CURRENT REVI EW: BASI C SCI ENCE

Migraine and genetic and acquired

vasculopathies
AH Stam
1
, J Haan
1,2
, AMJM van den Maagdenberg
1,3
, MD Ferrari
1
& GM Terwindt
1
Departments of
1
Neurology and
3
Human Genetics, Leiden University Medical Centre, Leiden, and
2
Department of Neurology, Rijnland Hospital, Leiderdorp,
the Netherlands
It is remarkable that migraine is a prominent part of the
phenotype of several genetic vasculopathies, including
cerebral autosomal dominant arteriopathy with subcortical
infarcts and leucoencephalopathy (CADASIL), retinal
vasculopathy with cerebral leukodystrophy (RVCL) and
hereditary infantile hemiparessis, retinal arteriolar
tortuosity and leukoencephalopahty (HIHRATL). The
mechanisms by which these genetic vasculopathies give
rise to migraine are still unclear. Common genetic
susceptibility, increased susceptibility to cortical spreading
depression (CSD) and vascular endothelial dysfunction are
among the possible explanations. The relation between
migraine and acquired vasculopathies such as ischaemic
stroke and coronary heart disease has long been
established, further supporting a role of the (cerebral)
blood vessels in migraine. This review focuses on genetic
and acquired vasculopathies associated with migraine. We
speculate how genetic and acquired vascular mechanisms
might be involved in migraine.
Key words: migraine, RVCL, TREX1, CADASIL, comorbidity,
ischaemic stroke
INTRODUCTION
A vascular component in the aetiology of migraine has been
debated for many years (1). Recent experimental data suggest that
vasodilatation of intra- and extracerebral vessels is no more than an
epiphenomenon of migraine or even may not occur at all (14).
On the other hand, several studies provide evidence for a strong
vascular component in migraine (57), which is supported by the
clinical observation that migraine, in particular migraine with
aura (MA), and several genetic and acquired vasculopathies can
co-occur. Acquired vasculopathies including ischaemic stroke (8),
ischaemic heart disease (8), and arterial dissection (9) have been
associated with migraine. In addition, it is known that vascular
anomalies such as arteriovenous malformations or small angiomas
can cause MA (1012). Also, migraine has been associated
with reversible cerebral vasoconstriction syndromes (RCVS) (13).
Genetic vasculopathies where migraine can co-occur in patients
include cerebral autosomal dominant arteriopathy with subcorti-
cal infarcts and leukoencephalopathies (CADASIL) (14), retinal
vasculopathy with cerebral leukodystrophy (RVCL) (15, 16) and
hereditary infantile hemiparesis, retinal arterial tortuosity, and
leukoencephalopathy (HIHRATL) (17). The aim of this review is
to discuss acquired and genetic vasculopathies that are associated
with migraine in the light of the vascular component in the
migraine pathophysiology.
CEREBRAL BLOOD VESSELS AND MIGRAINE
Traditionally, two theories regarding the aetiology of migraine
exist: the neuronal and the vascular theory (18). In the classical
vascular hypothesis the migraine aura is related to ischaemia
caused by intracerebral vasoconstriction, whereas the headache is
attributed to (rebound) vasodilatation of cerebral and meningeal
blood vessels (19). This purely vascular hypothesis has nowadays
been discarded (1). Instead, migraine is considered a primary
brain disorder with neuronal events (e.g. cortical spreading
depression (CSD)) causing the aura (20). Dysfunction of certain
brainstem nuclei, associated with nociceptive processing, may
also play a role (21). In this theory, vasodilatation of cerebral and
meningeal vessels, if present, is considered a secondary phenom-
enon that may occur after activation of the trigeminovascular
system (TGVS) (22). Activation of trigeminovascular efferents
leads to the release of vasoactive neuropeptides (e.g. CGRP,
Substance P and NO), which are believed to cause neurogenic
inammation, central pain transmission and headache.
Although the role of neurogenic inammation in patients has
never been shown, neurogenic inammation of the dura and
around the meningeal vessels has clearly been demonstrated in
experimental animal models of migraine (23). The same experi-
ments also have shown vasodilatation of these vessels (23). A role
for vasodilatation in migraine in humans is supported by the fact
that specic antimigraine drugs, the triptans and ergotamine,
deactivate the TGVS, can inhibit the release of vasoactive neu-
ropeptides from perivascular nerve terminals, and have a vaso-
constrictive effect (24). Recent studies have casted considerable
doubt on whether our idea about the role of vasodilatation in
migraine is correct. For instance, CGRP antagonists do not have
a vasoconstrictive effect, but are very effective in the treatment of
migraine (25).
In addition, despite common believe, there is very little factual
evidence that vasodilatation really exists during migraine head-
ache attacks. This is probably because studies were hampered by
the fact that sensitive non-invasive techniques to assess intracra-
nial blood ow were not available at the time. A recent study by
Schoonman and co-workers, however, using a sensitive 3 Tesla
MRA-technique, failed to show in vivo cerebral and meningeal
Address correspondences to Gisela M. Terwindt, MD, PhD, Department of Neurology,
Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands.
Tel +31 71 5262895, fax +31 71 5248253, e-mail g.m.terwindt@lumc.nl
Headache Currents
1006 Blackwell Publishing Ltd Cephalalgia, 2009, 29, 10061017
vasodilatation in humans during migraine headache (2). Never-
theless, although this study did not provide evidence for vasodi-
latation of large meningeal and cerebral vessels during migraine
headache, it does not rule out a role for small cerebral vessels.
The latter is relevant because small cerebral vessels were shown
to cause blood ow changes that occur during CSD. CSD is
characterized by a brief (seconds) wave of intense neuronal and
glial depolarization that slowly (25 mm/min) propagates across
the cerebral cortex. The wave is followed by a potent, relatively
long-lasting (20 min) neuronal suppression (20, 26). There is
increasing evidence that CSD is the underlying mechanism of the
clinical migraine aura (27). An experimental study in rats showed
that CSD can activate the TGVS, and thereby trigger headache
mechanisms (23). In humans, however, there is no direct proof
for the relevance of CSD in triggering headache mechanisms.
Functional neuroimaging studies that showed similarities
between blood ow changes in patients during visual auras and
CSD in experimental animal models suggest that CSD may also
occur in humans (28); the blood ow changes consisted of an
initial hyperaemia during depolarization of neuronal and glial
membranes, followed by a reduction of cerebral blood ow
during hyperpolarization, and suppression of neuronal and glial
membranes (20, 2831). This reduction in cerebral blood ow
does not seem to reach ischaemic threshold and therefore is
referred to as oligaemia (2831). Changes in blood ow are
considered to follow the virtually increased and then reduced
metabolic demand of neurons and glial cells during CSD.
Recently, it was demonstrated that a reverse order of events,
i.e. a vascular event that is able to trigger CSD, may also be
possible (57). Dreier et al. showed that the vasoconstrictive
peptide endothelin-1 (ET-1) induced changes characteristic of
CSD in the rat cortex, which were mediated by NMDA receptors
(5). As ET-1 is not capable of inducing CSD in rat brain slices
without intact perfusion, it was suggested that a vascular-
mediated event acted as a trigger for CSD. Dreier and co-workers
also showed that ET-1 induces neuronal damage that was due to
ET1A receptor activation (6). They proposed that a vascular
neuronal process is able to cause the migraine aura: a clinical
insignicant ischaemic micro-area (caused by vasoconstriction or
a small embolus) giving rise to CSD and neuronal dysfunction in
a larger volume of tissue. They put this theory forward as an
explanation for the association between migraine and patent
foramen ovale (PFO) (32), which increases the risk of small
cerebral emboli. Changes in vessel diameter and blood ow
changes secondary to neuronal activity were also the subject of a
study by Brennan and co-workers (7). Using optical intrinsic
signal imaging combined with electrophysiological techniques,
they demonstrated that vasomotor changes in the cerebral cortex
travel: (i) at a signicantly greater velocity than the neuronal
changes; (ii) with a different pattern (circuitous along arterioles as
opposed to the concentric parenchymal CSD pattern); and (iii)
dissociated from neuronal changes (it extended beyond the
margins of the spread of parenchymal CSD). Thus, although it is
generally accepted that during a migraine attack alterations in
neuronal activity (e.g. CSD, dysfunction in ion transport and
brainstem dysfunction) precede vascular changes, their data
suggest that vascular alterations may trigger neuronal dysfunc-
tion, and not the other way around.
The clinical observation that migraine is associated with several
acquired vasculopathies (i.e. ischaemic stroke, ischaemic heart
disease, arterial dissection, arteriovenous malformation (AVM)
and RCVS) as well as with monogenetic cerebral small vessel
diseases (RVCL, CADASILandHIHRATL) further indicates that
vascular changes may increase susceptibility to migraine. Here, we
will discuss these vasculopathies in more detail.
GENETIC VASCULOPATHIES
Cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy
Cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) is an autosomal
dominant late-onset arteriopathy that is clinically characterized
by recurrent transient ischaemic attacks (TIAs) and strokes
leading to cognitive decline, psychiatric symptoms and dementia
(33). In about one-third of patients migraine with aura occurs,
often as the presenting symptom several years before the other
symptoms (34).
CADASIL has distinct neuroradiological features that are
usually manifest prior to the rst stroke. The most important
features are white matter hyperintensities (WMH) and lacunar
infarcts. WMH are symmetrically distributed and located in the
deep and periventricular white matter. Typical for CADASIL is
the bilateral involvement of the anterior temporal lobes and
external capsule. Other neuroradiological features are subcortical
lacunar lesions, lacunar infarcts and microbleeds (35, 36).
Histopathologically, CADASIL is characterized by abnor-
malities of the wall of small arteries and arterioles. Typical for
CADASIL is the deposition of granular osmiophilic material
(GOM) in the basement membrane and surrounding extracel-
lular matrix of vascular smooth muscle cells (VSMCs) as well as
the degeneration and eventual disappearance of VSMCs. These
specic pathological changes are not limited to the cerebral vas-
culature, but are ubiquitously present in the arterial system,
allowing for histopathological conrmation of the diagnosis by
skin biopsy, in addition to genetic screening (37). Endothelial
structural changes have also been reported in CADASIL
(38).
CADASIL is caused by mutations in the NOTCH3 gene
(located on chromosome 19p13.2-p13.1), which encodes a cell
surface receptor that, in human adult tissue, is solely expressed on
vascular smooth muscle cells (39, 40). The Notch3 protein is a
heterodimeric receptor with an extracellular, ligand binding
domain, a transmembrane domaine and a cystoplastmic domain.
It is part of a signal transduction pathway, critical for aspects of
vascular development, homeostasis and VSMC differentation
(41).
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Most mutations in CADASIL are missense mutations
and involve the loss or gain of a cysteine residue in the Notch3
protein(specically the extracellular epidermal-growth-factor-like
repeat). The exact pathogenic mechanism by which NOTCH3
mutations lead to CADASIL has not yet been deciphered. More
insight comes fromthe study of a Notch3 transgenic mouse model
harbouring the archetypical R90C mutation, enabling the in vivo
study of mutated Notch3 and the time-course of its effects (42).
The mouse model showed that degeneration of VSMCs precedes
the accumulation of GOM and Notch3 as well as a disruption of
anchorage of VSMCs to adjacent cells and extracellular matrix.
The current idea is that mutations in the NOTCH3 gene have a
gain-of-function effect on the protein and that disrupted anchor-
age triggers VSMC degeneration (43). The variable disease course
of CADASIL, ranging fromrelatively mild to very severe (34, 44),
might be an indication for the involvement of other genetic (45)
and environmental modifying factors.
The prevalence of migraine with aura, but not without aura,
is signicantly increased in CADASIL. This suggests that
CADASIL is more associated with aura than with migraine
headache. It is unknown why migraine with aura prevalence is
increased in CADASIL. Possible mechanism will be discussed
later in this review.
Retinal vasculopathy with cerebral leukodystrophy
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a
neurovascular syndrome that primarily involves the retina and
the central nervous system (15). The most prominent symptom
is a vascular retinopathy, which often is difcult to distinguish
from diabetic or hypertensive retinopathy. This may lead to a
delay in the diagnosis when other symptoms of the disease are
(still) absent, or when the family history is not carefully evalu-
ated. Neurological manifestations may include cognitive distur-
bances, depression, migraine (mainly without aura) and focal
neurological symptoms. In later disease stages, cerebral MRI
scans often show characteristic contrast-enhancing intracerebral
mass lesions. Several systemic symptoms can be present as well,
including renal and liver dysfunction, Raynauds phenomenon
and gastro-intestinal bleeding.
What is now called RVCL was originally described in three
families under different disease names and abbreviations (i.e.
cerebroretinal vasculopathy (CRV) (46), hereditary vascular ret-
inopathy (HVR) (16) and hereditary endotheliopathy, retinopa-
thy, nephropathy and stroke (HERNS) (47)). Several years after
mapping of the disease locus in the three families to chromosome
3p21.1-p21.3 (48) the disease causing gene, encoding the
3-5exonuclease TREX1, was identied (15). With the discovery
of the gene, it is now well established that CRV, HVR and
HERNS are overlapping phenotypes of the same disease entity.
Histopathological examination of cerebral tissue (46, 47, 49)
showed white matter necrosis, brinoid necrosis, thrombosis of
microvessels with perivascular inammatory inltrates (plasma
cells and lymphocytes) and reactive gliosis of astroglia. In one of
the families, electronmicroscopic examination showed a multil-
aminated capillary basement membrane (47). In another family
ne calcium deposits within necrotic foci were described (46).
The exact function of the TREX1 gene has not been eluci-
dated yet. Currently, three different roles have been attributed to
the protein. First, it encodes a 3-5exonuclease, which might
suggest a role in DNA editing and repair (50). However, because
Trex1 knockout mice do not have an increased spontaneous
mutation rate or higher cancer incidence, it is less likely that this
exonuclease exerts such a function. Because these mice develop
an inammatory myocarditis it seems that Trex1 is involved in
auto-immune mediated processses (51). Secondly, the Trex1
protein is part of the SET complex, which is involved in a specic
form of apoptosis induced by cytoxic T-cells and killer lympho-
cytes (i.e. Granzyme A-mediated cell death) (52, 53). Normally,
the SET complex resides in the cytoplasm attached to the
membrane of the endoplasmatic reticulum, but in response to
Granzyme A-induced oxidative stress, it can move to the nucleus
and attack nuclear DNA, leading to apoptosis. Thirdly, recently,
a role for Trex1 in cell cycle homeostasis was proposed (54).
Trex1-decient cells have an impaired G1/S-transition and a
6065 bp ssDNA species accumulates in the cytoplasm (54). At
present, ve different TREX1 mutations in nine different RVCL
families have been reported, all causing a truncation of the
C-terminus of the Trex1 protein, resulting in altered cellular
localization, while leaving the exonuclease activity intact (15).
Next to RVCL, mutations in TREX1 have been identied in
several auto-immune related diseases (5558), including Aicardi-
Goutieres syndrome (AGS) (55, 56) and familial chilblain lupus
(FCL) (56, 57). Also, some patients from a large cohort of SLE
patients carried a TREX1 mutation (58). Both heterozygous
frameshift mutations causing C-terminal truncations, similar to
those found in RVCL, and missense mutations were identied in
SLE patients (58). Although most of the missense mutants have
not functionally been tested and it therefore is unclear whether
they indeed cause SLE, the R114H mutation that has a decient
exonuclease function and was previously found in AGS, can also
cause SLE. The possible relation with migraine comes from
the fact that migraine, especially MA, can co-occur with SLE
(59).
The current idea is that either dysfunctional Trex1 (that is
with impaired exonuclease acitivity) or Trex1 functioning in the
wrong cellular context because of mislocalization (in the case of
truncating RVCL mutations) can lead to accumulation of DNA
intermediates in the cell, which may trigger an abnormal
immune response and cause disease.
Because of the other prominent clinical features, especially the
retinopathy and intracerebral mass lesions, not much attention
was given to the occurrence of migraine in the RVCL families.
Only one of the nine TREX1 families has been systematically
investigated for migraine. In this large Dutch RVCL family
(n = 54) genetic evidence was obtained that TREX1 might act as
a genetic modier for migraine (16, 60). Currently, a study is
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Blackwell Publishing Ltd Cephalalgia, 2009, 29, 10061017
being undertaken to evaluate the presence of migraine in the
other RVCL families.
Hereditary infantile hemiparesis, retinal arteriolar tortuosity
and leucoencephalopathy
A third genetic vasculopathy that affects both cerebral and retinal
small vessels is caused by a mutation in the COL4A1 gene that is
located on chromosome 13qter (61). MA has been described in
a family with hereditary infantile hemiparesis, retinal arteriolar
tortuosity and leucoencephalopathy, carrying COL4A1 mutation
G652E (17, 62, 63).
Besides causing HIHRATL, mutations in COL4A1 are asso-
ciated with a diverse clinical spectrum in both humans and mice,
including familial porencephaly and intracerebral haemorrhage
(61, 62, 64). Familial porencephaly is considered to be caused by
peri- and antenatal cerebral haemorrhage (65, 66). In addition,
ocular anterior chamber abnormalities, including congenital
cataract (67), are part of the clinical spectrum. Systemic small
vessels and larger cerebral vessels (intracranial aneurysms) may
also be affected, as is seen in HANAC syndrome (hereditary
angiopathy, nephropathy, aneurysms and muscle cramps) (68).
Differences in type of COL4A1 mutations may explain this vari-
ability in clinical spectrum.
The COL4A1 gene encodes the a1 chain of type IV collagen,
a ubiquitous expressed basement membrane protein, including
the vascular basement membrane. Complex basement membrane
defects are associated with COL4A1 mutations and reported in
human skin (68), skin capillaries (65, 68) and kidney (including
basement membrane of tubules, interstitial capillaries and of
Bowmans capsule) (68). Histopathological examination of brain
tissue of COL4A1 mutation carriers has not been performed yet.
However, in Col4a1 mutant mice the cerebral vascular basement
membrane is also affected, in addition to kidney and eye where
similar abnormalities were found (68, 69). Abnormalities include
local disruptions, irregular thickening and enlargement of endot-
helial cells.
After diagnosing a child with familial porencencephaly, the
affected parent may appear to have leukoencephalopathy, lacunar
infarcts, microbleeds and macrobleeds later in life in the absence
of porencephaly, suggesting modifying genetic and environmen-
tal inuences (65). In line with this, in Col4a1 mutant mice
(Col4a1
+/Dex40
), a strong gene-environment interaction was seen
with a large effect of stressors such as birth trauma and hyper-
tension (62).
In the family with hereditary infantile hemiparesis, retinal
arteriolar tortuosity and leucoencephalopathy and COL4A1
mutation G652E, three out of six mutation carriers had MA (17,
62, 63). The association with MA has not been reported in
phenotypes caused by other mutations, therefore the co-
occurrence with MA may either be coincidental or mutation
specic. Of note, in a family with hereditary porencephaly, carry-
ing a COL4A1 mutation (a mutation affecting the methionine
start codon that results either in an absent or an abnormal
truncated protein), MOwas described in one patient, while in two
other patients the migraine subtype was not specied (70).
However, as in six other reported families with hereditary poren-
cephaly migraine was not described this nding may well be
coincidental.
Possible mechanisms for the association of migraine and
genetic small vessel diseases
RVCL, CADASIL and the syndrome associated with COL4A1
mutations share several features (Table 1). The most important of
these for the current review are that all three affect the integrity of
cerebral and systemic small vessels and that migraine is part of the
phenotype, at least for RVCL and CADASIL. The mechanisms
by which these vasculopathies can increase the risk of migraine is
unknown, but they may be similar. Several explanations can be
put forward that may partly overlap.
Spurious association: It is unlikely that the comorbidity of
migraine with CADASIL and RVCL may be explained solely by
the high population prevalence of migraine (71). It cannot be
excluded that the association of migraine and COL4A1 muta-
tions may be coincidental, considering the high population
prevalence of migraine and the low number of reported mutation
carriers with migraine. For CADASIL, investigation of large
patient series rmly established that the prevalence of MA is
increased (34). For RVCL, few families have been reported so far,
thus no large studies investigating the prevalence of migraine
have been performed. Evidence for an association with migraine
comes from a large Dutch family where migraine clearly is part of
the clinical spectrum (16).
Shared genetic factors: The co-occurrence with migraine may
be causally related to (certain) NOTCH3, TREX1 and COL4A1
mutations. Inthis case, the genes may be considered to increase the
susceptibility for migraine (i.e. serve as genetic modiers). For the
TREX1 gene a genetic, family-based, association study demon-
strated that the RVCLlocus slightly enhances the susceptibility for
migraine (60). However, other risk factors must be involved as
well, because migraine frequency was also increased in branches
from the family in which the mutation was not transmitted. For
the NOTCH3 gene, the evidence for a genetic association with
migraine is conicting. One study found an association between
the NOTCH3 polymorphism G684A and migraine, but this has
to be conrmed(72). Onthe other hand, no associationwas found
between the NOTCH3 polymorphism T6746C and migraine
(73). Unfortunately, studies performed thus far have important
limitations, including small sample size. The COL4A1 gene has
not been studied for genetic association with migraine.
Vascular: endothelial dysfunction: There is evidence that
migraine attacks are associated with endothelial dysfunction.
Migraine prevalence is increased in persons with polymor-
phisms linked to endothelial function (7480). Circulating
endothelial progenitor cell (EPC) numbers and function
have recently been shown to be reduced in migraine patients,
which suggests that migraine patients may have dysfunctional
Headache Currents
1009 | Cephalalgia | September 2009
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Headache Currents
1010 | Cephalalgia | September 2009
Blackwell Publishing Ltd Cephalalgia, 2009, 29, 10061017
endothelial regeneration (81). This may provide a biological link
between migraine and the increased cardiovascular risk found in
migraine patients. In addition, the brachial arteries of migraine
patients were shown to have a decreased capacity for endothelial-
dependent vasodilatation (8284). In CADASIL and RVCL,
pathological changes in endothelial cells may interfere with
endothelial function and alter vascular reactivity. This may be a
third possible explanation for the increased risk of migraine.
Endothelial function has been studied in CADASIL. Mice
expressing the mutated protein display early dysfunction
in vasoreactivity with decreased ow-induced dilatation and
increased pressure-induced myogenic tone (85). In CADASIL
patients, impaired endothelial function was also found in two
studies (86, 87). It would be interesting to study endothelial
function in RVCL and HIHRATL as well.
Neuronal: CSD is thought to be the underlying mechanism
of the migraine aura. A hypothesis for the increased prevalence of
MA in CADASIL could be that vascular changes make the cortex
more susceptible to CSD, thereby increasing the risk for MA.
Indeed in CADASIL patients a reduced cerebral baseline ow
(87) and decreased cerebrovascular reactivity (8890) and an
impaired endothelial function (86, 87) were demonstrated. Fur-
thermore, it was recently shown that vasomotor changes can
precede neuronal dysfunction (7) and that a vascular event, such
as a clinical insignicant ischaemia, is able to trigger CSD (5, 6).
These observations strengthen this hypothesis for CADASIL.
Increased susceptibility for CSD seems a less plausible mecha-
nism for RVCL, as this syndrome is mainly associated with MO.
However, it could also form an explanation for the occurrence of
MA in three out of six family members with HIHRATL.
ACQUIRED VASCULOPATHIES
From the above mentioned genetic vasculopathies it becomes
clear that genetic defects that give rise to loss of vessel wall
integrity and perhaps endothelial dysfunction may predispose to
migraine. Similarly, vasculopathic changes leading to endothelial
dysfunction may explain the association between migraine and
cardiovascular disease. Evidence for the association between
migraine and ischaemic stroke and ischaemic heart disease, as
well as possible mechanisms, will be discussed in the next section.
In addition, other acquired vasculopathies that can result in or
are associated with migraine, such as arterial dissection, arterio-
venous malformations and reversible cerebral vasoconstriction
syndromes, are discussed.
Ischaemic stroke
Several studies have shown that migraine, specically MA, is a risk
factor for ischaemic stroke (9196). A meta-analysis of 11 retro-
spective case-control and three prospective cohort studies showed
pooled relative risks of 1.83 (95% condence interval (CI) 1.06
3.15) for MO, and 2.27 (95% CI 1.613.19) for MA (91). This
risk was higher in young female migraineurs below 45 years old
[2.76 (95% CI 2.173.52)] and highest when using oral contra-
ceptives [8.72 (95% CI 5.0515.05)]. Since 2004, after the
meta-analysis, two large prospective studies (92, 93) and two
case-control studies (94, 95) have been performed. The prospec-
tive Womens Health Study also showed an increased risk for
ischaemic stroke for women with MA [hazard ratio (HR) 1.71
(95% CI 1.112.66)], which was more increased in the youngest
women in the cohort, aged between 45 and 55 (92). In a retro-
spective case control study in much younger women (aged 1549)
the increased risk of ischaemic stroke could also be detected [OR:
1.5 (95% CI:1.12.0)], increasing with higher attack frequency
(OR for migraine patients with more than 12 attacks per year 2.2
(95% CI 1.53.3)) and even up to seven- to 10-fold with the
combination of smoking and oral anticonceptive use (94). A
case-control study in older adult migraineurs above 55 suggested
that the higher risk of ischaemic stroke found in young and middle
aged women with MApersists (in this study men and women were
not separately analysed) (95). In the prospective Physicians
Health Study the risk of ischaemic stroke in male migraineurs was
not increased, but one of the main drawbacks of this survey is that
no distinction between MA and MO could be made (93). When
interpreting all these risk estimates, one must keep in mind that
the absolute increase in risk for MA patients is still low. In all
studies the increased risk for ischaemic stroke appeared to be
independent from traditional cardiovascular risk factors (except
OAC use, smoking or both) (92, 93, 95) or especially present
among individuals without cardiovascular risk factors (94).
Although the above-mentioned studies are well designed and
have included impressive numbers of patients, and long-term
follow-up was performed in the two prospective studies, they
were not specically designed to study the migraine-stroke rela-
tionship. The main drawbacks of these studies are: (i) migraine
and aura were self-reported and not diagnosed according to the
IHS-criteria, a limited number of written questions were used
and diagnosis was not veried by an interview; (ii) transient
ischemic attacks (TIAs) could have confounded the results as
they are a risk factor for ischaemic stroke and can be difcult to
distinguish from the migraine aura, especially when no direct
interview has been performed; and (iii) no information was given
about the use of triptans or ergotamines, which may increase the
risk of vascular events due to their vasoconstrictive effects. On the
other hand, a retrospective study of a pharmacology register
found that ergotamine overuse but not triptan overuse was asso-
ciated with an increased risk of ischaemic complications (97).
Another line of evidence for an association between migraine
and ischaemic stroke comes from imaging studies. In the
population-based CAMERA study evidence was presented that
MA patients have a 14-fold increased risk of silent infarct-like
lesions in the posterior circulation territory of the brain (i.e. the
cerebellar region), a risk which increases with increasing attack
frequency (98). The specic MRI characteristics of these lesions
suggest an infarct origin (99). As with the clinical association
between ischaemic stroke and migraine, the risk was not modi-
ed by traditional cardiovascular risk factors (except for age),
Headache Currents
1011 | Cephalalgia | September 2009
Blackwell Publishing Ltd Cephalalgia, 2009, 29, 10061017
which again suggests the involvement of other than atheroscle-
rotic mechanisms. A possible mechanism is that CSD, the under-
lying mechanism of the migraine aura, initiates a combination
of hypoperfusion and thrombo-embolism formation leading to
infarction (99).
Also, from the CAMERA study it became clear that in women
with migraine the risk for deep white matter lesions is increased
compared with controls, with no difference between MO and
MA patients. This risk increases with higher attack frequency.
A strength of the CAMERA study is that migraine diagnoses
were made according to the IHS criteria (100), after a telephone
interview and in consultation with a neurologist specialist in
headache. As the CAMERA study had a cross-sectional design a
causal explanation for the increase in MRI abnormalities in
migraineurs is speculative. The CAMERA follow-up study
(CAMERA II), in which a second MRI scan will be made after a
follow-up period of 89 years, should be able to clarify this
relationship. First results from this study are expected at the end
of 2009.
Ischaemic heart disease
Whether vascular changes in migraine are restricted to the cerebral
vasculature or also systemically present is not yet clear. Systemic
vascular dysfunction is suggested by the association of migraine
with an unfavourable cardiovascular risk factor prole (101),
prothrombotic and vasoactive factors (102), and the relation with
systemic endothelial dysfunction (81). The association of migra-
ine with ischaemic heart disease also points to systemic vascular
dysfunction. This association has been investigated in a large
number of studies, among which are the Womens Health Study
and Physicians Health Study (93, 96). In the rst study (mean
follow-up 10 years) women aged 45 years or older with active MA,
had an increased risk for major cardiovascular disease (CVD) after
controlling for traditional cardiovascular risk factors [HR 2.15
(95%CI 1.582.92)]. CVDwas dened as rst instance non-fatal
ischaemic stroke, non-fatal myocardial infarction, or death due to
ischaemic CVD. In addition, in women with MA, after control-
ling for traditional cardiovascular risk factors, anincreased risk was
found for myocardial infarction, angina, coronary revasculariza-
tion and for ischaemic CVDdeath. These risks were not increased
for women with MO compared with controls (96). A study in an
older cohort conrmed that in women, MA, but not MO, may be
associated with an increased risk of coronary heart disease (CHD)
(103). In the Physicians Health Study, which did not discriminate
MO from MA, an increased risk for major CVD was found
[adjusted HR 1.24 (95% CI 1.061.46)] for male migraineurs,
which was driven by the increased risk for myocardial infarction
[adjusted HR 1.42 (95% CI1.151.77)] (93).
Mechanisms for the association of migraine with stroke and
ischaemic heart disease
Several mechanisms have been proposed that may underlie the
increased risk of ischaemic stroke and ischaemic heart disease in
migraine patients (8). One candidate is CSD, the underlying
mechanism of the migraine aura, which is associated with
decrease in cerebral blood ow (2831). CSD (indirectly) alters
bloodbrain barrier permeability, which might lead to exacerba-
tion of local cellular injury caused by ischaemia. Together with
factors predisposing to co-agulopathy and release of local vaso-
active neuropeptides, this could result in further changes in cere-
bral haemodynamics, arterial thrombosis and infarction (99).
Other mechanisms that might predispose migraine patients to
ischaemic cardiovascular events include endothelial dysfunction,
migraine-specic medication, PFO or shared genetic factors.
Alternatively, the increased risk may be mediated by an unfavour-
able cardiovascular risk prole. In the population-based GEM
study, migraineurs were more likely to smoke and to report a
parental history of early myocardial infarction. Migraineurs with
aura were more likely to have an unfavourable cholesterol prole,
have elevated blood pressure, and report a history of early onset
coronary heart disease (CHD) or stroke. The odds of having an
elevated Framingham risk score for CHD were approximately
doubled for the migraineurs with aura. Thus, migraineurs, par-
ticularly with aura, have a higher cardiovascular risk prole than
individuals without migraine (101). In the Womens Health
Study this higher cardiovascular risk prole was found for women
with MA and myocardial infarction, implying that the associa-
tion with CHD is, at least in part, mediated by atherosclerosis
(104). For angina this was not entirely the case, with both more
risk of angina in the low risk and high risk category. The authors
propose two mechanisms for angina, one mediated by athero-
sclerosis and another one that alters the vasculature independent
of atherosclerosis.
Interestingly, in the Womens Health Study the association
between ischaemic stroke and MA in women appeared to be
signicant only in women with a low (1%) Framingham risk
score for coronary heart disease (CHD), which is particularly
mediated by low age and low total cholesterol concentrations
(104). As the Framingham risk score for CHD can be used as a
proxy for vascular risk status, this would imply that the biological
mechanism for the MA-ischaemic stroke association is not medi-
ated by atherosclerosis, but involves alterations in the cerebral
microvasculature. This hypothesis is supported by the data of the
CAMERA study, where no association was seen between poste-
rior circulation (PC) territory infarct-like lesions and types of
supratentorial brain changes, such as deep white matter lesions
or periventricular white matter lesions (99). Furthermore, there
were no large differences in cardiovascular risk factors in those
with and without PC territory infarct-like lesions. These two
factors suggest that the lesions are not atherosclerotic in origin
but reect small vessel disease. An impairment in the adaptive
cerebral haemodynamic mechanisms in the posterior circulation
in migraine patients with aura might be part of the underlying
mechanisms between migraine and brain infarcts (99).
In the Womens Health Study the relation between biomark-
ers of CVD and migraine was also analysed (i.e. lipids and a panel
Headache Currents
1012 | Cephalalgia | September 2009
Blackwell Publishing Ltd Cephalalgia, 2009, 29, 10061017
of inammatory biomarkers: C-reactive protein (CRP), brino-
gen, intercellular adhesion molecule-1, homocysteine and creati-
nine). Overall, the data suggest that these biomarkers are an
unlikely explanation for the observed association between MA
and CVD in this cohort (105). Migraine, and specically MA,
has been associated with the T allele of the C677T polymor-
phism in the methylenetetrahydrofolate reductase gene (78,
106), which is also associated with moderately increased levels of
homocysteine, a risk factor for CVD (107). Remarkably, in the
Womens Health Study no association was found for migraine
overall or for MA with increased levels of homocysteine (105),
whereas in the GEM study homocysteine levels were increased
only in the subgroup of male MAT/T homozygote carriers of the
polymorphism (78).
Arterial dissection
Several studies found an increased migraine prevalence in patients
with spontaneous cervical artery dissection (CAD) compared with
controls with non-CAD ischaemic stroke, controls without vas-
cular history or both (9, 108111). CADis an arteriopathy related
to extracellular matrix abnormalities. This suggests that similar
vessel wall defects form a risk factor for development of migraine.
The association has also been put forward to explain (part of ) the
relation between migraine and ischaemic stroke. However, in two
recent studies (9, 109), the association was merely signicant for
MO, but not for MA, while the risk of ischaemic stroke is only
increased in patients with MA. Whether the CAD migraine
association is true and indeed specic for MO remains to be
conrmed in larger cohorts, as studies performed thus far had
small sample sizes, were retrospective and had several limitations,
including selection bias, lack of blind assessment and correction
for confounders. Interestingly, in a family with familial aortic
dissection carrying the R460H mutation in the transforming
growth factor b receptor 2 (TGFbR2) gene, migrainous headache
was reported in no less than 10 of 14 mutation carriers (112).
Arteriovenous malformations and angiomas
Occipital arteriovenous malformations have been reported to
cause migraine with aura (11, 12). In addition, migraine can
develop after bleeding from cavernous angiomas in the brain
stem (10, 113). These observations once more suggest that vas-
cular events are able to initiate neuronal deregulation, leading to
migraine.
Reversible cerebral vasoconstriction syndromes
Reversible cerebral vasoconstriction syndromes (RCVS) is a
descriptive term for a group of conditions, all characterized by
multifocal areas of constriction involving the cerebral arteries that
resolve within days to weeks (13). RCVS patients present with
acute onset headache (thunderclap headache) with or without
neurological signs and symptoms due to ischaemia distal to severe
vasoconstriction. Diagnostic evaluation to exclude other causes,
such as subarachnoid haemorrhage, primary angiitis of the central
nervous system and arterial dissection, is critical. Some 25% of
RCVS patients have a history of migraine and the syndrome has
been termed migrainous vasospasms or crash migraine (13).
Indeed parallels between migraine and RCVS exist, such as the
throbbing headache and associated features (nausea, vomiting,
photophobia), the topography of migraine-associated and RCVS-
associated stroke (posterior circulation) and the serotonergic
mechanisms that have been implicated in both disorders (114).
However, important differences betweenmigraine and RVCS exist
as well. Migraine is not accompanied by cerebral angiography
abnormalities. Also, migraine patients can distinguish the present-
ing acute headache in RCVS clearly from previous migraine
attacks, and aura symptoms or premonitory symptoms are absent
in RCVS. Diagnosis and management of RVCS in migraine
patients is similar to other conditions. Simple observation may be
justied. Because of the moderate risk for ischaemic stroke, treat-
ment options such as calcium channel blockers (Verapamil and
Nimodipine) or high dose glucocorticoids have been suggested;
however, these options are based on observational data only (13).
CONCLUSION
A vascular component in the aetiology of migraine is supported
by the association between migraine and genetic and acquired
vasculopathies. In genetic small vessel diseases such as CADASIL
and RVCL, vascular changes, including endothelial dysfunction,
may directly or via neuronal pathways increase the risk for
migraine. Alternatively, DNA variants in the susceptibility genes
may directly form a risk factor for both migraine and the syn-
drome itself. The relation between migraine and increased risk of
ischaemic stroke and cardiovascular disease may be explained by
CSD, associated with decrease in cerebral blood ow and pro-
thrombotic mechanisms. Other mechanisms include endothelial
dysfunction, migraine-specic medication, PFO or shared
genetic factors. For genetic as well as acquired vasculopathies
research into endothelial function and shared genetic factors will
be important in order to unravel the pathophysiological mecha-
nisms that can explain their comorbidity with migraine.
ACKNOWLEDGEMENTS
This work was supported by grants of the Netherlands Organi-
zation for Scientic Research (NWO) (903-52-291, M.D.F., Vici
918.56.602, M.D.F., 907-00-217 GMT and 920-03-473, AHS),
and by a grant from the Centre for Medical Systems Biology
(CMSB) established by the Netherlands Genomics Initiative/
Netherlands Organisation for Scientic Research (NGI/NWO).
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