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.     

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.     

Patent foramen ovale and migraine--bringing closure to the subject

There is increasing interest in the relationship between migraine and patent foramen ovale (PFO). PFO is more common in migraineurs with aura, and migraine with aura is more prevalent in patients with PFO. Retrospective analyses of PFO closure for stroke prevention and decompression illness in divers have suggested that migraineurs with and without aura may derive significant benefit from PFO closure, but to date no prospective, randomized, sham-controlled study to confirm this has been completed. Herein we review published data regarding the relationship between migraine and PFO and discuss the rationale, justification, and important factors to consider in the conduct of prospective, controlled, clinical trials designed to evaluate the efficacy and safety of percutaneous device closure of PFO for migraine prevention.     

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.     

To close or not to close: contemporary indications for patent foramen ovale closure

Introduction: Patent foramen ovale (PFO) is a common congenital cardiac abnormality and that has been associated with several disease processes including transient ischemic attacks (TIA), stroke, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis. Controversy exists regarding closure of PFO as a therapeutic treatment modality for these disease processes. This review addresses the contemporary clinical indications for PFO closure.

Areas covered: We conducted a comprehensive literature search of contemporary research studies focusing on randomized trials and meta-analyses comparing medical therapy and device closure of PFOs for the treatment of PFO associated clinical syndromes. We synthesized this literature into a review addressing indications for PFO closure in stroke, TIA, migraine headaches with aura, decompression sickness, platypnea-orthodeoxia syndrome, and shunt induced cyanosis.

Expert commentary: Because in many PFO associated conditions it can be difficult to determine the degree to which the PFO is a causative factor in the disease process, we recommend a comprehensive diagnostic evaluation to exclude other obvious etiologies of PFO associated conditions before implicating the PFO and proceeding with closure. However in the properly selected patient population there is growing clinical experience and experimental evidence suggesting that closure of PFO is a safe and effective treatment modality.     

Clinical manifestation and current management of patent foramen ovale

There is increasing interest in the evaluation and treatment of patent foramen ovale, which has been associated with various pathologic conditions, such as cryptogenic stroke, platypnea–orthodeoxia syndrome and migraine. However, optimal treatment of patients with patent foramen ovale has not been established. This article aims to review the clinical manifestation and current therapeutic options for patent foramen ovale.     

Patent foramen ovale (PFO): is there life before death in the presence of PFO?

Patent foramen ovale (PFO) is an embryologic remnant with incomplete postnatal adhesion of the cardiac atrial septum primum and secundum. After birth, the prevalence of PFO decreases from about 35% at young to approximately 20% at old age. PFO has been associated with numerous conditions such as decompression illness in divers, migraine, high‐altitude pulmonary oedema, cerebrovascular and coronary ischaemia, and obstructive sleep apnoea syndrome. PFO is the cause of intermittent atrial right‐to‐left shunt, and it can be the source of cardiac paradoxical embolism. So far, randomized controlled trials have not documented a reduced rate of cerebrovascular recurrent events in patients receiving PFO device closure as compared to those on medical treatment. The purpose of this article was to critically evaluate evidence on the pathophysiologic, clinical as well as prognostic relevance of PFO.     

Patent foramen ovale transcatheter closure device thrombosis

The role of patent foramen ovale (PFO) in patients with cryptogenic stroke (stroke of unknown cause) remains controversial, although an association seems likely in younger patients with atrial septal aneurysms and PFO. The mechanism of cryptogenic stroke in these patients is presumed to be paradoxical embolism via right-to-left shunt across the PFO. The available options for treatment include medical therapy with antiplatelet or anticoagulant therapy or closure of the PFO surgically or with use of transcatheter PFO closure devices. We describe 2 cases of bilateral device thrombosis associated with use of a transcatheter PFO closure device (CardioSEAL). To our knowledge, only 1 other case of thrombosis associated with use of this device has been reported.     

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.     

Clinical impact of patent foramen ovale diagnosis with transcranial Doppler.

The role of patent foramen ovale (PFO) in cryptogenic stroke is still debated, but from recent follow-up studies it seems that the amount of right-to-left shunt (RLS) and the association with atrial septal aneurysm (ASA) are major determinants of stroke recurrence. PFO and RLS through the atrial chambers have been recently studied in a number of conditions not or marginally related to cerebrovascular disease. Historically the first studies addressed the presence of RLS in scuba divers as a possible abnormality related to decompression sickness (DS) of unknown aetiology. Despite initial debate there is now robust evidence to claim that patency of foramen ovale increases the risk of developing DS by two and half to four times. Patients with PFO-related DS tend to have early occurrence of symptoms after surfacing and a clinical presentation that indicates brain or upper cervical spinal cord involvement. Recent reports suggest that divers with hemodynamically significant RLS may have an increased risk of developing clinically asymptomatic multiple brain lesions. PFO has been found in patients suffering from migraine with aura with approximately the same frequency as that encountered in cryptogenic stroke patients. This finding has prompted speculations on the possible role of RLS in increasing the stroke risk in migraineurs and in the pathophysiology of the aura. Recent reports showing that migraine with aura is dramatically improved after transcatheter closure of PFO suggest that migraine with aura may indeed be triggered by humoral factors that reach the brain by escaping the pulmonary filter. A RLS is involved in a rare condition known as platypnea-orthodeoxia and perhaps underlies an increased risk of cerebral complications after major orthopedic surgery. Valsalva-like activities often precede the occurrence of attacks of transient global amnesia (TGA) and abnormalities consistent with hypoperfusion of deep limbic structures have been reported during a typical TGA episode. This had raised the hypothesis that TGA may be triggered by paradoxical embolism of platelets aggregates in the posterior circulation, but the search for an increased frequency of PFO in TGA patients has yielded conflicting results. Conditions that determine an increase in pulmonary pressure may facilitate the opening of the virtual interatrial valve and thus promoting shunting of blood to the left heart chambers which in turn might contribute to further desaturation of arterial blood. It is therefore not surprising that RLS has been found in 70% of patients with chronic obstructive pulmonary disease and increased pulmonary pressure and in the same proportion of patients with obstructive sleep apnoea, a condition that ultimately may result in pulmonary hypertension. In conclusion, from the evidence gathered so far the picture is emerging of an important role of PFO in a number of non-stroke conditions, either as causative factor or as associated condition predisposing to complications. The availability of simple diagnostic techniques such as transcranial Doppler (TCD) to assess RLS will undoubtedly contribute a great deal of knowledge on the relevance in medicine of this hitherto neglected condition.     

Percutaneous closure of patent foramen ovale: safe and effective but underutilized

With three recently published randomized trials on patent foramen ovale (PFO) closure, the concept of PFO closure to reduce recurrent strokes has been proven; however, PFO closure is currently only considered for secondary prevention. Given the potential devastating consequences of a PFO-related event, we advocate screening for and closure of a PFO for primary prevention in high-risk populations. Such populations include patients who are suffering from a disease that is associated with PFO (e.g., migraine) or patients with high-risk hobbies/professions (e.g., weight-lifters, frequent-flyers, and deep sea divers). Looking at young people with a remaining average life expectancy of 50 years, we have to close 2.4 PFOs to prevent one stroke. This should support a more proactive attitude toward PFO screening and closure.     

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.     

Patent foramen ovale and migraine

Results from several observational studies indicate an association between migraine and patent foramen ovale (PFO). Several biological mechanisms have been proposed to explain this link, including shared genetic inheritance. However, there is currently insufficient evidence to support a causal link between PFO and migraine. Although the results of uncontrolled observational studies suggest the PFO closure may have a beneficial effect on migraine frequency, a large randomized trial failed to support such a conclusion. Until there is more evidence from ongoing large controlled trials, PFO closure should not be performed in clinical practice for the prophylaxis of migraine.     

卵圆孔未闭与偏头痛发病相关性的Meta分析

目的:采用Meta分析探讨卵圆孔未闭(PFO)与偏头痛发病的相关性。方法:计算机检索PubMed、EMbase、The Cochrane Library、Web of Science、CNKI、VIP、WanFang Data及CBM数据库,收集观察PFO与偏头痛发病相关性的病例对照研究或横断面研究或队列研究,检索时限从建库至2018年8月1日。由两名评价者按照纳入与排除标准筛选文献、提取资料,并进行NOS文献质量评价,采用RevMan 5.3软件进行Meta分析。结果:共纳入30篇文献,样本量为9 177例。Meta分析结果显示偏头痛组与健康对照组PFO发生率差异有统计学意义(OR=3.19,95%CI为2.20～4.63,P0.01),先兆偏头痛组与健康对照组PFO发生率差异有统计学意义(OR=3.71,95%CI为2.13～6.46,P0.01),无先兆偏头痛组PFO发生率高于健康对照组(OR=1.48,95%CI为1.09～2.00,P=0.01),先兆性偏头痛组PFO发生率高于无先兆性偏头痛组(OR=2.32,95%CI为1.96～2.76,P0.01)。PFO组的偏头痛率高于健康对照组(OR=2.58,95%CI为1.57～4.25,P0.01)。结论:PFO与偏头痛存在明显相关性。     

Migraine and cerebrovascular disease

Migraine and cerebrovascular disease are linked in different ways: migraine may be a potential cause of stroke as in migrainous infarction, headache may be a symptom of cerebrovascular disease and also a risk factor for stroke, the association of migraine and stroke may constitute specific syndromes such as CADASIL and MELAS. The new IHS 2003 criteria, though preserving their main structure, have changed the terminology regarding secondary headaches, now described as “attributed to” another disease rather than “associated with” it. The more detailed knowledge of causal links between the underlying disorder and headache, has allowed to strengthen the terminology. Many cerebrovascular disorders as cerebral haemorrhage, venous sinus thrombosis, carotid or vertebral dissections and ischaemic stroke may present with a headache or be followed by it. In subarachnoid haemorrhage (SAH) headache may constitute an important warning sign before the bleeding. An interesting issue is the hypothesis that migraine may be a potential risk factor for stroke. Recent studies have underlined the increased relative risk of ischemic stroke in female migraineurs. Many potential mechanisms have been hypothesized: (1) alterations of vasoreactivity due to vessel wall dysfunction, (2) release of vasoactive substances during migraine, (3) platelet hyperactivity as expression of serotoninergic dysfunction in migraineurs, (4) intriguing studies have described a high prevalence of migraine with aura in stroke patients with patent foramen ovale (PFO). Differential diagnosis between migraine and stroke remains fundamental: some types of migraine can mimic cerebrovascular disease such as familial hemiplegic migraine, and basilar migraine. Migraine and stroke may be part of syndromic complexes as in CADASIL and MELAS. In conclusion migraine is a risk factor for cerebrovascular disease, it may be the cause of stroke as in migrainous infarctions, stroke may induce headache which may be a relevant symptom of cerebrovascular disease, yet migraine remains an essentially benign condition.     

Relationship between migraine and patent foramen ovale: a study of 121 patients with migraine

BACKGROUND: Migraine is a common neurological disorder, the origins of which remain unknown. Patent foramen ovale (PFO) is considered to have a role in migraine. The relationship between migraine and patent foramen ovale may be stronger in patients suffering from migraine with aura compared to patients with common migraine. OBJECTIVES: The aim of the study was to evaluate the frequency of PFO in patients with migraine with aura (MA+) and compare it with the prevalence of PFO in migraine patients without aura (MA-), and in a healthy age-matched control group. We investigated PFO association with migraine, considering such factors as: A type of migraine aura, frequency of attacks, familial occurrence, sex and age of patients. Patients.-121 patients: 61 patients suffering from migraine with aura, 60 without aura and 65 normal controls. The group of patients with migraine with aura was divided into subgroups regarding to the type of aura. METHODS: In order to detect PFO the contrast transcranial Doppler was performed during Valsalva maneuver. RESULTS: The presence of PFO was found in 33/61 (54%) patients with MA(+) compared to 15/60 (25%) without aura and 16/65 (25%) control subjects. The difference between MA(+) patients and MA(-) patients and the difference between MA(+) patients and control group was statistically significant (P < .05). There was no association between type of migraine aura and PFO, as well as we found no association between PFO and frequency of attacks, familial occurrence, sex and age of patients and PFO. CONCLUSIONS: Our findings suggest possible association of migraine with aura and PFO. It seems that PFO does not influence the type of aura and frequency of attacks of migraine as well as it is not associated with familial occurrence of migraine.     

An unusual case of stroke in a young patient

The patent foramen ovale (PFO) has been increasingly implicated in the aetiology of stroke, particularly in young patients with no other identifiable cause (cryptogenic stroke). A case of Parinaud's syndrome secondary to thromboembolism from a PFO is reported here.     

Cardioembolic Stroke in Patients with Patent Foramen Ovale and Implanted Cardiac Leads

Implanted cardiac devices, including pacemakers, defibrillators, and resynchronization devices, are known to develop thrombus on their intravascular leads. Patent foramen ovale (PFO) occurs in approximately one‐quarter of the adult population. It is unclear whether paradoxical cardioembolism and clinically relevant stroke occur in patients with implanted cardiac leads and PFO. We present a case series of four patients with cardioembolic stroke, presumed to arise from intravascular cardiac leads and associated PFO that required device closure of the PFO. (PACE 2013; 36:50–54)