known. METHODS/DESIGN: This study is an investigator-initiated, randomized, multicenter, single-masked (outcomes assessor), and active-controlled parallel-group trial (ClinicalTrials.gov Identifier: NCT05546320), with the objective of evaluating the prevention efficacy of antithrombotic agents compared to first-line migraine medication in PFO patients. The trial involves 1,000 migraine patients with a right-to-left shunt at the atrial level, randomized in a 1:1:1:1 fashion to receive either aspirin 300 mg QD, clopidogrel 75 mg QD, rivaroxaban 20 mg QD, or the active-control metoprolol 25 mg BID. The primary efficacy end point is the response rate, defined as a 50% or greater reduction in the average migraine attack days per month or in the average number of migraine attacks per month at 12-week visit compared to baseline. CONCLUSIONS: The COMPETE trial aims to provide valuable insights into the comparative effectiveness of antithrombotic agents and standard migraine therapies in patients with PFO. This study holds the promise of advancing treatment approaches for individuals having migraines associated with PFO, thus addressing an important gap in current migraine management strategies.

Left atrial appendage occlusion and patent foramen ovale closure using a steerable sheath and intracardiac echocardiography.

A patient presenting with acute ischemic stroke associated with patent foramen ovale (PFO) had concurrent deep vein thrombosis, pulmonary embolism, and new-onset atrial fibrillation. Upon initiation of anticoagulation therapy, the patient developed hemorrhagic transformation of the stroke. The patient's multiple potential sources of embolic stroke were treated with concomitant left atrial appendage occlusion and PFO closure through the PFO, made possible by using the Steerable Amulet Sheath under 3D-intracardiac echocardiography guidance.

Headache patterns in patent foramen ovale patients: beyond migraine with aura.

Patent foramen ovale (PFO) is a common cardiac anomaly linked with cryptogenic strokes and migraine, particularly migraine with aura. This study aims to explore the spectrum of headache disorders in PFO patients, focusing on identifying patterns beyond the well-established migraine-PFO connection. A retrospective observational study was conducted on patients diagnosed with PFO. Headache types were classified using the International Classification of Headache Disorders, 3rd edition. The study analyzed headache prevalence and patterns in PFO patients, comparing those with and without a history of stroke. Of 177 participants, 63 (35.59%) reported headaches. Tension-type headache was the most common (15.25%), followed by migraine without aura (11.30%) and migraine with aura (8.47%). Notably, migraine without aura was more prevalent than migraine with aura, contrasting previous assumptions. No significant differences were found in headache types based on stroke history. The study reveals a diverse spectrum of headache types in PFO patients, with migraine without aura being more common than migraine with aura. These findings suggest a need for broader diagnostic perspective and individualized treatment approaches in PFO patients with headaches.

Undiagnosed major risk factors in acute ischaemic stroke patients: frequency, profile, stroke mechanisms and outcome.

BACKGROUND AND PURPOSE: There is scarce clinical information about the clinical profile of patients with acute ischaemic stroke with previously undiagnosed major vascular risk factors (UMRFs). METHODS: This was a retrospective analysis of data from the Acute Stroke Registry and Analysis of Lausanne registry between 2003 and 2018 with univariate and multivariate logistic regression analyses comparing clinical profiles of patients with UMRFs to patients with at least one previously diagnosed MRF (DMRF). RESULTS: In all, 4354 patients (median age 70 years [interquartile range 15.2], 44.7% female) were included after excluding 763 (14.9%) for lack of consent and three for missing information. Amongst 1125 (25.8%) UMRF patients, 69.7% (n = 784) had at least one newly diagnosed MRF and the others none. The newly detected MRFs were dyslipidaemia (61.4%), hypertension (23.7%), atrial fibrillation (10.2%), diabetes mellitus (5.2%), ejection fraction <35% (2.0%) and coronary disease (1.0%). Comparing UMRF patients to DMRF patients, multivariate analysis showed a positive association with lower age, non-Caucasian ethnicity, contraceptive use (<55 years old), smoking (≥55 years old) and patent-foramen-ovale-related stroke mechanism. A negative association was found with pre-stroke antiplatelet use and higher body mass index. Functional outcome did not differ. Cerebrovascular recurrences were similar between groups. CONCLUSIONS: In this large single-centre cohort, 69.7% of patients with acute ischaemic stroke and UMRF were newly diagnosed with at least one new MRF, the most common being dyslipidaemia, hypertension or atrial fibrillation. Patients of the UMRF group were younger, more often smokers and on contraceptives, and had more patent-foramen-ovale-related strokes.

Calcitonin gene-related peptide: a possible biomarker in migraine patients with patent foramen ovale.

BACKGROUND: Serum CGRP has been found to increase during migraine attack. However, whether CGRP can identify MA with PFO subtypes in MA remains unknown. This study aimed to investigate the differential expression of calcitonin gene-related peptide (CGRP) between migraine (MA) patients with and without patent foramen ovale (PFO), and to evaluate the predictive value of CGRP for MA with PFO. METHODS: A total of 153 patients with MA, 51 patients with PFO and 102 patients without. Venous blood was drawn and HIT-6 score was calculated during the onset of MA, and blood routine, inflammatory indexes and serum CGRP were detected. The differences in serum markers and HIT-6 scores were compared between the two groups, and the risk factors of MA with PFO were determined by univariate and multivariate logistics regression. Furthermore, the correlation between CGRP level with right-to-left shunt (RLS) grades and headache impact test-6 (HIT-6) score in MA patients with PFO were assessed. Independent risk factors were screened out by multivariate Logistic regression analysis. We used the receiver operating characteristic (ROC) curve to analyze the diagnostic value of these risk factors in MA complicated with PFO. RESULTS: The serum CGRP level and HIT-6 scores in the MA with PFO group were significantly higher than those in the MA group (P < 0.001). Multivariate regression analysis showed that CGRP was an independent risk factor for MA with PFO (OR = 1.698, 95% CI = 1.325-2.179, P < 0.001). CGRP values ​​increased with the increase of RLS grade(Spearmen rho = 0.703, P < 0.001). Furthermore, a positive correlation between CGRP and HIT-6 scores was found (Spearmen rho = 0.227; P = 0.016). ROC curve showed that the optimal cut-off value for diagnosing MA with PFO was 79 pg/mL, the area under the curve (AUC) for predicting MA with PFO was 0.845, with 72.55% sensitivity and 78.43% specificity. CONCLUSIONS: MA patients with PFO have higher serum CGRP level. elevated CGRP concentration was associated with higher RLS grade and increased HIT-6 score. Higher serum CGRP level has certain clinical value in predicting PFO in MA patients. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine (Ethics batch number: 20,201,215,005).

Paradoxical Embolic Stroke Following Percutaneous Transluminal Angioplasty in a Hemodialysis Patient.

Paradoxical embolism is a medical condition characterized by the migration of an embolus from a venous source into the systemic circulation. This occurs through a specific cardiac abnormality known as a right-to-left shunt, ultimately resulting in the possibility of arterial embolism. Patent foramen ovale (PFO) is the most common cause of intracardiac shunting. We reported a rare case of a 56-year-old man on hemodialysis with PFO and arteriovenous fistula dysfunction who suffered a paradoxical embolic ischemic stroke after percutaneous transluminal angioplasty. This case emphasized the potential risk of paradoxical embolism in hemodialysis patients with vascular access problems. We aimed to highlight the importance of searching for PFO, as it may serve as a possible source of embolism in these patients.

Rationale and design of the SPRING trail: effectivity and safety of Pfo closuRe vs medIcine in alleviatiNg migraine, a multicenter, randomized and open-label trail.

BACKGROUND: Migraine is a leading cause of disability worldwide. Several retrospective studies have suggested that the closure of the Patent Foramen Ovale (PFO) may provide relief from migraines. However, three randomized controlled trials did not meet their primary endpoints regarding migraine cessation, reduction in monthly migraine days, and responder rates. METHODS: The SPRING study is a multicenter, prospective, randomized, and open-label trial designed to compare the effectiveness and safety of PFO closure versus medication in the relief of migraines. The primary endpoint is the total cessation of migraines, as recorded in patient headache diaries during the follow-up period. Additional diagnostic tools include echocardiography with agitated saline contrast, transcranial Doppler, and routine laboratory measurements. CONCLUSION: The SPRING trial aims to assess the effectiveness and safety of PFO closure versus medication in mitigating migraines in real-world settings. (Clinical Trails ID: NCT04946734).

Left atrial appendage closure in a patient previously implanted with an interatrial shunt device: a case report.

Patients with previous interatrial shunt device (IASD) implantation may face greater challenges during future left atrial interventional procedures. Herein, we report the first case of left atrial appendage closure (LAAC) in a patient with previous IASD implantation. The patient successfully underwent LAAC using the LAmbre device without complications.

Patent foramen ovale closure in ischemic stroke patients with and without thrombophilia: a systematic review and meta-analyses.

Ischemic stroke patients with thrombophilia and patient foramen ovale (PFO) may have an increased risk of recurrent stroke and transient ischemic attack (TIA), and may benefit from PFO closure. However, screening for thrombophilia is not routinely performed and the impact of thrombophilia on prognosis after PFO closure is uncertain. We aim to compare the risk of recurrent stroke and TIA after PFO closure in patients with thrombophilia versus those without. We performed a systematic review and meta-analyses of the literature, with a comprehensive literature search performed on 12 January 2023. Studies comparing the outcomes of patients with and without thrombophilia after PFO closure were included. The primary outcome evaluated was a recurrence of acute cerebrovascular event (ACE), a composite of recurrent ischemic stroke and recurrent TIA. The secondary outcomes included recurrent ischemic stroke only or TIA only. A total of 8 cohort studies were included, with a total of 3514 patients. There was an increased risk of stroke/TIA in patients with thrombophilia compared to those without thrombophilia after PFO (OR: 1.42, 95% CI: 1.01-1.99, I2 = 50%). The association between risk of TIA only (OR: 1.36, 95% CI: 0.77-2.41, I2 = 0%) and stroke only (OR: 1.09, 95% CI: 0.54-2.21, I2 = 0%) with thrombophilia did not reach statistical significance. There is an increased risk of recurrent cerebral ischemia event in patients with thrombophilia compared to those without thrombophilia after PFO closure. Future large prospective studies are necessary to characterise the risk and benefits of PFO closure, as well as the appropriate medical treatment to reduce the risk of recurrent stroke and TIA in this high-risk population.

Recurrent stroke in a reproductive age women with patent foramen ovale.

BACKGROUND: Patent foramen ovale (PFO) is a known cause of ischemic stroke in young adults and combined oral contraceptives (COCs) are widely used by women of reproductive age. If young women with PFO are taking COCs, they may be subjected to a synergistic increase in the occurrence of stroke, though reports of ischemic stroke in this population are rare. We report a woman of reproductive age who was taking COC suffered repetitive ischemic strokes before a patent foramen ovale (PFO) was detected and closed, which may raise concerns in this field. CASE PRESENTATION: A 31-year-old woman presented to the emergency department with sudden-onset right upper- and lower-limb weakness and dysarthria for 1 hour, whose only risk factor of stroke was oral contraceptive use. On admission, she was alert with left gaze deviation, dysarthria, and right-sided hemiplegia. Her symptoms improved after receiving the revascularization therapy. About 24 hours later, her left eye experienced sudden painless vision loss. Then the PFO with a substantial right-to-left shunt was detected and then she received a trans-catheter closure of the defect. Over 3 months of follow-up, there were no signs of stroke, but visual loss persisted. CONCLUSION: This case of disabling stroke raises concerns regarding optimal management in primary and secondary prevention of stroke in young women on COCs with additional risk factors of stroke.

The paradox of platypnoea-orthodeoxia syndrome.

Platypnoea-orthodeoxia is a rare clinical syndrome characterised by dyspnoea and oxygen desaturation in the upright position which improves when supine. It requires two components: a sufficiently sized anatomical vascular defect (typically intra-cardiac or intra-pulmonary) combined with a functional component that promotes positional right-to-left shunting. We describe the rare occurrence of a patient with platypnoea-orthodeoxia syndrome (POS) because of a paradoxical shunt through a patent foramen ovale caused by a large right atrial line-associated thrombus in a male with metastatic oesophageal cancer undergoing chemotherapy. This case is a timely reminder to consider POS amongst differentials for hypoxia as it is often treatable if recognised.

Pediatric frequent relapsing nephrotic syndrome with multiple cerebral infarctions accompanied by patent foramen ovale and cerebral venous sinus thrombosis: a case report.

BACKGROUND: Idiopathic nephrotic syndrome (NS) presents as a hypercoagulable state, of which thromboembolism (TE) is a well-known life-threatening complication. Although TE is more likely to occur in venous vessels than arterial vessels, arterial TE is important because it may cause after-effects, including tissue necrosis and cerebral infarction (CI); therefore, prompt diagnosis and appropriate treatment are required. We report a pediatric NS case with multiple CIs. CASE PRESENTATION: A 14-year-7-month-old Japanese girl was diagnosed with frequent relapsing NS, accompanied by headache and disturbance of consciousness during the second relapse. Brain magnetic resonance imaging (MRI) and four-dimensional computed tomography revealed multiple CIs, vasogenic edema, and cerebral venous sinus thrombosis (CVST). The patient had no underlying thrombophilia other than hypercoagulability due to NS and prednisolone (PSL), and no cardiac arrhythmia; however, a right-to-left shunt through the patent foramen ovale (PFO) was observed with the Valsalva maneuver by echocardiography. Therefore, we assumed that a potential cause of multiple CIs might be an embolic stroke, caused by thrombosis formed from a hypercoagulable state due to NS and PSL treatment and reached through PFO. Antiplatelet and anticoagulant therapies were administered for TE. She was treated with PSL and mycophenolate mofetil (MMF) for NS. Rituximab (RTX) was administered to prevent NS relapse after complete remission (CR). She underwent transcatheter PFO closure at age 14 years and 9 months because we considered that the right-to-left shunt through the PFO would be one of the risks for recurrent cerebral embolism when NS relapses. One year after the onset of CIs, an MRI indicated that the CVST had resolved, leaving no neurological sequelae due to CI; therefore, anticoagulant therapy was discontinued. And then she has been in CR for NS with only MMF therapy. CONCLUSIONS: CI is a serious complication in patients with NS. The pathogenesis of multiple CIs is various, including right-to-left shunt through PFO, in addition to the hypercoagulability due to NS. It is important to investigate and manage underlying risks such as PFO, besides preventing the relapses of NS by aggressive treatments using MMF and RTX, in patients with NS.

Comparison of echocardiographic and clinical characteristics in embolic stroke and migraine patients with patent foramen ovale.

BACKGROUND: This single-center observational study aimed to compare the echocardiographic and clinical features in patients diagnosed with migraine and embolic stroke of undetermined source (ESUS) who presented with a known patent foramen ovale (PFO). METHODS: Two-dimensional and color Doppler images were obtained using various transthoracic echocardiography views for both migraine and ESUS patients. Suspected PFO cases underwent further assessment through contrast echocardiography and transesophageal echocardiography (TEE). High-risk PFO characteristics were evaluated using TEE, and the Risk of Paradoxical Embolism (RoPe) score was calculated. RESULTS: The study included 310 participants (age range: 18-60, 73.2% female), with 43.5% diagnosed with migraine and 56.5% with ESUS. Common comorbidities included diabetes (26.1%). High-velocity shunting through the interatrial septum was observed in 35.5% of patients. ESUS patients were older, with higher rates of diabetes and hypertension, while active smoking was more prevalent among migraine patients. Basic echocardiographic parameters were mostly similar, except for elevated pulmonary artery systolic pressure in ESUS. ESUS patients exhibited a greater occurrence of large microbubble passage through the interatrial septum and longer PFO lengths compared to migraine patients. However, the RoPe and High-risk PFO scores were similar between the groups. CONCLUSIONS: ESUS patients, characterized by older age and higher rates of diabetes and hypertension, demonstrated increased pulmonary artery pressure, more significant microbubble crossings, and longer PFO lengths. Conversely, migraine patients had a higher prevalence of active smoking. Despite differing clinical profiles, the risk scores for PFO-related embolic events were comparable between the groups. These findings underscore potential distinctions between ESUS and migraine patients with PFO and their implications for management strategies.

Updates on Patent Foramen Ovale (PFO) Closure.

PURPOSE OF REVIEW: Patent foramen ovale (PFO) has been previously linked to left circulation thromboembolism and stroke. This review article aims to discuss the latest evidence, updated societal guidelines, diagnostic algorithms and novel therapeutic devices for PFO closure. RECENT FINDINGS: PFO closure for cryptogenic stroke and systemic embolization is supported by a large body of evidence and has a strong societal recommendation. Limited data are available for platypnea-orthodeoxia syndrome, although closure appears to be beneficial. Current data do not support routine closure for migraines and decompression Illness. Development of heart-brain teams can improve identification of patients most likely to benefit from closure, utilizing a combination of imaging test and risk score algorithms. Multiple novel devices aiming at reducing complications and improving the long-term impact of current available devices are being evaluated. PFO closure has significantly progressed over the last years, with new data supporting its superiority in reducing risk of recurrent embolic stroke in patients with PFO-related stroke. Additional clinical data are required to provide further refinements on patient selection and guidance on treatment of specific subgroups.

Decompression sickness of the inner ear and relationship with a patent oval foramen: a study of 61 cases.

OBJECTIVE: To discuss the link between inner ear decompression sickness and patent foramen ovale. MATERIALS AND METHODS: Monocentric and retrospective study on decompression sickness of the inner ear requiring hyperbaric chamber treatment, from 2014 to 2021. RESULTS: Sixty-one patients of inner ear decompression sickness were included in this study. Twenty-four patients had vestibular injuries, 28 cochlear injuries and 9 cochleo-vestibular injuries. Compression chamber treatment was given, using an oxygen-helium mixture with oxygen partial pressure (PIO2) limited to 2.8 atmosphere absolute (ATA). All vestibular accidents completely recovered without clinical sequelae. For cochlear accident only 10 out of 37 patients (27%) recovered completely. A right-left shunt (patent foramen oval or intra-pulmonary shunt) was found in 31.1% of patients with inner ear decompression sickness (p > 0.05). CONCLUSION: The presence of patent foramen oval in patients with inner ear decompression was not statistically significant in our study. Understanding of the pathophysiology of decompression illness and the physiology and anatomy of the labyrinth would suggest a mechanism of supersaturation with degassing in intra-labyrinthine liquids.

Management of patent foramen ovale; findings from a nationwide survey.

OBJECTIVES: Several clinical trials have provided evidence supporting the transcatheter closure of patent foramen ovale (PFO) in selected patients following a cryptogenic stroke. However, it remains unknown to what extent these guidelines have been implemented in everyday clinical practice and the familiarity of physicians from different specialties with PFO closure. The aim of our nationwide survey is to explore the implementation of transcatheter PFO occlusion in Greek clinical practice. MATERIALS AND METHODS: Attending level cardiologists, internal medicine physicians and neurologists involved in the management of PFO-related strokes working in Greece were invited to complete an online questionnaire. The questionnaire consisted of 19 questions and was designed to obtain comprehensive data on provider demographics, PFO characteristics, and specific clinical scenarios. RESULTS: A total of 51 physicians (56.9 % cardiologists, 25.5 % neurologists and 17.6 % internal medicine physicians) completed the survey, resulting in a response rate of 53 %. Cardiologists, internal medicine physicians and neurologists agree on several issues regarding PFO closure, such as PFO closure as first line treatment, management of patients with DVT or prior decompression sickness, and post-closure antithrombotic treatment, but different approaches were reported regarding closure in patients with thrombophilia treated with oral anticoagulation (p=0.012) and implantable loop recorder placement for atrial fibrillation exclusion (p=0.029 and p=0.020). CONCLUSIONS: Our findings show that cardiologists, internal medicine physicians and neurologists agree in numerous issues, but share different views in the management of patients with thrombophilia and rhythm monitoring duration. These results highlight the significance of collaboration among physicians from different medical specialties for achieving optimal results.

Comparison of atrial septal defect and patent foramen ovale in cryptogenic strokes.

OBJECTIVES: Paradoxical embolism from right-to-left shunt through atrial septal defect (ASD) and patent foramen ovale (PFO) is a well-accepted cause of "cryptogenic" strokes (CS). To better understand the pathogenic role of ASD, we compared ASD patients with CS having a high and low likelihood of being PFO-related. METHODS: In the Acute Stroke Registry and Analysis of Lausanne, we calculated prevalence of PFO and ASD in CS patients undergoing echocardiography, and calculated odds ratios (OR) when compared to non-CS. Using the Risk of Paradoxical Embolism (RoPE) score, we divided CS PFO patients in high (HL-PFO, RoPE 8-10) and low-likelihood (LL-PFO, RoPE 0-4) PFO-related stroke. We then performed univariate comparison of epidemiological, clinical and radiological variables of ASD patients with both PFO groups. RESULTS: Among all CS, prevalence of ASD and PFO were 1.3% and 36.8% respectively. When compared to non-CS, ASD and PFO were associated with CS (OR of 5.2, CI= 1.6-16.6, and 2.8, CI= 2.1-3.8). Compared with HL-PFO, ASD patients were older, more often female, had more cardiovascular risk factors and silent strokes. Compared with LL-PFO, ASD patients were younger, more often female, and had less risk factors. No differences were found for clinical and radiological characteristics and clinical outcome. CONCLUSION: ASD is a rare stroke risk factor for CS. Since characteristics of such patients lie in-between high and low-likelihood paradoxical PFO-strokes, a thorough work-up for other stroke mechanisms is warranted. Individual evaluation of the likelihood of the ASD being causative for stroke may be preferable over routine ASD closure.

Is Moderate/Large Residual Shunt After PFO Closure Justifiable for a Patient with a Prior History of Cryptogenic Stroke and Transient Ischemic Attack?

A 36-year-old woman suffered from an embolic stroke of an undetermined source documented by magnetic resonance imaging with residual right arm weakness. She underwent percutaneous patent foramen ovale (PFO) closure with an 18/25 mm device in another center. One year later, the patient suffered from a transient ischemic attack with dysarthria. She asked for a second opinion at our institution and a contrast-transthoracic (cTTE) /transesophageal echocardiography showed a large residual right-to-left shunt (RLS) through a still patent tunnel after PFO closure. Written informed consent for a redo procedure was obtained from the patient. A catheter-based closure of the residual shunt was therefore planned under local anesthesia and rotational intracardiac echo monitoring. A second equally sized disc (18/18 mm) device was successfully implanted without complications. The patient was discharged home the following day in good clinical condition. Dual antiplatelet therapy was recommended for the first 2 months and then single antiplatelet therapy up to 6 months. At the 6-month follow-up, the cTTE color Doppler showed the stable position of the two nitinol double-disc devices and the c-transcranial Doppler confirmed the abolition of the residual RLS.

In young patients with stroke of undetermined etiology, large vessel occlusions are less frequent in the group with high-risk patent foramen ovale.

INTRODUCTION: Patent foramen ovale (PFO) is present in a significant proportion of young patients with stroke of undetermined etiology, but is not always causal. Therefore, classifications (RoPE, PASCAL) have been developed to determine the probability that PFO is the stroke cause. However, the presence of an initial arterial occlusion as a prediction factor was not studied when these classifications were built. Our aim was to evaluate the presence of arterial occlusion in young patients with stroke of undetermined etiology with/without high-risk PFO. METHODS: From a prospectively-built monocentric database, we identified patients aged≥18 to<60-years with strokes of undetermined etiology and complete etiological work-up, including transesophageal echocardiography. We divided patients in two groups: (i) with high-risk PFO [i.e. PFO with large interatrial shunt (>30 microbubbles) or associated with atrial septal aneurysm] and (ii) with low-risk/without PFO. We recorded the presence of arterial occlusion and large vessel occlusion (LVO) in the acute phase. RESULTS: We included 96 patients; 55 (57%) had high-risk PFO. Their median age was 48 (40-52) years, and 28 (29%) were women. The percentages of patients with arterial occlusion and with LVO were lower in the high-risk PFO group than in the low-risk/without PFO group: 11 (20%) versus 19 (46%) (P=0.008), and 5 (9%) versus 15 (37%) (P=0.002), respectively. There was no difference in the median RoPE score between groups (P=0.30). CONCLUSION: The presence of LVO could represent a "red flag" of PFO causality in stroke of undetermined etiology, and could be implemented in future PFO-related stroke classifications.