Closing the gap on patent foramen ovale and cryptogenic stroke

Introduction: The treatment options for prevention of recurrent of cryptogenic stroke in patients with patent foramen ovale (PFO) have been intensely debated in the recent decades. The suggested options were percutaneous closure of PFO versus medical therapy. However, up to these date there is a controversy regarding the indication of percutaneous closure. Multiple meta-analysis and recent randomized control trials showed the benefit of PFO closure when compared with medical therapy alone.

Areas covered: The article reviews the prevalence, physiology, diagnosis and treatment options of PFO after cryptogenic stroke. Furthermore, it will discuss the results of randomized control trials that compared the PFO closure to medical therapy.

Expert opinion: The association between PFO and unexplained cryptogenic stroke has been well established in the multiple studies. The diagnosis and management of PFO might be challenging in some cases. Although multiple studies showed that PFO closure is associated with lower rates of recurrent stroke in patients presenting with cryptogenic stroke, the indication and patient selection for this intervention are not well established yet in the guidelines.     

Patent foramen ovale: a nonfunctional embryological remnant or a potential cause of significant pathology?

A patent foramen ovale (PFO) is an embryological remnant found in 27% of adults. It is a potential right-to-left intracardiac shunt. Shunting may be the result of reversal in the interatrial pressure gradient or abnormal streaming of blood in the right atrium. The pathologic consequences of right-to-left shunting include hypoxemia and paradoxical embolism. PFO may exacerbate preexisting hypoxemia or be its primary cause. Paradoxical embolism through a PFO is well documented. Its role in cryptogenic stroke remains controversial. A PFO may be detected by both invasive and noninvasive techniques. Contrast transesophageal echocardiography with provocative maneuvers is the diagnostic method of choice allowing visualization of the shunt. Patients with cryptogenic stroke should be screened for a PFO. If detected, noninvasive studies for deep vein thrombosis are recommended. Treatment must be tailored to the presentation. Surgical or transcatheter closure is recommended for hypoxemia. Prevention of venous embolism (air or thrombus) with or without closure of the PFO is recommended for paradoxical embolism.     

Patent Foramen Ovale: Pivotal Role of Transesophageal Echocardiography in the Indications for Closure,Assessment of Varying Anatomies and Post-procedure Follow-up

Patent foramen ovale (PFO) is present in 15%–30% of the general population and has been associated with various pathologic states, including cryptogenic stroke, platypnea–orthodeoxia syndrome, decompression sickness and migraine with auras. Transesophageal echocardiography (TEE) has a major role in the diagnostic evaluation of PFO, as well as in the post-procedural assessment after transcatheter closure. The goals of this article were to synthesize the echocardiographic transesophageal techniques required for accurate PFO diagnosis and careful anatomic assessment of its anatomic variants, to focus TEE indications for device closure as complementary to clinical indications and to assess the role of TEE in the post-procedure follow-up.     

MIGRAINE EPIDEMIOLOGY, CLINICAL PRESENTATIONS, AND COMORBIDITY

A patent foramen ovale (PFO) is a frequent remnant of embryological development with clinical importance in thromboembolism, paradoxical embolism, stroke, platypnea-orthodeoxia, decompression sickness, and migraine headache. The proposed mechanisms of stroke with PFO include paradoxical embolization, in situ thrombosis within the canal of the PFO, associated atrial arrhythmias, and concomitant hypercoagulable states. Prospective trials using aspirin treatment to reduce recurrent stroke showed a significant recurrence of neurologic events in patients with a PFO and atrial septal aneurysm. Use of warfarin anticoagulation does not further reduce recurrent stroke rates compared with antiplatelet therapy. Both surgical and catheter-based modes of closure have been shown to decrease the rate of subsequent embolic events substantially. Successful closure, defined by transesophageal echocardiography, appears to predict freedom from subsequent embolic events. To our knowledge, no randomized trials comparing anticoagulation with surgical or catheter-based closure have been performed.     

Patent foramen ovale and stroke

A patent foramen ovale (PFO) is a frequent remnant of embryological development with clinical importance in thromboembolism, paradoxical embolism, stroke, platypnea-orthodeoxia, decompression sickness, and migraine headache. The proposed mechanisms of stroke with PFO include paradoxical embolization, in situ thrombosis within the canal of the PFO, associated atrial arrhythmias, and concomitant hypercoagulable states. Prospective trials using aspirin treatment to reduce recurrent stroke showed a significant recurrence of neurologic events in patients with a PFO and atrial septal aneurysm. Use of warfarin anticoagulation does not further reduce recurrent stroke rates compared with antiplatelet therapy. Both surgical and catheter-based modes of closure have been shown to decrease the rate of subsequent embolic events substantially. Successful closure, defined by transesophageal echocardiography, appears to predict freedom from subsequent embolic events. To our knowledge, no randomized trials comparing anticoagulation with surgical or catheter-based closure have been performed.     

Intra-atrial thrombus after surgical closure of patent foramen ovale.

Patent foramen ovale (PFO) represents a potential path for paradoxical embolism and is associated with cryptogenic stroke. It has been suggested that because a PFO represents a repairable lesion (by surgical or transcatheter methods), repair may be the optimal treatment to prevent recurrent stroke. This report describes a patient with recurrent neurologic and peripheral embolic events, which occurred approximately 6 months after the surgical closure of a PFO. The diagnosis of an intra-atrial thrombus with a small residual PFO was made by subsequent transesophageal echocardiography. Thrombus formation at the closure site needs to be considered in a patient with recurrent embolic events after closure of a PFO.     

Current evidence for closure of a patent foramen ovale for cryptogenic stroke prevention

A patent foramen ovale (PFO) has long been implicated as a potential mechanism for cryptogenic stroke (CS), which accounts for up to 40% of all cases of ischaemic stroke. Although there is a strong association between a PFO and CS, there is less evidence that percutaneous closure of the defect, as opposed to medical therapy with antithrombotics or anticoagulants, is the most effective form of secondary prevention. The aim of this review is to examine the evidence comparing percutaneous closure with medical therapy, with a particular focus on three recently published randomised controlled trials.     

Patent foramen ovale closure: past, present and future

Patent foramen ovale (PFO) is a common congenital abnormality that has been implicated in a number of disease processes, including cryptogenic stroke and migraine headaches. Medical treatment for these processes is often considered inadequate and mechanical closure of the PFO is an attractive, albeit controversial, alternative. PFO closure has become common practice in many centers, although recent guidelines limit its indication to certain subsets of patients. This review first focuses on the anatomy, physiology and pathophysiology of PFO, and then reviews the currently available and experimental devices for PFO closure, as well as the present clinical data pertaining to them. Finally, we present our perspective of the PFO closure, with regard to its current use and future directions.     

Patent foramen ovale closure: past,present and future

Patent foramen ovale (PFO) is a common congenital abnormality that has been implicated in a number of disease processes, including cryptogenic stroke and migraine headaches. Medical treatment for these processes is often considered inadequate and mechanical closure of the PFO is an attractive, albeit controversial, alternative. PFO closure has become common practice in many centers, although recent guidelines limit its indication to certain subsets of patients. This review first focuses on the anatomy, physiology and pathophysiology of PFO, and then reviews the currently available and experimental devices for PFO closure, as well as the present clinical data pertaining to them. Finally, we present our perspective of the PFO closure, with regard to its current use and future directions.     

经食管超声心动图联合PLR、NLR对卵圆孔未闭合并隐源性卒中患者的诊断价值

  目的  探讨经食道心脏超声(TEE)联合血小板/淋巴细胞比值(PLR)、中性粒细胞/淋巴细胞比值(NLR)在卵圆孔未闭(PFO)患者合并隐源性卒中的评估应用。  方法  选取本院2019年8月~2021年8月收治的卵圆孔未闭患者132例,其中合并隐源性卒中23例。所有患者均接受TEE检测,测量PFO直径,并行血常规检测,根据血小板、淋巴细胞、中性粒细胞计数计算PLR、NLR比值,比较PFO合并隐源性卒中和未合并隐源性卒中PLR、NLR比值的差异性,采用Spearman法分析PFO直径、PLR、NLR与PFO合并隐源性卒中的相关性,采用ROC曲线分析PFO直径和PLR、NLR检测在卵圆孔未闭合并隐源性卒中的评估价值。  结果  TEE检测发现PFO未合并隐元性卒中患者PFO直径低于合并隐源性卒中(P < 0.05),造影可见房水平不同级别的右向左分流;PFO患者合并隐源性卒中PLR、NLR比值高于未合并隐源性卒中患者(P < 0.05);Spearman分析显示:PFO直径及PLR、NLR比值与PFO合并隐源性卒中风险呈正相关关系(r=0.385、0.429、0.378,P < 0.05);ROC曲线显示:PFO直径联合PLR、NLR评估PFO合并隐源性卒中风险曲线下面积高于PLR、NLR单项指标曲线下面积(P < 0.05)。  结论  TEE可以较好地分辨PFO直径,结合PLR、NLR检测有助于评估PFO合并隐源性卒中的发生风险。      

PFO closuRE and CryptogenIc StrokE (PRECISE) registry: a multi-center, international registry

Background

The Premere? PFO closure device has a special design for closure of patent foramen ovale (PFO) including a flexible distance and angulation between the right and left disc providing minimal septal distortion. The primary objective of the study was to determine the degree of risk for stroke or transient ischemic attack (TIA) in patients after Premere? PFO closure device implantation.

Methods

In this multicenter, prospective observational registry, patients with a clinical indication for PFO closure were included. Patients had a history of stroke or TIA with right to left shunt. Follow-up visits were scheduled according to routine clinical practice.

Results

In 23 centers from 10 countries, 267 patients with successful device implantation were included. Assessment of right to left shunt after device implantation revealed no residual shunt in 71?%, small shunts in 16.8?%, and moderate or large residual shunts in 5.6 and 6.5?%. With common clinical practice, use of Coumadin or heparin decreased from 27?% pre- to 3?% post-implantation, while use of acetylsalicylic acid or thienopyridines increased from 64 to 95?% and 27 to 80?%, respectively; 18?% of patients were discharged with anti-platelet monotherapy. Mean follow-up was 11?±?9?months (range 1–24?months). There was no stroke or TIA. During follow-up, there was one sudden death. Atrial fibrillation occurred in five (1.9?%) patients. One (0.4?%) patient with a thrombophilic diathesis developed a thrombus.

Conclusions

In this prospective, international, multicenter PRECISE registry, the use of the Premere? PFO closure device for closure of PFO after stroke or TIA resulted in good clinical results with no recurrent event.     

Persisting eustachian valve in adults: relation to patent foramen ovale and cerebrovascular events.

BACKGROUND: The eustachian valve (EV) (valvula venae cavae inferioris) is a remnant of the embryonic right valve of the sinus venosus. Embryologically, the EV directs oxygenated blood from the inferior vena cava across the patent foramen ovale (PFO) into the systemic circulation. Transthoracic echocardiography shows the EV in the majority of newborns, but the prevalence of EV in adults studied with transesophageal echocardiography is unknown. We studied whether the presence of an EV is associated with PFO or with cryptogenic stroke. METHODS: The frequency and size of the EV was studied in 211 consecutive patients undergoing transesophageal echocardiography after a cryptogenic stroke and in 95 consecutive patients without cerebrovascular events. In all 306 patients, the presence of a PFO was studied with 2-dimensional transesophageal echocardiographic, color Doppler, and contrast echocardiographic studies. RESULTS: An EV was seen in 174 of 306 patients overall (57%). The mean size was 1.0 +/- 0.4 cm (range: 0.5-2.0); 70% of patients with an EV had a PFO (Cohen's kappa = 0.75; P <.001). This relationship was not significantly influenced by a cryptogenic stroke. The prevalence of PFO was 30% in the control group and 61% for those with presumed paradoxical embolism (P <.001). Thus, an EV was more common for patients with presumed paradoxical embolism than in control patients (143 of 211 68% vs 31 of 95 33%, respectively, P <.001). There was no significant difference in the size of the EV between the 2 groups (1.1 vs 1.0 cm; P =.24). CONCLUSION: A persisting EV is a frequent finding in patients with a PFO. By directing the blood from the inferior cava to the interatrial septum, a persisting EV may prevent spontaneous closure of PFO after birth and may, therefore, indirectly predispose to paradoxical embolism.     

Patent foramen ovale and cryptogenic stroke: contemporary evidence and treatment

Introduction: Patent foramen ovale (PFO) is a common anatomical variant in the adult circulation. It is a channel allowing communication between the left and right atria and is a remnant of the foetal circulation. In approximately 25% of the population, this channel persists into adulthood. PFO has been proposed as a potential pathophysiological mechanism for cryptogenic stroke.

Areas covered: This review will examine the contemporary evidence for both the association between cryptogenic stroke and PFO and the management of this condition. The authors hope to provide a comprehensive overview of the current evidence and best practice in relation to PFO closure. In addition, the authors will propose some potential avenues for future research in this controversial area and try to predict how PFOs in cryptogenic stroke will be managed in the near future.

Expert commentary: In carefully selected patients with cryptogenic stroke, PFO closure represents an evidence based treatment option for the prevention of further ischemic neurological events. A multidisciplinary approach is necessary to ensure appropriate patient selection for the procedure. This should include a vascular neurologist/stroke physician and an interventional cardiologist with an interest in PFO closure.     

Percutaneous closure of patent foramen ovale: a case series and literature review

Patent foramen ovale (PFO) is an anatomical variant of the interatrial septum with an overall prevalence of 27% in autopsy studies. PFOs have a potential role in causation of stroke, platypneaorthodeoxia, decompression sickness, right to left shunt and migraine headaches. Data regarding percutaneous closure of PFO in low volume tertiary care centers is lacking. Retrospective review of 14 percutaneous PFO closures done in our facility from March 2005 to August 2006 was performed for efficacy of procedure and safety. All patients received clopidogrel for a period of 3 months, and aspirin and subacute bacterial endocarditis prophylaxis for 6 months. Mean age of the study population was 54 years. Fifty percent (7 of 14) of patients experienced an atrial septal aneurysm and 14% (2 patients) exhibited a hypercoagulable state. The indication for closure in 13 patients was transient ischemic attacks or strokes, while one patient had persistent hypoxia due to a severe right to left shunt at PFO. Patients received either a CardioSEAL or Amplatzer device. Deployment rate was 100%. All patients completed a minimum of 6 months of follow-up, with a mean follow-up time of 14.9 +/- 7.6 months. No immediate or late bleeding complication occurred in any patient. One patient developed paroxysmal atrial fibrillation and one patient developed thrombotic complications at 7 months post-procedure secondary to the progression of her anal carcinoma and subsequently died. Pending the results of the four large randomized trials that are enrolling patients, percutaneous closure of PFO for cryptogenic strokes is an attractive alternative to lifelong anticoagulation with relatively few complications, even in low volume centers. There are many challenges in the management of this subset of patients, the foremost being the selection of a target patient population. Role of PFO in migraines is less clear.     

Impact of Patent Foramen Ovale Anatomic Features on Right-to-Left Shunt in Patients with Cryptogenic Stroke

The purpose of this study was to investigate the impact of the morphologic characteristics of patent foramen ovale (PFO) on right-to-left shunt (RLS) in patients with PFO and cryptogenic stroke using transesophageal echocardiography and saline contrast transthoracic echocardiography (c-TTE). Of the 165 patients with PFO stroke, both the height and the length of PFO in the provoked RLS group were smaller than those in the constant RLS group. PFO height, interatrial septum mobility and proportion of atrial septal aneurysms were greater in the severe RLS group than in the mild and moderate RLS groups. Multivariate analysis revealed that PFO height and interatrial septum mobility were independent predictors of severe RLS. Multiple territorial ischemic lesions were more common in the severe RLS or constant RLS group. Our findings indicated that the severity of RLS was related to the anatomic features in PFO, inducing different cerebral ischemia lesion patterns in cryptogenic stroke patients with PFO.     

Prevalence of patent foramen ovale in migraine patients with and without aura compared with stroke patients. A transcranial Doppler study

The aim of this study was to investigate the prevalence of patent foramen ovale (PFO) in a consecutive unselected cohort of migraine patients (with and without aura) and compare it with a group of ischaemic young and elderly stroke patients. One hundred and forty-one migraine patients were compared with 330 stroke patients (130 young patients; 200 elderly patients) selected from our hospital stroke data bank. PFO was assessed with transcranial Doppler sonography with i.v. injection of agitated saline. The prevalence of PFO was 51.7% in migraine with aura (MA) patients, 33.7% in migraine without aura (MoA) patients, 33.8% in young stroke patients and 20.5% in elderly stroke patients (P < 0.001). The prevalence of PFO in cryptogenic stroke in young and elderly stroke patients was, respectively, 41.1% and 25% (P = 0.04). The difference between MA and MoA patients was significant (odds ratio = 2.1). The prevalence of PFO in MA patients is higher than in MoA patients and in young cryptogenic stroke patients.     

卵圆孔未闭介入封堵预防隐源性脑卒中复发

目的 探究卵圆孔未闭(PFO)封堵治疗的安全性、有效性,进一步讨论介入封堵治疗PFO的临床意义。方法 选取2019年1-7月我院行PFO介入封堵术的PFO患者90例,术前所有患者均行经胸超声心动图右心声学造影（cTTE）及经食道超声心动图（TEE）证实为卵圆孔未闭并存在右向左分流。封堵成功即刻予床旁经胸超声心动图（TTE）,观察封堵器及分流情况。术后3个月,行cTTE及颅脑CT。结果 所有患者均成功置入封堵器,即刻经胸超声心动图证实封堵器位置正常,二、三尖瓣功能正常,未见残余分流,均未出现术中、术后并发症。术后随访3个月,58.9%患者头痛症状完全消失,34.4%患者头痛症状明显改善,发作频率较前明显减少,总的有效率为93.3%。术前27例一侧肢体麻木乏力患者中19例术后肢体麻木乏力症状完全消失,8例肢体麻木乏力症状虽未完全消失但较前不同程度缓解;术前8例恶心呕吐患者,术后症状完全消失。术后3个月复查经胸壁超声心动图右心声学造影示阳性率为5.6%（5/90）。术后3个月复查颅脑CT,提示本研究中90例患者均未发现新发梗死灶,再发脑卒中发生率为0%。结论 介入封堵治疗PFO可明显缓解患者临床症状,解除患者痛苦,减少分流量,降低脑卒中的再发风险,是一种安全、有效的治疗方法,对PFO的治疗具有指导意义。     

右心声学造影与经颅多普勒发泡试验诊断隐源性卒中患者卵圆孔未闭的对比研究

目的：探讨右心声学造影(c-TTE)及经颅多普勒发泡试验(c-TCD)对隐源性卒中患者并卵圆孔未闭(PFO)的诊断价值。方法：选取2020年1月～2022年12月在我院诊治的隐源性卒中患者102例,均行c-TCD及c-TTE检查,以经食管超声心动图(TEE)作为诊断金标准,比较c-TTE、c-TCD检查对隐源性卒中患者PFO的诊断价值。结果：TEE检查证实102例隐匿性卒中患者有44例PFO,c-TCD检查结果显示,真阳性36例,假阳性10例,假阴性8例,真阴性48例；c-TTE检查结果显示,真阳性42例,假阳性3例,假阴性2例,真阴性55例。受试者工作特征(ROC)曲线分析显示,c-TCD检查、c-TTE诊断隐匿性卒中患者PFO的AUC分别为0.823,0.951,c-TCD检查诊断隐源性卒中患者PFO的敏感度、特异度、准确率分别为81.82%、82.76%、82.35%,明显低于c-TTE检查的95.45%、94.83%、95.10%(P<0.05)。c-TCD检查对右向左分流半定量分级低于c-TTE(P<0.05),c-TCD检查对右向左分流的检出率为30.39%,明显低于c-TTE的58.82%(P<0.05)。结论：与c-TCD检查相比较,c-TTE对隐源性卒中患者PFO具有更高的诊断价值,且对隐源性卒中PFO患者的右向左分流半定量分级程度更高、检出率更高。     

Clinical evaluation of a novel occluder device (Occlutech<Superscript>®</Superscript>) for percutaneous transcatheter closure of patent foramen ovale (PFO)

Background

We investigated the safety, feasibility and usefulness for closure of PFO with the new nitinol meshwire PFO-occluder device (Occlutech Figulla^®-single layer occluder) with an unique braiding technology which allows a 50% reduction of meshwork material on the left atrial side in combination with a greater flexibility as compared to the Amplatzer^® occluder device.

Methods

The retention discs of the new PFO Occlutech Figulla^® single layer device (23/25 mm) are connected by a 3 mm waist in the centre with only one right atrial side hub. The left atrial disc is a single flat layer covered by an ultrathin polyethylene terephthalate (PET) patch. We investigated the safety, feasibility and usefulness for closure of PFO in a multicenter clinical trial. Indications for closure included cryptogenic stroke with evidence of a patent foramen ovale in transesophageal echocardiography (PFO max. diameter 13 mm according to sizing balloon). The device was implanted in 36 patients (mean age 57, 18–80 years) by means of fluoroscopy and transesophageal echocardiography (TEE) using a 9 French delivery sheath and employing a femoral vein approach. Both acetylsalicylacid 100 mg/d (6 months) and clopidogrel 75 mg/d (3 months) were administered post interventional. A transthoracal (TTE) and transesophageal echocardiography follow-up examination was performed after 1, 2 and 6 months (TTE day 30 and 180; TEE day 60).

Results

The device was successfully implanted in 36 pts. In one patient PFO implantations was attempted but not crossed with a guide wire. Perioperativly there were no major in-hospital-adverse events or complications thromboembolism, occluder dislodgement, infection or myocardial infarction. One patient had transient atrial fibrillation 2 h after implantation, which terminated medically after 12 h. TEE studies in the remaining 35 pts (one pt was unwilling to further participate) showed a residual shunt in 8.6% (3/35) after 60 days and a left-to-right shunt in 2.6% (1/35) of pts. After 180 days one pt with severe arteriosclerotic heart disease and A.carotic stenosis revealed a stroke without evidence of cardioembolic origin or devices thrombosis.

Conclusions

The novel Occlutech Figulla^® PFO N single layer device appears to be safe, feasible and useful for PFO closure despite a 50% reduction of the meshwire, no distal hub and an improved flexibility of the left atrial disc.

     

超声心动图诊断卵圆孔未闭

卵圆孔未闭（PFO）在成人的发生率约20%~25%,其与年轻患者的隐源性卒中、短暂性脑缺血发等多种疾病有关。超声心动图在PFO的诊断、经皮封堵术中监测及术后随访中均有重要价值。本文对PFO的超声心动图诊断做一综述。