Stroke in Young Military Men With Heterozygous for MTHFR Gene Mutation or Factor V Leiden Gene Mutation Associated With Patent Foramen Ovale: Report of Two Cases and Therapeutic Strategy.

We report two cases of Brazilian patients (a 22-year-old male and a 48-year-old male) with ischemic stroke, whose arterial vascular study and echocardiographic investigation did not reveal any steno-occlusive arterial disease or typical cardioembolic finding, such as atrial fibrillation or myocardial dysfunction. A transcranial Doppler ultrasound and a transesophageal echocardiogram showed a patent foramen ovale (PFO), and the laboratory screening for coagulation abnormalities showed heterozygosity for MTHFR C677T and A1298C in one of the patients and heterozygosity for factor V Leiden gene mutations in the other patient. The significance of the association of PFO with Methylenetetrahydrofolate (MTHFR) C677T and A1298C variants or factor V Leiden mutation is discussed as a possible cause of ischemic stroke through paradoxical embolism from a venous source. There is a high prevalence of these two mentioned conditions in the general population, so we discuss two cases in which indication for anticoagulant therapy or percutaneous closure of PFO prevails.

Mechanisms of platypnea-orthodeoxia syndrome. / Mecanismos del síndrome de platipnea-ortodesoxia

Platypnea orthodeoxia syndrome (POS) is a clinical entity described in the middle of the last century. It is characterized by dyspnea and hypoxemia triggered by standing and relieved with recumbency. The diagnosis is predominately clinical. The degree of hypoxemia is variable; however, the diagnostic criteria include the decrease in arterial oxygen pressure more than 4 mmHg or oxygen saturation more than 5%. Even though many diseases cause this syndrome, there are only two responsible mechanisms, intracardiac, and intrapulmonary shunts. The coexistence of diverse structural and physiological abnormalities joined to gravitational forces that induce blood shunt after standing is crucial in each mechanism. The intracardiac mechanism is characterized by right to left blood shunt through atrial septal communications and, the right atrium pressure could be normal or increased. In addition, some patients have one or more coexistent aortic, spinal, or intracardiac alterations. The intrapulmonary mechanism is less frequent and is caused by parenchymal or vascular pathologies. Transthoracic echocardiogram is the first diagnostic modality; however, understanding the pathophysiology is the key for a rational diagnostic approach and subsequent diagnostic studies. Treatment is possible and effective in the majority of intracardiac mechanisms and some intrapulmonary. This review focuses on the pathophysiologic mechanisms of POS and their diagnostic workup.

El síndrome de platipnea ortodesoxia es una entidad clínica descrita a mediados del siglo pasado. Se caracteriza por disnea e hipoxemia que se desencadenan con la bipedestación y se alivia con el decúbito. El diagnóstico es predominantemente clínico. El grado de hipoxemia es variable; sin embargo, los criterios de diagnóstico incluyen disminución de la presión arterial de oxígeno de más de 4 mmHg o saturación de oxígeno de más de 5%. A pesar de que este síndrome es causado por gran cantidad de enfermedades, solo hay dos mecanismos responsables: los cortocircuitos intracardiacos e intrapulmonares. En cada mecanismo es crucial la coexistencia de diversas anomalías estructurales y fisiológicas que, unidas a las fuerzas gravitacionales, inducen un cortocircuito sanguíneo después de la bipedestación. En el mecanismo intracardiaco hay un cortocircuito sanguíneo de derecha a izquierda a través del del tabique interauricular y la presión auricular derecha puede ser normal o aumentada; además, algunos pacientes tienen una o más alteraciones aórticas, espinales, o intracardiacas coexistentes. El mecanismo intrapulmonar es menos frecuente y es causado por patologías parenquimatosas o vasculares. El ecocardiograma transtorácico es la primera modalidad de diagnóstico, sin embargo, comprender la fisiopatología es la clave para un enfoque de diagnóstico racional y estudios diagnósticos subsecuentes. El tratamiento es posible y eficaz en la gran mayoría de los mecanismos intracardiacos y en algunos intrapulmonares. Esta revisión se centra en los mecanismos fisiopatológicos del síndrome de platipnea ortodesoxia y su diagnóstico.

[Persistent foramen ovale as a cause of persistent hypoxemia after a pneumonia caused with COVID-19. Report of one case]. / Foramen oval persistente como causa de hipoxemia persistente en un paciente con neumonía grave COVID-19. Reporte de un caso.

In patients with severe COVID-19, it has been proposed as mechanism of respiratory failure, intra and extrapulmonary shunt. However, there are no reported or documented cases of this mechanism. Also, there are studies showing this mechanism is not relevant. In this report, we present the case of a patient with severe COVID-19 pneumonia, who after two months, during his rehabilitation period, presented persistent hypoxemia with orthodeoxia. Persistent oval foramen with shunt from right to left was diagnosed. The patient underwent a percutaneous closure of the defect and at 48 hours oxygen therapy could be discontinued and the patient discharged.

Comparison of right-to-left shunt characteristics in cryptogenic embolic ischemic stroke and non-cardioembolic ischemic stroke.

BACKGROUND: Patent foramen ovale (PFO) has been considered a potential mechanism of embolic stroke of undetermined origin. OBJECTIVE: The aim of the present study was to identify the features of the right-to-left shunt (RLS) in patients with undetermined embolic ischemic stroke and compare them with those of patients with non-cardioembolic ischemic stroke. METHODS: A retrospective study was conducted with 168 patients with stroke and RLS separated into the following two groups: the undetermined embolic stroke group (UES group) and non-cardioembolic stroke group (NCES group). All patients were assessed by transcranial Doppler to evaluate the presence and quantification of microembolic signals (MES) at rest and under Valsalva maneuver. RESULTS: Of all patients evaluated in the current study, 96 were included in the UES group and 72 in the NCES group. In the UES group, 65 patients had RLS with ≥10 MES (67.7%), which was higher than that observed in the NCES group (51.4%, p=0.038). According to the moment of the cardiac cycle, 75 patients (78.1%) in the UES group had a positive test at rest compared to 42 (58.3%) in the NCES group (p=0.007). CONCLUSIONS: The current study demonstrated that almost 70% of patients with undetermined embolic stroke and PFO presented a large RLS and more than 75% had RLS at rest. These findings suggest that the size of the shunt should be taken into account when evaluating whether PFO could be a possible mechanism underlying cryptogenic stroke.

Comparison of right-to-left shunt characteristics in cryptogenic embolic ischemic stroke and non-cardioembolic ischemic stroke / Comparação das características do shunt direita-esquerda em pacientes com AVC isquêmico criptogênio e AVC não cardioembólico

Abstract Background: Patent foramen ovale (PFO) has been considered a potential mechanism of embolic stroke of undetermined origin. Objective: The aim of the present study was to identify the features of the right-to-left shunt (RLS) in patients with undetermined embolic ischemic stroke and compare them with those of patients with non-cardioembolic ischemic stroke. Methods: A retrospective study was conducted with 168 patients with stroke and RLS separated into the following two groups: the undetermined embolic stroke group (UES group) and non-cardioembolic stroke group (NCES group). All patients were assessed by transcranial Doppler to evaluate the presence and quantification of microembolic signals (MES) at rest and under Valsalva maneuver. Results: Of all patients evaluated in the current study, 96 were included in the UES group and 72 in the NCES group. In the UES group, 65 patients had RLS with ≥10 MES (67.7%), which was higher than that observed in the NCES group (51.4%, p=0.038). According to the moment of the cardiac cycle, 75 patients (78.1%) in the UES group had a positive test at rest compared to 42 (58.3%) in the NCES group (p=0.007). Conclusions: The current study demonstrated that almost 70% of patients with undetermined embolic stroke and PFO presented a large RLS and more than 75% had RLS at rest. These findings suggest that the size of the shunt should be taken into account when evaluating whether PFO could be a possible mechanism underlying cryptogenic stroke.

RESUMO Antecedentes: Uma das potenciais fontes embólicas no acidente vascular cerebral (AVC) de origem indeterminada é o forame oval patente (FOP). Objetivo: O objetivo do presente estudo foi identificar as características do shunt direita-esquerda em paciente com AVC de etiologia indeterminada, presumidamente embólica, e comparar tais características com pacientes apresentando AVC por outras causas não embólicas. Métodos: Trata-se de um estudo retrospectivo com 168 pacientes com AVC e forame oval patente, separados em dois grupos: AVC embólico de etiologia indeterminada e AVC por outras causas não embólicas. Todos os pacientes foram submetidos a Doppler transcraniano, para avaliar a presença de shunt direita-esquerda por meio do teste de embolia paradoxal. Além da quantificação de microbolhas, também foi avaliada a presença de shunt em repouso e sob manobra de Valsalva. Resultado: Do total, 96 pacientes foram incluídos no primeiro grupo (AVC indeterminado) e 72, no segundo grupo (AVC não embólico). No primeiro grupo, 65 pacientes exibiram shunt com passagem de mais de 10 microbolhas (67,5%), enquanto no segundo grupo isso aconteceu em 51,4% (p=0,038) dos casos. Além disso, 75 pacientes (78,1%) do primeiro grupo tiveram teste positivo ao repouso, comparados com 42 pacientes (58,3%) no segundo grupo (p=0,007). Conclusão: O presente estudo demonstrou que até 70% dos pacientes com AVC de etiologia indeterminada e forame oval apresentaram shunts maiores; em mais de 75%, houve passagem de microbolhas ao repouso. Esses achados sugerem que as características do shunt, como quantidade de microbolhas e passagem ao repouso, devem ser levadas em consideração na avaliação do FOP como possível mecanismo subjacente ao AVC.

Central retinal artery occlusion associated with patent foramen ovale: a case report and literature review.

Patent foramen ovale might cause cryptogenic strokes, including retinal artery occlusion. Herein, we describe a previously healthy young man who presented with central retinal artery occlusion in the setting of patent foramen ovale and explore the need for transesophageal echocardiogram for its diagnosis. Cardiovascular workup and neuroimaging were unremarkable. Transthoracic echocardiogram bubble study revealed a right to left atrial shunt and subsequent transesophageal echocardiogram disclosed patent foramen ovale. This congenital cardiac anomaly was the likely conduit for a thrombo-embolic central retinal artery occlusion. We identified seven patients with patent foramen ovale associated with central retinal artery occlusion in the literature. Transthoracic echocardiogram was diagnostic in only one patient (14.3%), whereas transesophageal echocardiogram was required to reveal patent foramen ovale in the remaining six (85.7%). Our case and the previous reports support the link between central retinal artery occlusion and patent foramen ovale. Therefore, providers should consider the more sensitive transesophageal echocardiogram during the initial evaluation of young patients without immediately identifiable causes of retinal artery occlusion.

Foramen oval persistente como causa de hipoxemia persistente en un paciente con neumonía grave COVID-19. Reporte de un caso / Persistent foramen ovale as a cause of persistent hypoxemia after a pneumonia caused with COVID-19. Report of one case

In patients with severe COVID-19, it has been proposed as mechanism of respiratory failure, intra and extrapulmonary shunt. However, there are no reported or documented cases of this mechanism. Also, there are studies showing this mechanism is not relevant. In this report, we present the case of a patient with severe COVID-19 pneumonia, who after two months, during his rehabilitation period, presented persistent hypoxemia with orthodeoxia. Persistent oval foramen with shunt from right to left was diagnosed. The patient underwent a percutaneous closure of the defect and at 48 hours oxygen therapy could be discontinued and the patient discharged.

Investigation of patent foramen ovale as a mechanism for brain metastasis in patients without prior lung involvement.

PURPOSE: The mechanisms of brain metastasis are incompletely understood. Circulating tumor cells travel to the right heart and through the pulmonary circulation, where they may become lung metastases, and can circulate further to the left heart and brain. In patients who develop brain metastases without lung involvement, we hypothesized that cancer cells may travel directly from the right atrium to left atrium via a patent foramen ovale (PFO), akin to paradoxical embolism. If the prevalence of PFO is greater in these individuals compared to the general population (20-30%), PFO may play a role in brain metastasis, and prophylactic closure may provide benefit. Accordingly, we investigated the prevalence of PFO in patients with brain metastases without prior lung involvement. METHODS: We prospectively identified patients with brain metastases from a non-lung primary cancer with no preceding or concurrent lung involvement. Nine eligible participants underwent a transcranial Doppler study with intravenous agitated saline to assess for PFO. RESULTS: Among nine participants, primary cancers were breast (n = 6), upper gastrointestinal (n = 2), and thyroid (n = 1). A positive bubble study was identified in 2/9 (22.2%) participants: one female with breast cancer and one male with duodenal adenocarcinoma. No participants developed lung metastases on subsequent chest imaging. CONCLUSION: In this prospective pilot study, we found a similar prevalence of PFO in patients who developed brain metastases without preceding lung involvement compared to estimates for the general population. Through a larger study is needed, the development of brain metastases in these individuals may primarily reflect tumor-specific biological factors diecting metastasis organotropism.

Practice advisory update summary: Patent foramen ovale and secondary stroke prevention: Report of the Guideline Subcommittee of the American Academy of Neurology.

OBJECTIVE: To update the 2016 American Academy of Neurology (AAN) practice advisory for patients with stroke and patent foramen ovale (PFO). METHODS: The guideline panel followed the AAN 2017 guideline development process to systematically review studies published through December 2017 and formulate recommendations. MAJOR RECOMMENDATIONS: In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke (level B). In patients with a higher risk alternative mechanism of stroke identified, clinicians should not routinely recommend PFO closure (level B). Clinicians should counsel patients that having a PFO is common; that it occurs in about 1 in 4 adults in the general population; that it is difficult to determine with certainty whether their PFO caused their stroke; and that PFO closure probably reduces recurrent stroke risk in select patients (level B). In patients younger than 60 years with a PFO and embolic-appearing infarct and no other mechanism of stroke identified, clinicians may recommend closure following a discussion of potential benefits (absolute recurrent stroke risk reduction of 3.4% at 5 years) and risks (periprocedural complication rate of 3.9% and increased absolute rate of non-periprocedural atrial fibrillation of 0.33% per year) (level C). In patients who opt to receive medical therapy alone without PFO closure, clinicians may recommend an antiplatelet medication such as aspirin or anticoagulation (level C).

Updated Meta-analysis on the Closure of Patent Foramen Ovale in Reduction of Stroke Rates: the DEFENSE-PFO Trial Does not Change the Scenario.

OBJECTIVE: We aimed to analyze whether patent foramen ovale (PFO) closure reduces the risk of stroke, assessing also some safety outcomes after the publication of a new trial. INTRODUCTION: The clinical benefit of closing a PFO has been an open question, so it is necessary to review the current state of published medical data in regards to this subject. METHODS: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles were used to search for randomized controlled trials (RCTs) that reported any of the following outcomes: stroke, death, major bleeding or atrial fibrillation. Six studies fulfilled our eligibility criteria and included 3560 patients (1889 for PFO closure and 1671 for medical therapy. RESULTS: The risk ration (RR) for stroke in the "closure" group compared with the "medical therapy" showed a statistically significant difference between the groups, favouring the "closure" group (RR 0.366; 95%CI 0.171-0.782, P=0.010). There was no statistically significant difference between the groups regarding the safety outcomes, death and major bleeding, but we observed an increase in the risk of atrial fibrillation in the "closure" group (RR 4.131; 95%CI 2.293-7.443, P<0.001). We also observed that the larger the proportion of effective closure, the lower the risk of stroke. CONCLUSION: This meta-analysis found that stroke rates are lower with percutaneously implanted device closure than with medical therapy alone, being these rates modulated by the rates of hypertension, atrial septal aneurysm and effective closure. The publication of a new trial did not change the scenario in the medical literature.

Trombo a través de foramen oval permeable: embolia paradojal cerebral y factores de alto riesgo de recurrencia. Caso clínico / Paradoxical embolism due to a persistent patent foramen ovale: report of one case

Abstract: Patent Foramen Ovale (PFO) is one of the most frequent congenital defects in adults. Its prevalence in middle-aged adults is close to 25-30% and may cause paradoxical embolic phenomena. We report a 45 years old male admitted for an ischemic stroke with an occlusion of the left terminal internal carotid artery. A thrombectomy was performed. Searching for possible sources of emboli, a patent foramen ovale was detected in an echocardiography, with an hypoechogenic examination image passing through it. Anticoagulant therapy was started and the patient had an uneventful evolution.

Updated meta-analysis on the closure of patent foramen ovale in reduction of stroke rates: the defense-pfo trial does not change the scenario

Abstract Objective: We aimed to analyze whether patent foramen ovale (PFO) closure reduces the risk of stroke, assessing also some safety outcomes after the publication of a new trial. Introduction: The clinical benefit of closing a PFO has been an open question, so it is necessary to review the current state of published medical data in regards to this subject. Methods: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles were used to search for randomized controlled trials (RCTs) that reported any of the following outcomes: stroke, death, major bleeding or atrial fibrillation. Six studies fulfilled our eligibility criteria and included 3560 patients (1889 for PFO closure and 1671 for medical therapy. Results: The risk ration (RR) for stroke in the "closure" group compared with the "medical therapy" showed a statistically significant difference between the groups, favouring the "closure" group (RR 0.366; 95%CI 0.171-0.782, P=0.010). There was no statistically significant difference between the groups regarding the safety outcomes, death and major bleeding, but we observed an increase in the risk of atrial fibrillation in the "closure" group (RR 4.131; 95%CI 2.293-7.443, P<0.001). We also observed that the larger the proportion of effective closure, the lower the risk of stroke. Conclusion: This meta-analysis found that stroke rates are lower with percutaneously implanted device closure than with medical therapy alone, being these rates modulated by the rates of hypertension, atrial septal aneurysm and effective closure. The publication of a new trial did not change the scenario in the medical literature.