Patent foramen ovale and migraine: a quantitative systematic review

Initial studies indicate an increased prevalence of patent foramen ovale (PFO) in migraineurs with aura, and an increased prevalence of migraine and migraine with aura in persons with PFO. Retrospective analyses of PFO closure suggest clinically significant improvements in migraine patterns. The aim of this study was to examine the prevalence of migraine in patients with PFO, the prevalence of PFO in migraineurs, and the effect of PFO closure on migraine. We conducted a quantitative systematic review of articles on migraine and PFO that met inclusion criteria, then reviewed, appraised, and subjected them to data extraction. Of 134 articles identified, 18 met a priori selection criteria. The estimated strength of association between PFO and migraine, reflected by summary odds ratios (ORs), was 5.13 [95% confidence interval (CI) 4.67, 5.59], and between PFO and migraine with aura the OR was 3.21 (95% CI 2.38, 4.17). The grade of evidence was low. The association between migraine and PFO was OR 2.54 (95% CI 2.01, 3.08). The grade of evidence was low to moderate. Six studies of PFO closure suggested improvement in migraine, but had a very low grade of evidence. The low-to-moderate grade of evidence from observational studies supports an apparent association between PFO and migraine. Although PFO closure seemed to affect migraine patterns favourably, the very low grade of available evidence to support this association precludes definitive conclusions.     

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.     

Is migraine associated with right-to-left shunt a separate disease? Results of the SAM study

Migraine with aura (MA) is associated with the persistence of patent foramen ovale (PFO) in about 50% of cases, and migraineurs tend to have larger shunts than controls, suggesting that right-to-left shunt (RILES) determined by PFO could play a role in triggering migraine attacks. Moreover, some preliminary reports have suggested that PFO closure may give relief to both migraine and aura attacks. The aim of this study was to clarify if shunt-associated migraine (SAM) has clinical features that allow a distinction from shunt-unrelated migraine (SUM), in a prospective, multicentre, observational study (SAM study). We enrolled consecutive MA patients, who underwent a structured, standardized questionnaire for family and personal history and for detailed migraine features. All were systematically screened for RILES with transcranial Doppler, and for coagulation disorders. Overall, 460 patients were included; the SUM and SAM classes comprised 58% and 42% of patients, respectively. SAM patients were significantly younger (34.1 ± 10 vs. 37.1 ± 11 years), had a more frequent family history of migraine (76% vs. 66%) and a higher frequency of sensory symptoms of aura (51% vs. 41%); by contrast, there was a lesser association of SAM with other cardiac abnormalities and with coagulation disorders. The SAM study suggests that the effect of RILES on migraine features is not relevant. The higher family history of migraine in SAM suggests a possible genetic linkage between migraine and RILES.     

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.     

Patent foramen ovale and migraine: Association, causation, and implications of clinical trials

Patent foramen ovale (PFO) appears to be associated with migraine with aura (MA), probably through cardiac shunting. PFOs may also be comorbid with cryptogenic strokes. Although multiple open-label, retrospective, and case-controlled studies have noted sometimes dramatic reductions of MA after PFO closure, the only prospective sham-controlled study of PFO closure for MA, MIST, was negative for all primary and secondary measures of migraine improvement. MIST did demonstrate an association between MA and severe PFO shunts prospectively. Difficulty with recruitment closed the MIST II and ESCAPE trials; the PREMIUM and PRIMA randomized controlled trials are ongoing at the time of this writing.     

Two-dimensional echocardiography using second harmonic imaging for the diagnosis of intracardiac right-to-left shunt: a meta-analysis of prospective studies

Right-to-left shunting (RLS), usually through a patent foramen ovale (PFO), has been associated with migraine, cryptogenic stroke and hypoxemia. With emerging observational studies and clinical trials on the subject of PFO, there is a need for accurate diagnosis of PFO in patients being considered for transcatheter closure. While transesophageal echo (TEE) bubble study is the current standard reference for diagnosing PFO, transthoracic echo with second harmonic imaging (TTE-HI) may be a preferable screening test for RLS due to its high accuracy and non-invasiveness. The aim of this meta-analysis was to determine the accuracy of TTE-HI compared to TEE as the reference. A systematic review of Medline, Cochrane and Embase was done for all the prospective studies assessing for intracardiac RLS using TTE-HI compared to TEE as the reference; both TTE-HI and TEE were performed with a contrast agent and a maneuver to provoke RLS in all studies. A total of 15 studies with 1995 patients fulfilled the inclusion criteria. The weighted mean sensitivity and specificity for TTE-HI were 91 and 93 % respectively. Likewise, the positive and negative likelihood ratios were 13.52 and 0.13 respectively. TTE-HI is a reliable, non-invasive test with proficient diagnostic accuracies. The high sensitivity and specificity of TTE-HI make it a useful initial screening test for RLS. If the precise anatomy is required, then TEE can be obtained before scheduling a patient for transcatheter PFO closure.     

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.     

Patent foramen ovale: assessment, clinical significance and therapeutic options

Foramen ovale plays an important function in the fetus but is of no physiologic significance after birth and closes in most individuals. In about one fourth of the population, however, foramen ovale remains open for life and has been associated with cerebrovascular accidents, especially in younger patients, presumably through paradoxical embolism. Patent foramen ovale (PFO) has also been associated with hypoxia, migraine headaches and neurologic findings of decompression illness in scuba divers. Availability of transesophageal echocardiography and its frequent use in the management of patients with stroke has lead to frequent detection of PFO. In addition, the recent development of devices and techniques for percutaneous closure of PFO has resulted in widespread enthusiasm for such interventions, even when a clear etiologic role for PFO may not be established. In the United States, the Federal Drug Administration (FDA) has approved two such devices through compassionate investigational device exemption without adequate data from large randomized clinical studies. Other such devices are undergoing evaluation in clinical trials. Expert opinions have been helpful for clinical decision making in management of patients with PFO associated with stroke, hypoxia, decompression sickness and migraine headaches.     

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。     

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.     

卵圆孔封堵术治疗偏头痛合并右向左分流的临床研究

目的:评价卵圆孔封堵术治疗偏头痛合并右向左分流(RLS)的临床疗效及安全性。方法:偏头痛合并RLS患者114例随机分为手术组及对照组,各57例;手术组采用卵圆孔封堵术治疗,对照组采用常规药物治疗。观察治疗后1年2组HIT-6评分与评分差值;术后1月内与1年后并发症发生率;术后24 h与1年后残余分流及新发梗死灶情况。结果:治疗1年后,手术组HIT-6评分为(49.57±4.58)分,差值为(14.38±3.57)分;对照组HIT-6评分为(56.85±5.69)分,差值为(8.64±2.24)分,2组差异均有统计学意义(P0.05)。术后1月内发生并发症11例(19.30%),1年后并发症均消失。术后24 h大量残余分流患者8例(14.04%),1年后仅1例(1.92%)存在大量残余分流。治疗1年后,手术组患者7例出现新发梗死灶,对照组17例,2组差异有统计学意义(P0.05)。结论:卵圆孔封堵术可有效改善患者偏头疼症状,安全性高,并可降低脑卒中发病风险。     

A case of atypical sporadic hemiplegic migraine associated with PFO and hypoplasia of vertebro-basilar system

We describe the case of a patient with atypical hemiplegic migraine and associated basilar symptoms, where a large patent foramen ovale (PFO) and hypoplasia of basilar artery were found. The longer period of 4-year remission of the headache attacks was coincident with the percutaneous PFO closure. When 5 years after, hemiplegic migraine attacks relapsed, with more relevant basilar symptoms, a mild re-opening of PFO was found. The atypical presentation of attacks with basilar symptoms and prolonged hemiplegia does not strictly fit the diagnostic criteria of ICHD-II.     

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.     

Current views of the risk of stroke for migraine with and migraine without aura

The association between migraine and stroke is complex and is a continued focus of attention. Several observational studies have identified migraine as an independent risk factor for ischemic stroke. However, a distinction should be made between migraine with and migraine without aura. The migraine-stroke association is mostly apparent for young women with migraine with aura. The association between migraine with aura and stroke is weaker in older age groups, which may be due to the fact that traditional cardiovascular risk factors are more prominent with increasing age. Most studies have not found an association between migraine without aura and ischemic stroke. Although there are several hypotheses about the biologic link between migraine with aura and ischemic stroke, the precise mechanisms remain unclear. However, because the absolute risk of stroke is low in patients with migraine with aura, and migraine without aura is likely not associated with ischemic stroke, most migraine patients will not experience a stroke event.     

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.     

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: 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.     

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.