Patent Foramen Ovale in Children with Migraine Headaches

Rachel T. McCandless, MD, Cammon B. Arrington, MD, Douglas C. Nielsen, James F. Bale, Jr., MD, and L. LuAnn Minich, MD

Objective To determine the prevalence of patent foramen ovale (PFO) in children with migraine.
Study design Children aged 6.0 to 18.0 years with migraine headache were evaluated for PFO and right-to-left
shunting with color-flow Doppler scanning, saline solution contrast transthoracic echocardiography, and contrast
transcranial Doppler scanning.
Results The population consisted of 109 children with migraine; 38 (35%) with aura and 71 (65%) without aura. The
overall PFO prevalence was 35%, similar to the general population (35% vs 25%; P = .13). However, compared with
the general population (25%), the PFO prevalence was significantly greater in subjects with aura (50%, P = .0004)
but similar in those without aura (27%, P = .73). Atrial shunt size was not associated with the presence or absence of
aura.
Conclusion Children with migraine with aura have a significantly higher prevalence of PFO compared with those
without aura or the general population. These data suggest that PFO may contribute to the pathogenesis of migraine
with aura in children and have implications for clinical decision making. (J Pediatr 2011;159:243-7).

M
igraine, a recurrent headache disorder of children and adults, significantly affects quality of life and results in a sub-
stantial financial and social burden.1,2 Migraine occurs in about 15% of the pediatric population, with approximately
one-third of cases associated with an aura.3 Patency of the foramen ovale (PFO), a normal fetal connection between
the atria allowing blood from the placenta to bypass the lungs, has been implicated in the pathogenesis of migraine. Agitated
saline solution contrast echocardiographic studies and autopsy reports have found that the foramen ovale remains patent in
10%-25% of the general population, and most studies of adults with migraine with aura find a significantly higher prevalence
of PFO ranging from 41%-62% (composite of 56% by meta-analysis).4-12
The high prevalence of PFO in adults with migraine with aura has led to the hypothesis that a right-to-left shunt across the
atrial septum allows metabolic or microembolic triggers that would normally be cleared by the lungs to pass unfiltered into the
cerebral circulation, leading to the migraine. However, studies exploring the effectiveness of PFO closure on the frequency and
severity of migraine headaches in adults have had conflicting results.13-19
No comparable studies have been published in children. We hypothesized that children with migraine with aura also have
a higher prevalence of PFO compared with the general population and children with migraine without aura. The purposes of
this study were to determine the prevalence of PFO in pediatric patients with migraine and to investigate the relationships be-
tween the amount of right-to-left atrial shunting and migraine subtype.

Methods
From February 2008 to September 2009, children 6 to 18 years of age diagnosed with migraine by the pediatric neurologists at
Primary Children’s Medical Center were invited to participate in this study. Primary Children’s Medical Center is the major
referral center for children living in the Intermountain West, a large geographic region encompassing Utah and parts of Wyom-
ing, Idaho, Montana, Nevada, and Colorado. The diagnosis of migraine with or without aura was made according to the revised
International Headache Society criteria.20 Children with known congenital heart disease and patients unable to cooperate with
imaging modalities were excluded. Parental consent and participant assent were obtained as appropriate. The study was ap-
proved by the Institutional Review Boards of the University of Utah and Intermountain Healthcare.
Complete 2-dimensional and Doppler transthoracic echocardiography (TTE) and transcranial Doppler (TCD) scanning
were performed on all participants with either an Acuson Sequoia C512 (Siemans, Mountain View, California) or a Philips
iE33 (Philips, Bothell, Washington). The protocol (Table I; available at www.jpeds.com) was developed a priori, and all
sonographers were trained and certified in its performance.21 Shunting across
the atrial septum was evaluated with two established methods: 2-dimensional
From the Divisions of Cardiology (R.M., C.A., D.N., L.M.)
TTE by use of agitated saline solution contrast and agitated saline solution and Division of Neurology (J.B.), Department of
Pediatrics, Primary Children’s Medical Center and the
University of Utah, Salt Lake City, UT
Supported by Primary Children’s Medical Center
PedMIDAS Pediatric Migraine Disability Assessment Foundation, the Division of Pediatric Cardiology, and
PFO Patent foramen ovale the Thrasher Foundation. The authors declare no
conflicts of interest.
TCD Transcranial Doppler
TTE Transthoracic echocardiography 0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2011.01.062

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www.jpeds.com
contrast TCD. Recordings were obtained with both normal
breathing and with a Valsalva maneuver to increase right
atrial pressure and maximize detection of right-to-left
shunting through a PFO. For contrast TTE and TCD,
sterile normal saline solution 5 mL was agitated between
two syringes connected by a three-way stopcock and
injected by rapid bolus into a catheter inserted into the
forearm. The foramen ovale was considered patent by TTE
if contrast was seen crossing the atrial septum within four
cardiac cycles after full opacification of the right atrium
(Figure 1).22,23 Contrast TCD was performed by placing
a 4- or 5-MHz probe over the temporal bone and
recording flow velocity in the middle cerebral artery during
injection of agitated saline solution. Contrast TCD was
considered positive for right-to-left atrial shunting if
microcavitations (transient spikes superimposed on the
velocity curve) were detected within 10 seconds of agitated
saline solution injection. Shunt size was quantified
according to previous standards with TCD.21 Briefly, this
includes four possible results (Figure 2): (1) no spikes (no
right-to-left shunt); (2) 1-10 spikes (small shunt); (3) >10
individual spikes but no shower of spikes (medium shunt);
and (4) shower of spikes where individual spikes cannot be
identified (large shunt). Although a PFO is the most-
frequent cause of a right-to-left shunt, other sources
(intrapulmonary, for example) may also result in a positive
contrast TCD result. Therefore, contrast TTE with direct
visualization of microcavitations crossing the atrial septum
was chosen a priori to be the best method to detect PFO if
TTE and TCD results were discrepant (ie, contrast TTE–
negative but contrast TCD–positive). For each study
participant, the contrast TTE and contrast TCD results
were interpreted by the same echocardiographer. All
echocardiographers were blinded to migraine subtype.
Study subjects completed the Pediatric Migraine Disability
Assessment (PedMIDAS) to determine migraine frequency
Figure 1. A, Contrast TTE (apical four-chamber view) showing contrast (white arrows) filling the right atrium (RA) and right
ventricle (RV). No contrast is seen in the left atrium (LA) or left ventricle (LV). B, Apical four-chamber images from a study
participant showing contrast crossing the atrial septum through a PFO into the LA.
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Vol. 159, No. 2
and measure migraine disability. The PedMIDAS scoring sys-
tem is a validated tool to quantify the impact of migraine on
the individual’s quality of life.24 A score >30 indicates at least
moderately disabling headaches.25
Using previously published data, we estimated that the
PFO prevalence in older children and adults is between
10% and 25%.4-6 For this study, we assumed the PFO preva-
lence in otherwise healthy children to be at the upper end of
this range. The PFO prevalence was compared between sev-
eral groups: (1) all pediatric migraine participants versus
the general population; (2) pediatric migraine participants
with aura versus the general population; (3) pediatric mi-
graine participants without aura versus the general popula-
tion; and (4) pediatric migraine participant subtypes—aura
versus no aura.
As an additional contemporary control, we reviewed TTE
results of consecutive age-matched children referred during
the study period for evaluation of a heart murmur and found
to have no other cardiac abnormalities. Because children with
murmur do not routinely undergo intravenous catheter
placement for contrast echocardiography, only color-flow
Doppler results were available to compare PFO prevalence
between subjects with migraine and these control subjects
with murmur.
Statistics
Continuous data between groups were compared by use of
the Student t test or Mann Whitney rank sum test. We
used a binomial test of proportion to compare the literature
control group with the PFO prevalence demonstrated by
contrast Doppler TTE in pediatric participants with migraine
with and without aura. The Fisher exact test was used to com-
pare the PFO prevalence between groups and to compare dif-
ferences in PFO detection among the various imaging
modalities. Parametric linear regression was used to compare
the log-transformed PedMIDAS scores between pediatric
McCandless et al
August 2011
Figure 2. TCD recordings from study participants showing
each of the four standardized results. A, No microcavitations
(no right to left shunt). B, One to 10 microcavitations (small
shunt). C, >10 microcavitations but no ‘‘shower’’ (medium
shunt). D, Shower of microcavitations (large shunt). Micro-
cavitations appear as bright spikes (white arrow in B) super-
imposed on the velocity curves.
participants with migraine with and without aura, as well as
comparing the scores for those with and without a PFO.
Results
The study group (Table II) consisted of 109 children with
migraine; 38 (35%) with aura and 71 (65%) without aura.
Two-thirds of pediatric migraine participants were girls.
Participants with and without aura were similar in age and
sex.
With contrast TTE, the prevalence of PFO in all study par-
ticipants (38/109) was similar to the general population (35%
vs 25%; P = .13). In contrast (Figure 3), the subtype analysis
showed that children with aura (19/38) were significantly
more likely to have a PFO than the general population
(50% vs 25%; P = .0004), and the PFO prevalence in
children without aura (19/71) was the same as the
estimated PFO prevalence in the general population (27%
Patent Foramen Ovale in Children with Migraine Headaches
ORIGINAL ARTICLES
vs 25%; P = .73). Compared with 27% of those without
aura, 50% of pediatric subjects with migraine with aura
had a PFO (P = .02).
By color-flow Doppler interrogation of the atrial septum,
10/120 (8%) control subjects with murmur and 12/109
(11%) pediatric subjects with migraine had evidence of
a PFO (P = .51). When migraine subtypes were compared
with the control subjects with murmur, a PFO was seen by
color-flow Doppler scanning in 7/38 participants with aura
(18% vs. 8%, P = .12) and in 5/71 without aura (7% vs
8%, P = 1.0).
With contrast TCD, a PFO was detected in 37 participants,
and findings correlated well with contrast TTE (P = .99).
Only one subject with a positive contrast TTE had a negative
contrast TCD result, and all subjects with a positive contrast
TCD result had a positive contrast TTE result. Compared
with contrast TTE, contrast TCD had a sensitivity of 95%
(95% CI: 0.81-0.99) and a specificity of 100% (95% CI:
0.94-1.0).
Of the 37 patients with contrast TCD evidence of a PFO
(Figure 4; available at www.jpeds.com), 9 had small shunts
(5 with aura, 4 without aura), 17 had medium shunts (6
with aura, 11 without aura), and 11 had large shunts (7 with
aura, 4 without aura). Shunt size did not correlate with
migraine subtype.
Many subjects (37/109, 34%), regardless of migraine sub-
type, had moderately disabling migraines.25 The mean Ped-
MIDAS score was similar between participants with and
without aura (30.1  32.1 vs 40.6  43.0, respectively;
P = .18). There was also no significant difference in the
mean PedMIDAS score between patients with a PFO versus
those without a PFO (mean 32.2 vs. 36.7, respectively,
P = .72).
Discussion
The increasing number of studies in adults describing an as-
sociation between PFO and migraine with aura has led to
growing public and physician interest in the use of PFO clo-
sure as a therapy for migraines, particularly for those individ-
uals for whom medical management has failed.13-19 Despite
the absence of rigorous evidence supporting PFO closure as
a safe and effective treatment for migraines, increasing num-
bers of children are being referred to our institution for PFO
evaluation and closure. This study demonstrates a signifi-
cantly higher PFO prevalence in children with migraine
with aura compared with the general population and thus
provides a basis for further research on the role of PFO in pe-
diatric migraines.
Independent reports of migraine cessation or improve-
ment in adults after PFO closure for non-migraine indica-
tions, such as cryptogenic stroke or decompression illness,
led to the hypothesis that a PFO may permit vasoactive met-
abolic or microembolic triggers to enter the cerebral circula-
tion directly, bypassing the pulmonary circulation where they
are normally filtered or metabolized into an inactive
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Table II. Demographics of the study population
Migraine (all) (n = 109) Aura (n = 38)
Female 73 (67%) 29 (76%)
Age (years) 12.2  2.9 13.0  2.8
Weight (kg) 47.8  18.1 52.3  19.6
*P = .07, females in aura vs no aura group.
†P = .0001, females and age in control subjects with murmur vs migraine group.
zP = .13, age in aura vs no aura group.
form.26,27 This hypothesis is supported by reports of a higher
prevalence of PFO in adults with migraine with aura. In ad-
dition, several single-center PFO closure studies have dem-
onstrated treatment success rates, defined as migraine
cessation or reduction in migraine frequency and severity af-
ter PFO device closure, as high as 70% to 100%.15-19,28 How-
ever, the Migraine Intervention with STARFlex Technology
study, a prospective, blinded (sham device control arm), ran-
domized trial that evaluated the effectiveness of PFO closure
on headache relief in adults with migraine with aura failed to
show that PFO closure was an effective treatment option.13
The Migraine Intervention with STARFlex Technology study
cannot be considered conclusive, however, because of techni-
cal issues and potential design flaws involving patient selec-
tion and study endpoints.13,29,30 Results from our study of
children ages 6 to 18 years are similar to those reported in
adults, showing that the prevalence of PFO in migraine
with aura is roughly double that found in migraine without
aura and suggest that spontaneous closure of a PFO is un-
likely after 6 years of age.
Some adult studies have shown that those with migraine
with aura have larger right-to-left atrial shunts than those
without aura.10 Although contrast TCD data from our study
showed a trend toward larger right-to-left atrial shunting in
migraine with aura, it was underpowered to identify a signif-
icant difference. We estimate that a sample size of nearly 500
is needed to detect a significant difference in the degree of
atrial shunting between pediatric patients with migraine
with and without aura.
Figure 3. Prevalence of PFO in children with migraine with
and without aura compared to the general population.
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Vol. 159, No. 2
No aura (n = 71) Control subjects with murmur (n = 120)
44 (62%)* 46 (38%)†
11.9  3.0z 10.8  3.1†
45.4  17.0 42.4  18.1
The role of TCD in children with migraine headache is not
completely clear. Contrast TCD findings correlated well with
contrast TTE results (sensitivity and specificity $95%) and
TCD has an advantage in allowing quantification of the
amount of right-to-left atrial shunting; however, the impor-
tance of this information in the pediatric population remains
unknown. Contrast TCD imaging may have a primary role in
PFO detection in children with suboptimal TTE windows ob-
viating the need for transesophageal imaging and the risks as-
sociated with this technique in children. TCD could be
incorporated in future trials that investigate the impact of
the right-to-left shunt size on pediatric migraine headache.
This study had several limitations. Because of ethical issues
and concerns regarding recruitment, we were not able to
place intravenous lines in a healthy control group to perform
contrast TTE and TCD. Consequently, we compared our data
to the upper bound estimate of PFO prevalence in the general
population obtained from previously published data.31-35
We also attempted to address this issue of a contemporary
healthy control group by use of color-flow Doppler scanning
results in control subjects with murmur. This comparison re-
vealed a trend toward a higher PFO prevalence in patients
with migraine with aura, but because color-flow Doppler
scanning is less sensitive than contrast TTE, it did not reach
statistical significance.
Because our results are similar to those reported in most
adult studies, spontaneous PFO closure must be rare after
6 years of age. Furthermore, if a causal link is established
between PFO and migraine, routine investigation for PFO
with contrast TTE may be indicated for all children with
migraine headaches. n
Submitted for publication Aug 27, 2010; last revision received Dec 16, 2010;
accepted Jan 28, 2011.
Reprint requests: Rachel T. McCandless, MD, 100 N. Mario Capecchi Drive,
Salt Lake City, UT 84113. E-mail: rachel.mccandless@hsc.utah.edu
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Table I. Protocol for agitated saline TTE/TCD imaging

Figure 4. Percentage of subjects with varying sizes of right-
to-left shunt as determined by contrast TCD in migraine with
and without aura.

Placement of an intravenous catheter into a forearm vein.

All participants are coached on how to perform a Valsalva maneuver by
exhaling air against a closed glottis to increase right atrial pressure.

The standard 2-dimensional and Doppler echocardiography is performed by
experienced pediatric sonographers trained in this protocol.

While obtaining an image of the heart in the apical four-chamber view,
a cardiologist experienced in this protocol infuses contrast using sterile
normal saline solution 5 mL that has been agitated between two syringes
connected by a three-way stopcock. One injection is performed with the
subject resting and breathing normally. A second injection is performed
while the patient is performing a Valsalva maneuver. The Valsalva
maneuver is terminated suddenly when contrast medium arrives in the right
atrium. Residual atrial shunting is present if microcavitations cross the
septum within four cardiac cycles after full opacification of the right atrium.

A TCD probe is placed over the middle cerebral artery. Agitated saline
solution is injected during Doppler recording in this vessel. Microcavitations
detected within 10 seconds of the injection appear as transient spikes in the
velocity curve. Injections are recorded at rest and with Valsalva maneuver.

Four possible results have been standardized for the TCD recordings:
No microcavitations (no right to left shunt)
1-10 microcavitations (small shunt)
>10 microcavitations but no shower of microcavitations where a single
microcavitation cannot be identified (medium shunt)

Shower of microcavitations where individual microcavitations cannot be
counted (large shunt)

247.e1 McCandless et al