CLINICAL RESEARCH STUDY
Patent Foramen Ovale and Migraine Attacks: A Systematic Review Philomena Z.Y. Lip, (Student), Gregory Y.H. Lip, MD Department of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom.
ABSTRACT BACKGROUND: Migraine headache and the presence of a patent foramen ovale have been associated with each other, although the precise pathophysiological mechanism(s) are uncertain. The purpose of this systematic review was to identify the extent of patent foramen ovale prevalence in migraineurs and to determine whether closure of a patent foramen ovale would improve migraine headache. METHODS: An electronic literature search was performed to select studies between January 1980 and February 2013 that were relevant to the prevalence of patent foramen ovale and migraine, and the effects of intervention(s) on migraine attacks. Of the initial 368 articles presented by the initial search, 20 satisfied the inclusion criteria assessing patent foramen ovale prevalence in migraineurs and 21 presented data on patent foramen ovale closure. RESULTS: In case series and cohort studies, patent foramen ovale prevalence in migraineurs ranged from 14.6% to 66.5%. Case-control studies reported a prevalence ranging from 16.0% to 25.7% in controls, compared with 26.8% to 96.0% for migraine with aura. The extent of improvement or resolution of migraine headache attack symptoms was variable. In case series, intervention ameliorated migraine headache attack in 13.6% to 92.3% of cases. One single randomized trial did not show any benefit from patent foramen ovale closure. The data overall do not exclude the possibility of a placebo effect for resolving migraine following patent foramen ovale closure. CONCLUSION: This systematic review demonstrates firstly that migraine headache attack is associated with a higher prevalence of patent foramen ovale than among the general population. Observational data suggest that some improvement of migraine would be observed if the patent foramen ovale were to be closed. A proper assessment of any interventions for patent foramen ovale closure would require further large randomized trials to be conducted given uncertainties from existing trial data. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 411-420 KEYWORDS: Migraine; Migraine headache; Patent foramen ovale
Migraine is a chronic neurological condition that is estimated to be prevalent in approximately 6% of men and 15%-17% of women between 20 and 64 years of age.1 It is characterized by headaches, preceded by aura of a visual or Funding: None. Conflict of Interest: None. Authorship: PZYL: original idea, conducted the systematic searches and synthesized the review data, wrote the first draft and made revisions; GYHL.: supervised the research, edited and drafted revisions to the article. Both authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, UK. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.12.006
sensory kind in 4.4% of adults, and can vary in the intensity, frequency, and duration.2 Severe migraines can result in significant functional impairment until the subsequent full recovery is achieved. The onset of migraine has been suggested to occur from a mixture of environmental stimuli and hereditary factors. For example, Valsalva-provoking activities such as strenuous exercise are considered to be one of the most common causes.3 Patent foramen ovale is a remnant of a flap between the septae primum and secundum, which permits blood flow from the right atrium to the left4 and can be present in up to 27.3% of the population.5 Patent foramen ovale is asymptomatic in many cases, but its association with cerebrovascular events such as migraine has long been studied. The
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precise pathophysiological mechanism(s) linking patent foWe excluded studies that detailed results about other ramen ovale to migraine attacks remain unclear. forms of congenital heart disease or other neurovascular One hypothesis is that the patent foramen ovale causes disorders such as cryptogenic stroke, as the purpose of the metabolites and subclinical emboli, which are normally systematic review is to identify the specific relationship that removed by passage through the lungs to enter the systemic exists between migraine and patent foramen ovale alone. circulation, resulting in irritation to the trigeminal nerve and No distinction was made between patent foramen ovale vascular network. Normally, sepresence and right-to-left shunt for rotonin also is metabolized by the the selection of articles to review. CLINICAL SIGNIFICANCE lung monoamine oxidase, but if For articles achieving the the blood is shunted, thereby eligibility criteria stated, the full Migraine headache is associated with a avoiding the pulmonary circulatexts were obtained and the referhigh prevalence of patent foramen ovale tion, the increased platelet activaence lists scanned for further rele(PFO). tion and aggregation in response vant articles. If the PFO were to be closed, some to serotonin could possibly trigger migraine and aura.6 Patent foraobservational data suggest improvement RESULTS men ovale also is linked typically of migraine. Of the initial 368 articles preto some degree of arterial blood The one single randomized trial did not sented by the initial search, 59 oxygen desaturation; hypoxia inshow any benefit on migraine headache papers were screened in full, then creases the expression of plasfrom PFO closure. 10 were excluded for not focusing minogen activator-1, which in turn on patent foramen ovale or misuppresses fibrinolysis overall, A proper assessment of any interventions graine, 5 assessed the triggers of increasing the likelihood of a for PFO closure would require further migraine, and 3 studies investiparadoxical microembolism formlarge randomized trials to be conducted gated other factors in the freing.7 Paradoxical emboli have given uncertainties from existing trial quency of migraine, such as the been shown to stimulate migraine data. timing of a preprocedural migraine from studies where air microheadache attack. Finally, 41 artiembolism has been introduced and cles met the eligibility criteria for observed through the posterior inclusion in the review, with 20 articles being related to the cerebral artery, resulting in a migraine headache shortly association between patent foramen ovale and migraine, afterwards.8 Of note, patent foramen ovale can arise in latent and 21 articles assessed the effect of patent foramen ovale and permanent forms,9 but it is unknown whether this corclosure on migraine (Figure 1). relates to a significant change in migraine prevalence. Our objective was to conduct a systematic review of relevant existing literature to assess the relationship between Studies Examining the Relationship Between patent foramen ovale presence and migraine attacks. SecPatent Foramen Ovale and Migraine ond, the review aims to examine the effect of patent foramen ovale closure on the improvement (or otherwise) of Case Series and Cohort Studies (Table 1). Table 1 migraine symptomatology. summarizes the prevalence of patent foramen ovale in migraineurs from 12 case series.9-20 The results showed a higher prevalence of patent foramen ovale amongst METHODS migraineurs, ranging from 14.6% to 66.5%, compared with a cited figure of 27.3% in the general population.5 A comprehensive search using PubMed/Medline was undertaken, which yielded 368 articles published between There was a noticeable difference between the presence January 1980 and February 28, 2013. The search terms used of patent foramen ovale in migraine with aura and migraine in combination were “migraine,” “migraine headache,” and without aura. The prevalence of patent foramen ovale in “patent foramen ovale.” migraine-with-aura patients ranged from 46.3% to 88.0%, as The articles obtained were filtered on the basis of releassessed from 6 case series,9,12,14,15,18,19 when compared vancy of abstract and title. The selection criteria prepared with a range of 16.2%-34.9% in migraine-without-aura were intended to include studies that concerned the relapatients as assessed from 2 case series.18,19 tionship between migraine and patent foramen ovale, or Three studies10,11,17 considered migraine headache attack the effects of patent foramen ovale closure on migraine prevalence within a population of patent foramen ovale attack symptomatology. Therefore, articles that were repatients, which ranged from 9.13% to 51.7%. Only one views or case reports were omitted, as were those relating to study15 considered typical and atypical aura in migraine, children. Although selection criteria did pertain to articles with aura patients as a possible factor for patent foramen only in the English language, because migraine and patent ovale prevalence—the results showed a greater prevalence foramen ovale are both present in patients worldwide, the of 79.2% in migraineurs with atypical aura when compared decision was made not to exclude any particular population. with 46.3% in those with typical aura.
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Figure 1
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CONSORT Diagram.
Three studies9,12,14 made a distinction between a permanent shunt and a latent shunt, with a permanent shunt being the prevailing characteristic in 66.7%-72.1% of patent foramen ovale patients with migraine, whereas a latent shunt ranged from 27.9% to 33.3%. As illustrated in Table 1, one study9 also addressed the difference in the prevalence of large or small patent foramen ovale, yielding results of 75% and 25%, respectively.
One study examined the prevalence of patent foramen ovale in patients suffering from aura symptoms without migraine headache attack, and found this to be 66.7%21 (Table 2).
Case-control Studies (Table 2). Table 2 summarizes findings from 8 case-control studies21-28 assessing the relationship between migraine and patent foramen ovale presence, allowing direct comparison between a control that is representative of the general population and those with migraine. The results show a range from 16.0% to 25.7% for prevalence of patent foramen ovale in the controls (7 studies21-23,25-28), 26.8% to 96.0% for migraine-with-aura patients (7 studies21-23,25-28), and 22.6% to 72.4% for migraine-without-aura patients (5 studies21-23,25,27). One study24 presented data on patent foramen ovale prevalence in migraineurs (51.9%) and in controls (15.4%).
Case series (Table 3). The 18 case series21,29-45 selected to represent the effect of patent foramen ovale closure on migraine headache attack severity are summarized in Table 3. The results varied between migraine with aura and migraine without aura patients, and can be categorized into “resolved,” “improvement,” “no change,” and “worsened.” Migraine with aura resolution ranged from 28.6% to 92.3%, whereas migraine without aura resolution varied from 13.6% to 82.9%. Migraine with aura improvement ranged from 4.17% to 64.3%; migraine without aura improvement varied from 0% to 68.2%. Of note, 9 studies made the distinction between migraine with aura and
The Effect of Patent Foramen Ovale Closure on Migraine Headache Severity
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Table 1
Case Series and Cohort Studies Examining the Relationship Between Patent Foramen Ovale and Migraine
First Author/Year Case Series
Reference
Sample Size
Results
Comment
Faggiano et al, 2012 Dao & Tobis, 2011 Caputi et al, 2010
10 11 12
n ¼ 446 PFO n ¼ 416 PFO n ¼ 159 MA
Found prevalence of MH not prevalence of PFO. Found prevalence of MH not prevalence of PFO. Only MA patients.
Nahas et al, 2010
13
Caputi et al, 2009
14
n ¼ 131 MH n ¼ 53 MA n ¼ 120 MA
n ¼ 47 MH (10.5%) n ¼ 38 MH (9.13%) RLS overall: n ¼ 79 (49.7%) Permanent RLS: n ¼ 56 (70.9%) Latent RLS: n ¼ 23 (29.1%) n ¼ 86 (65.6%) RLS
Only MA patients.
Marchione et al, 2008
15
RLS overall: n ¼ 61 (50.8%) Latent RLS: n ¼ 17 (27.9%) Permanent RLS: n ¼ 44 (72.1%) Large RLS: n ¼ 32 (52.4%) PFO prevalence: Group 1 (typical aura) n ¼ 19 (46.3%) Group 2 (atypical aura) n ¼ 19 (79.3%)
Rundek et al, 2008
16
Prevalence of PFO: n ¼ 26 (14.6%)
Migraine history self-reported.
Liboni et al, 2008
9
Test subjects only women. Used near-infrared spectroscopy to detect which had 79% sensitivity and 90% specificity. Some false positives later identified as permanent shunts.
Truong et al, 2008
17
n ¼ 147 RLS n ¼ 118 LRS
Carod-Artal et al, 2006
18
n ¼ 58 MA n ¼ 83 MO
Dalla Volta et al, 2005
19
n ¼ 260 MA n ¼ 74 MO
Ferrarini et al, 2005
20
n ¼ 25 MA
PFO: n ¼ 48 (54.5%) Large PFO: n ¼ 36 (75.0%) Small PFO: n ¼ 12 (25.0%) Permanent RLS: n ¼ 32 (66.7%) Latent RLS: n ¼ 16 (33.3%) RLS: n ¼ 61 MA (41.5%) n ¼ 15 MO (10.2%) LRS: n ¼ 39 MA (33.1%) n ¼ 12 MO (10.2%) PFO prevalence: n ¼ 30 MA (51.7%) n ¼ 29 MO (34.9%) PFO prevalence: n ¼ 161 MA (61.9%) n ¼ 12 MO (16.2%) PFO prevalence: n ¼ 22 (88.0%)
Only MA patients.
Self-reported questionnaire used to diagnose migraine.
Small sample size. Only MA patients.
LRS ¼ left-to-right shunt; MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale; RLS ¼ right-to-left shunt.
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n ¼ 65 MA n ¼ 41 with typical aura (group 1) and n ¼ 24 with atypical aura (group 2) n ¼ 178 MH n ¼ 143 MA n ¼ 88 MA
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Case-Control Studies Examining the Relationship between Patent Foramen Ovale and Migraine
First Author/Year Case-control Studies
Reference
Sample Size
Results
Comment
Khessali et al, 2012
21
RLS prevalence: 1) MA ¼ 168 (96.0%) 2) MO ¼ 21 (72.4%) 3) Aura only ¼14 (66.7%) 4) Control ¼ 36 (18.0%)
Control: Patients undergoing cardiac catheterization unrelated to PFO.
Garg et al, 2010
22
n ¼ 225 visual aura with or without MH. n ¼ 91 aura without headache. 1) MA ¼ 175 2) MO ¼ 29 3) Aura only ¼ n ¼ 21 4) Control ¼ 200 n ¼ 144 control n ¼ 144 migraineurs, MA present in 39%
Control: No MH
Tatlidede et al, 2007
23
n ¼ 15 MA n ¼ 38 MO n ¼ 27 control
Kimmelstiel et al, 2007
24
n ¼ 104 PFO n ¼ 65 control
Domitrz et al, 2007
25
n ¼ 61 MA n ¼ 60 MO n ¼ 65 control group
Schwerzmann et al, 2005
26
n ¼ 93 MA and n ¼ 93 control
Anzola et al, 1999
27
n ¼ 113 MA n ¼ 53 MO n ¼ 25 control
Del Sette et al, 1998
28
n ¼ 44 MA n ¼ 50 control
PFO prevalence: n ¼ 37 control (25.7%) MA: 26.8% MO: 26.1% PFO prevalence: n ¼ 10 MA (66.7%) n ¼ 18 MO (47.4%) n ¼ 6 control (22.2%) MH prevalence: n ¼ 54 PFO (51.9%) n ¼ 10 control (15.4%) PFO prevalence: n ¼ 33 MA (54.1%) n ¼ 15 MO (25.0%) n ¼ 16 control (24.6%) PFO prevalence: n ¼ 44 in MA (47.3%) n ¼ 16 in control (17.2%) Small shunt equally prevalent in control and MA. Shunt size larger in MA. PFO prevalence: n ¼ 54 (47.8%) MA n ¼ 12 (22.6%) MO n ¼ 5 (20.0%) control RLS prevalence: n ¼ 18 (40.9%) MA n ¼ 8 (16.0%) control
Small sample size. Control: Healthy
Control: No PFO
Control: Healthy
Control: Healthy
Control: No MH
Small sample size. Control: Healthy
MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale.
migraine without aura, allowing for a comparison between the 2. As shown in Table 3, the greatest worsening experienced was 4.47%, whereas up to 29.4% experienced no change.
In this trial,47 74 patients were randomized to patent foramen ovale closure with septal repair implant, whereas 73 received the sham procedure. The primary end point of migraine cessation was achieved by 4.05% of patients who underwent patent foramen ovale closure, and by 4.11% of patients subjected to the sham procedure. Thus, no significant differences were seen between the patent foramen ovale and sham trial arms for the primary end point, but on exploratory analysis, excluding 2 study result outliers, the implant group “demonstrated a greater reduction in total migraine headache days” (P ¼ .0027).
Case-control Studies (Table 4). There were 2 case-control studies24,46 comparing the effects of intervention and medication (Table 4). With intervention, there was a reported 83%-87% improvement of migraine symptoms in patients, compared with 0%-21% in those where the patent foramen ovale remained open. One study24 used a control group of migraineurs without a patent foramen ovale and on medication, and reported a 10% improvement with intervention.
DISCUSSION
Randomized Controlled Trials (Table 5). Only one published prospective randomized controlled trial (shown in Table 5) was found regarding the closure of patent foramen ovale to improve migraine.
This systematic review clearly identifies that the prevalence of patent foramen ovale in patients with migraine is greater than that seen in the general population. Second, there was a stronger correlation between prevalence of patent foramen ovale in migraine-with-aura patients compared with
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Table 3
Case Series Examining the Effect of Patent Foramen Ovale Closure on Migraine Severity
First Author/Year Case Series
Reference
Sample Size
Results
Comment
Khessali et al, 2012
21
PFO closure in n ¼ 80 n ¼ 67 MA n ¼ 8 MO n ¼ 200 control
Small sample size. Follow-up: 12 months.
Rigatelli et al, 2012
29
RLS closure in n ¼ 80 MH n ¼ 63 MA
Trabattoni et al, 2011
30
RLS closure in n ¼ 77 MH (MA¼13, MO¼64)
Wahl et al, 2010
31
PFO closure in n ¼ 150 MH n ¼ 96 MA n ¼ 54 MO
Rigatelli et al, 2010a
32
PFO closure in n ¼ 40 MH
Rigatelli et al, 2010b check stats as changed in table Papa et al, 2009
33
PFO closure in n ¼ 34 MA
34
PFO closure in n ¼ 76 MH
Wahl et al, 2009
35
PFO closure in n ¼ 17 MH n ¼ 14 MA n ¼ 3 MO
Chessa et al, 2009
36
PFO closure in n ¼ 42 MH
MA: n ¼ 35 (52.2%) resolved n ¼ 16 (23.9%) improvement n ¼ 1 (1.49%) no change n ¼ 3 (4.48%) worse MO: n ¼ 6 (75.0%) resolved n ¼ 0 (0%) improvement n ¼ 1 (12.5%) no change n ¼ 0 (0%) worse n ¼ 70 (87.5%) improvement n ¼ 10 (22.5%) no change n ¼ 0 worse (0%) n ¼ 61 (96.8%) complete resolution of aura MH: n ¼ 23 (29.9%) resolved n ¼ 20 (26.0%) improvement MO resolved n ¼ 14 (25.9%) MO improvement n ¼ 30 (55.6%) MA resolved n ¼ 37 (38.5%) MA improvement n ¼ 47 (49.0%) All patients improved. Aura disappeared in all patients with pre-procedural aura. n ¼ 19 (55.9%) resolved n ¼ 6 (17.6%) improvement n ¼ 2 (5.88%) unchanged n ¼ 35 (46.1%) MH resolved n ¼ 27 (35.5%) MH improved n ¼ 14 (18.4%) MH unchanged MA: Resolved ¼ 4 (28.6%) Improvement ¼ 9 (64.3%) Unchanged ¼ 4 (28.6%) MO: Improvement ¼ 2 (66.7%) Unchanged ¼ 1 (33.3%) MH resolved: n ¼ 11 (26.2%) MH improvement: n ¼ 22 (52.4%)
Follow-up: 12 months
Small sample size. Follow-up: mean ¼ 13.7 2.4 months Small sample size.
Small sample size. Patients rated own severity of MH. Follow-up: 6 months
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Small sample size. Follow-up: from 6 to 48 months (mean ¼ 29.2 14.8 months) Small sample size. Follow up: mean ¼ 9 2.9 months
Continued Reference
Sample Size
Results
Comment
Luermans et al, 2008
37
PFO closure in n ¼ 89 MH n ¼ 24 MO n ¼ 10 MA
Small sample size for MH. Follow-up: 6 months
Jesurum et al, 2008
38
PFO closure in n ¼ 67 MH n ¼ 55 MA
Dubiel et al, 2008
39
PFO closure in n ¼ 46 MH n ¼ 24 MA n ¼ 22 MO
Giardini et al, 2006a
40
PFO closure in n ¼ 35 MA
Giardini et al, 2006b
41
PFO closure in n ¼ 13 MA
Follow-up of n ¼ 84 MO: n ¼ 15 (62.5%) resolved n ¼ 9 (37.5%) improvement/no change MA: n ¼ 8 (80.0%) resolved n ¼ 2 (20.0%) improvement/no change n ¼ 36 (53.7%) MH resolved n ¼ 17 (25.4%) improvement n ¼ 11 (16.4%) no relief n ¼ 3 (4.47%) worse MA: n ¼ 8 (33.3%) resolved n ¼ 14 (58.3%) improved n ¼ 2 (8.33%) persistent MO: n ¼ 3 (13.6%) resolved n ¼ 15 (68.2%) improved n ¼ 4 (18.2%) persistent n ¼ 29 (82.9%) resolved n ¼ 3 (8.57%) improvement n ¼ 3 (8.57%) unchanged n ¼ 12 (92.3%) resolved
Mortelmans et al, 2005
42
Reisman et al, 2005
43
n ¼ 14 MO n ¼ 8 MA underwent PFO closure PFO closure in n ¼ 57 MH n ¼ 37/57 MA
Azarbal et al, 2005
44
PFO closure in n ¼ 37 MH n ¼ 24 MA n ¼ 13 MO
Schwerzmann et al, 2004
45
PFO closure in n ¼ 48 MH
MA: n ¼ 4 (50.0%) resolved MO: n ¼ 6 (42.9%) resolved n ¼ 50 follow-up n ¼ 28 (56.0%) resolved n ¼ 14 (28.0%) improvement n ¼ 15 (30.0%) minimal or no relief MA: n ¼ 18 (75.0%) resolved n ¼ 1 (4.17%) improvement MO: 4 (30.8%) resolved n ¼ 5 (38.5%) improvement 3 months post-op: 75% MA resolved 31% MO resolved 54% MA improved 62% MO improved
Small sample size. Follow-up: mean ¼ 38 months
Small sample size; assessment only of MA pts. Follow-up: 1.7 1.3 years Subjects had cryptogenic stroke and only MA assessed. Small sample size. Follow-up: 4.9 1.4 years Small sample size. Follow-up: median ¼ 29 months Small sample size. Follow-up: 12 months
Small sample size. Follow-up: 3 months
Small sample size.
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ASD ¼ atrial septal defect; MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale.
Based on patients’ self-completed questionnaires.
Patent Foramen Ovale and Migraine
First Author/Year Case Series
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Table 3
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Table 4
Case Control Studies Examining Comparing Effects of Intervention and Medication
First Author/Year Case-Control
Reference
Sample Size
Results
Comment
Kimmelstiel et al, 2007
24
n ¼ 63 open PFO no intervention n ¼ 41 underwent PFO closure
Open PFO: no intervention performed Control: no PFO follow-up: 90 days
Vigna et al, 2009
46
n ¼ 82 MH, PFO and subclinical brain lesions PFO closure n ¼ 53 Control n ¼ 29
PFO closure: 83% improvement Open PFO: 0% improvement Control: 10% improvement PFO closure: 34% resolved 87% improvement Control: 7% resolved 21% improvement
Control: preventative migraine medication. Small sample size. Follow-up: mean ¼ 16 7 months
MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale.
patients suffering from migraine without aura alone, but only 11 studies presented data on this, with 2 being unsupportive of this link; thus, the relationship may be open to debate. Third, the effect of patent foramen ovale closure on migraine yielded more tenuous results: only 18 observational studies reported improvement of migraine but varied in their specificity of amelioration, and there was variation as to whether resolution or improvement of migraine headache attack was more prevalent, and one study42 even demonstrated some exacerbation of migraine headache attack at follow-up. These data were mainly from case series and case-control studies of varying sample sizes. The one single randomized trial did not show any benefit of patent foramen ovale closure. The sample sizes for published observation studies were variable, ranging from as few as 13 patients41 with migraine to as many as 334.19 The investigations for effect of migraine post-patent foramen ovale closure also used variable follow-up periods, which would be likely to make a significant contribution to the differences in results; indeed, the follow-up period ranged from 90 days to a mean of 4.9 years. Also, the exact follow-up periods for each study were not always specified. Only a select few studies investigated the differences between migraine with aura and migraine without aura, which therefore may not give an accurate Table 5
depiction of the existing differences in the overall population. A number of limitations are evident in assessing the data for amelioration of migraine headache attack following patent foramen ovale closure. Firstly, each study varied in the length of follow-up, making it difficult to make valid comparisons; several studies also failed to make a distinction between improvement and no change in migraine headache attack, choosing to document only full resolution, which does not necessarily give a true representation of the potential benefits of patent foramen ovale closure on migraine headache attack. The majority of studies also failed to provide data on whether patients had worsening or no change; when the data were present, the sample size was often too small to make reliable comparisons. Second, migraine headache attack was largely assessed using a patient questionnaire from which a neurologist would then designate a Migraine Disability Assessment (MIDAS) score—even in cases where migraine headache attack was diagnosed upon examination, the subjectivity of these methods could give rise to potential bias. The most important difficulty in gaining certainty of results for this hypothesis was the “placebo effect.” The placebo effect in migraineurs ranges from 35% to 40%, which could have significant effects on the outcome of the results
Randomized Controlled Trials
First Author/Year Randomized Controlled Trials Reference Sample Size Dowson et al, 2008
47
n ¼ 432 MH assessed for RLS. n ¼ 260 shunt n ¼ 163/260 moderate/large PFO n ¼ 96/260 small/pulmonary shunt n ¼ 1 ASD Randomized: n ¼ 74 PFO closure n ¼ 73 sham procedure
Results
Comment
Mean frequency of migraine attacks and Data concerns50 median MIDAS score decreased for sham and implant procedures; difference not statistically significant. Reached primary endpoint of migraine cessation in PFO: n ¼ 3 (4.05%) Sham: n ¼ 3 (4.11%)
ASD ¼ atrial septal defect; MH ¼ migraine headache; MIDAS ¼ Migraine Disability Assessment Score; PFO ¼ patent foramen ovale; RLS ¼ right-to-left shunt.
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postprocedure.48 Further studies would be required to investigate the distinctions between migraine with aura and patent foramen ovale, compared with migraine without aura and patent foramen ovale, to increase our understanding of the relationship, as well as to support the suggestion that the amelioration of migraine following patent foramen ovale closure is not largely due to the placebo effect. Indeed, the current data overall do not exclude the possibility of a placebo effect for resolving migraine following patent foramen ovale closure. The Migraine Intervention with STARFlex technology (MIST) trial, sponsored by NMT Medical (Boston, Mass, no longer in business), is currently the only published large randomized controlled trial to have been undertaken to explore the effect of patent foramen ovale closure on migraine.47 This trial did not show any significant difference in the primary end point, but on exploratory analysis, excluding 2 study result outliers, the implant group was reported to have “demonstrated a greater reduction in total migraine headache days.” In an accompanying editorial, Carroll49 highlighted the high frequency of patients not found to have a patent foramen ovale during their procedure, thus questioning the quality of the echocardiographic screening process. Also, there was the higher-than-expected rate of serious adverse events in the device-treated patients, again raising concerns about the quality of the procedures.49 Lastly, there was an “unclear number” of residual shunts, and thus, the efficacy of the device itself. Of note, one of the initial co-authors (Peter Wilmhurst) alleged that the sponsor (NMT Medical) removed clinical members of the steering committee and overruled the clinicians on aspects such as trial design and presentation of the data.50 As reported by Medscape (www.medscape.com), the 2 lead investigators of MIST were brought before a Medical Practitioners Tribunal Service in a fitness-to-practice hearing for suspected misconduct in the trial and for submitting an abstract containing false data.51 The MIST data also had to be somewhat amended following the report that the trial may have had poor echocardiographic assessment, resulting in inclusion of patients with pulmonary, not intracardiac, shunting. Considering all these factors, the results from this one single randomized trial should therefore be viewed with caution. Nonetheless, patent foramen ovale closure has been subject to discussion in terms of its benefits for other neurological conditions, most notably for stroke risk prevention. Although this systematic review article is focusing solely on migraine, there have been 2 large randomized controlled trials assessing the relationship of patent foramen ovale to stroke. Both trials, the RESPECT (Randomized Evaluation of recurrent Stroke comparing patent foramen ovale closure to Established Current standard of care Treatment) and the PC (Patent foramen ovale and Cryptogenic stroke) trials, failed to show significant results on reducing risk of recurrent stroke following percutaneous closure of the patent foramen ovale.52,53 A third trial, CLOSURE I sponsored by NMT Medical, used a device (STAR-FLEX) that is currently no longer used in practice,
419 and the results did not show any significant benefit either.54 The CLOSURE I trial was subject to criticism as the patients selected for inclusion were not typical of patients who undergo patent foramen ovale closure following stroke, and therefore the results were not representative of the patient population that the intervention would target. Following the debate about the MIST trial by NMT Medical, the CLOSURE I trial should also perhaps be treated cautiously.
CONCLUSION This systematic review demonstrates firstly that migraine headache is associated with a higher prevalence of patent foramen ovale than among the general population, and if the patent foramen ovale were to be closed, observational data suggest some improvement of migraine would be observed in patients. The one single randomized trial did not show any benefit. A proper assessment of any interventions for patent foramen ovale closure would require further large randomized trials to be conducted given uncertainties from existing randomized trial data.
References 1. Stewart WF, Roy J, Lipton RB. Migraine prevalence, socioeconomic status and social causation. Neurology. 2013;10(81):948-955. 2. Merikangas KR. Contributions of epidemiology to our understanding of migraine. Headache. 2013;53(2):230-246. 3. Tembl J, Lago A, Sevilla T, Solis P, Vilchez J. Migraine, patent foramen ovale and migraine triggers. J Headache Pain. 2007;8(1):7-12. 4. Fisher DC, Fisher EA, Budd JH, Rosen SE, Goldman ME. The incidence of patent foramen ovale in 1,000 consecutive patients. A contrast transesophageal echocardiography study. Chest. 1995;107(6): 1504-1509. 5. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clinic. 1984;59(1):17-20. 6. Sharma A, Gheewala N, Silver P. Role of patent foramen ovale in migraine etiology and treatment: a review. Echocardiography. 2011;28(8):913-917. 7. Prandota J. Migraine associated with patent foramen ovale may be caused by reactivation of cerebral toxoplasmosis triggered by arterial blood oxygen desaturation. Int J Neurosci. 2010;120(2):81-87. 8. Sevgi EB, Erdener SE, Demirci M, Topcuoglu MA, Dalkara T. Paradoxical air microembolism induces cerebral bioelectrical abnormalities and occasionally headache in patent foramen ovale patients with migraine. J Am Heart Assoc. 2012;1(6):e001735. 9. Liboni W, Molinari F, Allais GB, et al. Patent foramen ovale detected by near-infrared spectroscopy in patients suffering from migraine with aura. Neurol Sci. 2008;29(Suppl 1):S182-S185. 10. Faggiano P, Frattini S, Piovesana P, et al. Low cerebrovascular event rate in subjects with patent foramen ovale and different clinical presentations: results from a prospective non randomized study on a population including patients with and without patent foramen ovale closure. Int J Cardiol. 2012;156(1):47-52. 11. Dao CN, Tobis JM. PFO and paradoxical embolism producing events other than stroke. Catheter Cardiovasc Interv. 2011;77(6):903-909. 12. Caputi L, Usai S, Carriero MR, et al. Microembolic air load during contrast-transcranial Doppler: a trigger for migraine with aura? Headache. 2010;50(8):1320-1327. 13. Nahas SJ, Young WB, Terry R, et al. Right-to-left shunt is common in chronic migraine. Cephalalgia. 2010;30(5):535-542. 14. Caputi L, D’Amico D, Usai S, Grazzi L, Parati EA, Bussone G. Prevalence and characteristics of right-to-left shunt in migraine with aura: a survey on 120 Italian patients. Neurol Sci. 2009;30(Suppl 1):S109-S111.
420 15. Marchione P, Ghiotto N, Sances G, et al. Clinical implications of patent foramen ovale in migraine with aura. Funct Neurol. 2008;23(4): 201-205. 16. Rundek T, Elkind MS, Di Tullio MR, Carrera E, Jin Z, Sacco RL, Homma S. Patent foramen ovale and migraine: a cross-sectional study from the Northern Manhattan Study (NOMAS). Circulation. 2008;118(14):1419-1424. 17. Truong T, Slavin L, Kashani R, et al. Prevalence of migraine headaches in patients with congenital heart disease. Am J Cardiol. 2008;101(3): 396-400. 18. Carod-Artal FJ, da Silveira Ribeiro L, Braga H, Kummer W, Mesquita HM, Vargas AP. Prevalence of patent foramen ovale in migraine patients with and without aura compared with stroke patients. A transcranial Doppler study. Cephalalgia. 2006;26(8):934-939. 19. Dalla Volta G, Guindani M, Zavarise P, Griffini S, Pezzini A, Padovani A. Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationship with clinical phenotype. J Headache Pain. 2005;6(4):328-330. 20. Ferrarini G, Malferrari G, Zucco R, Gaddi O, Norina M, Pini LA. High prevalence of patent foramen ovale in migraine with aura. J Headache Pain. 2005;6(2):71-76. 21. Khessali H, Mojadidi MK, Gevorgyan R, Levinson R, Tobis J. The effect of patent foramen ovale closure on visual aura without headache or typical aura with migraine headache. JACC Cardiovasc Interv. 2012;5(6):682-687. 22. Garg P, Servoss SJ, Wu JC, et al. Lack of association between migraine headache and patent foramen ovale: results of a case-control study. Circulation. 2010;121(12):1406-1412. 23. Tatlidede AD, Oflazo glu B, Celik SE, Anadol U, Forta H. Prevalence of patent foramen ovale in patients with migraine. Agri. 2007;19(4):39-42. 24. Kimmelstiel C, Gange C, Thaler D. Is patent foramen ovale closure effective in reducing migraine symptoms? A controlled study. Catheter Cardiovasc Interv. 2007;69(5):740-746. 25. Domitrz I, Mieszkowski J, Kaminska A. Relationship between migraine and patent foramen ovale: a study of 121 patients with migraine. Headache. 2007;47(9):1311-1318. 26. Schwerzmann M, Nedeltchev K, Lagger F, et al. Prevalence and size of directly detected patent foramen ovale in migraine with aura. Neurology. 2005;65(9):1415-1418. 27. Anzola GP, Magoni M, Guindani M, Rozzini L, Dalla Volta G. Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study. Neurology. 1999;52(8):1622-1625. 28. Del Sette M, Angeli S, Leandri M, et al. Migraine with aura and rightto-left shunt on transcranial Doppler: a case-control study. Cerebrovasc Dis. 1998;8(6):327-330. 29. Rigatelli G, Dell’avvocata F, Cardaioli P, et al. Improving migraine by means of primary transcatheter patent foramen ovale closure: long-term follow-up. Am J Cardiovasc Dis. 2012;2(2):89-95. 30. Trabattoni D, Fabbiocchi F, Montorsi P, et al. Sustained long-term benefit of patent foramen ovale closure on migraine. Catheter Cardiovasc Interv. 2011;77(4):570-574. 31. Wahl A, Praz F, Tai T, et al. Improvement of migraine headaches after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism. Heart. 2010;96(12):967-973. 32. Rigatelli G, Dell’Avvocata F, Ronco F, et al. Primary transcatheter patent foramen ovale closure is effective in improving migraine in patients with high-risk anatomic and functional characteristics for paradoxical embolism. JACC Cardiovasc Interv. 2010;3(3):282-287. 33. Rigatelli G, Cardaioli P, Dell’Avvocata F, et al. Transcatheter patent foramen ovale closure is effective in reducing migraine independently from specific interatrial septum anatomy and closure devices design. Cardiovasc Revasc Med. 2010;11(1):29-33. 34. Papa M, Gaspardone A, Fragasso G, et al. Usefulness of transcatheter patent foramen ovale closure in migraineurs with moderate to large
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35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48. 49.
50. 51.
52.
53.
54.
right-to-left shunt and instrumental evidence of cerebrovascular damage. Am J Cardiol. 2009;104(3):434-439. Wahl A, Praz F, Findling O, et al. Percutaneous closure of patent foramen ovale for migraine headaches refractory to medical treatment. Catheter Cardiovasc Interv. 2009;74(1):124-129. Chessa M, Colombo C, Butera G, et al. Is it too early to recommend patent foramen ovale closure for all patients who suffer from migraine? A single-centre study. J Cardiovasc Med (Hagerstown). 2009;10(5): 401-405. Luermans JG, Post MC, Temmerman F, et al. Closure of a patent foramen ovale is associated with a decrease in prevalence of migraine: a prospective observational study. Acta Cardiol. 2008;63(5):571-577. Jesurum JT, Fuller CJ, Kim CJ, et al. Frequency of migraine headache relief following patent foramen ovale “closure” despite residual rightto-left shunt. Am J Cardiol. 2008;102(7):916-920. Dubiel M, Bruch L, Schmehl I, et al. Migraine headache relief after percutaneous transcatheter closure of interatrial communications. J Interv Cardiol. 2008;21(1):32-37. Giardini A, Donti A, Formigari R, et al. Transcatheter patent foramen ovale closure mitigates aura migraine headaches abolishing spontaneous right-to-left shunting. Am Heart J. 2006;151(4):922.e1-922.e5. Giardini A, Donti A, Formigari R, et al. Long-term efficacy of transcatheter patent foramen ovale closure on migraine headache with aura and recurrent stroke. Catheter Cardiovasc Interv. 2006;67(4):625-629. Mortelmans K, Post M, Thijs V, Herroelen L, Budts W. The influence of percutaneous atrial septal defect closure on the occurrence of migraine. Eur Heart J. 2005;26(15):1533-1537. Reisman M, Christofferson RD, Jesurum J, et al. Migraine headache relief after transcatheter closure of patent foramen ovale. J Am Coll Cardiol. 2005;45(4):493-495. Azarbal B, Tobis J, Suh W, Chan V, Dao C, Gaster R. Association of interatrial shunts and migraine headaches: impact of transcatheter closure. J Am Coll Cardiol. 2005;45(4):489-492. Schwerzmann M, Wiher S, Nedeltchev K, et al. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology. 2004;62(8):1399-1401. Vigna C, Marchese N, Inchingolo V, et al. Improvement of migraine after patent foramen ovale percutaneous closure in patients with subclinical brain lesions: a case-control study. JACC Cardiovasc Interv. 2009;2(2):107-113. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008;117(11): 1397-1404. van der Kuy PH, Lohman JJ. A quantification of the placebo response in migraine prophylaxis. Cephalalgia. 2002;22(4):265-270. Carroll JD. Migraine Intervention with STARFlex Technology trial: a controversial trial of migraine and patent foramen ovale closure. Circulation. 2008;117(11):1358-1360. Wilmhurst P. CLOSURE I seen through the MIST. BMJ. 2005;344: e2226. Miller R. MIST Investigator accused of submitting false data to conference; 2012. Available at: http://www.medscape.com/viewarticle/ 791339. Accessed January 12, 2013. Carroll JD, Saver JL, Thaler DE, et al; RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092-1100. Meier B, Kalesan B, Mattle HP, et al; PC Trial Investigators. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368(12):1083-1091. Furlan AJ, Reisman M, Massaro J, et al; CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991-999.
Patent Foramen Ovale and Migraine Attacks: A Systematic Review Philomena Z.Y. Lip, (Student), Gregory Y.H. Lip, MD Department of Cardiovascular Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom.
ABSTRACT BACKGROUND: Migraine headache and the presence of a patent foramen ovale have been associated with each other, although the precise pathophysiological mechanism(s) are uncertain. The purpose of this systematic review was to identify the extent of patent foramen ovale prevalence in migraineurs and to determine whether closure of a patent foramen ovale would improve migraine headache. METHODS: An electronic literature search was performed to select studies between January 1980 and February 2013 that were relevant to the prevalence of patent foramen ovale and migraine, and the effects of intervention(s) on migraine attacks. Of the initial 368 articles presented by the initial search, 20 satisfied the inclusion criteria assessing patent foramen ovale prevalence in migraineurs and 21 presented data on patent foramen ovale closure. RESULTS: In case series and cohort studies, patent foramen ovale prevalence in migraineurs ranged from 14.6% to 66.5%. Case-control studies reported a prevalence ranging from 16.0% to 25.7% in controls, compared with 26.8% to 96.0% for migraine with aura. The extent of improvement or resolution of migraine headache attack symptoms was variable. In case series, intervention ameliorated migraine headache attack in 13.6% to 92.3% of cases. One single randomized trial did not show any benefit from patent foramen ovale closure. The data overall do not exclude the possibility of a placebo effect for resolving migraine following patent foramen ovale closure. CONCLUSION: This systematic review demonstrates firstly that migraine headache attack is associated with a higher prevalence of patent foramen ovale than among the general population. Observational data suggest that some improvement of migraine would be observed if the patent foramen ovale were to be closed. A proper assessment of any interventions for patent foramen ovale closure would require further large randomized trials to be conducted given uncertainties from existing trial data. Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 411-420 KEYWORDS: Migraine; Migraine headache; Patent foramen ovale
Migraine is a chronic neurological condition that is estimated to be prevalent in approximately 6% of men and 15%-17% of women between 20 and 64 years of age.1 It is characterized by headaches, preceded by aura of a visual or Funding: None. Conflict of Interest: None. Authorship: PZYL: original idea, conducted the systematic searches and synthesized the review data, wrote the first draft and made revisions; GYHL.: supervised the research, edited and drafted revisions to the article. Both authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham B18 7QH, UK. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2013.12.006
sensory kind in 4.4% of adults, and can vary in the intensity, frequency, and duration.2 Severe migraines can result in significant functional impairment until the subsequent full recovery is achieved. The onset of migraine has been suggested to occur from a mixture of environmental stimuli and hereditary factors. For example, Valsalva-provoking activities such as strenuous exercise are considered to be one of the most common causes.3 Patent foramen ovale is a remnant of a flap between the septae primum and secundum, which permits blood flow from the right atrium to the left4 and can be present in up to 27.3% of the population.5 Patent foramen ovale is asymptomatic in many cases, but its association with cerebrovascular events such as migraine has long been studied. The
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precise pathophysiological mechanism(s) linking patent foWe excluded studies that detailed results about other ramen ovale to migraine attacks remain unclear. forms of congenital heart disease or other neurovascular One hypothesis is that the patent foramen ovale causes disorders such as cryptogenic stroke, as the purpose of the metabolites and subclinical emboli, which are normally systematic review is to identify the specific relationship that removed by passage through the lungs to enter the systemic exists between migraine and patent foramen ovale alone. circulation, resulting in irritation to the trigeminal nerve and No distinction was made between patent foramen ovale vascular network. Normally, sepresence and right-to-left shunt for rotonin also is metabolized by the the selection of articles to review. CLINICAL SIGNIFICANCE lung monoamine oxidase, but if For articles achieving the the blood is shunted, thereby eligibility criteria stated, the full Migraine headache is associated with a avoiding the pulmonary circulatexts were obtained and the referhigh prevalence of patent foramen ovale tion, the increased platelet activaence lists scanned for further rele(PFO). tion and aggregation in response vant articles. If the PFO were to be closed, some to serotonin could possibly trigger migraine and aura.6 Patent foraobservational data suggest improvement RESULTS men ovale also is linked typically of migraine. Of the initial 368 articles preto some degree of arterial blood The one single randomized trial did not sented by the initial search, 59 oxygen desaturation; hypoxia inshow any benefit on migraine headache papers were screened in full, then creases the expression of plasfrom PFO closure. 10 were excluded for not focusing minogen activator-1, which in turn on patent foramen ovale or misuppresses fibrinolysis overall, A proper assessment of any interventions graine, 5 assessed the triggers of increasing the likelihood of a for PFO closure would require further migraine, and 3 studies investiparadoxical microembolism formlarge randomized trials to be conducted gated other factors in the freing.7 Paradoxical emboli have given uncertainties from existing trial quency of migraine, such as the been shown to stimulate migraine data. timing of a preprocedural migraine from studies where air microheadache attack. Finally, 41 artiembolism has been introduced and cles met the eligibility criteria for observed through the posterior inclusion in the review, with 20 articles being related to the cerebral artery, resulting in a migraine headache shortly association between patent foramen ovale and migraine, afterwards.8 Of note, patent foramen ovale can arise in latent and 21 articles assessed the effect of patent foramen ovale and permanent forms,9 but it is unknown whether this corclosure on migraine (Figure 1). relates to a significant change in migraine prevalence. Our objective was to conduct a systematic review of relevant existing literature to assess the relationship between Studies Examining the Relationship Between patent foramen ovale presence and migraine attacks. SecPatent Foramen Ovale and Migraine ond, the review aims to examine the effect of patent foramen ovale closure on the improvement (or otherwise) of Case Series and Cohort Studies (Table 1). Table 1 migraine symptomatology. summarizes the prevalence of patent foramen ovale in migraineurs from 12 case series.9-20 The results showed a higher prevalence of patent foramen ovale amongst METHODS migraineurs, ranging from 14.6% to 66.5%, compared with a cited figure of 27.3% in the general population.5 A comprehensive search using PubMed/Medline was undertaken, which yielded 368 articles published between There was a noticeable difference between the presence January 1980 and February 28, 2013. The search terms used of patent foramen ovale in migraine with aura and migraine in combination were “migraine,” “migraine headache,” and without aura. The prevalence of patent foramen ovale in “patent foramen ovale.” migraine-with-aura patients ranged from 46.3% to 88.0%, as The articles obtained were filtered on the basis of releassessed from 6 case series,9,12,14,15,18,19 when compared vancy of abstract and title. The selection criteria prepared with a range of 16.2%-34.9% in migraine-without-aura were intended to include studies that concerned the relapatients as assessed from 2 case series.18,19 tionship between migraine and patent foramen ovale, or Three studies10,11,17 considered migraine headache attack the effects of patent foramen ovale closure on migraine prevalence within a population of patent foramen ovale attack symptomatology. Therefore, articles that were repatients, which ranged from 9.13% to 51.7%. Only one views or case reports were omitted, as were those relating to study15 considered typical and atypical aura in migraine, children. Although selection criteria did pertain to articles with aura patients as a possible factor for patent foramen only in the English language, because migraine and patent ovale prevalence—the results showed a greater prevalence foramen ovale are both present in patients worldwide, the of 79.2% in migraineurs with atypical aura when compared decision was made not to exclude any particular population. with 46.3% in those with typical aura.
Lip and Lip
Patent Foramen Ovale and Migraine
Figure 1
413
CONSORT Diagram.
Three studies9,12,14 made a distinction between a permanent shunt and a latent shunt, with a permanent shunt being the prevailing characteristic in 66.7%-72.1% of patent foramen ovale patients with migraine, whereas a latent shunt ranged from 27.9% to 33.3%. As illustrated in Table 1, one study9 also addressed the difference in the prevalence of large or small patent foramen ovale, yielding results of 75% and 25%, respectively.
One study examined the prevalence of patent foramen ovale in patients suffering from aura symptoms without migraine headache attack, and found this to be 66.7%21 (Table 2).
Case-control Studies (Table 2). Table 2 summarizes findings from 8 case-control studies21-28 assessing the relationship between migraine and patent foramen ovale presence, allowing direct comparison between a control that is representative of the general population and those with migraine. The results show a range from 16.0% to 25.7% for prevalence of patent foramen ovale in the controls (7 studies21-23,25-28), 26.8% to 96.0% for migraine-with-aura patients (7 studies21-23,25-28), and 22.6% to 72.4% for migraine-without-aura patients (5 studies21-23,25,27). One study24 presented data on patent foramen ovale prevalence in migraineurs (51.9%) and in controls (15.4%).
Case series (Table 3). The 18 case series21,29-45 selected to represent the effect of patent foramen ovale closure on migraine headache attack severity are summarized in Table 3. The results varied between migraine with aura and migraine without aura patients, and can be categorized into “resolved,” “improvement,” “no change,” and “worsened.” Migraine with aura resolution ranged from 28.6% to 92.3%, whereas migraine without aura resolution varied from 13.6% to 82.9%. Migraine with aura improvement ranged from 4.17% to 64.3%; migraine without aura improvement varied from 0% to 68.2%. Of note, 9 studies made the distinction between migraine with aura and
The Effect of Patent Foramen Ovale Closure on Migraine Headache Severity
414
Table 1
Case Series and Cohort Studies Examining the Relationship Between Patent Foramen Ovale and Migraine
First Author/Year Case Series
Reference
Sample Size
Results
Comment
Faggiano et al, 2012 Dao & Tobis, 2011 Caputi et al, 2010
10 11 12
n ¼ 446 PFO n ¼ 416 PFO n ¼ 159 MA
Found prevalence of MH not prevalence of PFO. Found prevalence of MH not prevalence of PFO. Only MA patients.
Nahas et al, 2010
13
Caputi et al, 2009
14
n ¼ 131 MH n ¼ 53 MA n ¼ 120 MA
n ¼ 47 MH (10.5%) n ¼ 38 MH (9.13%) RLS overall: n ¼ 79 (49.7%) Permanent RLS: n ¼ 56 (70.9%) Latent RLS: n ¼ 23 (29.1%) n ¼ 86 (65.6%) RLS
Only MA patients.
Marchione et al, 2008
15
RLS overall: n ¼ 61 (50.8%) Latent RLS: n ¼ 17 (27.9%) Permanent RLS: n ¼ 44 (72.1%) Large RLS: n ¼ 32 (52.4%) PFO prevalence: Group 1 (typical aura) n ¼ 19 (46.3%) Group 2 (atypical aura) n ¼ 19 (79.3%)
Rundek et al, 2008
16
Prevalence of PFO: n ¼ 26 (14.6%)
Migraine history self-reported.
Liboni et al, 2008
9
Test subjects only women. Used near-infrared spectroscopy to detect which had 79% sensitivity and 90% specificity. Some false positives later identified as permanent shunts.
Truong et al, 2008
17
n ¼ 147 RLS n ¼ 118 LRS
Carod-Artal et al, 2006
18
n ¼ 58 MA n ¼ 83 MO
Dalla Volta et al, 2005
19
n ¼ 260 MA n ¼ 74 MO
Ferrarini et al, 2005
20
n ¼ 25 MA
PFO: n ¼ 48 (54.5%) Large PFO: n ¼ 36 (75.0%) Small PFO: n ¼ 12 (25.0%) Permanent RLS: n ¼ 32 (66.7%) Latent RLS: n ¼ 16 (33.3%) RLS: n ¼ 61 MA (41.5%) n ¼ 15 MO (10.2%) LRS: n ¼ 39 MA (33.1%) n ¼ 12 MO (10.2%) PFO prevalence: n ¼ 30 MA (51.7%) n ¼ 29 MO (34.9%) PFO prevalence: n ¼ 161 MA (61.9%) n ¼ 12 MO (16.2%) PFO prevalence: n ¼ 22 (88.0%)
Only MA patients.
Self-reported questionnaire used to diagnose migraine.
Small sample size. Only MA patients.
LRS ¼ left-to-right shunt; MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale; RLS ¼ right-to-left shunt.
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n ¼ 65 MA n ¼ 41 with typical aura (group 1) and n ¼ 24 with atypical aura (group 2) n ¼ 178 MH n ¼ 143 MA n ¼ 88 MA
Lip and Lip Table 2
Patent Foramen Ovale and Migraine
415
Case-Control Studies Examining the Relationship between Patent Foramen Ovale and Migraine
First Author/Year Case-control Studies
Reference
Sample Size
Results
Comment
Khessali et al, 2012
21
RLS prevalence: 1) MA ¼ 168 (96.0%) 2) MO ¼ 21 (72.4%) 3) Aura only ¼14 (66.7%) 4) Control ¼ 36 (18.0%)
Control: Patients undergoing cardiac catheterization unrelated to PFO.
Garg et al, 2010
22
n ¼ 225 visual aura with or without MH. n ¼ 91 aura without headache. 1) MA ¼ 175 2) MO ¼ 29 3) Aura only ¼ n ¼ 21 4) Control ¼ 200 n ¼ 144 control n ¼ 144 migraineurs, MA present in 39%
Control: No MH
Tatlidede et al, 2007
23
n ¼ 15 MA n ¼ 38 MO n ¼ 27 control
Kimmelstiel et al, 2007
24
n ¼ 104 PFO n ¼ 65 control
Domitrz et al, 2007
25
n ¼ 61 MA n ¼ 60 MO n ¼ 65 control group
Schwerzmann et al, 2005
26
n ¼ 93 MA and n ¼ 93 control
Anzola et al, 1999
27
n ¼ 113 MA n ¼ 53 MO n ¼ 25 control
Del Sette et al, 1998
28
n ¼ 44 MA n ¼ 50 control
PFO prevalence: n ¼ 37 control (25.7%) MA: 26.8% MO: 26.1% PFO prevalence: n ¼ 10 MA (66.7%) n ¼ 18 MO (47.4%) n ¼ 6 control (22.2%) MH prevalence: n ¼ 54 PFO (51.9%) n ¼ 10 control (15.4%) PFO prevalence: n ¼ 33 MA (54.1%) n ¼ 15 MO (25.0%) n ¼ 16 control (24.6%) PFO prevalence: n ¼ 44 in MA (47.3%) n ¼ 16 in control (17.2%) Small shunt equally prevalent in control and MA. Shunt size larger in MA. PFO prevalence: n ¼ 54 (47.8%) MA n ¼ 12 (22.6%) MO n ¼ 5 (20.0%) control RLS prevalence: n ¼ 18 (40.9%) MA n ¼ 8 (16.0%) control
Small sample size. Control: Healthy
Control: No PFO
Control: Healthy
Control: Healthy
Control: No MH
Small sample size. Control: Healthy
MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale.
migraine without aura, allowing for a comparison between the 2. As shown in Table 3, the greatest worsening experienced was 4.47%, whereas up to 29.4% experienced no change.
In this trial,47 74 patients were randomized to patent foramen ovale closure with septal repair implant, whereas 73 received the sham procedure. The primary end point of migraine cessation was achieved by 4.05% of patients who underwent patent foramen ovale closure, and by 4.11% of patients subjected to the sham procedure. Thus, no significant differences were seen between the patent foramen ovale and sham trial arms for the primary end point, but on exploratory analysis, excluding 2 study result outliers, the implant group “demonstrated a greater reduction in total migraine headache days” (P ¼ .0027).
Case-control Studies (Table 4). There were 2 case-control studies24,46 comparing the effects of intervention and medication (Table 4). With intervention, there was a reported 83%-87% improvement of migraine symptoms in patients, compared with 0%-21% in those where the patent foramen ovale remained open. One study24 used a control group of migraineurs without a patent foramen ovale and on medication, and reported a 10% improvement with intervention.
DISCUSSION
Randomized Controlled Trials (Table 5). Only one published prospective randomized controlled trial (shown in Table 5) was found regarding the closure of patent foramen ovale to improve migraine.
This systematic review clearly identifies that the prevalence of patent foramen ovale in patients with migraine is greater than that seen in the general population. Second, there was a stronger correlation between prevalence of patent foramen ovale in migraine-with-aura patients compared with
416
Table 3
Case Series Examining the Effect of Patent Foramen Ovale Closure on Migraine Severity
First Author/Year Case Series
Reference
Sample Size
Results
Comment
Khessali et al, 2012
21
PFO closure in n ¼ 80 n ¼ 67 MA n ¼ 8 MO n ¼ 200 control
Small sample size. Follow-up: 12 months.
Rigatelli et al, 2012
29
RLS closure in n ¼ 80 MH n ¼ 63 MA
Trabattoni et al, 2011
30
RLS closure in n ¼ 77 MH (MA¼13, MO¼64)
Wahl et al, 2010
31
PFO closure in n ¼ 150 MH n ¼ 96 MA n ¼ 54 MO
Rigatelli et al, 2010a
32
PFO closure in n ¼ 40 MH
Rigatelli et al, 2010b check stats as changed in table Papa et al, 2009
33
PFO closure in n ¼ 34 MA
34
PFO closure in n ¼ 76 MH
Wahl et al, 2009
35
PFO closure in n ¼ 17 MH n ¼ 14 MA n ¼ 3 MO
Chessa et al, 2009
36
PFO closure in n ¼ 42 MH
MA: n ¼ 35 (52.2%) resolved n ¼ 16 (23.9%) improvement n ¼ 1 (1.49%) no change n ¼ 3 (4.48%) worse MO: n ¼ 6 (75.0%) resolved n ¼ 0 (0%) improvement n ¼ 1 (12.5%) no change n ¼ 0 (0%) worse n ¼ 70 (87.5%) improvement n ¼ 10 (22.5%) no change n ¼ 0 worse (0%) n ¼ 61 (96.8%) complete resolution of aura MH: n ¼ 23 (29.9%) resolved n ¼ 20 (26.0%) improvement MO resolved n ¼ 14 (25.9%) MO improvement n ¼ 30 (55.6%) MA resolved n ¼ 37 (38.5%) MA improvement n ¼ 47 (49.0%) All patients improved. Aura disappeared in all patients with pre-procedural aura. n ¼ 19 (55.9%) resolved n ¼ 6 (17.6%) improvement n ¼ 2 (5.88%) unchanged n ¼ 35 (46.1%) MH resolved n ¼ 27 (35.5%) MH improved n ¼ 14 (18.4%) MH unchanged MA: Resolved ¼ 4 (28.6%) Improvement ¼ 9 (64.3%) Unchanged ¼ 4 (28.6%) MO: Improvement ¼ 2 (66.7%) Unchanged ¼ 1 (33.3%) MH resolved: n ¼ 11 (26.2%) MH improvement: n ¼ 22 (52.4%)
Follow-up: 12 months
Small sample size. Follow-up: mean ¼ 13.7 2.4 months Small sample size.
Small sample size. Patients rated own severity of MH. Follow-up: 6 months
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Small sample size. Follow-up: from 6 to 48 months (mean ¼ 29.2 14.8 months) Small sample size. Follow up: mean ¼ 9 2.9 months
Continued Reference
Sample Size
Results
Comment
Luermans et al, 2008
37
PFO closure in n ¼ 89 MH n ¼ 24 MO n ¼ 10 MA
Small sample size for MH. Follow-up: 6 months
Jesurum et al, 2008
38
PFO closure in n ¼ 67 MH n ¼ 55 MA
Dubiel et al, 2008
39
PFO closure in n ¼ 46 MH n ¼ 24 MA n ¼ 22 MO
Giardini et al, 2006a
40
PFO closure in n ¼ 35 MA
Giardini et al, 2006b
41
PFO closure in n ¼ 13 MA
Follow-up of n ¼ 84 MO: n ¼ 15 (62.5%) resolved n ¼ 9 (37.5%) improvement/no change MA: n ¼ 8 (80.0%) resolved n ¼ 2 (20.0%) improvement/no change n ¼ 36 (53.7%) MH resolved n ¼ 17 (25.4%) improvement n ¼ 11 (16.4%) no relief n ¼ 3 (4.47%) worse MA: n ¼ 8 (33.3%) resolved n ¼ 14 (58.3%) improved n ¼ 2 (8.33%) persistent MO: n ¼ 3 (13.6%) resolved n ¼ 15 (68.2%) improved n ¼ 4 (18.2%) persistent n ¼ 29 (82.9%) resolved n ¼ 3 (8.57%) improvement n ¼ 3 (8.57%) unchanged n ¼ 12 (92.3%) resolved
Mortelmans et al, 2005
42
Reisman et al, 2005
43
n ¼ 14 MO n ¼ 8 MA underwent PFO closure PFO closure in n ¼ 57 MH n ¼ 37/57 MA
Azarbal et al, 2005
44
PFO closure in n ¼ 37 MH n ¼ 24 MA n ¼ 13 MO
Schwerzmann et al, 2004
45
PFO closure in n ¼ 48 MH
MA: n ¼ 4 (50.0%) resolved MO: n ¼ 6 (42.9%) resolved n ¼ 50 follow-up n ¼ 28 (56.0%) resolved n ¼ 14 (28.0%) improvement n ¼ 15 (30.0%) minimal or no relief MA: n ¼ 18 (75.0%) resolved n ¼ 1 (4.17%) improvement MO: 4 (30.8%) resolved n ¼ 5 (38.5%) improvement 3 months post-op: 75% MA resolved 31% MO resolved 54% MA improved 62% MO improved
Small sample size. Follow-up: mean ¼ 38 months
Small sample size; assessment only of MA pts. Follow-up: 1.7 1.3 years Subjects had cryptogenic stroke and only MA assessed. Small sample size. Follow-up: 4.9 1.4 years Small sample size. Follow-up: median ¼ 29 months Small sample size. Follow-up: 12 months
Small sample size. Follow-up: 3 months
Small sample size.
417
ASD ¼ atrial septal defect; MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale.
Based on patients’ self-completed questionnaires.
Patent Foramen Ovale and Migraine
First Author/Year Case Series
Lip and Lip
Table 3
418
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Table 4
Case Control Studies Examining Comparing Effects of Intervention and Medication
First Author/Year Case-Control
Reference
Sample Size
Results
Comment
Kimmelstiel et al, 2007
24
n ¼ 63 open PFO no intervention n ¼ 41 underwent PFO closure
Open PFO: no intervention performed Control: no PFO follow-up: 90 days
Vigna et al, 2009
46
n ¼ 82 MH, PFO and subclinical brain lesions PFO closure n ¼ 53 Control n ¼ 29
PFO closure: 83% improvement Open PFO: 0% improvement Control: 10% improvement PFO closure: 34% resolved 87% improvement Control: 7% resolved 21% improvement
Control: preventative migraine medication. Small sample size. Follow-up: mean ¼ 16 7 months
MA ¼ migraine with aura; MH ¼ migraine headache; MO ¼ migraine without aura; PFO ¼ patent foramen ovale.
patients suffering from migraine without aura alone, but only 11 studies presented data on this, with 2 being unsupportive of this link; thus, the relationship may be open to debate. Third, the effect of patent foramen ovale closure on migraine yielded more tenuous results: only 18 observational studies reported improvement of migraine but varied in their specificity of amelioration, and there was variation as to whether resolution or improvement of migraine headache attack was more prevalent, and one study42 even demonstrated some exacerbation of migraine headache attack at follow-up. These data were mainly from case series and case-control studies of varying sample sizes. The one single randomized trial did not show any benefit of patent foramen ovale closure. The sample sizes for published observation studies were variable, ranging from as few as 13 patients41 with migraine to as many as 334.19 The investigations for effect of migraine post-patent foramen ovale closure also used variable follow-up periods, which would be likely to make a significant contribution to the differences in results; indeed, the follow-up period ranged from 90 days to a mean of 4.9 years. Also, the exact follow-up periods for each study were not always specified. Only a select few studies investigated the differences between migraine with aura and migraine without aura, which therefore may not give an accurate Table 5
depiction of the existing differences in the overall population. A number of limitations are evident in assessing the data for amelioration of migraine headache attack following patent foramen ovale closure. Firstly, each study varied in the length of follow-up, making it difficult to make valid comparisons; several studies also failed to make a distinction between improvement and no change in migraine headache attack, choosing to document only full resolution, which does not necessarily give a true representation of the potential benefits of patent foramen ovale closure on migraine headache attack. The majority of studies also failed to provide data on whether patients had worsening or no change; when the data were present, the sample size was often too small to make reliable comparisons. Second, migraine headache attack was largely assessed using a patient questionnaire from which a neurologist would then designate a Migraine Disability Assessment (MIDAS) score—even in cases where migraine headache attack was diagnosed upon examination, the subjectivity of these methods could give rise to potential bias. The most important difficulty in gaining certainty of results for this hypothesis was the “placebo effect.” The placebo effect in migraineurs ranges from 35% to 40%, which could have significant effects on the outcome of the results
Randomized Controlled Trials
First Author/Year Randomized Controlled Trials Reference Sample Size Dowson et al, 2008
47
n ¼ 432 MH assessed for RLS. n ¼ 260 shunt n ¼ 163/260 moderate/large PFO n ¼ 96/260 small/pulmonary shunt n ¼ 1 ASD Randomized: n ¼ 74 PFO closure n ¼ 73 sham procedure
Results
Comment
Mean frequency of migraine attacks and Data concerns50 median MIDAS score decreased for sham and implant procedures; difference not statistically significant. Reached primary endpoint of migraine cessation in PFO: n ¼ 3 (4.05%) Sham: n ¼ 3 (4.11%)
ASD ¼ atrial septal defect; MH ¼ migraine headache; MIDAS ¼ Migraine Disability Assessment Score; PFO ¼ patent foramen ovale; RLS ¼ right-to-left shunt.
Lip and Lip
Patent Foramen Ovale and Migraine
postprocedure.48 Further studies would be required to investigate the distinctions between migraine with aura and patent foramen ovale, compared with migraine without aura and patent foramen ovale, to increase our understanding of the relationship, as well as to support the suggestion that the amelioration of migraine following patent foramen ovale closure is not largely due to the placebo effect. Indeed, the current data overall do not exclude the possibility of a placebo effect for resolving migraine following patent foramen ovale closure. The Migraine Intervention with STARFlex technology (MIST) trial, sponsored by NMT Medical (Boston, Mass, no longer in business), is currently the only published large randomized controlled trial to have been undertaken to explore the effect of patent foramen ovale closure on migraine.47 This trial did not show any significant difference in the primary end point, but on exploratory analysis, excluding 2 study result outliers, the implant group was reported to have “demonstrated a greater reduction in total migraine headache days.” In an accompanying editorial, Carroll49 highlighted the high frequency of patients not found to have a patent foramen ovale during their procedure, thus questioning the quality of the echocardiographic screening process. Also, there was the higher-than-expected rate of serious adverse events in the device-treated patients, again raising concerns about the quality of the procedures.49 Lastly, there was an “unclear number” of residual shunts, and thus, the efficacy of the device itself. Of note, one of the initial co-authors (Peter Wilmhurst) alleged that the sponsor (NMT Medical) removed clinical members of the steering committee and overruled the clinicians on aspects such as trial design and presentation of the data.50 As reported by Medscape (www.medscape.com), the 2 lead investigators of MIST were brought before a Medical Practitioners Tribunal Service in a fitness-to-practice hearing for suspected misconduct in the trial and for submitting an abstract containing false data.51 The MIST data also had to be somewhat amended following the report that the trial may have had poor echocardiographic assessment, resulting in inclusion of patients with pulmonary, not intracardiac, shunting. Considering all these factors, the results from this one single randomized trial should therefore be viewed with caution. Nonetheless, patent foramen ovale closure has been subject to discussion in terms of its benefits for other neurological conditions, most notably for stroke risk prevention. Although this systematic review article is focusing solely on migraine, there have been 2 large randomized controlled trials assessing the relationship of patent foramen ovale to stroke. Both trials, the RESPECT (Randomized Evaluation of recurrent Stroke comparing patent foramen ovale closure to Established Current standard of care Treatment) and the PC (Patent foramen ovale and Cryptogenic stroke) trials, failed to show significant results on reducing risk of recurrent stroke following percutaneous closure of the patent foramen ovale.52,53 A third trial, CLOSURE I sponsored by NMT Medical, used a device (STAR-FLEX) that is currently no longer used in practice,
419 and the results did not show any significant benefit either.54 The CLOSURE I trial was subject to criticism as the patients selected for inclusion were not typical of patients who undergo patent foramen ovale closure following stroke, and therefore the results were not representative of the patient population that the intervention would target. Following the debate about the MIST trial by NMT Medical, the CLOSURE I trial should also perhaps be treated cautiously.
CONCLUSION This systematic review demonstrates firstly that migraine headache is associated with a higher prevalence of patent foramen ovale than among the general population, and if the patent foramen ovale were to be closed, observational data suggest some improvement of migraine would be observed in patients. The one single randomized trial did not show any benefit. A proper assessment of any interventions for patent foramen ovale closure would require further large randomized trials to be conducted given uncertainties from existing randomized trial data.
References 1. Stewart WF, Roy J, Lipton RB. Migraine prevalence, socioeconomic status and social causation. Neurology. 2013;10(81):948-955. 2. Merikangas KR. Contributions of epidemiology to our understanding of migraine. Headache. 2013;53(2):230-246. 3. Tembl J, Lago A, Sevilla T, Solis P, Vilchez J. Migraine, patent foramen ovale and migraine triggers. J Headache Pain. 2007;8(1):7-12. 4. Fisher DC, Fisher EA, Budd JH, Rosen SE, Goldman ME. The incidence of patent foramen ovale in 1,000 consecutive patients. A contrast transesophageal echocardiography study. Chest. 1995;107(6): 1504-1509. 5. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clinic. 1984;59(1):17-20. 6. Sharma A, Gheewala N, Silver P. Role of patent foramen ovale in migraine etiology and treatment: a review. Echocardiography. 2011;28(8):913-917. 7. Prandota J. Migraine associated with patent foramen ovale may be caused by reactivation of cerebral toxoplasmosis triggered by arterial blood oxygen desaturation. Int J Neurosci. 2010;120(2):81-87. 8. Sevgi EB, Erdener SE, Demirci M, Topcuoglu MA, Dalkara T. Paradoxical air microembolism induces cerebral bioelectrical abnormalities and occasionally headache in patent foramen ovale patients with migraine. J Am Heart Assoc. 2012;1(6):e001735. 9. Liboni W, Molinari F, Allais GB, et al. Patent foramen ovale detected by near-infrared spectroscopy in patients suffering from migraine with aura. Neurol Sci. 2008;29(Suppl 1):S182-S185. 10. Faggiano P, Frattini S, Piovesana P, et al. Low cerebrovascular event rate in subjects with patent foramen ovale and different clinical presentations: results from a prospective non randomized study on a population including patients with and without patent foramen ovale closure. Int J Cardiol. 2012;156(1):47-52. 11. Dao CN, Tobis JM. PFO and paradoxical embolism producing events other than stroke. Catheter Cardiovasc Interv. 2011;77(6):903-909. 12. Caputi L, Usai S, Carriero MR, et al. Microembolic air load during contrast-transcranial Doppler: a trigger for migraine with aura? Headache. 2010;50(8):1320-1327. 13. Nahas SJ, Young WB, Terry R, et al. Right-to-left shunt is common in chronic migraine. Cephalalgia. 2010;30(5):535-542. 14. Caputi L, D’Amico D, Usai S, Grazzi L, Parati EA, Bussone G. Prevalence and characteristics of right-to-left shunt in migraine with aura: a survey on 120 Italian patients. Neurol Sci. 2009;30(Suppl 1):S109-S111.
420 15. Marchione P, Ghiotto N, Sances G, et al. Clinical implications of patent foramen ovale in migraine with aura. Funct Neurol. 2008;23(4): 201-205. 16. Rundek T, Elkind MS, Di Tullio MR, Carrera E, Jin Z, Sacco RL, Homma S. Patent foramen ovale and migraine: a cross-sectional study from the Northern Manhattan Study (NOMAS). Circulation. 2008;118(14):1419-1424. 17. Truong T, Slavin L, Kashani R, et al. Prevalence of migraine headaches in patients with congenital heart disease. Am J Cardiol. 2008;101(3): 396-400. 18. Carod-Artal FJ, da Silveira Ribeiro L, Braga H, Kummer W, Mesquita HM, Vargas AP. Prevalence of patent foramen ovale in migraine patients with and without aura compared with stroke patients. A transcranial Doppler study. Cephalalgia. 2006;26(8):934-939. 19. Dalla Volta G, Guindani M, Zavarise P, Griffini S, Pezzini A, Padovani A. Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationship with clinical phenotype. J Headache Pain. 2005;6(4):328-330. 20. Ferrarini G, Malferrari G, Zucco R, Gaddi O, Norina M, Pini LA. High prevalence of patent foramen ovale in migraine with aura. J Headache Pain. 2005;6(2):71-76. 21. Khessali H, Mojadidi MK, Gevorgyan R, Levinson R, Tobis J. The effect of patent foramen ovale closure on visual aura without headache or typical aura with migraine headache. JACC Cardiovasc Interv. 2012;5(6):682-687. 22. Garg P, Servoss SJ, Wu JC, et al. Lack of association between migraine headache and patent foramen ovale: results of a case-control study. Circulation. 2010;121(12):1406-1412. 23. Tatlidede AD, Oflazo glu B, Celik SE, Anadol U, Forta H. Prevalence of patent foramen ovale in patients with migraine. Agri. 2007;19(4):39-42. 24. Kimmelstiel C, Gange C, Thaler D. Is patent foramen ovale closure effective in reducing migraine symptoms? A controlled study. Catheter Cardiovasc Interv. 2007;69(5):740-746. 25. Domitrz I, Mieszkowski J, Kaminska A. Relationship between migraine and patent foramen ovale: a study of 121 patients with migraine. Headache. 2007;47(9):1311-1318. 26. Schwerzmann M, Nedeltchev K, Lagger F, et al. Prevalence and size of directly detected patent foramen ovale in migraine with aura. Neurology. 2005;65(9):1415-1418. 27. Anzola GP, Magoni M, Guindani M, Rozzini L, Dalla Volta G. Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study. Neurology. 1999;52(8):1622-1625. 28. Del Sette M, Angeli S, Leandri M, et al. Migraine with aura and rightto-left shunt on transcranial Doppler: a case-control study. Cerebrovasc Dis. 1998;8(6):327-330. 29. Rigatelli G, Dell’avvocata F, Cardaioli P, et al. Improving migraine by means of primary transcatheter patent foramen ovale closure: long-term follow-up. Am J Cardiovasc Dis. 2012;2(2):89-95. 30. Trabattoni D, Fabbiocchi F, Montorsi P, et al. Sustained long-term benefit of patent foramen ovale closure on migraine. Catheter Cardiovasc Interv. 2011;77(4):570-574. 31. Wahl A, Praz F, Tai T, et al. Improvement of migraine headaches after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism. Heart. 2010;96(12):967-973. 32. Rigatelli G, Dell’Avvocata F, Ronco F, et al. Primary transcatheter patent foramen ovale closure is effective in improving migraine in patients with high-risk anatomic and functional characteristics for paradoxical embolism. JACC Cardiovasc Interv. 2010;3(3):282-287. 33. Rigatelli G, Cardaioli P, Dell’Avvocata F, et al. Transcatheter patent foramen ovale closure is effective in reducing migraine independently from specific interatrial septum anatomy and closure devices design. Cardiovasc Revasc Med. 2010;11(1):29-33. 34. Papa M, Gaspardone A, Fragasso G, et al. Usefulness of transcatheter patent foramen ovale closure in migraineurs with moderate to large
The American Journal of Medicine, Vol 127, No 5, May 2014
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48. 49.
50. 51.
52.
53.
54.
right-to-left shunt and instrumental evidence of cerebrovascular damage. Am J Cardiol. 2009;104(3):434-439. Wahl A, Praz F, Findling O, et al. Percutaneous closure of patent foramen ovale for migraine headaches refractory to medical treatment. Catheter Cardiovasc Interv. 2009;74(1):124-129. Chessa M, Colombo C, Butera G, et al. Is it too early to recommend patent foramen ovale closure for all patients who suffer from migraine? A single-centre study. J Cardiovasc Med (Hagerstown). 2009;10(5): 401-405. Luermans JG, Post MC, Temmerman F, et al. Closure of a patent foramen ovale is associated with a decrease in prevalence of migraine: a prospective observational study. Acta Cardiol. 2008;63(5):571-577. Jesurum JT, Fuller CJ, Kim CJ, et al. Frequency of migraine headache relief following patent foramen ovale “closure” despite residual rightto-left shunt. Am J Cardiol. 2008;102(7):916-920. Dubiel M, Bruch L, Schmehl I, et al. Migraine headache relief after percutaneous transcatheter closure of interatrial communications. J Interv Cardiol. 2008;21(1):32-37. Giardini A, Donti A, Formigari R, et al. Transcatheter patent foramen ovale closure mitigates aura migraine headaches abolishing spontaneous right-to-left shunting. Am Heart J. 2006;151(4):922.e1-922.e5. Giardini A, Donti A, Formigari R, et al. Long-term efficacy of transcatheter patent foramen ovale closure on migraine headache with aura and recurrent stroke. Catheter Cardiovasc Interv. 2006;67(4):625-629. Mortelmans K, Post M, Thijs V, Herroelen L, Budts W. The influence of percutaneous atrial septal defect closure on the occurrence of migraine. Eur Heart J. 2005;26(15):1533-1537. Reisman M, Christofferson RD, Jesurum J, et al. Migraine headache relief after transcatheter closure of patent foramen ovale. J Am Coll Cardiol. 2005;45(4):493-495. Azarbal B, Tobis J, Suh W, Chan V, Dao C, Gaster R. Association of interatrial shunts and migraine headaches: impact of transcatheter closure. J Am Coll Cardiol. 2005;45(4):489-492. Schwerzmann M, Wiher S, Nedeltchev K, et al. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology. 2004;62(8):1399-1401. Vigna C, Marchese N, Inchingolo V, et al. Improvement of migraine after patent foramen ovale percutaneous closure in patients with subclinical brain lesions: a case-control study. JACC Cardiovasc Interv. 2009;2(2):107-113. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008;117(11): 1397-1404. van der Kuy PH, Lohman JJ. A quantification of the placebo response in migraine prophylaxis. Cephalalgia. 2002;22(4):265-270. Carroll JD. Migraine Intervention with STARFlex Technology trial: a controversial trial of migraine and patent foramen ovale closure. Circulation. 2008;117(11):1358-1360. Wilmhurst P. CLOSURE I seen through the MIST. BMJ. 2005;344: e2226. Miller R. MIST Investigator accused of submitting false data to conference; 2012. Available at: http://www.medscape.com/viewarticle/ 791339. Accessed January 12, 2013. Carroll JD, Saver JL, Thaler DE, et al; RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368(12):1092-1100. Meier B, Kalesan B, Mattle HP, et al; PC Trial Investigators. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368(12):1083-1091. Furlan AJ, Reisman M, Massaro J, et al; CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991-999.
