Migraine and circle of Willis anomalies
Brett Cucchiara*, John Detre
Department of Neurology, University of Pennsylvania Medical Center, 3400 Spruce Street,
Philadelphia, PA 19104, United States
Received 15 May 2007; accepted 16 May 2007
neuronal hyperexcitability, cortical spreading depression underlying the symptom of aura, and trigeminal nerve
activation at a peripheral and central level. However, these mechanistic concepts incompletely explain migraine
susceptibility in individual patients and do not fully account for the well documented association between migraine and
ischemic cerebrovascular disease, including increased risk of both clinical stroke and subclinical brain lesions in
The circle of Willis is a major source of collateral blood flow supply in the human brain, and developmental
morphologic variants of the circle of Willis are extremely frequent. Altered cerebral blood flow (CBF) has been
demonstrated in regions supplied by variant circle of Willis vessels. Our central hypothesis is that circle of Willis
anomalies correlate with alterations in cerebral hemodynamics and contribute to migraine susceptibility and ischemic
complications of migraine. Dysregulation of CBF may allow relative ischemia to develop in the setting of increased
metabolic demand related to neuronal hyperexcitability, may trigger cortical spreading depression, and may
predispose individuals with migraine to ischemic lesions and stroke.
Identification of structural alterations in the cerebral vasculature in migraine patients would have several important
pathophysiological and clinical implications. First, it would provide a developmental mechanism for migraine
susceptibility that may lead to further insights into genetic predisposition to migraine. Second, it would expand
understanding of potential mechanisms underlying migraine aura and linking migraine with both clinical and subclinical
cerebral infarction. Third, it could help to identify the subpopulation of patients at risk of progressive cerebral
ischemia so as to target preventative therapies appropriately. Fourth, it would suggest a role for further diagnostic
evaluation to determine migraine mechanism in individual patients, analogous to the current paradigm in ischemic
stroke in which determination of stroke mechanism is critical to therapeutic decision-making.
Several mechanisms are currently thought to contribute to migraine pathogenesis, including interictal
c 2007 Elsevier Ltd. All rights reserved.
Migraine is an extremely common disorder. A re-
cent population based study estimated the one
year prevalence of migraine in the United States
at 18.2% in women and 6.5% in men . Migraine
with aura occurs in about 40–50% of the total mi-
graine population [2,3]. Beyond the immediate
0306-9877/$ - see front matter ?
c 2007 Elsevier Ltd. All rights reserved.
*Corresponding author. Tel.: +1 215 662 6738; fax: +1 215 614
E-mail address: email@example.com (B. Cuc-
Medical Hypotheses (2008) 70, 860–865
implications of disability related to acute migraine
pain, there is also considerable evidence that mi-
graine, particularly migraine with aura, increases
the risk of ischemic stroke [3–6]. For instance, in
the Women’s Health Study, which consisted of wo-
men 45 years of age or older, an increased risk of
ischemic stroke was seen in those with migraine
with aura; this increased risk translated to 3.8
additional strokes per year per 10,000 total women
. While this risk increase is small, given the high
prevalence of migraine the population attributable
risk may be quite substantial. Approximately 52
million women age P45 years were identified in
the 2000 United States Census, suggesting that mi-
graine with aura could contribute to almost 20,000
ischemic strokes in women in this age group in the
United States each year.
Migraine as a ‘‘cerebrovascular’’ disease
In addition to epidemiologic data, a number of
additional observations suggest a link between
migraine and cerebral ischemia. In a population-
based study of brain MRI findings in patients with
migraine (with and without aura) and healthy
controls, an increased prevalence of subclinical
cerebral infarction was found in the posterior cir-
culation territory, particularly the cerebellum, of
migraine patients (5.4% vs. 0.7%, p = 0.02) .
Patients with migraine with aura and higher fre-
quency of migraine attacks were at increased risk.
In this same study, an increased risk for deep white
matter lesions was also found with migraine in wo-
men, but not men. Detailed topographic analysis of
the visualized brain lesions suggested a combina-
tion of embolism and hypoperfusion as the most
likely etiology . Other studies have reported
similar findings [8,9].
Additional evidence supporting a role for brain
embolism in migraine comes from studies demon-
strating an increased prevalence of patent foramen
ovale (PFO) in patients with migraine, particularly
migraine with aura . PFO is a common cardiac
anomaly present in up to 25% of normal subjects;
it allows passage of blood from the right to left at-
rium of the heart, potentially increasing the risk of
paradoxical embolism to the brain . A PFO is
found in approximately 50% of patients with mi-
graine with aura. A number of uncontrolled, obser-
vational studies have suggested a reduction in
migraine with procedures designed to close the
PFO . Recently, a randomized controlled trial
comparing endovascular PFO closure to a sham pro-
cedure (MIST) demonstrated a significant reduction
in headache frequency with treatment; 42% of the
patients with endovascular PFO closure reported a
50% reduction in headache days, compared to 23%
in the sham procedure group (p = 0.038) . This
well-designed trial represents proof of principle
that PFO plays a pathogenic role in some patients
present in many patients with migraine. Transcra-
nial Doppler studies show evidence of altered vas-
cular reactivity in response to hypocapnia and
ergometer stress in patients with migraine with
aura [13–15]. These alterations might be mediated
by endothelial dysfunction, supported by studies
demonstrating an increase in endothelin-1 levels
(an endothelium derived factor with vasoconstric-
tive properties) during migraine attacks [16,17]. A
link between migraine and a polymorphism in the
endothelin receptor gene has also been found in a
mechanism by which regulation of vascular tone
might be impaired . The observation that ni-
trates can reliably trigger migraine, and that nitric
oxide synthase inhibition may abort migraine, has
led to speculation that nitric oxide may play a role
in migraine through its regulation of vascular tone
In addition, several small studies have suggested
that coagulation activation may be present in pa-
tients with migraine [21–24]. There also may be
a greater prevalence of cardiovascular risk factors
in patients with migraine with aura .
Mechanisms of migraine
(CSD) plays a critical role in migraine with aura,
and possibly migraine without aura. Characteristic
blood flow changes in CSD include a brief early
hyperemic phase followed by a more prolonged
phase of hypoperfusion. These blood flow changes
have been correlated with migrainous aura .
Reduction in cerebral blood flow has also been
demonstrated during headache in patients with mi-
graine without aura . While it has been sug-
gested that the hypoperfusion which accompanies
CSD might precipitate cerebral ischemia in some
cases, particularly if other contributing factors
are present, it appears likely that aura symptoms
themselves are not due to cerebral ischemia, but
rather are caused by aberrant neuronal activity
with perfusion changes a secondary phenomenon
[28,26,29]. However, the trigger for initiation of
CSD in patients with migraine remains incompletely
understood. Clinical reports of migraine headache
triggered by cerebral ischemia and experimental
Migraine and circle of Willis anomalies861
evidence of cerebral ischemia as a trigger for cor-
tical spreading depression may provide a plausible
hypothesis by which migraine and cerebral ische-
mia might be linked [30,31]. Additionally, endothe-
lial irritation caused by catheter angiography can
trigger CSD and migraine in patients, and in exper-
imental models endothelin-1, an endothelium de-
rived factor, is a potent inducer of CSD [29,32].
Taken together, these data suggests that the rela-
tionship between migraine and cerebral ischemia
might in fact be bidirectional and complex. For in-
stance, in the setting of a dysregulated cerebral
vasculature, triggers such as endothelial injury or
brain embolism might allow relative ischemia to
develop, which in the presence of increased meta-
bolic demand related to neuronal hyperexcitability
might trigger CSD. Once triggered, the hypoperfu-
sion accompanying CSD might then increase the risk
of either clinical or subclinical cerebral infarction.
Within this theoretical framework, one impor-
tant factor not previously well investigated is the
contribution of structural alterations in the cere-
bral vasculature, specifically anomalies in the cir-
cle of Willis, to migraine pathogenesis.
Circle of Willis
The circle of Willis refers to the interconnected
major arterial vessels supplying the brain (Fig. 1).
An anterior communicating artery connects the
right and left anterior cerebral arteries and two
posterior communicating arteries connect the
anterior and posterior circulations on the right
and left sides. In the setting of parent vessel nar-
rowing or occlusion, flow in these arteries provides
an important collateral pathway to maintain cere-
bral blood flow.
The anatomy of the circle of Willis is highly var-
iable, particularly with regard to the anastomoses
in the posterior circulation (Fig. 2). These varia-
tions are largely the result of developmental
changes occurring during the fetal period. As early
as seven weeks after conception, a preliminary
form of the circle of Willis is present with approx-
imately equal diameters of all vessels. As fetal
growth occurs, the relative sizes of the various
components of the circle of Willis change signifi-
cantly to assume the eventual adult morphology.
A well-designed prospective study of healthy volun-
teers imaged with MRA to evaluate the circle of
Willis found an incomplete anterior portion of the
circle in 39/150 (26%) subjects, and an incomplete
posterior circle in 72/150 (48%) . Overall, only
63/150 (42%) subjects had an entirely complete
circle of Willis. Similar findings have been reported
in autopsy studies and other studies using MRA
In addition to the classically defined circle of
Willis anomalies, variations in the intracranial ver-
tebral arteries are also common and have impor-
tant implications in terms of posterior circulation
internal carotid artery; ACA: anterior cerebral artery;
MCA: middle cerebral artery; PCA; posterior cerebral
artery; BA: basilar artery; VA: vertebral artery; Acomm:
anterior communicating artery; Pcomm: posterior com-
municating artery; A1, A2, P1, P2: branches of the
anterior and posterior cerebral arteries.
Arteries comprising the circle of Willis. ICA:
Willis anomalies. The right A1 segment of the anterior
cerebral artery is absent (asterisk), the right posterior
cerebral artery has a fetal configuration (arrowhead),
and the intracranial right vertebral artery is absent
Example of a patient with multiple circle of
862 Cucchiara and Detre
blood supply. Asymmetry in the size of the two ver-
tebral arteries is present in roughly 75% of sub-
jects, but one vertebral artery is significantly
hypoplastic in only about 10% . In 1% of normal
subjects, a vertebral artery ends in the posterior
inferior cerebellar artery and does not communi-
cate with the basilar artery .
At least two large studies (n = 571 and n = 3780,
respectively) have reported an increased preva-
lence of a specific circle of Willis anomaly – fetal
type posterior cerebral artery, with the posterior
cerebral artery supplied primarily by the internal
carotid artery – in women [38,39]. A smaller study
reported no significant sex differences in the fre-
quency of individual anomalies; however, when
all fetal type posterior cerebral artery variants
(i.e. unilateral and bilateral, hypoplastic and ab-
sent P1 segments) were pooled, a 10.6% absolute
excess in women was seen .
Circle of Willis anomalies are associated with
alterations in blood flow volume in individual intra-
cranial vessels. In patients with a fetal-type PCA,
internal carotid artery volume flow is significantly
increased and basilar artery flow significantly de-
creased. Large asymmetries in flow volume be-
tween the carotid arteries are seen in patients
with absent A1 segments of the anterior cerebral
artery . One small study of patients with verte-
bral artery hypoplasia demonstrated both regional
and global decreased cerebral blood flow .
Circle of Willis as a potential migraine
On a theoretical basis, circle of Willis anomalies
might contribute to decreased regional CBF and,
ment flow in the setting of increased metabolic de-
mand. This might increase the likelihood of
triggering CSD, or alternatively contribute to the
development of cerebral infarction in the setting
of CSD. The ability to increase regional blood
shown to be impaired during migraine . In the
presence of circle of Willis anomalies, the conse-
quencesof this impairment
Several independent observations provide cir-
cumstantial evidence of a possible connection
between migraine and circle of Willis anomalies.
First, migraine aura and the associated cortical
spreading depression largely involve the posterior
circulation territory. Second, subclinical brain
infarction seen on MRI in patients with migraine
preferentially affects the posterior circulation ter-
ritory, particularly the cerebellum . Third,
compared to the anterior circulation, the posterior
circulation is known to be more vulnerable to
vascular dysregulation, possibly due to reduced
autonomic innervation . Fourth, circle of Willis
anomalies are far more frequent in the posterior
circulation compared to the anterior circulation
territory. Finally, migraine disproportionately af-
fects women, and at least some limited preliminary
evidence suggests that certain circle of Willis
anomalies may be more common in women.
To our knowledge, there have been only two lim-
ited reports investigating circle of Willis anomalies
graine without aura, and 481 healthy controls .
Circle of Willis assessment was only performed for
presence of a fetal PCA; other circle of Willis anom-
icant absolute excess of 5% in the frequency of fetal
PCA variants in patients with migraine with aura
compared to matched controls (OR 1.32, 95% CI
0.6–2.6). Patients with migraine without aura had
a frequency of fetal PCA variants intermediate be-
tween normal controls and patients with migraine
cle of Willis, may have similar significance. Indeed,
greater prevalence of vertebral artery hypoplasia
with aura compared to migraine without aura and
controls(29%vs.7%vs.8%,p < 0.05forbothcompar-
If in fact circle of Willis anomalies do play a role
in the genesis of migraine, this is clearly not the
sole or even major factor. However, if one accepts
that migraine is a complex disorder, it seems plau-
sible that developmental abnormalities in the
structure of the cerebrovascular circulation, in
conjunction with alterations in endothelial func-
tion, coagulation activation, possible cerebral em-
boli, and neuronal hyperexcitability might work
synergistically to increase susceptibility to cortical
spreading depression. Furthermore, in the setting
of the hypoperfusion associated with CSD, the
presence of circle of Willis anomalies might com-
promise hemodynamic reserve and increase the
likelihood of cerebral ischemia.
The identification of circle of Willis variations as a
risk factor for migraine and/or ischemic complica-
Migraine and circle of Willis anomalies863
tions of migraine could have important clinical
implications. It could lead to new pharmacological
strategies for treating migraine based on an
evolving understanding of migraine mechanisms.
It might be useful from a diagnostic perspective
to help classify migraine patients according to spe-
cific factors contributing to their disease, which in
turn might have implications for selection of ther-
apeutic strategies. Finally, it might help identify
patients at risk of cumulative brain insults related
to the interaction between migraine and ischemia
and who would particularly benefit from treat-
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