Patent Foramen Ovale and Migraine Hans-Christoph Diener, MD, Tobias Kurth, MD, ScD, and David Dodick, MD
Corresponding author Hans-Christoph Diener, MD Department of Neurology, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail:
[email protected] Current Pain and Headache Reports 2007, 11:236–240 Current Medicine Group LLC ISSN 1531-3433 Copyright © 2007 by Current Medicine Group LLC
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.
Introduction Cardiac embolism is the most frequent cause of ischemic stroke in hospital- and population-based studies. Patent foramen ovale (PFO) with and without atrial septal aneurysm (ASA) has been recognized as a potential risk factor for ischemic stroke. The mechanism of PFOrelated stroke is unclear but may be due to paradoxical embolism from small thrombi that arise in the venous system, cardiac thrombus formation secondary to PFO/ ASA-related cardiac arrhythmia, and/or thrombus formation in the PFO. An emerging body of evidence appears to indicate that PFO is more common in migraineurs with aura, and migraine with aura is more common in patients with PFO. In addition, studies, mostly retrospective and uncontrolled, have examined the effect of PFO closure on migraine headache frequency and severity. This review evaluates the evidence that PFO and migraine are comorbid conditions and the evidence that PFO closure has an effect on migraine outcomes.
PFO in Patients with Migraine Several studies have investigated a possible link between PFO and migraine. Using transcranial Doppler, Del Sette et al. [1] evaluated and compared 44 patients with migraine with aura and 73 patients aged less than 50 years with focal cerebral ischemia with 50 control individuals without cerebrovascular disease or migraine. The prevalence of right-to-left shunt was significantly higher in patients with migraine with aura (41%) and cerebral ischemia (35%) than in controls (8%). Anzola et al. [2] performed a case-control study of 113 consecutive patients with migraine with aura, 53 patients with migraine without aura, and 25 age-matched nonmigraine individuals. The prevalence of PFO was significantly higher in patients with migraine with aura (48%), compared with patients with migraine without aura (23%) and controls (20%). A combined analysis of the two studies showed that female gender does not explain the higher prevalence of PFO in migraine patients [3]. Using different methods (transcranial Doppler, transesophageal echocardiography), several additional studies confirmed the relationship between PFO and migraine with aura (Table 1). In a cross-sectional case-control study, Schwerzmann et al. [4] performed transesophageal contrast echocardiography in 93 consecutive patients with migraine with aura and 93 healthy controls. A PFO was present in 44 (47%) patients with migraine with aura and 16 (17%) control subjects (P < 0.001). A moderate-sized or large shunt was found more often in the migraine group than in controls (38% vs 8%; P < 0.001). Dalla Volta et al. [3] also found a higher prevalence of PFO in 260 patients with migraine with aura (62%), compared with 74 (16%) patients with migraine without aura. In another study, the prevalence of PFO in migraine with aura patients was similar to a group of patients with cryptogenic stroke [5]. Summarizing the available evidence (Table 1) [6,7•,8], there is a relationship between migraine with aura and PFO. The prevalence of PFO is 54% in this group of patients from these studies. There is a much weaker association with migraine without aura (16%). A possible explanation might be that migraine with aura and PFO could be dominantly inherited and share a common genetic background [9].
Patent Foramen Ovale and Migraine Diener et al.
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Table 1. Prevalence of patent foramen ovale in migraine patients and controls Migraine without aura
Controls 8/50 (16%)
< 0.005
54/113 (48%)
12/53 (23%)
5/25 (20%)
0.01
TTE
42/120 (35%)
11/120 (9%)
Schwerzmann et al. [4], 2005
TEE
44/93 (47%)
NA
Dalla Volta et al. [3], 2005
TCD
161/260 (62%)
12/74 (16%)
Dowson et al. [20••], 2006
TTE
220/370 (59%)
NA
NA
Carod-Artal et al. [5], 2006
TCD
9/28 (32%)
52/170 (31%)
Study, year
Method
Any migraine Migraine with aura
Del Sette et al. [1], 1998
TCD
18/44 (41%)
Anzola et al. [2], 1999
TCD
Wilmshurst and Nightingale [33], 2001
Composite
58/141 (41%)
16/30 (53%)
76/185 (41%) 537/986 (54%)
P
NA 16/93 (17%)
< 0.001 NA
44/275 (16%) 81/338 (24%)
NA—not available; TCD—transcranial Doppler; TEE—transesophageal echocardiography; TTE—transthoracic echocardiography.
Table 2. Prevalence of migraine in patients with PFO Study, year
Method
Migraine
With PFO
Without PFO
P
Lamy et al. [14], 2002
TEE
Any migraine
73/267 (27%)
44/314 (14%)
0.02
Sztajzel et al. [13], 2002
TTE, TEE
Migraine with aura
16/44 (36%)
4/30 (13%)
0.03
Sztajzel et al. [13], 2002
TTE, TEE
Migraine without aura
11/44 (25%)
10/30 (33%)
NS
NS—not significant; PFO—patent foramen ovale; TEE—transesophageal echocardiography; TTE—transthoracic echocardiography.
There are two other conditions with right-to-left shunt—pulmonary arteriovenous malformations and atrial septal defects. Pulmonary shunts seem to be associated with a high migraine prevalence [10,11], whereas atrial septal defect shunts are not [12•].
PFO. Migraine was more common in patients with PFO (27.3%) than in those without PFO (14%). PFO was significantly and independently associated with migraine after adjustment for age and sex (odds ratio [OR] = 1.75; 95% CI = 1.08–2.82). This association was particularly strong in patients with PFO and ASA (OR = 2.71; 95% CI = 1.36–5.41).
Migraine in Patients with PFO Sztajzel et al. [13] investigated the prevalence of PFO and migraine in 74 consecutive patients with acute stroke (Table 2). The diagnosis of migraine was ascertained retrospectively according to the criteria of the International Headache Society. PFO was found in 44 of these 74 patients. A total of 41 patients reported migraine, 20 had migraine with aura, and 14 had migraine without aura. Of the patients with PFO, 16 (36%) had migraine with aura, compared to only four (13%) of the patients without PFO (P = 0.03). Of the patients with migraine, 39 were then studied over a mean follow-up of 13 months. Seven of 15 patients with migraine with aura and PFO, treated either with surgical closure or anticoagulants, noticed complete disappearance of migraine with aura attacks. The aim of a study performed by Lamy et al. [14] was to evaluate possible differences in stroke risk factors such as migraine among patients with and without PFO that might give clues to the mechanism of PFO-associated stroke. The prospective, multicenter study involved 581 young cryptogenic stroke patients. The presence of PFO and ASA was assessed by transesophageal echocardiography. Of the 581 stroke patients, 267 (45.9%) had
Is There a Causal Relationship Between PFO and Migraine? The association between migraine and PFO has led to speculation that there may be a causal relationship. Specifically, the right-to-left shunt may serve as a conduit for the passage of particulate or humoral factors from the venous to arterial circulation, which then, in a predisposed migraineur, could serve to trigger an attack by either inducing cortical spreading depression or by some other mechanisms. It has been proposed that paradoxical emboli appear to have a propensity for the posterior circulation [15]. Because most auras are visual, and the occipital cortex appears to be particularly susceptible to cortical spreading depression, embolism of thrombi across a PFO could access the occipital cortex through the posterior circulation and provide a trigger for cortical spreading depression in migraineurs with aura. These thrombi could be composed of fibrin or platelets. Platelet activation has frequently been found in patients with migraine, particularly migraine with aura, and
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Migraine Headache
Table 3. Migraine prevalence before and after patent foramen ovale or atrial septal defect closure Improvement
Resolved or improved
No change
Migraine, 10/21 (48%) decompression illness
8/21 (38%)
18/21 (86%)
3/21 (14%)
Morandi et al. [34], 2003
Migraine
5/17 (29%)
10/17 (59%)
15/17 (88%)
2/17 (12%)
Schwerzmann et al. [23], 2004
Migraine
NA
NA
35/43 (81%)
8/43 (19%)
Azarbal et al. [27], 2005
Migraine
19/30 (63%)
5/30 (17%)
24/30 (80%)
6/39 (20%)
Reisman et al. [26], 2005
Migraine
28/50 (56%)
7/50 (14%)
35/50 (70%)
15/50 (30%)
Mortelmans et al. [12•], 2005
Atrial septal defect
12/22 (54%)
Study, year
Comments
Wilmshurst et al. [25], 2000
Anzola et al. [2], 1999
Migraine, stroke
Giardini et al. [35], 2006
Migraine, stroke
Resolution
10/22 (46%) 18/50 (36%)
12/13 (92%)
32/50 (70%) 1/13 (8%)
NA—not available. (Modified from Schwedt and Dodick [7•].)
symptomatic migraine with aura has been reported in platelet diseases such as essential thrombocythemia [16]. Because pulmonary monoamine oxidase is responsible for the metabolism of serotonin released by platelet activation in the venous circulation, bypassing this pulmonary filter could allow access by an amine that could trigger migraine either by vascular or neuronal mechanisms. The hypothetical link between platelet activation or platelet emboli in the arterial circulation and migraine with aura is supported by evidence of exacerbation of migraine aura or new-onset aura in patients undergoing PFO closure, the reduction in aura and migraine episodes with the use of antiplatelet agents, and the high prevalence of migraine with aura in other conditions with a right-to-left shunt [17–19]. Although there may be feasible mechanisms that support a speculative causal association between the PFO and migraine with aura, the proof and the issue germane to patients and clinicians is whether repair or closure of a PFO leads to improvement in clinical migraine outcomes.
Should PFO Be Closed in Patients with Migraine? To date, only one randomized and controlled trial of PFO closure in migraineurs has been performed. The MIST (Migraine Intervention with STARFlex Technology) trial is not yet published, but the results were reported at an international meeting [20••]. This trial recruited patients with frequent migraine refractory to preventive treatment. Refractoriness was defined as having failed to respond to two preventive migraine medications (topiramate and lamotrigine were not used) [21,22]. Although patients were required to have a history of migraine with aura, only two aura episodes in a lifetime were required. The trial randomized 147 patients to either transcutaneous PFO closure with the STARFlex device (NMT Medical Inc., Boston, MA) or a sham procedure. A total of 135 patients completed the trial after 6 months. The primary
endpoint, cure of migraine (complete freedom from migraine attacks between months 3–6 after closure), was not significantly different between the two treatment groups. There was a trend for a reduction of migraine frequency in the verum-treated group, which, however, was not significant after adjustment for the imbalance in migraine frequency at baseline. The procedure was associated with some serious adverse events such as cardiac tamponade, pericardial effusion, retroperitoneal bleed, atrial fibrillation, and chest pain. Adverse events in the sham group included incisional site bleeding, anemia, epistaxis, and a brainstem stroke. In a study of 215 patients with presumed PFO-mediated paradoxical embolism (175 with cerebral infarction) who were referred for closure of the PFO, headache was ascertained retrospectively for the 1-year period before and the 1-year period after closure of the PFO to determine whether this intervention affected migraine attacks [23]. Of the 215 patients with PFO, 48 (22%) fulfilled the criteria for migraine before the PFO closure; 37 had migraine with aura and 11 had migraine without aura. Percutaneous PFO closure reduced the frequency of migraine attacks by 54% in patients with migraine with aura (1.2 ± 0.8 vs 0.6 ± 0.8 migraine attacks per month; P = 0.001) and by 62% in patients with migraine without aura (1.2 ± 0.7 vs 0.4 ± 0.4 migraine attacks per month; P = 0.006). PFO closure did not have a statistically significant effect on headache frequency in patients with nonmigraine headaches. Several other retrospective studies found a similar relationship between PFO closure and improvement of migraine frequency (Table 3) [2,12•,24–27]. However, with one exception, all these studies had major limitations. First, despite migraine improving spontaneously with age, none of the observational studies had a control group. Second, it is well known that any kind of procedure in migraine has a high placebo response and can reduce the frequency of migraine by up to 70%. Third, after PFO closure, most patients received aspirin, which has a
Patent Foramen Ovale and Migraine Diener et al.
modest migraine prophylactic effect, at least in men [28– 30]. Clopidogrel, given as an aspirin alternative, might also reduce migraine frequency [17,31]. Fourth, retrospective collection of headache data is highly unreliable; recall bias has a major influence on the results. Furthermore, the most recent study observed that as many patients develop new-onset migraine after PFO closure as improve [12•]. Another study showed that in many patients with PFO and stroke and concomitant migraine, headache improves in the time interval between stroke and PFO closure [32].
Conclusions There is emerging evidence suggesting that the prevalence of PFO in patients with migraine with aura is significantly higher than in migraineurs without aura and nonmigraine controls. The basis for this comorbidity may be a shared genetic inheritance. However, there is currently no evidence to support a causal relationship. That is, there is insufficient evidence that PFO closure has a beneficial effect on migraine frequency, severity, or its natural history. Properly conducted, randomized, long-term, prospective, sham-controlled studies in migraine patients are required before any conclusions regarding the effect of PFO closure in migraine patients can be drawn. Several such studies are underway in Europe and the United States. Until the results of these studies are available, PFO closure should not be performed in clinical practice for the prophylaxis of migraine.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
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