C 2011, Wiley Periodicals, Inc.

DOI: 10.1111/j.1540-8175.2011.01460.x

REVIEW ARTICLE

Role of Patent Foramen Ovale in Migraine Etiology

and Treatment: A Review
Ambika Sharma, B.A., Neil Gheewala, M.D., and Paul Silver, M.D.

George Washington University School of Medicine, Washington, DC; Department of Medicine, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Medicine,
George Washington University Medical Center, Washington, DC

An increased prevalence between patent formen ovale (PFOs) and migraine exists but there is conflicting
data regarding causal relationship between these two conditions. It is controversial whether cardiac
screening and intervention like PFO closure provides any benefit in this population and so this area
still remains under intense investigation. The management of migraine lies at the intersection between
the practice of primary care physicians, neurologists, and cardiologists. There is no consensus as to
what is the best practice for the evaluation of these patients with difficult to control migraine given the
millions of dollars spent on physician visits and pharmacotherapy. This review seeks to summarize the
current literature on this association and studies that have investigated PFO closure in this population.
(Echocardiography 2011;28:913-917)
Key words: migraine, PFO, paradoxical embolism, stroke
Migraine headaches affect approximately 13%
of US population, affecting women in a 3:1 ratio
and with a 6080% familial inheritance. Onset of
migraine is usually between the ages of 2064,
with over 80% having their first episode before
age 30 and tend to decrease in middle age. Migraine with aura (MA), is a variant characterized
by transient neurological visual, verbal, sensory
or motor symptoms that last from five to sixty
minutes. MA is also known as classic migraine
though only 25% of migraneurs experience an
aura.
An increased prevalence between patent formen ovale (PFOs) and migraine exists but there
is conflicting data of a causal relationship between these two conditions. It remains controversial whether cardiac screening and intervention
provides a treatment benefit in migraineurs and
is an area currently investigated for additional indications for PFO closure. This topic is an intersection between the practice of primary care physicians, neurologists, and cardiologists on the best
practice and management of patients with difficult to control migraines given the billions spent
on physician visits and pharmacotherapy. This review seeks to summarize the current literature on
this association and studies that have investigated
PFO closure in this population.
There was no funding source.
Address for correspondence and reprint requests: Ambika
Sharma, #718 922 24th St. NW, Washington, DC 20037. Fax:
412-726-0737; E-mail: hina246@gwmail.gwu.edu

PFOMigraine Relationship:
Despite intuitive relationship between PFO and
paradoxical embolism, there is significant debate
of whether PFO closure in patients with recurrent
cryptogenic stroke provides benefit over medical
management alone. This is a common indication
in many centers for PFO closure, despite a paucity
of randomized trials demonstrating benefit. Over
the past decade, many investigators have looked
to make an association between this concept of
right to left shunting and migraines as another indication for PFO closure. In general, the majority
of the data has been low grade of evidence from
observational studies for patient undergoing PFO
closure for a secondary etiology, such as cryptogenic stroke or decompression illness in divers.
Though PFO is the most common right-to-left
shunt, other causes include other such as atrial
septal defects and pulmonary arteriovenous malformations. PFO is a remnant of the fetal foramen
ovale that during development is required for
right to left shunting (RLS) of oxygenated blood
from the placenta to the systemic circulation. By
age two, about 75% have complete fusion of the
septum primum and septum secundum, with the
remainder developing a PFO. Typically, PFOs are
of no hemodynamic significance and only with
Valsalva maneuvers are they readily visualized on
contrast echocardiography. PFOs comprise about
95% of all RLS.1
One postulated mechanism which implicates
a role for right to left shunting (RLS), suggests
that subclinical emboli and metabolites from the
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Sharma, Gheewala, and Silver

venous system circumvent the lungs and directly enter the systemic circulation causing irritation of the trigeminal nerve and vasculature
near the brain, triggering a migraine. Migraineurs
have increased platelet activation and aggregation in response to serotonin. Normally serotonin is metabolized by lung MAO, but if blood
is shunted through a PFO and avoids the pulmonary circulation it has been postulated that
this can trigger migraine onset and precipitate
aura.2
Another mechanism could possibly be transient hypoxemia caused by the PFO, causing subclinical infarcts in the brain, leading to irritation
and propensity for migraines. Naqvi et al. report
different manifestations of PFO including resting and stress hypoxemia related to left to right
shunting across a PFO in the absence of pulmonary hypertension.3
Despite these plausible scientific explanations,
clinically it remains unclear whether a causal relationship between PFO and Migraine actually exists. Multiple case control studies have examined
the prevalence of PFO in patients with migraine,
and a meta-analysis by Schwedt et al found a
PFO prevalence among these studies between
40% and 72% with a OR ranging from 1.87 to
5.88, however these generally of low grade evidence. This heterogeneous odds ratio supports
the association between this relationship, however does not fully rest this controversy.4 NOMAS,
a large epidemiological study examining subjects
in Northern Manhattan found that PFO was not
associated with self reported migraine, however
the results may not fully represent the age demographic of most migaineurs as most of the
patients in this study were elderly.5 A large case
control study from two large academic centers in
Boston found that the prevalence of PFO in case
and control subjects were similar and that there is
no difference in PFO prevalence in patients with
aura as other studies have suggested.6
Variation in findings may be due to differences in identification of the shunt and inclusion
of different types of migraine. Imaging methods
may also vary in sensitivity to PFO. One useful investigation was conducted by Zito et al.
which compared the diagnostic modalities for
PFO in migraineurs with cryptogenic stroke, or
subclinical ischemic lesions. This study compared
transthoracic echocardiogram (TTE) and transcranial Doppler ultrasonography (TCD) with transesophageal echocardiography (TEE). A prolonged
valsava maneuver was performed to improve test
sensitivity. TEE was able to identify PFO in 56.5%
of the 36 patients with migraine and 43.5% in the
cryptogenic stroke cohort (36 patients), while TTE
detected 55% of the PFOs imaged by TEE, and
TCD was able to identify 97% of the positive pa914

tients with TEE.7 This study showed that TCD and

TEE has significant concordance (0.89), whereas
TTE had less sensitivity. These differences in imaging modalities should be kept in mind when analyzing the following studies.
To further evaluate the relationship between
RLS, Woods and colleagues designed a study using rigorous saline contrast echocardiogram using SCE protocol on 104 healthy volunteers. Interestingly, they found a surprisingly high rate of
RLS (71%), of which 40% had PFO and 28% had
pulmonary artery venous malformation (PAVM).
Of interest is that 40% of the healthy volunteers had migraine with aura, however the PFOmigraine correlation was not apparent (OR 0.59;
95% CI[0.162.12]; P = 0.54).8 Based on these
findings, it appears that PFO has no relation to
migraine occurrence, however only 13% of volunteers had evidence of large RLS. This study used
a very sensitive measure for PFO detection: peripheral venous agitated saline contrast Echocardiography and measured any PFO by one clear
bubble. Any appearance of left sided microcavitations during venous SCE was considered evidence of RLS. On further analysis, correlation between variable sized PFO and migraine without
aura had an OR of 1.7 with a P value of 0.269,
indicating a slight, but insignificant relationship.
This study does not show a relationship between
small sized PFO and migraine with aura; they did
not get a large enough sample of large RLS to
analyze. In contrast, Del Sette et al. looked for
PFO using TCD and considered three microbubbles to be indicated of PFO, focusing on larger
size RLS. They imaged 44 patients with migraine
and 50 control, finding that 41% of migraine patients had PFO versus control patients with 16%
PFO with a P value < 0.005.9
Discrepancy between the two studies indicate that migraine with aura may be associated
with only large RLS. Focusing on a larger RLS
size may have revealed a relationship between
migraine and PFO. Jesurum conducted a retrospective study investigating any correlation of migraineurs (n = 71) with a larger size RLS compared to controls (n = 149). This study found
higher occurrence of high grade (IV and V) RLS in
migraineurs compared to controls (P = 0.04).10
Given the inheritance pattern of RLS and migraine, one study proposed an underlying etiology. To investigate whether the correlation
between PFO and migraine is due to a common embryological etiology such as lateralization
defect, Kaaro measured displacement of the
pineal gland on 26 controls and 39 migraineurs.
Results showed significant asymmetry of the
pineal gland in migraineurs compared to controls.11 This study indicates that serotonin deregulation may be related to lateralization defect

Role of PFO in Migraine Etiology and Treatment

during embryogenesis, which could be the link

between PFO and circadian migraine rhythm.
A population-based assessment was conducted to investigate any familial inheritance pattern between RLS and stroke, TIA and migraine.
This study included 6,179 patients of which only
65% had enough follow-up data for analysis. This
study found a relationship between RLS and increased risk of TIA, but no correlation with migraine compared to controls.12 A limitation of this
study was that they did not break down migraine
into its different types, such as without aura and
with aura. Also, size of the interarterial shunt was
not included in the analysis, which may have an
influence on migraine frequency.
In addition to pardoxial emboli/circulation,
PFOs can be related to platypnea-orthodeoxia
syndrome. This syndrome is associated with dyspnea while sitting up, accompanied by arterial desaturation. While other etiologies (such as liver cirrhosis) can lead to this disorder, this concept has
led to one proposal linking PFOs to migranes. It is
theorized that hypoxia may cause arterial desaturation which would increase plasminogen activator inhibitor-1 (PAI-1). This would decrease fibrinolysis, increasing chance of hypercoagulability
and possibly paradoxical embolism.13 In congruence with this proposal, Botto et al. indicates that
prothrombotic mutations are risk factors for cerebral ischemia in patients with PFO, which would
influence MA frequency Prothrombotic mutations
in addition to PFO would increase paradoxical
embolism, contributing to subclinical cerebral ischemia, also triggering migraine.14
Contradicting the paradoxical emboli theory
is a small study conducted by Di Fabio et al.,
which investigated the temporal relationship between embolism and migraine onset. They provoked cerebral embolization with agitated saline
during contrast echocardiography and followed
twenty four patients up to 24 hours after the procedure. Eight of 24 patients were found to have
minimal to medium sized PFOs and none of these
patients developed migraine. Also of note is that
the average size of PFO detected in their patient
sample was minimal to medium sized, whereas
other studies found increased embolism and MA
associated with larger RLS.15
Also in contrast to the theory of RLS shunt
leading to paradoxical embolism is a prospective, observational study by Adami et al. This
study included 185 consecutive patients, ages
1555 presenting with MA. Each patient received
MRI brain, hypercoagulability testing, neurological exam, and TCD. 46% of patients showed
RLS, and this percentage increased to 67% with
Valsalva maneuver. White matter hyperintensities
(WMH) were also present in these patients, indicating subclinical cerebral ischemia. 19% had

WMH in periventricular area, 47% showed WMH

in deep white matter and 21% of patients had
WMH in both areas. Although both RLS and
WMH were observed in this patient population,
the study found no association between cardiac
shunting and WMHs. Patients with RLS detected
with normal breathing had decreased deep WMH
(P < 0.05). Overall, RLS was equally distributed
in presence and grade between patients with or
without periventricular or deep matter WMH.16 In
light of this studys results, perhaps RLS could influence migraine frequency by allowing serotonin
and other harmful products (normally metabolized in the lungs) into the systemic circulation
and not necessarily through subclinical ischemic
lesions.
Traditionally, generally accepted indications
for PFO closure include recurrent stoke, however
closure in the setting of MA has emerged as a
new area of investigation surrounding the potential benefits in altering MA frequency. This topic
is controversial and the studies range from retrospective chart reviews, to case control study,
to randomized control study. A key difference
between the studies is inclusion criteria for the
patients. Some exclude those with preexisting
conditions such as stroke, cardiovascular disease, seizure, hypertension, or known pregnancy,
whereas other studies require vascular risk factors
as inclusion criteria.
Wahl conducted a retrospective chart review
of 603 people getting closure for secondary prevention of embolism and history of migraine. Of
these patients, 150 complained of migraine with
and without aura. The patients with migraine had
episode frequency of 23 per month, duration of
472 hours, intensity of 7 2. Of the 96 patients
with MA he found 51 (34%) had no migraine reoccurrence, while 48% had improved migraine,
with a P value < 0.001 compared to their previous
frequency of migraine. He found that intense pain
and aura presence were predictors of response.
The frequency of headaches after PFO closure decreased by 50% in 84% of the MA group (P =
0.03). These patients were followed for up to 9
years and were free to use their migraine medications during follow-up. The number of patients
taking medications decreased from 90% to 50%
(P < 0.001).17 This study indicated that closure
of the PFO did improve migraine frequency, especially those with migraine with aura.
To date, MIST is the only randomized control
trial that evaluates the therapeutic benefit of PFO
closure in MA. Dowsen enrolled 432 patients fitting migraine criteria, of which 163 had moderate
to large PFO, measured by >10 bubbles seen on
TCD. Most of the patients had at least 5 days
migraine per month and 30 days of headache
in previous 3 months. Randomizing 147 patients
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Sharma, Gheewala, and Silver

with migraine and PFO to a closure group and

sham procedure group did not show a significant
difference with primary end point of complete
migraine cessation. However, on secondary analysis they found a significant decrease in frequency
of migraine in the closure group (P = 0.02).18
These patients were followed up for 36 months
and the effect of aspirin and clopidogrel may still
have been residual. Therefore, this study showed
likely effect of PFO closure on frequency of migraine. Complete cessation of migraine may not
have been an accurate measure of improvement.
Although there is only one published randomized control trial, many prospective cohort and
case control studies have been conducted. These
following studies help to identify what criteria migraineurs should meet in order to benefit from
PFO closure.
Migraine with aura has a different pathophysiology than tension and cluster headaches. Transesophageal echocardiography reveals a significantly higher prevalence of PFO in migraineurs
(50%) when compared with sex and age matched
patients with tension headache (P < 0.001).19
Vigna et al., through a case control study, investigated effect of PFO closure on migraineurs
with evidence of subclinical cerebral ischemic lesions. The 82 patients included had moderate to
severe migraine, PFO with a large RLS shunt, and
subclinical ischemic lesions on MRI. Fifty-three
patients underwent closure while 29 patients remained as a control. Results showed that the total number of attacks in the closure group decreased significantly (mean decrease from 32 to
7 episodes, P <0.001), compared to the control
group (mean decrease from 15 to 12 episodes,
P < 0.001). Complete relief from migraine
episodes was found in 34% of closure groups and
7% of control (P = 0.007).20 This prospective case
control study was able to demonstrate that closure significantly decreased migraine frequency
in those patients with cerebral ischemic lesions.
Therefore, migraineurs with cerebral ischemic lesions and large RLS would fit the criteria for
closure of PFO.
Similarly, in a prospective cohort study of
76 migraineurs, the main presenting symptom
was stroke in 16, repeated TIA in 32, migraine
with cerebral ischemic lesions on MRI in 28 patients. Unique to this study was assessment of migraine occurrence 6 months after discontinuation
of antiplatelet therapy for PFO closure, whereas
most other studies assess migraine while continuing the antiplatelet therapy. Also the baseline
self-evaluation of migraine was done 2 months
prior to the closure, eliminating any preoperational bias. This study found complete migraine
cessation in 46% of patients, improvement in
frequency in 36%, and no change in 18% of
916

patients.21 Therefore, this study shows that in

migraineurs with evidence of cerebral embolism
via stroke, TIA or ischemic lesions on MRI, transcatheter PFO closure can reduce symptoms
without the confounding factor of antiplatelet
therapy.
Some studies indicate that even partially closing the PFO, specifically for migraineurs with evidence of paradoxical embolism, can decreased
the migraine frequency. This indicates a neuronal
threshold for metabolites needed to trigger a
headache. One retrospective analysis included 77
migraineurs with paradoxical embolism, who underwent closure for secondary stroke prevention.
TCD was used to assess residual RLS size baseline,
at 6 months, 12 and 24 months after closure. After the PFO closure, patients showed >50% decreased migraine frequency (P < 0.001). Results
showed that reduction in frequency of migraine
was independent of closure status at late followup of 540 days. Migraine frequency of those with
complete (average 2/month) and incomplete closure (1/month) was not significantly different
(P = 0.25).22 There was slight discrepancy between migraineurs with aura and those without aura. Those with aura experienced relief 4.5
times more than migraineurs without aura. This
study indicates that PFO closure would benefit
migraineurs with aura and evidence of paradoxical embolism, by reducing burden of PFO even if
residual RLS remains. A strength of this study was
its late follow up of 24 months, whereas other
studies usually had a shorter follow up of 6 or 12
months.
Further supporting the effect of PFO closure on
migraine, via preventing paradoxical embolism
is a study by Rigatelli.23 The procedure of transcatheter closure itself can prolong the opening
of the PFO which can trigger a migraine immediately after the closure. Those patients who
reported a migraine immediately after the procedure experienced the greatest relief from migraine on follow up. This indicated that their
migraines were directly related to the PFO and
closing the PFO provided relief. The study used
the following criteria for closure of PFO: basal
shunt, presence of interarterial septal aneurysm,
34 class MIDAS score, symptomatic and significant aura, coagulation abnormalities and migraine refractory to medications. Patients were
given aspirin 100 mg/day up to 6 months after intervention, and follow up occurred at 1, 6,
and 12 months. Results showed that all of the
migraineurs symptoms improved (P < 0.03)
based on MIDAS score at a follow-up of
10 3 months. They recommended using
5 days of migraine a month and stroke risk
as a criterion for PFO closure shown on
TCD.23

Role of PFO in Migraine Etiology and Treatment

Inclusion criteria of cryptogenic stroke or TIA

for identifying migraineurs that would benefit
from PFO closure was shown to be effective in
a retrospective analysis by Reisman.24 They found
complete resolution of migraine symptoms in
56% of patients and 14% showed greater than
50% reduction in frequency. There was a significant mean reduction in mean number of migraine
episodes per month (P < 0.001). However, use
of antiplatelet therapy: clopidogrel 75 mg and
aspirin 325 mg may have had an influence on
migraine frequency up to 6 or 7 months after
closure.24 Many of the patients were taking aspirin before the closure, however were likely not
on dual antiplatelet therapy at this dose. Also migraine relief occurred independent of the completeness of PFO closure, which supports the idea
of neural threshold of metabolites needed to trigger migraine.
To date, no randomized controlled trial has
shown a clear benefit of PFO closure on the reduction in the frequency of migraine as the primary end point. However, the majority of studies
have shown a significant correlation between MA
and large PFO which is difficult to ignore. Additionally, several studies have also shown that
closing a PFO in a patient with history of paradoxical embolism or stroke did indeed reduce the
frequency of migraine. Therefore, screening for
PFO in migraineurs should also include such criteria as history of embolism, hypercoagulopathy,
stroke or subclinical lesions on MRI. Given the invasive nature of PFO closure, it should not be used
as a primary treatment of migraine, but could be
considered as a secondary or tertiary option when
the above mentioned comorbidities are present.
More randomized studies need to be conducted
before firm guidelines can be developed about
the role of cardiac screening and PFO closure in
patients with difficult to treat migraine.
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