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).

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.

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.

Periodontitis, Dental Procedures, and Young-Onset Cryptogenic Stroke.

Periodontitis is associated with an increased risk of ischemic stroke, and the risk may be particularly high among young people with unexplained stroke etiology. Thus, we investigated in a case-control study whether periodontitis or recent invasive dental treatments are associated with young-onset cryptogenic ischemic stroke (CIS). We enrolled participants from a multicenter case-control SECRETO study including adults aged 18 to 49 y presenting with an imaging-positive first-ever CIS and stroke-free age- and sex-matched controls. Thorough clinical and radiographic oral examination was performed. Furthermore, we measured serum lipopolysaccharide (LPS) and lipotechoic acid (LTA) levels. Multivariate conditional regression models were adjusted for stroke risk factors, regular dentist visits, and patent foramen ovale (PFO) status. We enrolled 146 case-control pairs (median age 41.9 y; 58.2% males). Periodontitis was diagnosed in 27.5% of CIS patients and 20.1% of controls (P < 0.001). In the fully adjusted models, CIS was associated with high periodontal inflammation burden (odds ratio [OR], 95% confidence interval) with an OR of 10.48 (3.18-34.5) and severe periodontitis with an OR of 7.48 (1.24-44.9). Stroke severity increased with the severity of periodontitis, having an OR of 6.43 (1.87-23.0) in stage III to IV, grade C. Invasive dental treatments performed within 3 mo prestroke were associated with CIS, with an OR of 2.54 (1.01-6.39). Association between CIS and invasive dental treatments was especially strong among those with PFO showing an OR of 6.26 (1.72-40.2). LPS/LTA did not differ between CIS patients and controls but displayed an increasing trend with periodontitis severity. Periodontitis and recent invasive dental procedures were associated with CIS after controlling for multiple confounders. However, the role of bacteremia as a mediator of this risk was not confirmed.

Atrial septum anatomy as a predictor of ischemic neurological episodes in patients with a patent foramen ovale.

BACKGROUND: The correlation between atrial septum anatomy and the risk of ischemic neurological events remains underexplored. AIMS: This study aimed to examine both the functional and anatomical attributes of the atrial septum and identify predictors of stroke and/or transient ischemic attack (TIA) in patients diagnosed with patent foramen ovale (PFO). METHODS: A total of 155 patients diagnosed with PFO, with a cardiological cause of neurological events, were enrolled. Transesophageal echocardiography was utilized to assess the anatomy of the PFO canal, size of the right-to-left shunt, thickness of the primary and secondary atrial septum, presence of atrial septum aneurysm, and anatomical structures of the right atrium. RESULTS: Regression analysis showed that factors such as female sex, hypercholesterolemia, PFO canal width, and a large right-to-left shunt were significantly associated with stroke and/or TIA. Receiver operating characteristic analysis indicated that the width of the PFO canal holds a relatively weak, although significant predictive, value for ischemic neurological episodes (area under the curve = 0.7; P = 0.002). A PFO canal width of 4 mm was associated with 70% sensitivity and 55% specificity for predicting stroke and/or TIA. CONCLUSIONS: The atrial septum's anatomy, especially the dimensions of the PFO canal and the magnitude of the right-to-left shunt, combined with specific demographic and clinical factors, are linked to ischemic neurological incidents in PFO patients.

Patent foramen ovale closure versus drug therapy in patients over 60 years and a follow-up of 5 years.

BACKGROUND: The advantages of patent foramen ovale (PFO) closure as protection from a recurrence of stroke remains controversial compared to drug therapy, especially in patients over 60 years. HYPOTHESIS: The aim of the study is to compare recurrence of stroke in patients over 60 years old with PFO closure versus drug therapy alone. METHODS: We included 342 patients over 60 years who suffered a crytopgenic stroke, and were also accepted for a PFO closure. 199 patients refused a PFO closure and were treated with medical therapy alone, whereas 143 patients underwent a PFO closure procedure. RESULTS: The mean follow up time was 5.5 ± 1.5 years. All patients in Group B showed persistent shunt in the follow-up period (n = 199, 100%). In Group A, seven patients were diagnosed with residual shunt during echocardiography examination (5%). A new onset of atrial fibrillation occurred in seven patients in Group A (5%) and six patients in Group B (3%), p = .117. Recurrent stroke occurred in 3 patients in Group A (2%) and 11 patients in Group B (6%), p = .021. One patient died of unknown reason (1%) and two patients were lost due to neurological death (1%) in Group B, whereas no patients in Group A died during the follow-up period. CONCLUSION: Our results show that strict exclusion of patients over 60 years from PFO closure should be reconsidered. As life expectancies are increasing, patients should be considered for same treatment as younger patients, since the outcomes are improved compared to patients treated with medical therapy alone.

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.

Does Atrial Septal Anatomy Still Matter in the Etiological Evaluation of Ischemic Stroke Beyond the Age of 60?

BACKGROUND: Patent foramen ovale (PFO) is causally associated with stroke in some patients younger than 60 years, especially when it is large or associated with an atrial septal aneurysm (ASA). After 60 years of age, this association is less well understood. We assessed the relationships between detailed atrial septal anatomy and the cryptogenic nature of stroke in this population. METHODS AND RESULTS: We reviewed all patients aged 60 to 80 years admitted to our stroke center for ischemic stroke who underwent contrast echocardiography between 2016 and 2021. The atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection (ASCOD) classification was used to reevaluate the etiological workup. Associations between cryptogenic stroke and (1) PFO presence or (2) categories of PFO anatomy (nonlarge PFO without ASA, nonlarge PFO with ASA, large PFO without ASA, and large PFO with ASA) were assessed using logistic regression. Among 533 patients (median National Institutes of Health Stroke Scale score=1), PFO was present in 152 (prevalence, 28.5% [95% CI, 24.9-32.5]). Compared with noncryptogenic stroke, cryptogenic stroke (n=218) was associated with PFO presence (44.5% versus 17.5%; P<0.0001). Among patients with a PFO, septal anatomy categories were associated with cryptogenic stroke (P=0.02), with a strong association for patients with both large PFO and ASA (38.1% versus 14.5%, P=0.002). CONCLUSIONS: PFO presence remains strongly associated with cryptogenic stroke between 60 and 80 years of age. Large PFO, ASA, and their association were strongly associated with cryptogenic stroke in this age group. Our results support performing contrast echocardiography even after 60 years of age, although the optimal secondary prevention therapy in this population remains to be determined in randomized trials.

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.

Platypnea-orthodeoxia syndrome (POS) in a patient who had undergone partial liver resection.

A South Asian male in his early 60s presented with acute-onset dyspnoea on postoperative day 4 after undergoing middle hepatic vein sacrificing partial liver resection for epithelioid angiomyolipoma. The patient's SpO2 on presentation was 65% in standing position which improved to 90% in left lateral decubitus. He was suspected of having platypnea-orthodeoxia syndrome (POS) which was confirmed on echocardiogram with microbubble contrast showing a large intracardiac right-to-left shunt. The patient was taken up for transcatheter closure of patent foramen ovale (PFO). A 30 mm Amplatzer PFO Occluder was deployed across the PFO which reduced the intracardiac shunt resulting in an improved arterial saturation as well as immediate relief of patient's symptoms. This case illustrates the importance of suspecting and recognising POS clinically as well as the efficacy of transcatheter closure of PFO in such cases leading to resolution of hypoxaemia in a short span of time.

Risk factors for the development of cryptogenic stroke and the predictive value of right-to-left shunt in patent foramen ovale.

OBJECTIVE: The purpose of this study was to evaluate the relationship between the right-to-left shunt of the patent foramen ovale and the risk score for paradoxical embolism in cryptogenic stroke, as well as the risk factors for the development of cryptogenic stroke. PATIENTS AND METHODS: A retrospective analysis was performed on 257 patients with cryptogenic stroke who were diagnosed and treated in our hospital from February 2020 to January 2022 as a study group, and 98 patients who were diagnosed and treated at the Department of Neurology in our hospital at the same time and excluded from stroke, were selected as the control group. Transcranial Doppler ultrasound acoustic contrast testing was used to grade right-to-left shunts of patent foramen ovale. Clinical information of individuals who had cryptogenic strokes was examined. The correlation between the right-to-left shunt of patent foramen ovale and the risk score for both cryptogenic stroke and paradoxical embolism was analyzed. The factors affecting the occurrence of cryptogenic stroke were investigated. The correlation between right-to-left shunt and paradoxical embolism risk score was explored. Receiver operator characteristic curve (ROC) analysis was used to evaluate each factor's clinical usefulness in predicting the occurrence of cryptogenic stroke. RESULTS: No difference was observed in the history of hypertension, low-density lipoprotein, C-reactive protein and fibrinogen between the control group and the study group (p<0.05). In the study group with patent foramen ovale, the proportion of patients with grades I and II of the right-to-left shunt of patent foramen ovale was significantly lower than that in the control group, while the percentage of patients with grades III and IV was obviously greater than that in the control group (p<0.05). Right-to-left shunt grade, C-reactive protein, and fibrinogen were independent risk factors for cryptogenic stroke by logistic multivariate regression analysis (p<0.05). With an increase in the right-to-left shunt of the patent foramen ovale, patients' risk scores for paradoxical embolism increased considerably (p<0.05). In patients with cryptogenic stroke, the right-to-left shunt grade of the patent foramen ovale was positively connected with the paradoxical embolism risk score (r=0.331, p<0.001). ROC analysis results showed that the areas under the curves (AUC) of right-to-left shunt grading, C-reactive protein, and fibrinogen were 0.651, 0.871, and 0.779, respectively. The combination of the three indexes had an AUC of 0.908, a sensitivity of 87.90%, a specificity of 82.70%, and a Youden index of 0.706, indicating a high predictive value of the combination. CONCLUSIONS: The right-to-left shunt of patent foramen ovale was an independent risk factor for cryptogenic stroke, which was positively correlated with the paradoxical embolic risk score. Its combination with clinical serologic indexes had a high clinical value for predicting cryptogenic stroke.

Embolic stroke of undetermined source: Focusing on atrial cardiopathy and patent foramen ovale.

BACKGROUND: Atrial cardiopathy(AC) and patent foramen ovale (PFO) are two etiologies of embolic strokes of undetermined source (ESUS). We aimed to explore the relationship between them in ESUS. METHODS: A total of 1146 participants were included from January 2019 to June 2022, which included the ESUS group and non-embolic stroke which includes LAA(large arterial atherosclerosis) + SAO(small artery occlusion) group. AC was defined as the presence of at least one of the following: PTFV1(P-wave terminal force in lead V1) > 4000 µV*ms in the electrocardiograms, NT-proBNP(N-terminal probrain natriuretic peptide) > 250 pg/mL in laboratory tests or LAD(left atrial diameter) > 3.8 cm for women and > 4.0 cm for men in cardiac ultrasound. The presence of PFO was assessed by transthoracic echocardiography, transcranial Doppler ultrasound, transesophageal echocardiography or cardiac MRI. PFO was considered pathogenic if the RoPE score was 7 to 10. RESULTS: The prevalence of AC and PFO was higher in the ESUS group than the LAA + SAO group. The prevalence of AC was lower in ESUS patients with pathogenic PFO (37.9%) than those without PFO (68.4%) and with incidental PFO (64.0%) (p = 0.006). The prevalence of pathogenic PFO was lower in ESUS patients with AC than those without AC (6.0% vs. 17.8%, p = 0.006). The AUC(area under the curve) of PTFV1 for predicting ESUS was 0.724 [95%CI (0.686-0.762), p < 0.05)], indicating that PTFV1 the most valuable AC biomarker. CONCLUSIONS: The prevalence of AC is inversely related to the prevalence of pathogenic PFO in ESUS patients. PTFV1 was the most valuable index to predict ESUS among the AC biomarkers.

Presentation of basilar artery stroke secondary to patent foramen ovale: a diagnosis made with a 'selfie'.

We report the case of a woman in her late 20s, with no significant medical history, who was found unresponsive at home. Her mother revealed a 'selfie' sent to her by the patient 30 min prior to collapse which revealed bilateral ptoses. Initial brain imaging with non-contrast CT of the brain revealed nil of note. A multiphase CT angiogram revealed an acute basilar artery thrombosis. She underwent timely thrombolysis and was transferred for endovascular thrombectomy. Further evaluation with an aim to define the aetiology revealed the diagnosis of patent foramen ovale with a resultant paradoxical embolism. The differential diagnoses of unexplained rapidly evolving neurology with reduced Glasgow coma scale, and relevant appropriate investigations are discussed in this case report.

The association between patent foramen ovale and unexplained syncope in pediatric patients.

BACKGROUND: Patent foramen ovale (PFO) is associated with transient ischemia attack (TIA) or stroke, paradoxical embolism, and migraines. PFO closure decreases the recurrent incidence of cerebral ischemic events and reduces the incidence of syncope in adults. However, whether PFO is associated with syncope in pediatric patients has not been investigated. METHODS: 1001 pediatric patients (aged 4 to 17 years, mean age 10.31 ± 2.61 years, 519 males) who complained of unexplained syncope, palpitation, headache, dizziness and chest pain and were hospitalized in the Syncope Ward, The Second Xiangya Hospital, Central South University between January 2013 and April 2022 were recruited. Children with definite etiology of syncope, neurological, cardiogenic, psychological and other system diseases were excluded. PFO was measured by transthoracic echocardiography and right-heart contrast echocardiography was performed to identify the presence of right-to-left shunting. The demographic data and medical records were retrospectively reviewed and analyzed. RESULTS: 276 cases were included in the simple syncope group, 379 cases in the headache/dizziness group, 265 cases in the chest pain group, and 81 cases in the palpitation group. The incidence of PFO between the four groups was insignificant (4.71%, 4.74%, 4.15%, 6.17%, respectively, P = 0.903). Multivariate Logistic regression demonstrated that PFO is not associated with the increased risk of syncope (P = 0.081). CONCLUSION: PFO may not increase the risk of syncope in pediatric patients. Further study may include a large and multicenter sample to investigate the association between PFO and unexplained syncope.

NET-Induced Carcinoid Heart Disease Affecting Both Tricuspid and Aortic Valves Due to Patent Foramen Ovale and Right/Left Shunt: A Multi-imaging Challenge to Nuclear Medicine.

ABSTRACT: Carcinoid heart disease (Hedinger syndrome) is a long-term consequence in hormone-active neuroendocrine tumors with hepatic metastases and carcinoid syndrome. Because of serotonin, excess multiple cardiac and pulmonary symptoms evolve, which are further complicated by a patent foramen ovale due to right-left shunting. We present a 53-year-old man with an ileum-neuroendocrine tumor including gross liver metastases and long-term stable disease who subsequently developed Hedinger syndrome. Initially experiencing progressive dyspnea, he eventually experienced severe hypoxemia due to patent foramen ovale. 99mTc-MAA lung perfusion scintigraphy quantitatively identified the right-left shunting, whereas 68Ga-FAPI-46 PET/CT characterized the typical fibrous heart valve thickening due to serotonin-induced fibroblast proliferative properties.

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.