IJCA-16474; No of Pages 5

International Journal of Cardiology xxx (2013) xxxxxx

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Association of migraine aura with patent foramen ovale and atrial

septal aneurysms,
John Chambers a,b,,1, Paul T. Seed a,b,1, Leone Ridsdale a,b,1
a
King's College London, London, UK
b
Guy's ans St Thomas' Hospitals, London, UK

a r t i c l e i n f o a b s t r a c t

Article history: Background: The relationship between migrainous aura and patent foramen ovale (PFO) remains uncertain
Received 27 April 2013 Methods: We performed bubble contrast transthoracic echocardiography on 80 migraineurs with 415
Accepted 29 June 2013 headache days per calendar month, mean age 45 (75% female) with mean 9.4 headache days. A large PFO
Available online xxxx was dened by passage of an uncountable bolus of bubbles or complete opacication of the left-heart in
3 cycles, while a moderate PFO was dened by passage of 20 bubbles but not sufcient to form a bolus
Keywords:
or opacify the whole of the left heart.
Migraine
Patent foramen ovale
Results: There was a moderate or large PFO in 28 (35%; 95% CI 2446%). There were atrial septal aneurysms in
Atrial septal aneurysm 11 (15%) and the relationship with PFO was moderately strong (spearman rank correlation 0.493, CI 0.308 to
0.643; p b 0.0001). Seven (9%) had a valve abnormality and one had a closure device for an atrial septal
defect. Aura were reported in 31 (39%) and in these the PFO was large in 9 (29%) compared with 8 (16%;
p = 0.143) without aura. There was no relationship between the size of the PFO and the number of headache
days (difference between no PFO and large PFO = 0.6 days; 95% CI 2.6 to + 1.4; p-value for any difference
between groups = 0.316).
Conclusions: The prevalence of moderate or large patent foramen ovale was 35% and was not associated with
the presence of aura or the frequency of the headache.
2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction After cryptogenic stroke or TIA, an atrial septal aneurysm associated

The prevalence and signicance of a patent foramen ovale (PFO) in
migraineurs is not known. Some studies suggest a higher prevalence
compared with control subjects [1], but others nd no difference [2]. It
is important to establish the prevalence because of a growing trend
towards percutaneous closure. In patients with cryptogenic stroke or de-
compression sickness in divers, closure of a PFO [3,4], but not of an ASD
[5], has been reported to reduce coexistent migraine. Non-randomised
trials have suggested that closure is a reasonable treatment for migraine
as sole pathology [68], but the only randomised trial [9] showed no
effect. This trial was criticised for using insufciently robust criteria for
diagnosing a PFO [10].
Grant support: This study was supported by the Dunhill Medical Trust
Conicts of interest: None
Corresponding author at: Cardiothoracic Centre, St Thomas' Hospital, London SE1
7EH, UK. Tel.: +44 20 7188 1047; fax: +44 20 7188 0728.
E-mail address: john.chambers@gstt.nhs.uk (J. Chambers).
1
This author takes responsibility for all aspects of the reliability and freedom from
bias of the data presented and their discussed interpretation.
with a PFO increases the risk of future cerebro-vascular events [11]. The
strength of association between atrial septal aneurysm and migraine,
however, remains unknown.
We recruited a series of patients with migraine referred to headache
specialists for a therapeutic trial. In this paper we describe the preva-
lence of PFO, atrial septal aneuryms and other structural abnormalities,
and their association with aura and the frequency of headache.
2. Methods
2.1. Patients
Echocardiograms were performed as part of a randomised trial of clopidogrel vs place-
bo as treatment for migraine (ISRCTN 36114412). The results of this trial will be reported
separately. The inclusion criteria were age N18, denite migraine with or without aura
according to International Headache Criteria [12], and migraine (headache or aura) occur-
ring on 4 or more days in a 28 day month [13]. Exclusions were high risk features
suggesting cerebral malignancy or other pathology (e.g. arterio-venous malformation),
more than 15 headache days in a 28 day period, contraindications to clopidogrel treatment
(hypersensitivity, active bleeding including menorrhagia, warfarin therapy, known hepatic
dysfunction), requirement for clopidogrel treatment (e.g. coronary stent) or for routine
non-steroidal anti-inammatory agent or aspirin other than for acute headache, use of
an investigational product within 3 months, inability to understand English, pregnancy
or breast-feeding, clinically signicant abnormalities of platelet or liver function.

0167-5273/$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijcard.2013.06.054

Please cite this article as: Chambers J, et al, Association of migraine aura with patent foramen ovale and atrial septal aneurysms, Int J Cardiol
(2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.054
2 J. Chambers et al. / International Journal of Cardiology xxx (2013) xxxxxx

2.2. Headache
The frequency of headache was calculated as headache days using a diary lled out
for 28 days before randomisation. For a headache or aura lasting b24 h, one headache
day was counted. For a headache or aura lasting 2448 h, two headache days were
counted. The patient was asked to indicate which headaches were associated with an
aura. The patient was taken as having migraine with aura if one or more headache
was associated with aura. If no headaches were associated with aura, the patient was
dened as having migraine without aura.
2.3. Echocardiography
Participants had echocardiography after randomisation, but at no xed visit. A full
standard transthoracic study was performed. Zoomed views of the atrial septum were
obtained in the apical 4-chamber and subcostal views and an off-axis 4-chamber view
with the transducer moved medially within the 5th space to better show the septum. A
search for a left-to-right atrial shunt on colour mapping was made. The size of the right
and left atria were measured. A bubble study was then performed, by one operator (JC)
in all but one case which was instead performed by a sonographer trained to conduct a
specialist sonographer-led clinical bubble list. A 21G cannula was positioned in an
antecubital fossa vein usually on the left. This was then connected to a three-way
tap. One dry syringe and 6 syringes lled with 78 ml N saline were drawn up. For
each injection, approximately 0.5 ml air was left in the syringe and 0.5 ml venous
blood was drawn back into the syringe. The dry syringe was then attached to the
other port of the 3-way tap and the mixture agitated between the two syringes until
a dense froth containing no air bubbles was obtained. This was injected with no
delay. For the rst injection the subject was asked to produce a short, sharp cough un-
less there was already spontaneous passage of microcavitations (bubbles). All other
injections were made with a Valsalva manoeuvre. The patient was instructed to breath
out then hold the breath and strain against a closed glottis with minimal movement of
the chest. This was practised until the effort and release were optimal with deviation of
the septum to the left but with minimal disturbance to the image quality. Up to 5 injec-
tions with Valsalva were given unless dense opacication of the left heart occurred
sooner [11].
2.4. Echocardiographic analysis
A PFO was said to be present for this study if there was passage of bubbles into the
left atrium within 3 or fewer cycles after the injection. The PFO was classed [1] as: large
if there was light or dense opacication of the left heart (Fig. 1A, B) or passage of a large
bolus of bubbles too dense for counting; moderate if there were 20 bubbles, but no
bolus or opacication; and small if there were b20 bubbles.

Fig. 1. Examples of patent foramen ovale. Examples of a large shunt with light (A) and dense (B) opacication of the whole of the left heart.

Please cite this article as: Chambers J, et al, Association of migraine aura with patent foramen ovale and atrial septal aneurysms, Int J Cardiol
(2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.054
 J. Chambers et al. / International Journal of Cardiology xxx (2013) xxxxxx 3

For comparison with the literature, an analysis was also performed using the same
bubble criteria numbers but a cut-off of 5 cycles rather than 3 cycles [14,15]. We
also used the criteria as used in MIST [9] with a small shunt classed as 15 bubbles, a
moderate shunt as 620 bubbles and a large shunt N20 bubbles seen within the left
atrium in 5 cycles. The rationale for the different grading criteria adopted for this
study is that, probably as a result of advances in machine technology it is common to
see dense opacication of the whole left heart and it is likely that this denotes a
shunt which is larger than one causing 20 [14] or 25 [15], 30 [2] or even 50 bubbles
which are previously-described cut-points for a signicant shunt.
An atrial septal aneurysm was dened by a base 10 mm wide and an apex moving
during spontaneous respiration between left and right atria with an excursion 10 mm
(Fig. 2) [11,16,17]. A mobile septum was dened by an excursion of b10 mm. A normal
septum was dened by no movement or trivial movement. All abnormalities were
noted including the presence of a bicuspid aortic valve or mitral prolapse, aortic valve
thickening and mitral annular calcication.
2.5. Statistical analysis
Mean values were calculated for age and headache days per calendar month. The
relationship between PFO and atrial septal mobility was tested using a Spearman's
rank test. The relationship between PFO and aura or headache days was tested with
the Wilcoxon rank-sum test.
3. Results
A total of 80 participants had echocardiography between 14 May
2009 and 28 June 2012. The mean age was 45 (range 1868) and 62
(75%) were female. The mean number of headache days was 9.4 (range
414).
3.1. Incidence of echocardiographic abnormalities
Echocardiograms with bubble studies were successfully performed
in all 80 subjects. There was a moderate or large PFO in 28 (35%; 95%
CI 2446%) (Table 1).
Using the broader criterion of bubbles appearing within 5 cycles,
the number of moderate or large PFOs increased by only one although
the number of small PFOs increased from 5 (6%) to 11 (15%). Using
the MIST criteria, a larger proportion, 43%, had moderate or large PFOs.
There were atrial septal aneurysms in 11 (15%) which were associat-
ed with a large PFO in 6 (55%) (Table 2). There was a mobile septum in

Fig. 2. Atrial septal aneurysm. The atrial septum in its most rightward (A) and its most leftward (B) positions at rest.

Please cite this article as: Chambers J, et al, Association of migraine aura with patent foramen ovale and atrial septal aneurysms, Int J Cardiol
(2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.054
4 J. Chambers et al. / International Journal of Cardiology xxx (2013) xxxxxx

Table 1 Table 3
Frequency of patent foramen ovale in 80 patients with chronic migraine. Association of aura and presence or size of pfo.

Bubbles crossing Bubbles crossing in
in 3 cycles 5 cycles
No pfo 47 (59%) 40 (50%)
Small 5 (6%) 11 (14%)
Moderate 11 (14%) 12 (15%)
Large 17 (21%) 17 (21%)
Ashunt was large if there was light or dense opacication of the left heart (Fig. 1A, B)
or passage of a large bolus of bubbles too dense for counting; moderate if there were 20
bubbles, but no bolus or opacication; small shunt if there were 120 bubbles.
MIST criteria [9]: Small shunt 15 bubbles, moderate shunt 620 bubbles, large shunt
N20 bubbles within the left atrium within 5 or fewer cycles.
11 (15%) which was associated with a large PFO in 3 (27%) (Table 2).
The relationship between PFO and mobility was moderately strong
(Spearman's rank correlation = 0.493, CI 0.308 to 0.643; p b 0.0001).
Seven (9%) had a valve abnormality, a bicuspid aortic valve in 3
(4%), mitral prolapse in 2 (2.5%), mitral annular calcication in one
(1.3%) and mild aortic valve thickening in one (1.3%). These were as-
sociated with no PFO in 3, a moderate PFO in one and large PFO in 3. A
further case had a closure device for an atrial septal defect and this
was associated with a moderate passage of bubbles.
3.2. Association between aura and frequency of headaches
Aura were reported in 31 (39%) cases. There was no evidence of
larger PFOs in patients with aura (Table 3; p = 0.143 by Wilcoxon
rank-sum test). There was likewise no evidence of differences in the
proportion of people with mobile or aneurysmal atrial septa and
those with aura compared with no aura (Table 4).
There was no relationship between the size of the PFO and the
number of headache days. The difference between no PFO and large
PFO was 0.6 days (95% CI 2.6 to + 1.4; p-value for any difference
between groups = 0.316).
4. Discussion
This study showed a 35% prevalence of moderate or large patent
foramina ovale (PFO). A PFO was not more common with aura than
without aura, and was not related to the frequency of headache. An
atrial septal aneurysm was found in 15% of patients, and was not
more frequent with aura. There was a valve abnormality present in
7 (9%), most commonly a bicuspid aortic valve.
The relationship between PFO and migraine has been difcult to de-
termine. Early studies included migraine associated with cerebral in-
farction or decompression sickness as the main reason for recruitment
[4]. This may have introduced bias in the study population. In a system-
atic review [3], the prevalence of PFO was 4172% in patients with
migraine and aura, but 1634% without aura. This range contains the
prevalence shown in the present study. However, in a case-control
study excluding patients with prior stroke [2] the incidence of PFO
was similar in patients with migraine with or without aura and also in
controls. In a large population-based study [18] of 1101 patients who
had not had a stroke, the incidence of PFO was 15% for those both
MIST criteria No pfo Small pfo Moderate pfo Large pfo
Aura (n = 31) 15 (48%) 2 (6%) 5 (16%) 9 (29%)
40 (50%) No aura (n = 49) 32 (65%) 3 (6%) 6 (12%) 8 (16%)
5 (6%)
6 (7%)
29 (36%)
with and without migraine. The incidence was slightly higher, 16% in
those with aura compared with 11% in those without aura.
These differences may have arisen from variations in selection
criteria or in measurement methods. The cut-point for a signicant
PFO is variously taken as 10 bubbles, [19], 20 bubbles [15,2022], 25
or 30 bubbles [2,10] or occasionally 50 bubbles [23]. However these
are relatively similar numbers particularly bearing in mind the difculty
of counting individual bubbles. It is common for too many bubbles to
count to cross as a bolus or ll the whole of the left atrium and left ven-
tricle either lightly (Fig. 1A) or densely (Fig. 1B) and these are graded as
large. In this we agree with others [1]. We grade a shunt as moderate if
20 bubbles cross but not enough to opacify the whole left heart. A
more important difference is in the timing. We allowed bubbles only
within 3 or fewer cycles [2,24] while other studies allow 4 or fewer
[15] or 5 or fewer cycles [9]. Allowing 45 cycles is likely to increase
the false positive rate by including transpulmonary shunting. In
the MIST trial, which used 5 cycles, a PFO could not be found at
attempted closure in 5 of 74 patients. Reanalysing our results using
the MIST criteria we obtained an incidence of moderate or large PFO
of 43% rather than 36%. There are other differences. Studies vary in the
number of injections. We used up to 6 although large shunts were usu-
ally obvious with fewer. We used N-saline mixed with air and blood
while some use gelofuscin and this may produce more bubbles. We
used transthoracic rather than transoesophageal echocardiography. A
number of comparisons show that sensitivities are similar for the two
techniques [2427], and sometimes slightly better for transthoracic
echocardiography [15].
There is little information on atrial septal aneurysms. The septum
moves more with coughing or a Valsalva manoeuvre than with quiet
respiration and there is a continuous spectrum in excursion at rest or
with manoeuvres. The difference between a mobile and an aneurymal
septum is dened by an arbitrary, but frequently used [17], cut-off ex-
cursion of 10 mm. We found a mobile septum in 11 (15%) and an an-
eurysmal septum also in 11 (15%). Garg et al. [2] showed a similar
incidence of hypermobile septa in 9% of migraineurs compared with
7.6% of controls. However the same study found no aneurysmal septa.
Other series also showed a far lower incidence, 1.7% [28] or 2.5% [29]
than in our study. The atrial septum is in the far-eld of a transthoracic
echocardiogram and its accurate delineation depends on good image
quality which is more likely with modern instruments. We showed
that 75% of atrial septal aneurysms were associated with a moderate
or large PFOs which is similar to previous work in patients after crypto-
genic stroke [29,30].
It is possible that platelet aggregates can form on a mobile or aneu-
rysmal atrial septum and either vasoactive substances formed or the
platelets themselves may then pass across a PFO. In patients after cryp-
togenic stroke, one study found that the incidence of a further event
was signicantly higher if there was a combination of an atrial septal
aneurysm and PFO rather than aneurysm or PFO alone [11]. This was
not conrmed in another study [16] and whether a similar effect occurs
in migraine remains speculative.

Table 2
Association between IAS mobility and pfo.
Table 4
PFO size Normal IAS N = 58 Mobile IAS N = 11 Aneurysmal IAS N = 11 Association between aura and septal mobility.
No 41 (71%) 4 (36%) 2 (18%)
Normal Mobile Aneurysmal
Small 3 (5%) 1 (9%) 1 (9%)
Moderate 6 (10%) 3 (27%) 2 (18%) Aura (n = 31) 23 (74%) 5 (16%) 3 (10%)
Large 8 (14%) 3 (27%) 6 (55%) No aura (n = 49) 35 (71%) 6 (12%) 8 (16%)

Please cite this article as: Chambers J, et al, Association of migraine aura with patent foramen ovale and atrial septal aneurysms, Int J Cardiol
(2013), http://dx.doi.org/10.1016/j.ijcard.2013.06.054
 J. Chambers et al. / International Journal of Cardiology xxx (2013) xxxxxx
The higher than expected incidence of heart valve abnormalities
particularly bicuspid aortic valve has not previously been shown in mi-
graine. The incidence of bicuspid aortic valve was 3.7% compared with a
population prevalence of 0.50.8% [31,32]. The incidence of mitral pro-
lapse was 2.5% which is similar to the expected population prevalence
of 2% [33,34]. Bicuspid valves and mitral prolapse can rarely be associat-
ed with platelet aggregation causing stroke or peripheral emboli. It is
possible that they are also related to migraine via platelet function as
for atrial septal aneurysms, either as a result of emboli or release of va-
soactive substances from aggregating platelets.
4.1. Limitations
Our conclusions are limited by the sample size and the fact that we
had no control group without headache. We note that, at 35%, our prev-
alence is higher than found in population-based studies, using different
methodologies: 15% using echocardiography [18], 27% at autopsy [35]
and 24% at cardiac surgery [28]. However the different methods used
limit the values of such comparisons.
5. Conclusion
This study shows a high incidence of structural abnormalities on
echocardiography in subjects with 415 headache days per calendar
month. The prevalence of patent foramen ovale was affected by the
reporting criteria. A patent foramen ovale was not statistically more
common with aura and was not associated with the frequency of the
headache.
Acknowledgement
We thank the nurses who collected the data for his study, Sr Elaine
Wong, Thanuja Weerasinghe, Azanu Golda-Grace.
We thank the following for helping with recruitment: Dr Sam Chong,
Ranjan Das, Dr Jane Docherty, Dr Tyrrel Evans, Dr Raj Mitra, Dr Rob
Weeks, Dr Rachael Kilner, Dr Alex Pothen and the staff at Albion Street
Surgery, Crofton Surgery, Bromley Common Surgery, Streatham Com-
mon Surgery and the Hurley Clinic,
We also thank members of the steering committee: Prof Anish Bahra,
Dr Richard Peateld and the Data Monitoring Committee: Dr Richard
Peateld and Prof Nicola Crichton
Sano donated the clopidogrel and placebo for the therapeutic trial
but took no part in the design or analysis of the main, or any substudy
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