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Lancet Neurol. 2010 March ; 9(3): 309–317. doi:10.1016/S1474-4422(09)70358-8.
Migraine aura pathophysiology: the role of blood vessels and

microembolisation
Turgay Dalkara, MD, Ala Nozari, MD, and Michael A Moskowitz, MD

Stroke and Neurovascular Regulation Laboratory, Department of Radiology (T Dalkara MD, A
Nozari MD, M A Moskowitz MD) and Department of Anesthesia and Critical Care (A Nozari),
Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; and
Department of Neurology, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey (T
Dalkara)
Abstract
Migraine attacks with auras are sometimes associated with underlying hereditary or acquired
cerebrovascular disorders. A unifying pathophysiological explanation linking migraine to these

conditions has been diffcult to identify. On the basis of genetic and epidemiological evidence, we
suggest that changes in blood vessels, hypoperfusion disorders, and microembolisation can cause
neurovascular dysfunction and evoke cortical spreading depression, an event that is widely
thought to underlie aura symptoms. In fact, recent experimental data have indicated that focal,
mild, and transient ischaemia can trigger cortical spreading depression without an enduring tissue
signature. Although migraine with aura has many causes (eg, neuronal network excitability), it
seems that migraine and stroke might both be triggered by hypoperfusion and could therefore exist
on a continuum of vascular complications in a subset of patients who have these hereditary or
acquired comorbid vascular conditions.
Introduction
Migraine headache can occur as a comorbidity of ischaemic stroke, carotid or vertebral
artery dissection, arteriovenous malformations, cerebral auto somal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL syndrome), or platelet
disorders (eg, thrombocytosis) among other disorders (panel).1–5 Although diffcult to
identify a unifying hypothesis linking these disorders to migraine pathogenesis, a
disturbance within brain vessels might be common to a subset of patients who have migraine
with aura. Migraine with aura has been identified as an independent risk factor for ischaemic
stroke6 and possibly for white matter hyperintensities, suggesting common
pathophysiological mechanisms that implicate the neurovascular unit.7,8 Although several
possibilities can explain the comorbidity of migraine and vascular diseases (eg, shared
mutations or a consequence of repeated migraine attacks), an emerging hypothesis, which
we find persuasive, places stroke and migraine on a continuum of vascular complications
caused by, for example, focal and transient hypoperfusion. Recent experimental data in mice
indicate that cerebral microembolism triggers cortical spreading depression (CSD), a
biological substrate for migraine aura, without causing requisite tissue injury.9 Although the
Correspondence to: Michael A Moskowitz, Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, 149
13th Street, Room 6403, Charlestown, MA 02129, USA [email protected]. harvard.edu.
Contributors All authors contributed to the concept and design of this paper, acquisition, analysis, and interpretation of data, drafting
of the paper, critical revision, and administrative, technical, and material support. TD prepared the first draft and MAM supervised the
preparation of this paper.
Conflicts of interest We have no conflicts of interest.
Dalkara et al. Page 2
brain’s vulnerability to injury is well recognised, it is only with the help of emerging data
from experiments in animals that we are now able to examine the possibility that even focal,
brief hypoxic-ischaemic episodes could trigger CSD without an obvious or enduring tissue
signature. If this possibility is true in human beings, blood vessel and blood flow disorders
would then be acknowledged as a migraine trigger, and vascular causes and risk factors for
migraine with aura would be more aggressively sought.
In this Personal View, we first consider the evidence and possible mechanisms that link
CSD to migraine aura and local hypoperfusion. We then examine what is known about
blood vessel and microcirculatory disorders implicated in migraine with aura to identify the
important subset of patients in whom these conditions might be linked. Because migraine is
a disorder of brain function and CSD is a putative biological substrate for migraine aura, we
begin with a brief description of the relevance and pathophysiological importance of CSD.
Migraine aura and CSD

CSD is a slowly propagating wave of neuronal and glial depolarisation that can be evoked in
the cortex, cerebellum, basal ganglia, thalamus, and hippocampus. Although well
documented and easily evoked in the lissencephalic brain, only recently has its existence
been unequivocally shown in the human brain in the context of subarachnoid haemorrhage,
malignant stroke, and head injury.10–12 CSD provides the most likely explanation for
migraine visual aura, although the evidence from patients with migraine is still indirect. The
earliest and strongest support for this view came from blood flow imaging studies by Olesen
and colleagues,13 which showed that, during aura-like symptoms, slowly spreading
oligaemia propagated anteriorly from the occipital pole. This finding was corroborated
during a spontaneous migraine attack without aura seen during PET imaging,14 and also by
use of magneto encephalography, which showed multiple cortical areas activated in
spontaneous and visually induced migraine aura.15 The most technically advanced
demonstration was provided by a functional imaging study during visual aura, which
showed a slowly propagating perturbation of the magnetic resonance signal in the primary
visual cortex that had at least eight characteristics of CSD, including transient
hyperperfusion followed by sustained hypoperfusion.16
Not unlike migraine aura, CSD develops in response to several types of stress, including
excitotoxic or hypoxic-ischaemic stress. Unsurprisingly then, CSD is noxious in some
studies: it activates the trigeminovascular system in rodents17 and has been proposed as a
trigger for headache in human beings.18,19 CSD susceptibility is modulated by genetic and
environmental factors: increases in extracellular potassium ion and glutamate concentrations
might initiate CSD during intense cortical excitation, perhaps in response to local
depolarisation. Furthermore, migraine has a strong but complex genetic component that is
susceptible to modulation by endogenous biological and environmental factors such as
oestrogen withdrawal, sleep, and stress, and might also be an expression of neuronal
network excitability (figure 1).
In addition to intrinsic brain parenchymal mechanisms, as noted above, CSD is sometimes

triggered by brief hypoxic-ischaemic episodes, including endothelin-1-induced vasospasm
and microinfarcts or aneurysmal subarachnoid haemorrhage,10,20 as well as in vitro brief
hypoxia and mitochondrial inhibition.21,22 CSD develops during exposure to carbon
monoxide or before the development of terminal depolarisation in animals breathing a
fraction of inspired oxygen (FiO2) of less than 0·08.23,24 Recurrent and slowly propagating
peri-infarct depolarisations that resemble CSD are generated in focal cerebral ischaemia.12
In fact, perfusion pressure and oxygen levels have been reported to affect the
electrophysiological recovery of repetitive CSD events, or of CSD developing in the context

of ischaemia.25 Hence, CSD develops as a consequence of mild and transient hypoxic-

ischaemic perturbations, which in turn affect recovery; severe episodes eventually lead to
terminal anoxic depolarisation, as frequently found in prolonged ischaemia.
Migraine and cerebral microembolism

The association between migraine, stroke, and patent foramen ovale (PFO) remains
controversial and incomplete. Although the aggregate of the clinical evidence is more
convincing than individual reports, initial reports linking PFO with migraine aura had severe
selection bias and the quality of the evidence has therefore been judged as only moderate to
low. Furthermore, a recent population-based study in the elderly did not confirm this
association.26 However, data from most studies indicate that if there is an association, it is
between PFO and migraine with aura, not migraine without aura. In a meta-analysis of 1517
patients, increased prevalence of PFO was found in migraineurs with aura compared with
people without migraine, and a higher prevalence of migraine and migraine with aura was
found in individuals with PFO than in individuals without PFO.27 The estimated odds ratio
was 5·1 for an association between PFO and migraine and 3·2 for an association between
PFO and migraine with aura. The prevalence of PFO in 665 patients with migraine with aura
ranged from 41% to 72%.27 Calculations based on the available data suggest that PFO could
be a source of migraine attacks in a subset of patients, but we and others26 believe that PFO
probably does not account for all migraine attacks in these susceptible individuals.
Panel: Some comorbidities of migraine with aura

Cardiac and pulmonary
• Patent foramen ovale (associated with large openings, atrial septal aneursyms,
and right-to-left shunting)
• Mitral valve prolapse
• Pulmonary arteriovenous malformations
Vascular
• Stroke
• Carotid or vertebral artery dissection
• Carotid artery puncture
• Brain arteriovenous malformations
• Hereditary disorders (CADASIL, Col4A1 mutations, AD-RVCL, hereditary
vascular retinopathy)
Inflammatory
• Raynaud’s phenomenon
• Sjögren’s syndrome
• Antiphospholipid antibodies
• Coagulopathy
• Thrombocytosis
• Polycythemia vera

AD-RVCL=autosomal dominant retinal vasculopathy and cerebral leukodystrophy.

CADASIL=cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy.
Disorders that might make PFO a putative risk factor for stroke, such as right-to-left shunt
and an associated atrial septal aneurysm, have been documented; the same association is
beginning to emerge for migraine with aura.28 The presence of spontaneous right-to-left
cardiac shunt at rest has been implicated in the pathogenesis of stroke. The risk of systemic
embolisation increases when right atrial pressure exceeds that on the left, such as during the
Valsalva manoeuver or in disorders in which pulmonary artery pressure can be increased.
Patients with postulated paradoxical embolism can have larger PFOs than individuals
without paradoxical embolism, and MRI findings have implicated cerebral emboli as a
potential mechanism in patients with stroke and a large PFO.29.30 Thrombi have been
observed to traverse a PFO in some patients,31 thereby raising the probability that small
blood clots and microaggregates escape from being trapped within the lungs.
Although the association between migraine and ischaemic stroke is primarily seen in
patients with a low vascular risk profile,32 other comorbid disorders that increase the risk of
stroke might also increase the risk of migraine with aura. Right-to-left shunts within the
heart and also within the pulmonary circulation facilitate the transit of fibrin-rich, soft, red-
type venous thrombi.33 Venous emboli might be more susceptible to fibrinolysis and
disintegration by the intrinsic thrombolytic system than platelet-rich, white, often calcified
emboli originating from the wall of atherosclerotic arteries.34,35 Accordingly, these
fragmented, small emboli might have a higher probability of transiently occluding the
microcirculation, causing small foci of hypoxia/ischaemia. Moreover, these emboli might
create a surface for coagulation and platelet activation as well as release of vasoactive
chemicals and pro-inflammatory factors from the occluded microvessel wall and entrapped
blood cells that contribute to ischaemia and hypoxia.36 Thrombosis and micro embolisation
could thereby create a transient hypoxic-ischaemic focus to induce CSD followed by a
migraine attack, whereas more prolonged occlusion of larger vessels might cause transient
ischaemic attack or stroke.37
Migraine with aura also develops as a complication of injury to large vessels—for example,
after acute vertebral or carotid artery dissections.38 A clot can form within a narrow and
irregular arterial lumen in the dissected segment and trigger distal embolism before it is
completely thrombosed.39 Similarly, puncturing the carotid artery can cause embolism and
trigger the onset of migraine aura attacks.40 These pathophysiological considerations take on
greater importance in light of recent experimental studies indicating that microembolism can
serve as a trigger for CSD. Indeed, recent experimental data show that small brain foci of
ischaemia trigger CSD in mice.9 Small microemboli (microspheres of 10 μm) provide the
trigger, with minimum or no histological damage in some animals but microscopic infarcts
in less than half of the other animals. The small infarcts were found within the injected
carotid artery territory and not within the brainstem. Conversely, air microbubbles were
particularly effective as CSD triggers but did not cause any tissue damage. CSD occurrence
was associated with the depth and duration of blood flow deficit (figure 2) but did not
correlate with the presence of microscopic lesions regardless of whether air (0·8 μL),
microspheres (10 μm), or cholesterol crystals (<70 μm) were injected.
We believe that these findings are relevant to human beings because the terminal vascular
beds of the mouse and human brain are not too dissimilar. We also believe that these
findings are of relevance to migraine auras and headaches in patients that have PFO and
right-to-left cardiac shunts, wherein the filtering capacity of the lungs is bypassed. Lending
support to this view, a recent study in patients with migraine with aura as well as PFO

showed that injection of air bubbles into a peripheral vein induced multiple focal or bilateral
temporo-occipital electroencephalographic (EEG) disturbances.41 Bubble injection induced
an attack of migraine with aura in one of the seven patients, as is occasionally reported
during the microbubble studies used to detect PFO.42,43 Interestingly, the EEG abnormality
induced by bubble injection was not observed in patients without migraine history but in
patients with large PFOs and right-to-left shunts. Although the observed EEG changes are
not equivalent to CSD, they do indicate the susceptibility of the brain in patients with
migraine with aura to perturbations within the microcirculation.
The risk of developing a migraine attack during microembolisation most probably depends
not only on the location, size, and duration of transient vascular micro-occlusion, but also on
the susceptibility of the brain to developing CSD. Therefore, the fact that PFO closure
reduces attack frequency but does not eliminate migraine attacks is not surprising, although
published case series of PFO closure were not properly controlled. In fact, the results of the
only randomised trial were mostly negative, indicating the need for caution about PFO
closure as a routine treatment option.44 Nevertheless, a substantial reduction in frequency
and severity of migraine recurrence might be achieved by PFO closure in migraineurs with a
large PFO and subclinical brain MRI lesions,45 suggesting that only carefully selected
patients with migraine with aura who have PFO could benefit from this intervention; this
hypothesis would be best tested in the context of a new prospective randomised clinical trial.
Although there is little experimental evidence at present, alternative mechanisms for PFO-
induced migraine have been proposed, including hypoxia-induced migraine caused by brief
episodes of oxygen desaturation or migraine caused by high concentrations of serotonin or
other vasoactive substances in the arterial circulation. These explanations are not mutually
exclusive. A shared genetic predisposition for the atrial defect and tendency for migraine
with aura has also been suggested.
Susceptibility to migraine aura of vascular origin

CADASIL syndrome, an autosomal dominant disorder, is a prototypical disorder that
emphasises a strong link between blood vessels and migraine aura.4 20–40% of patients with
CADASIL have migraine with aura, often as the first symptom of the disease. Caused by
mutations in NOTCH3, which encodes a transmembrane receptor expressed by vascular
smooth muscle cells, this disorder affects both systemic and cerebral blood vessels. More
than 95% of point mutations have been identified in the extracellular domain of the affected
protein.
The precise pathophysiological explanation for attacks of migraine with aura in patients with
CADASIL is not known. After the onset of migraine aura in the second or third decade of
life, patients develop transient ischaemic attacks and strokes in their fourth or fifth decades,
accompanied by early cognitive decline.46 The constellation of complications is consistent
with a spectrum disorder in which migraine is an identifying feature of a subset of patients
with mild vascular dysfunction. On the basis of the clear association between transient
vascular occlusion and CSD, we suspect that transient occlusion within the microcirculation
that causes local hypoperfusion is the most likely trigger of CSD in susceptible individuals.
In studies in patients with CADASIL, reduced blood flow and low mean regional cerebral
metabolic rate for glucose were reported for the young adult patients.47 Hence, fluctuations
in the mean arterial blood pressure, normally compensated for by autoregulatory
mechanisms at the microcirculation level, might cause focal hypoperfusion and episodes of
compromised blood flow in the presence of reduced vascular compliance. Strokes are the
identifying feature for the severe end of the ischaemic continuum, whereas transient
ischaemic attacks and perhaps silent small infarcts indicate an intermediary stage.

Lending support to the idea that vascular dysfunction might underlie diverse clinical
phenotypes, patients with CADASIL have reduced cerebral vasoreactivity to carbon dioxide
inhalation,48 as well as impaired postocclusive hyperaemia in the skin.49 Similarly, mice
that express human mutations in Notch3 (Arg90Cys) have abnormal myogenic responses,
including constriction and dilation of cerebral and systemic vessels,50 and have significantly
larger brain infarcts after middle cerebral artery occlusion compared with mice without these
mutations,51 suggesting a deficit in compensatory mechanisms such as collateral blood flow.
As noted above, the mechanism(s) linking mutations in vascular smooth muscle cells and
CSD is poorly understood. In addition to a transient perfusion abnormality similar to the
complications of microembolisation, migraine aura or CSD could indicate dysfunction of the
neurovascular unit, a concept that emphasises the importance of cell-cell signalling between
component cells of the blood vessel wall, astrocytes, neurons, and the brain matrix.8
Astrocytic foot processes surround small brain vessels and can affect vascular smooth
muscle and regulate blood flow. These foot processes also provide spatial buffering of
potassium and promote glutamate uptake—two key players in the generation of CSD.
Precisely how the neurovascular unit is affected by NOTCH3 mutations in vascular smooth
muscle or other vascular disorders implicated in migraine aura pathogenesis needs further
study. Of interest, genetically engineered mice that overexpress the Arg90Cys mutation have
a lower threshold for evoking CSD than wild-type mice, consistent with a migraine aura
phenotype.52
Migraine is also associated with less frequent vascular syndromes, including the rare
angiopathy due to mutations in collagen type IV alpha-1 chain (Col4A1) and the three prime
repair exonuclease 1 (TREX1). Col4A1 is an essential component of the basal membrane.
TREX1 is a 3′→5′ DNA exonuclease and mutations in this protein might cause autosomal
dominant retinal vasculopathy with cerebral leukodystrophy (ADRVCL).53 Not unlike
patients with CADASIL, patients with hereditary vascular retinopathy can also have
migraine, cerebral infarcts, vascular dementia, and Raynaud’s phenomenon as shown in a
Dutch pedigree.54 Together, these genetic disorders strongly implicate neurovascular
dysfunction in migraine pathophysiology, particularly in the early events that precede
headache onset.
A strong association between migraine and some acquired vascular disorders is suggested by
epidemiological data. For example, migraine is diagnosed in 46% of patients with primary
Sjögren’s syndrome.55 An increased prevalence of migraine was found in patients with
Raynaud’s phenomenon (odds ratio 5·4; 95% CI 2·8–10·3).56 Chest pain was more common
in patients with Raynaud’s phenomenon who had coexisting migraine than in those without
coexisting migraine. Interestingly, migraine and Raynaud’s phenomenon are both reportedly
associated with endothelial cell dysfunction. In Japanese patients, the prevalence of

Raynaud’s phenomenon with vasospastic angina was higher than that reported from North
America, although the prevalence of migraine was the same, suggesting a genetic
component in the underlying vasculopathy.57 A history of migraine is reported to be
associated with vascular damage in the organs of patients with systemic lupus
erythematosus, lending support to the idea of an inherent vascular dysfunction in
migraineurs.58 Active migraine was associated with more severe disease activity, higher
concentrations of antiphospholipid antibodies, and worsening of Raynaud’s phenomenon.
Similarly, in a community-based prospective cohort of 15792 participants, Rose and
colleagues59 reported an increased incidence of retinopathy signs in individuals with
migraine and other headaches, lending support to the hypothesis that neurovascular
dysfunction might underlie some types of vascular headaches. These authors also reported
an association between migraine and exertional angina, although a direct correlation with
coronary artery disease was not identified.60 Consistent with these observations, an

increased incidence of migraine was reported in several vascular disorders (eg, moyamoya
disease,61 livedo reticularis,62 and preeclampsia63). An important role for immune factors
and inflammation is also suggested in some diseases noted above by links between migraine
and Sjögren’s syndrome, systemic lupus erythematosus, Raynaud’s phenomenon, and

evidence of endothelium dysfunction and its effect on the brain microcirculation. Taken
together, these findings lend support to the idea that migraine might share a common
pathophysiological mechanism with these vascular disorders, although whether there is an
association with migraine with aura requires further clarification.
In view of these findings, it might be possible someday to classify migraine vascular triggers
according to whether blood vessel dysfunction is caused by release of vasoactive substances,
disturbances in myogenic responses, or endothelial-dependent relaxation, by
hypercoagulable states, inflammation, platelet and white blood cellendothelial interactions,
or by a combination of the above.
Platelets, coagulation disorders, endothelial dysfunction, inflammation,

and migraine
Although insuffcient, some evidence from small, unvalidated clinical studies lends some
support to a possible association between platelet and coagulation disorders and migraine, as
well as between migraine and endothelial dysfunction.64 However, most of these early
studies were done on small samples with mostly unreliable and questionable methods that
are now not considered appropriate. In a recent study, patients with migraine had
significantly more platelet-leukocyte aggregates in their serum compared with controls.5
Thrombocytosis might have been implicated in attacks of migraine aura in patients with
polycythemia vera.65
Endothelial dysfunction might predispose individuals to ischaemic stroke and coronary

disease, possibly by impairing vascular reactivity or by promoting platelet activation and
enhancing the inflammatory process. We believe that the evidence for migraine is
incomplete at present. Antiphospholipid antibodies might increase risk of clotting or might
serve as a marker of endothelial perturbation, but are probably not causally associated with
migraine.66,67 Impaired endothelium-dependent relaxation of the cerebral and systemic
arteries has nevertheless been reported in migraineurs.68 Concentrations of von Willebrand
factor antigen activity levels, accepted biomarkers of endothelial dysfunction, are reportedly
increased between attacks in patients with migraine and are particularly high in migraineurs
with a history of livedo reticularis, a cutaneous marker of endothelial damage.69
Concentrations of von Willebrand factor are also reportedly increased during a migraine
attack.70 Additionally, migraineurs have decreased concentrations of circulating endothelial
progenitor cells, a non-specific marker of vascular function that is inversely associated with
the risk for cardiovascular disease.71 Lending support to the possibility of endothelial
dysfunction in migraineurs, forearm blood flow responses were impaired in response to the
cerebral vasodilators acetylcholine and sodium nitroprusside, indicating dysfunction at the
vascular smooth muscle level.72 Genetic susceptibility to endothelial dysfunction, such as a
deletion poly morphism in the angiotensin-converting enzyme gene (ACE-DD genotype) or
the methylenetetrahydrofolate reductase C677-TT polymorphism, have been associated with
migraine in some, but not all, studies73 and these mutations might increase the risk of
ischaemic stroke in patients with migraine aura. Finally, Dreier and colleagues20 have
implicated endothelin, the endothelium-derived peptide that causes powerful
vasoconstriction, in a proposed model of migraine by showing that local peptide infusion
causes CSD as well as brain microinfarcts.

Migraine as a risk factor for ischaemic cerebrovascular disorders

Migraine with aura has been consistently identified as an independent risk factor for
ischaemic stroke.6,74–78 Several potential mechanisms have been hypothesised, including
alterations in vasoreactivity and cerebral blood flow due to vessel wall dysfunction, release
of vasoactive substances such as prostaglandins and endothelins, and, as discussed above,
platelet hyperactivity and paradoxical embolism through a cardiac or extracardiac shunt. We
presume that focal areas of hypoperfusion trigger CSD as an underlying mechanism for
some of the attacks in patients with migraine aura (figure 3). It is likely that the brains of
patients with migraine with aura are particularly prone to generating CSD after such
perturbations, and the experimental model that has been proposed by Dreier and colleagues
supports this possibility.20 Possibly related is the observation that posterior circulation silent
microinfarcts occur with greater frequency in young patients,79 suggesting a cardiac source
for embolism.80 Kruit and colleagues81 reported MRI evidence of posterior circulation
territory microinfarcts in patients with migraine with aura (13 of 161; 8·1%), whereas the
occurrence was significantly smaller in patients with migraine without aura (three of 134;
2·2%) or controls (one of 140; 0·7%). A high number of migraine attacks predisposed
individuals to ischaemic lesions, as patients who had more than one attack per month
reportedly had the highest risk for posterior circulation territory infarcts (odds ratio 15·8).
Nevertheless, cardiovascular risk factors were not more prevalent in migraineurs, although
PFO was not specifically studied in this cohort of patients.
The small size and territorial distribution of these microinfarcts provide information about
their potential source and pathophysiology. In a systematic analysis of the topographical
details of these parenchymal defects, Kruit and colleagues82 found that more than 90% of
the infarct-like lesions were located in the deep arterial border zone areas of the cerebellum.
If implicated, CSD might directly decrease the cerebral perfusion pressure and blood flow
and increase the ischaemic burden by slowing the clearance of occluding particles.
Additional mechanisms noted above might also contribute, including the release of
procoagulant factors and enhanced susceptibility to platelet aggregation,70,83 decreased
endothelium-dependent relaxation,84 and increased oxidative stress and inflammation of the
vessel wall.5
Consistent with these observations, a recent publication by Scher and colleagues85

documented an increased risk of infarct-like lesions in women who had reported migraine
with aura earlier during their life (odds ratio 1·4). Similarly, Kurth and colleagues86 reported
a significantly increased risk for ischaemic stroke in women with active migraine aura.
Specifically, in a large prospective cohort of women aged more than 45 years, these
investigators found a greater than fourfold increase in the risk for ischaemic stroke in
individuals with active migraine with aura if the frequency of migraine attacks exceeded
once per week. Interestingly, the authors also reported an association between migraine and
major cardiovascular events, although the strength and direction of this association seemed
to vary with migraine frequency.
Search strategy and selection criteria

References for this Personal View were identified through searches of PubMed with the
search terms “migraine”, “cortical spreading depression”, “cerebrovascular”,
“cardiovascular”, “patent foramen ovale”, and “pathophysiology” in combination with
“stroke”, “ischemia”, “coagulation”, “hypoxia”, “CADASIL”, “white matter lesions”,
“carotid puncture”, “cholesterol”, “atherosclerosis”, “dissection”, “Raynaud”, “Sjögren’s
syndrome”, “SLE”, and “antiphospholipid antibody”. Preference was given to papers
published between January, 2000, and November, 2009. Only papers published in

English were reviewed in detail. The final reference list was selected on the basis of
relevance to the topics covered in this paper.
Conclusions
Although an increasing amount of evidence lends support to an association between
migraine with aura and ischaemic cerebrovascular disorders, a causative relationship is
diffcult to prove and a coherent vascular aetiology is unlikely to account for the triggering of
all types of migraine with aura. Nevertheless, the multitude of clinical observations, as well
as recent experimental data, suggest a common pathophysiology for these disorders, and
indicate that, at least in a subset of patients of underdetermined size, migraine aura exists on
a continuum of hypoperfusion disorders that includes transient ischaemic attacks and
cerebral infarcts. According to this view, brief periods of hypoperfusion, a final common
event for CSD initiation, develop as a consequence of local endothelial or smooth muscle
dysfunction together with changes in circulating blood elements, or develop as a
downstream complication of events that originate within larger blood vessels (figure 4). As
we begin to acquire new knowledge about the regulation of the microcirculation during
health and disease, and begin to understand the full effect of how perturbations in
microvasculature and neurovascular units modulate brain function in human beings, we will
better understand one important trigger for migraine aura.
Acknowledgments
Some of the studies cited in this paper were supported by a National Institute of Neurological Disorders and Stroke
grant NS35611 (MAM).
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Figure 1. CSD and factors involved in the initiation of vascularly triggered migraine aura
CSD has a fundamental role in the genesis of migraine aura. Susceptibility to CSD is
conferred by genes and modulated by hormones (ovarian and testicular) as well as by drugs
that suppress CSD and prevent migraine attacks. Recently identified vascular triggers
initiate CSD by causing transient, mild, and focal hypoperfusion, as determined
experimentally. CSD=cortical spreading depression.

Figure 2. Association between CSD and CBF

After microemboli were injected into a rodent carotid artery, CSD occurrence was
associated with the extent of CBF perturbation. (A) The time course of transient oligaemia
after microembolisation (shown at point 1), followed by a gradual increase until CSD
occurrence (shown at point 2). The shaded area (AUC) shows the ischaemic burden, a
measure of depth and duration of oligaemia, from point 1 to point 2 or until CBF returned to
baseline. (B) AUC values for individual animals with or without CSD show that the
ischaemic burden (AUC) was greater in animals with CSD than in those without CSD.
Evidence of cell or tissue damage was present in only a few animals with CSD. The shaded
area indicates the threshold above which CSD is likely to occur. Bars indicate median (25–

75% range). *Significant difference between animals with and without CSD. Modified from
Nozari and colleagues,9 with permission from the American Neurological Association.
AUC=area under the curve. CBF=cerebral blood flow. CSD=cortical spreading depression.

Figure 3. The risk of developing CSD after microembolisation partly depends on the location,
size, and duration of vascular occlusion
Although some microemboli can traverse the brain microcirculation without
pathophysiological consequence (A), other microemboli can transiently occlude the
circulation to a critical volume of tissue to initiate CSD (B) followed by recovery; more
prolonged occlusion (C) will cause tissue microinfarction. CSD=cortical spreading
depression.

Figure 4. Cerebral blood vessels are important for the triggering of cortical spreading depression
and the pathophysiology of migraine aura
We propose that in patients with patent foramen ovale, brief periods of local and mild
hypoperfusion develop as a consequence of microemboli arising from the venous
circulation, or might develop in other conditions in response to injury to the vessel wall,
local release of vasoactive substances, increased blood viscosity, circulating immune
complexes, endothelial dysfunction, enhanced platelet-endothelial interaction, or platelet-
leucocyte interaction among other mechanisms. The potentially important astrocytes and
other components of the neurovascular unit are not depicted.

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Lancet Neurol. 2010 March ; 9(3): 309–317. doi:10.1016/S1474-4422(09)70358-8.

Migraine aura pathophysiology: the role of blood vessels and

Turgay Dalkara, MD, Ala Nozari, MD, and Michael A Moskowitz, MD

cerebrovascular disorders. A unifying pathophysiological explanation linking migraine to these

Migraine aura and CSD

In addition to intrinsic brain parenchymal mechanisms, as noted above, CSD is sometimes

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

of ischaemia.25 Hence, CSD develops as a consequence of mild and transient hypoxic-

Migraine and cerebral microembolism

Panel: Some comorbidities of migraine with aura

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

AD-RVCL=autosomal dominant retinal vasculopathy and cerebral leukodystrophy.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Susceptibility to migraine aura of vascular origin

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

associated with endothelial cell dysfunction. In Japanese patients, the prevalence of

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

and Sjögren’s syndrome, systemic lupus erythematosus, Raynaud’s phenomenon, and

Platelets, coagulation disorders, endothelial dysfunction, inflammation,

Endothelial dysfunction might predispose individuals to ischaemic stroke and coronary

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Migraine as a risk factor for ischaemic cerebrovascular disorders

Consistent with these observations, a recent publication by Scher and colleagues85

Search strategy and selection criteria

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

in acutely injured human cerebral cortex. Brain 2006;129:778–90. [PubMed: 16364954]

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

52. Eikermann-Haerter K, Wang Y, Dilekoz E, et al. Increased susceptibility to cortical spreading

TREX1 in human disease. Cell Cycle 2008;7:1718–25. [PubMed: 18583934]

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Figure 2. Association between CSD and CBF

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

Lancet Neurol. Author manuscript; available in PMC 2010 August 16.

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