The fugitive was patent foramen ovale

NobleStitch Patent Foramen Ovales Closure for Recurrent Strokes in a Patient with COVID-19 on Extracorporeal Membrane Oxygenation

Stroke remains one of the most feared and devastating complications for patients to envisage. This remains true regardless of the age of the patient and the presence or absence of comorbidities, but it may be relatively more important the younger the patient is. Establishing the pathogenesis of stroke is fundamentally important for attempts at prevention. In some patients, the diagnosis of the underlying cause is relatively straightforward—eg, the presence of a high-grade, ulcerated lesion in the carotid artery in the distribution of the central nervous system symptoms or neurological deficit. In other cases, it may be considerably more difficult; then, the question of a cardiac source is often raised. See p 1121 Echocardiography has become an integral part of the evaluation in many such patients. Early in the history of this field, attention was focused on the left atrial appendage as a putative source. In addition, however, abnormalities of the atrial septum were documented and have since come to occupy an important position. These abnormalities were further characterized after the introduction of contrast studies and transesophageal echocardiography, which helped in the documentation of patent foramen ovale (PFO), atrial septal aneurysm (ASA), and right-to-left shunt. In such patients, emboli potentially could pass from the venous to the systemic arterial circulation.1,2⇓ It must be remembered that there may be other mechanisms, including thrombus forming in the ASA or thrombus from supraventricular arrhythmias. In a recent meta-analysis,3 there were 2738 references of case-control studies that identified the keywords PFO, ASA, or right-to-left shunt. In this meta-analysis, combined odds ratios were calculated with the use of both fixed and random-effect methods. There are several important issues that can be addressed, including: (1) the frequency of each of these conditions in control populations versus patients with cryptogenic stroke or stroke of known …

Background. In ≈ 40% of patients with acute ischemic stroke, the cause remains undefined (cryptogenic stroke). Previous studies, using contrast echocardiography, showed a significant prevalence of a patent foramen ovale (PFO) in patients with cryptogenic stroke < 55 years of age, suggesting a causal role through paradoxical embolism. Contrast transesophageal echocardiography (TEE) is considered the gold standard for PFO detection. Recently, however, cardiac magnetic resonance (CMR) was also shown to reliably detect PFO. In this study we compared the accuracy of CMR and TEE in detecting PFO in a group of patients with cryptogenic stroke. Methods and Results . Sixteen patients (age 50 ± 13 years, 9 males) with cryptogenic ischemic stroke underwent contrast-enhanced TEE and contrast CMR for detection of possible PFO. Both imaging studies were performed during Valsalva maneuver. PFO grading results were assessed visually both for TEE and CMR, according to the entity of contrast passage in the left atrium (grade 0 = no PFO; grades 1, 2 and 3 = mild, medium and wide PFO, respectively). Nine patients (56%) were identified to have a PFO by contrast TEE. Contrast-enhanced CMR identified a PFO in only 5 (56%) of these patients. None of the 7 patients without PFO at TEE was shown to have a PFO at CMR. TEE showed a grade 1 PFO in 4 patients, a grade 2 PFO in 3 and a grade 3 PFO in 2 patients. Of these patients, CMR failed to identify PFO in all patients with a grade 1 PFO at TEE and underestimated the degree of the shunt in the other patients. Conclusions. Our data suggest that TEE should be considered the non-invasive diagnostic reference test to detect and characterize PFO in patients with ischemic cryptogenic stroke.

Clinical management of patients with acute stroke and the approach used for secondary prevention depends upon clarification of pathogenesis. Although most strokes are a consequence of cerebrovascular disease, ≈15% to 20% of ischemic (nonhemorrhagic) strokes have been attributed to cardiogenic embolism.1 In practice, determination of the stroke mechanism is fraught with uncertainty, particularly when the possibility of thromboembolism emanating from atherosclerotic lesions in the aorta or cervical arteries is considered. When cardiogenic embolism is suspected, cardiac ultrasound is the principal method used to identify the potential source. The finding of left atrial enlargement has been shown to bear a significant relationship to the risk of stroke in a multivariate analysis of population-based data from the Framingham Heart Study2. The most frequent confounding variable is atrial fibrillation, occurring in >2 million patients in North America and in over half of all patients with cardiogenic embolism. Criteria for selection of patients with acute ischemic stroke for transesophageal echocardiography (TEE) to search for a potential cardiac source of embolism are controversial, particularly because cardiogenic embolism is often an uncertain diagnosis that is inferred merely on the basis of the finding of potential cardiac source. Even after extensive investigation, ≈40% of ischemic stroke patients have no clearly identifiable pathogenesis (cryptogenic stroke).3 In one study, 62% of patients younger than 60 years of age without an obvious source of cerebral infarction and 23% of those with arterial lesions had potential sources of cardiogenic embolism identified by TEE ( P =0.0007 for the difference).4 See p 2625 Among the cardiac anomalies detected by TEE that have been implicated as risk factors for stroke are patent foramen ovale (PFO) and atrial septal aneurysm (ASA).5,6⇓ The foramen ovale, a remnant of the fetal circulation, remains patent through adulthood in ≈1 in 4 …

HomeStrokeVol. 51, No. 11Response by Yaghi et al to Letter Regarding Article, “SARS-CoV-2 and Stroke in a New York Healthcare System” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Yaghi et al to Letter Regarding Article, “SARS-CoV-2 and Stroke in a New York Healthcare System” Shadi Yaghi, MD, Aaron Lord, MD and Jennifer Frontera, MD Shadi YaghiShadi Yaghi Department of Neurology, NYU Langone Health, New York. Search for more papers by this author , Aaron LordAaron Lord Department of Neurology, NYU Langone Health, New York. Search for more papers by this author and Jennifer FronteraJennifer Frontera https://orcid.org/0000-0002-0719-2522 Department of Neurology, NYU Langone Health, New York. Search for more papers by this author Originally published5 Aug 2020https://doi.org/10.1161/STROKEAHA.120.031676Stroke. 2020;51:e312–e313Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 5, 2020: Ahead of Print In Response:First, we would like to thank Albiero et al for the letter they submitted regarding our article.1 In their letter, they highlight the importance of paradoxical embolism as one of the plausible mechanisms in patients with cryptogenic stroke in the setting of coronavirus disease 2019 (COVID-19). This is particularly the case due to the increased prevalence of deep vein thrombosis and pulmonary embolism in hospitalized patients with COVID-19 infection.2,3We agree with the authors that paradoxical embolism is a potential mechanism, and it may be useful in some patients to look for a cardiac shunt in patients with COVID-19 and ischemic stroke. In our study, only 10% (3/32) had evidence of deep vein thrombosis/pulmonary embolism, which provides indirect evidence that paradoxical embolism may not be the most important mechanism for stroke in these patients. Another yet smaller study, however, reported a higher percentage of deep vein thrombosis/pulmonary embolism in patients with ischemic stroke and COVID-19 infection.4In our study, we found markedly elevated d-dimer levels (>2000 ng/mL) in 95% (20/21) of patients with cryptogenic stroke subtype suggesting that hypercoagulability is a more compelling mechanism. In addition, it should be noted that nearly 47% (10/21) of patients labeled as cryptogenic stroke in our study had an incomplete diagnostic evaluation and, therefore, it is difficult to consider paradoxical embolism as the mechanism of stroke given the lack of diagnostic tests needed to rule out other high-risk stroke mechanisms.Unfortunately, in our study and other studies, most patients did not receive a bubble study with the transthoracic echocardiogram. Thus, the true prevalence of patent foramen ovale (PFO) in patients with ischemic stroke and COVID-19 remains unknown, and future studies are needed to compare the prevalence of PFO in patients with cryptogenic stroke with or without COVID-19 to provide evidence whether paradoxical embolism is a compelling mechanism in cryptogenic stroke in the setting of COVID-19.As the relationship between COVID-19 and ischemic stroke remains uncertain, a complete diagnostic evaluation of ischemic stroke in patients with COVID-19 should be performed if possible to rule out conventional stroke mechanisms.5 It is suggested that COVID-19 can lead to ischemic stroke via inflammation and hypercoagulability leading to thrombosis, cardiac dysfunction leading to cardioembolism, and cervical artery dissection.5 These potential mechanisms, in addition to paradoxical embolism, should be considered, particularly in those patients whose ischemic stroke remained cryptogenic despite a complete diagnostic evaluation.Although studies have shown a benefit of PFO closure in select patients with PFO and cryptogenic stroke, it remains uncertain whether patients with cryptogenic stroke patients in the setting of COVID-19 would benefit from PFO closure. In fact, PFO closure trials excluded those patients with underlying hypercoagulability. Therefore, detecting a PFO in patients with ischemic stroke and COIVID-19 infection may not necessarily lead to a change in clinical management, especially that anticoagulation treatment has been suggested for primary and secondary prevention in patients with COVID-19 and elevated d-dimer levels.Again, we thank Albiero et al for their letter, and we hope that future studies address the possibility of paradoxical embolism as a potential mechanism in patients with cryptogenic ischemic stroke and COVID-19.DisclosuresNone.FootnotesThis manuscript was sent to Marc Fisher, Senior Consulting Editor, for editorial decision and final disposition.For Disclosures, see page e312.

Patent Foramen Ovale Closure for Remote Stroke: Better Late Than Never?

Patent foramen ovale: a review of associated conditions and the impact of physiological size

Objective: To describe whether there is an increased risk of cryptogenic ischemic stroke in patients with a patent foramen ovale (PFO) and SARS-CoV-2 infection in the Gandía health department. Method: Retrospective observational study conducted in the Primary Care Team (EAP) and Hospital Emergency-Cardiology Departments in the cardiovascular problems branch of the La Safor area of Valencia, Gandía department. A total of 335 selected patients were studied. These patients had to have experienced cryptogenic ischemic stroke associated with a patent foramen ovale and meet the inclusion criteria (patient >18 years, <65 years, and patient from the Gandía health department), during the years 2020, 2021, and 2022. Variables: age, sex, arterial hypertension, diabetes mellitus, cholesterol, patent foramen ovale and its structural characteristics, ischemic stroke, atrial septal aneurysm, SARS-CoV-2 infection. In terms of design, binary logistic regression models were performed, as well as a descriptive study where quantitative variables were described with the mean, standard deviation, and median; qualitative variables by frequency distribution. Subsequently, a multivariate model analysis was performed including variables with statistically significant or potentially relevant effects. Results: PFO was detected more frequently among patients with COVID-19 (p<0.026) and cryptogenic stroke, with a positive result in 41.5% of PFO patients compared to 27.4% in non- PFO patients. Regarding sex, while 60% of women with PFO are positive for SARS-CoV-2, this percentage is reduced to 33.3% in men (p=0.044). In a comparative study according to PFO characteristics (PFO, medium-large PFO, ASA, PFO+ASA, medium-large PFO + ASA) we found statistical significance only in those patients with cryptogenic stroke, COVID-19 infection, and a medium-large PFO without ASA (p<0.02). Conclusions: Women with PFO and cryptogenic stroke are diagnosed more frequently with SARS-CoV-2 than men. Patients in our health area who have medium-large PFO have an increased risk of experiencing an embolic cerebral accident after SARS-CoV-2 infection. This underscores the need to identify these patients in primary care, neurology, and cardiology consultations to ensure closer monitoring and develop multidisciplinary action protocols.

Response

To the Editor: Paradoxical embolism via a patent foramen ovale (PFO) has been suggested as a mechanism of otherwise unexplained, cryptogenic stroke.1 Paradoxical embolism, however, can be diagnosed only if there is evidence of a venous thrombosis coexisting with arterial embolism and right-to-left shunting via a PFO. When looking for venous thrombosis in suspected paradoxical embolism, the diagnostic yield depends on the interval between the event and the investigation and the used diagnostic methods.2 Diagnosing venous thrombosis in patients with suspected paradoxical embolism is sometimes difficult since the thrombosis (1) may be confined to the calf veins and thus only detectable by venography; (2) may be localized in places other than in the leg veins and thus not detectable by leg venography; (3) may be not the cause but the consequence of arterial embolism; or (4) may spontaneously dissolve, re-embolize, or recanalize.3 Due to these problems, a timely search for venous thrombosis is only rarely performed in patients with suspected paradoxical embolism, especially if they have no clinical symptoms of thrombosis. Several strategies are possible to overcome these obstacles. The first strategy is by improving noninvasive methods to visualize venous thrombosis in different locations, like magnetic resonance venography.4 Another strategy is by search for a clotting diathesis in patients with suspected paradoxical embolism. This indirect strategy is based on the assumption that hypercoagulability leads to a higher incidence of venous thrombosis and thus, in the presence of a PFO, might increase the possibility of paradoxical embolism. Hypercoagulability can be assessed by genetic testing for factor VG1691A mutation, prothrombinG20210A variant, and TT677 genotype of methylenetrahydrofolate reductase. The risk for venous thrombosis is increased 3- to 8-fold in heterozygous carriers of the factor VG1691A mutation, 3-fold in heterozygous carriers of the prothrombinG20210A variant, and …

Patent foramen ovale (PFO) is significantly associated with cryptogenic stroke (CS). However, even in patients with CS, a PFO can be an incidental finding. We sought to estimate the probability that a PFO in a patient with CS is incidental. A systematic search identified 23 case-control studies examining the prevalence of PFO in patients with CS versus control subjects with stroke of known cause. Using simple assumptions and Bayes' theorem, we calculated the probability a PFO is incidental in patients with CS. Random effects meta-analyses estimated the odds ratio (OR) of a PFO in CS versus control subjects in different age populations, with or without atrial septal aneurysms, and were used to summarize across studies the probability that a PFO in CS is incidental. The summary OR (95% CIs) for PFO in CS versus control subjects was 2.9 (CI, 2.1 to 4.0). The corresponding ORs for young and old patients (< or >or=55 years) were 5.1 (3.3 to 7.8) and 2.0 (>1.0 to 3.7), respectively. The corresponding probabilities that a PFO in patients with CS is incidental were 33% (28% to 39%) in age-inclusive studies, 20% (16% to 25%) in younger patients, and 48% (34% to 66%) in older patients. These probabilities were much lower when an atrial septal aneurysm was present. In patients with otherwise CS, approximately one third of discovered PFOs are likely to be incidental and hence not benefit from closure. This probability is sensitive to patient characteristics such as age and the presence of an atrial septal aneurysm, suggesting the importance of patient selection in therapeutic decision-making.

IS THE PATENT FORAMEN OVALE AN INNOCENT BYSTANDER OR THE REAL CULPRIT? THE MILLION-DOLLAR QUESTION

Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs is most likely because of a paradoxical embolus. Future cryptogenic stroke classification schemes should consider including PFO as a separate etiologic category.

Association between venous and arterial thrombosis

To the Editor, In the recently published Controversies in Stroke on the best treatment of patients with patent foramen ovale (PFO) and stroke, much emphasis is put on the association of PFO with atrial septal aneurysm as a marker of increased stroke risk as compared with PFO alone, whereas PFO size seems to be a negligible variable.1–3 Data in support of this contention mainly come from a large, multicenter, French study4 where 581 patients were included and assessed with transesophageal echocardiography. PFO was sized by counting the bubbles appearing in the left atrium after antecubital injection of agitated saline and PFO size failed to represent a significant predictor of recurrence. However, as is clearly stated in the paper, the interrater disagreement for the amount of shunting was substantial (about 26%), and the technique employed in the French …