doi:10.

1093/brain/awh542 Brain (2005), 128, 20682077

Infarcts in the posterior circulation territory
in migraine. The population-based MRI
CAMERA study
Mark C. Kruit,
1
Lenore J. Launer,
3,4
Michel D. Ferrari
2
and Mark A. van Buchem
1
Departments of
1
Radiology and
2
Neurology, Leiden University Medical Center, Leiden,
3
Department of Chronic Disease
and Environmental Epidemiology, National Institute of Public Health and the Environment, Bilthoven, The Netherlands
and
4
Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health,
Bethesda, MD, USA
Correspondence to: M. C. Kruit MD, Department of Radiology, Leiden University Medical Centre, PO Box 9600,
2300 RC Leiden, The Netherlands
E-mail: m.c.kruit@lumc.nl
In a previous study, migraine cases from the general population were found to be at signicantly increased risk
of silent infarct-like lesions in the posterior circulation (PC) territory of the brain, notably in the cerebellum. In
this study we describe the clinical and neuroimaging characteristics of migraine cases with and without aura and
controls with PC lesions. In total, 39 PC infarct-like lesions represented the majority (65%) of all 60 identied
brain infarct-like lesions in the study sample (n = 435 subjects with and without migraine). Most lesions (n = 33)
were located in the cerebellum, often multiple, and were round or oval-shaped, with a mean size of 7 mm. The
majority (88%) of infratentorial infarct-like lesions had a vascular border zone location in the cerebellum.
Prevalence of these border zone lesions differed between controls (0.7%), cases with migraine without aura
(2.2%) and cases with migraine with aura (7.5%). Besides higher age, cardiovascular risk factors were not more
prevalent in cases with migraine with PC lesions. Presence of these lesions was not associated with supra-
tentorial brain changes, such as white matter lesions. The combination of vascular distribution, deep border
zone location, shape, size and imaging characteristics on MRI makes it likely that the lesions have an infarct
origin. Previous investigators attributed cases of similar very small cerebellar infarcts in non-migraine patients
to a number of different infarct mechanisms. The relevance and likelihood of the aetiological options are placed
in the context of known migraine pathophysiology. In addition, the specic involvement of the cerebellum in
migraine is discussed. The results suggest that a combination of (possibly migraine attack-related) hypoper-
fusion and embolism is the likeliest mechanism for PC infarction in migraine, and not atherosclerosis or
small-vessel disease.
Keywords: migraine; magnetic resonance imaging; brain infarction; posterior circulation; cerebellum
Abbreviations: AICA = anterior inferior cerebellar artery; DWML = deep white matter lesion; MA = migraine with aura;
MO = migraine without aura; PC = posterior circulation; PICA = posterior inferior cerebellar artery;
PVWML = periventricular white matter lesion; SCA = superior cerebellar artery
Received January 31, 2005. Revised April 13, 2005. Accepted April 20, 2005. Advance Access publication July 8, 2005
Introduction
Migraine is a prevalent, chronic, multifactorial neurovascular
disorder characterized by recurrent attacks of debilitating
headache and autonomic nervous system dysfunction
(migraine without aura; MO); up to one-third of patients
also have neurological aura symptoms (migraine with aura;
MA) (Ferrari, 1998; Headache Classication Committee of
the International Headache Society, 1988). Migraine is
commonly thought to be acutely disabling during attacks,
without long-term consequences on the brain. However,
we found in our population-based CAMERA study (n = 435)
that migraine cases had a signicantly higher prevalence of
white matter hyperintense lesions and cerebellar infarct-like
# The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

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lesions (Kruit et al., 2004). Traditional cardiovascular risk
factors and specic antimigraine medication did not modify
the association between the structural brain changes and
migraine.
In total, 8.1% of 161 cases with MA compared with 2.2% of
134 cases with MO and 0.7% of 140 controls (P = 0.05) had
one or more lesions in the cerebellar region of the posterior
circulation (PC) territory of the brain (Kruit et al., 2004).
The highest risk was in participants with MA with at least
1 attack per month (odds ratio 15.8, 95% condence interval
1.8140), compared with controls. These cerebellar lesions
appear as infarcts on MRIs, although none of the patients
had a clinical history of stroke. Clinical infarcts in patients
with migraine were previously suggested (in some clinically-
based studies) to be over-represented in the PC territory,
notably in the occipital lobes, but not infratentorially
(Featherstone, 1986; Broderick and Swanson, 1987;
Bogousslavsky et al., 1988; Rothrock et al., 1988; Shuaib
and Lee, 1988; Sacquegna et al., 1989; Caplan, 1991;
Hoekstra-van Dalen et al., 1996; Milhaud et al., 2001). Reports
that detail the location, size and regional distribution patterns
of such infarcts in patients with migraine are lacking. Also,
little is known about the aetiology of these brain lesions.
Here we describe the clinical and neuroimaging character-
istics of cases from the CAMERA study with PC lesions, relate
these to what is known of migraine pathophysiology, and
provide evidence for an infarct origin of the identied
infarct-like lesions.
Methods
Study population
A complete description of the study population and methods has
been detailed elsewhere (Kruit et al., 2004). In brief, cases and con-
trols were randomly selected from the Genetic Epidemiology of
Migraine (GEM) study, a population-based survey of 6491 Dutch
adults aged 2060 years living in two representative Dutch muni-
cipalities (Maastricht and Doetinchem). With this procedure we
identied 863 cases of migraine according to International Headache
Society criteria; 54% of the cases had not been previously diagnosed
by a physician (Launer et al., 1999). For the Cerebral Abnormalities
in Migraine, an Epidemiological Risk Analysis (CAMERA) study,
two diagnostic groups (cases with migraine with aura and without
aura) were randomly selected from the earlier population-based
survey cases aged 3060 years; the control group was randomly
selected from the cohort to frequency-match the cases by sex, muni-
cipality and 5-year age strata. The study protocol was approved by
the ethics committee of the Leiden University Medical Center and
included a structured telephone interview and a clinic visit for a
brain MRI study, drawing of blood, and a standard physical and
neurological examination. A complete protocol was performed
in 435 participants (69% overall response): 134 MO, 161 MA and
140 controls. All participants gave written informed consent and
participated without any nancial reimbursement. The clinic visits
took place within 10 days of the telephone interview; patients
with migraine underwent examinations in a headache-free period
(3 days after a migraine attack).
Assessment of confounders, covariates and
migraine characteristics
Sociodemographic, medical and migraine characteristics were
assessed by interview. Education was categorized into low (primary
school or lower vocational education) and high. Smoking history was
dened as never, former and current, and, for ever-smokers, pack-
years of exposure. The average alcohol intake in the past year was
based on responses to questions on frequency and quantity of drinks
per occasion and categorized into none, moderate (13 drinks per
day) and high (3 drinks per day). Women reported the number of
years they had used oral contraceptives. Self-reported weight and
height were used to calculate body mass index (weight in kilograms
divided by the square of height in meters). Blood pressure was
the mean of three measurements obtained at 1-min intervals in
the upper arm with an electronic oscillometric blood pressure
monitor (Omron 711; Omron Healthcare Europe, Hoofddorp, the
Netherlands). Hypertension was dened as a systolic blood pressure
of 160 mmHg and higher or a diastolic blood pressure of 95 mmHg
and higher or current use of antihypertensive drugs. A measure of
total cholesterol was available from the baseline examination (Boer
et al., 1998). As previously detailed, migraine cases estimated head-
ache and aura attack frequency, and the frequency and amount of
specic antimigraine medication (ergotamines, triptans) they used in
the years they had migraine attacks (Kruit et al., 2004).
MRI
Brain MRIs were acquired on a 1.5-T unit in Maastricht (ACS-NT;
Philips Medical Systems, Best, The Netherlands) and a 1.0-T unit in
Doetinchem (Magnetom Harmony; Siemens, Erlangen, Germany).
Protocols in the two centres were comparable. Whole brain images
were acquired with 48 contiguous 3-mm axial slices (eld of view
22 cm, matrix 190205 256). Pulse sequences included a combined
proton density and T2-weighted fast spin-echo sequence [ACS-NT,
3000/27120/1/10; Magnetom Harmony, 3000/1485/2/5; relax-
ation time(ms)echo time(ms)excitations(number)/echo train length
(number; inversion time(ms))] and uid-attenuated inversion-
recovery sequence (ACS-NT: 8000/100/2000/2/19; Magnetom
Harmony, 8000/105/2000/2/7; relaxation time/echo time/inversion
time/excitations/echo train length).
One neuroradiologist (M.A.v.B.), who was blinded to migraine
diagnosis and clinical data, rated white matter lesions and infarct-like
lesions on hard copies. A complete description of the white matter
lesion rating methods has been given previously (Kruit et al., 2004).
Infarct-like lesions were dened as non-mass parenchymal defects,
witha vascular distribution, isointense tocerebrospinal uidsignal on
all sequences, and, when supratentorial, surrounded by a hyperin-
tense rim on uid-attenuated inversion-recovery and proton density
images. In total, 60 brain infarct-like lesions were detected in 31
individuals. The location and size of these lesions were recorded.
Supratentorially, VirchowRobin spaces were discriminated from
infarct-like lesions, based on location, shape, size and absence of
a hyperintense border on proton density and uid-attenuated
inversion-recovery images (Bokura et al., 1998; Song et al., 2000).
The topography and corresponding dominant arterial territory of
the identied infarct-like lesions were determined according to the
maps by Tatu and colleagues (Tatu et al., 1996, 1998). The PC
territory included all brainstem and cerebellar branches of the
vertebral and basilar arteries, and the posterior cerebral arteries
and their branches. The infratentorial PC infarct-like lesions were
further subclassied as either territorial or junctional (= border zone)
Posterior circulation lesions in migraine Brain (2005), 128, 20682077 2069

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according to previously published criteria (Amarenco, 1991;
Amarenco et al., 1993; Barth et al., 1993; Canaple and Bogousslavsky,
1999). In the assessment of infratentorial PC territory lesions the
following procedure was applied to minimize any form of potential
classication bias. First, the indications of the arterial (sub)territories
were dened in a diagram of the cerebellum and brainstem (Fig. 1,
coloured areas) (Amarenco, 1991; Tatu et al., 1996). Secondly, the
position, shape and size of an infratentorial PC lesion was copied
from hard copy onto a diagram of the cerebellum and brainstem
without the coloured vascular territories (Fig. 1, black lines). This
was repeated for each individual lesion in a separate (empty)
diagram. Thirdly, all separate drawings were superimposed over
the previously dened indications of the arterial (sub)territories
(Fig. 1). Thereafter, each infarct-like lesion was classied as either
territorial or junctional (= border zone). Territorial lesions occupied
the territory of the posterior inferior cerebellar artery (PICA), the
medial branch of the PICA (mPICA), the lateral branch of the PICA
(lPICA), the territory of the superior cerebellar artery (SCA), the
medial branch of the SCA (mSCA), the lateral branch of the SCA
(lSCA) or the territory of the anterior inferior cerebellar artery
(AICA). Junctional lesions were located at the boundary region
(dened as 5 mm from the indicated border in the template)
between two arterial territories.
Statistics
The x
2
test, the unpaired t-test and analysis of variance controlling
for age and sex were used to test for differences in the distributions
and means of measured characteristics among the study groups.
Analyses were conducted with SPSS statistical software (version
10.0.5; SPSS, Chicago, IL, USA).
Results
Table 1 shows data on the prevalence, characteristics and
distribution of the 39 infarct-like lesions identied in the
PC territory. These PC infarct-like lesions represent the
majority (65%) of all 60 identied infarct-like lesions in
the whole brain in the study sample. The percentage of the
PC lesions differed between the diagnostic groups: 81% of all
infarct-like lesions in MAwere in the PCterritory, 47%in MO
and 44% in controls. In cases with migraine, most PC infarct-
like lesions were located infratentorially: 96% of PC lesions
in MA and 89% in MO; among the four controls with PC
infarct-like lesions, only one subject had an infratentorial
lesion. Of the 39 PC infarct-like lesions, 33 were located in
the cerebellum (one in a control, eight in three MO, 24 in
13 MA), one in the pons (in an MA) and ve in the thalamus
(three in three controls, one in an MO and one in an MA).
Besides the thalamic infarct-like lesions, no other infarct-like
lesions were identied supratentorially in the posterior cir-
culation territory. The mean diameter of the PC infarct-like
lesions was 7.1 mm, ranging between 2 and 21 mm, and 69%
were located on the right side. The average number of lesions
per subject was 1.8. Lesion sizes and number of lesions per
subject did not differ between the diagnostic groups.
Infratentorial PC infarct-like lesions were subclassied as
either territorial or junctional, as dened previously. Of the 34
infratentorial PC lesions, 30 were classied as junctional. In
MA, 92% of the infratentorial lesions were junctional, 75% in
MO; the only infratentorial lesion in the one control was

l SCA
m SCA
AICA
l PICA
m PICA
Fig. 1 Infratentorial posterior circulation (PC) infarct-like lesions in the cerebellum (n = 33) superimposed over diagram with arterial
territories indicated: the CAMERA study. The size and position of all cerebellar PC infarct-like lesions were copied from hard copy into
the vascular territories template. Territories are supplied by the posterior inferior cerebellar artery (PICA), the medial branch of the PICA
(m PICA), the lateral branch of the PICA (l PICA), the territory of the superior cerebellar artery (SCA), the medial branch of SCA (m SCA),
the lateral branch of SCA (l SCA) or the territory of the anterior inferior cerebellar artery (AICA). Left-sided lesions (coloured red) are
mirrored to the right hemisphere for presentation purposes.
2070 Brain (2005), 128, 20682077 M. C. Kruit et al.

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also junctional. The mPICAmSCA border zone (37% of all
junctional infarct-like lesions; in seven of 16 subjects with
junctional infarct-like lesions) and the lSCAmSCA border
zone (33% of all junctional lesions; in eight of 16 subjects with
junctional lesions) were mostly involved. These distributions
over the separate border zones did not differ between the
diagnostic groups. In Fig. 1, all infratentorial PC infarct-
like lesions are superimposed over the respective arterial
territories of the cerebellar hemispheres. Most lesions were
round or oval in shape and more or less clustered in the
border zones. Orientation of the junctional infarct-like lesions
was mostly along the border between the respective territories.
One infarct-like lesion involved a part of the local cerebellar
cortex, but all other lesions were located in the deep cerebellar
regions. Figure 2 shows four examples of representative cases
with infratentorial PC (cerebellar) infarct-like lesions.
Table 2 lists sociodemographic and migraine characteristics
and other structural brain damage variables of the subjects
with PC infarct-like lesions. Information is provided on the
size, side and location of the separate infarct-like lesions, as
well as on concurrent infarct-like lesions located outside the
PC territory (e.g. anterior/carotid circulation). The presence
of a high load of periventricular white matter lesions (high
PVWML load) and/or a high load of deep white matter lesions
(high DWML load) is indicated for each subject. Eleven
subjects had more than one infarct-like lesion (multiple
infarct-like lesions; 59% of the migraine cases and 25% of
the controls). Multiple PC lesions were identied exclusively
in cases with migraine; in these seven cases, more than one
separate border zone was involved. Although the prevalence
of a high DWML load was greater in subjects with PC lesions,
this difference was not conrmed in subanalysis for migraine
patients separately.
Subjects with infarct-like lesions in the PC territory were
signicantly older, and had signicantly higher cholesterol
levels (both in crude data, and after adjusting for age and
sex; Table 3). However, differences in cholesterol level did not
remain statistically signicant in the subanalysis among the
cases with migraine. Other cardiovascular risk factors were
not more prevalent among those with PC infarct-like lesions.
The number of cases with PClesions was too small to compare
the prevalence of cardiovascular risk factors between migraine
cases and controls. Cases with migraine with PC lesions
tended to have a higher attack frequency, and had previously
consulted a physician for their migraine signicantly more
often (Table 4). Other migraine characteristics did not differ
between those with and without PC infarct-like lesions.
Discussion
In a previous population-based study, we found migraine to
be a signicant risk factor for PC infarct-like lesions, notably
in cases with migraine with aura. In the current study, the
Table 1 Prevalence and characteristics of posterior circulation (PC) infarct-like lesions (ILL): the CAMERA study
All Controls Migraine without aura Migraine with aura Signicance
(n = 435) (n = 140) (n = 134) (n = 161)
PC infarct-like lesions
Total number of PC ILL (% of all brain ILL) 39 (65%) 4 (44%) 9 (47%) 26 (81%) *
Subjects with 1 PC ILL (% of all participants) 21 (4.8%) 4 (2.9%) 4 (3.0%) 13 (8.1%) *
Location of PC infarct-like lesions (n = 39)
Supratentorial (e.g. occipital lobe, thalamus)
Total number (% of all PC ILL) 5 (13%) 3 (75%) 1 (11%) 1 (4%)
Subjects with 1 ILL of this type 5 (1.1%) 3 (2.1%) 1 (0.7%) 1 (0.6%)
Infratentorial
Total number (% of all PC ILL) 34 (87%) 1 (25%) 8 (89%) 25 (96%)
Subjects with 1 ILL of this type 17 (3.9%) 1 (0.7%) 3 (2.2%) 13 (8.1%)
Location of infratentorial ILL (n = 34)
Junctional/border zone
Total number (% of infratent. ILL) 30 (88%) 1 (100%) 6 (75%) 23 (92%)
Subjects with 1 ILL of this type 16 (3.7%) 1 (0.7%) 3 (2.2%) 12 (7.5%)
Territorial
Total number (% of infratent. ILL) 4 (12%) 2 (25%) 2 (8%)
Subjects with 1 ILL of this type 3 (0.7%) 1 (0.7%) 2 (1.2%)
Location of junctional ILL(n = 30)
lPICA-AICA border zone (% of junct. ILL) 4 (13%) 1 (17%) 3 (13%)
lPICA-mPICA border zone (% of junct. ILL) 3 (10%) 3 (13%)
lPICA-lSCA border zone (% of junct. ILL) 2 (7%) 2 (9%)
mPICA-mSCA border zone (% of junct. ILL) 11 (37%) 1 (100%) 2 (33%) 8 (35%)
lSCA-mSCA border zone (% of junct. ILL) 10 (33%) 3 (50%) 7 (30%)
Data are number of individuals (%) and number of infarct-like lesions (%). P values are from Pearsons x
2
test (unadjusted). mPICA = medial
branch of the posterior inferior cerebellar artery (PICA); lPICA = lateral branch of the PICA; mSCA = medial branch of the superior
cerebellar artery (SCA); lSCA = lateral branch of SCA; AICA = anterior inferior cerebellar artery. Unless stated otherwise, differences
were not statistically signicant.
*
P < 0.05;

P < 0.005.
Posterior circulation lesions in migraine Brain (2005), 128, 20682077 2071

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topographic details of these parenchymal defects were system-
atically characterized. All lesions fullled MRI criteria for
infarcts; therefore, we refer to these lesions in the text as
infarct-like lesions. Most pronounced were ndings in
MA: over 80% of all infarct-like lesions were located in the
PC territory areas, and over 90% of these were located in the
(deep) arterial border zone areas of the cerebellum. All PC
lesions were small, and often multiple PC infarct-like lesions

Case 21
Case 18
Case 9
Case 5
Fig. 2 Cerebellar infarct-like lesions: the CAMERA study. Corresponding T2-weighted (left) and uid-attenuated inversion-recovery images
(right) showing (multiple) cerebellar infarct-like lesions (arrows) in four representative cases (numbers refer to case numbers in Table 2).
2072 Brain (2005), 128, 20682077 M. C. Kruit et al.

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Posterior circulation lesions in migraine Brain (2005), 128, 20682077 2073

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were identied in a single subject. No previous studies repor-
ted on the prevalence and size of cerebellar infarct-like lesions
in migraine, and although a small number of clinicopatho-
logical and clinicoradiological studies report on small cere-
bellar infarcts, in none of these studies was migraine status
known or included in the analyses (Amarenco et al., 1990,
1993, 1994; Amarenco, 1991; Barth et al., 1993; Canaple and
Bogousslavsky, 1999). However, the very small cerebellar
lesions identied in our sample have diameters (220 mm),
shapes and typical border zone locations similar to those of
the small cerebellar infarcts reported in these previous studies.
Border zone infarction is probably best explained by invok-
ing a combination of low ow and embolism: a decrease in
cerebral perfusion pressure and associated changes in the
cerebral haemodynamics affects the clearance and destination
of embolic particles; narrowing of the arterial lumen and
intimal and endothelial abnormalities stimulate formation
of thrombi; occlusive thrombi further reduce blood ow
and brain perfusion (Caplan and Hennerici, 1998). Because
the deep cerebellar territories have a pattern of progressively
tapering arteries with only few anastomoses present, they are
likely to be particularly vulnerable to hypoperfusion-related
border zone infarct mechanisms (Duvernoy et al., 1983;
Fessatidis et al., 1993). The prevalent involvement of SCA
watershed zones might be explained by a longer course of
SCA branches compared with PICA and AICA branches
(Duvernoy et al., 1983). This hypoperfusion-related concept
matches the ndings of previous studies in which the small
cerebellar border zone infarcts, in particular when multiple,
were strongly associated with severe occlusive and/or (artery-
to-artery) embolic disease based on vertebrobasilar athero-
sclerosis, likely to result in hypoperfusion and infarction
(Amarenco et al., 1993, 1994; Barth et al., 1993; Canaple
and Bogousslavsky, 1999). Non-border zone territorial
infarcts were suggested to result from coagulopathy, arteritis
and microembolism, due to involvement of small distal arter-
ies (Canaple and Bogousslavsky, 1999). Since we found very
small territorial infarct-like lesions (n = 3) only in a minority
of cases, this suggests that focal hypoperfusion rather than
microembolic occlusion is responsible for the observed
cerebellar lesions in migraine.
During and after migraine attacks, sluggish low cerebral
ow below an ischaemic threshold has been described (Olesen
et al., 1990; Friberg et al., 1994; Woods et al., 1994; Bednarczyk
Table 3 Age- and sex-adjusted characteristics of subjects with and without posterior circulation infarct-like lesions
(PC ILL): the CAMERA study
Characteristic Total Migraine cases Controls
PC ILL PC ILL PC ILL
No Yes No Yes No Yes
(n = 414) (n = 21) (n = 278) (n = 17) (n = 136) (n = 4)
Sociodemographic
Mean age (years) 48.0 (0.4) 54.9 (1.4)

48.2 (0.5) 53.6 (1.6)

47.7 (0.7) 60.5 (0.9)

Female 73% 65% 74% 65% 72% 63%

Low education

52% 50% 53% 41% 50% 91%

Clinical
Body mass index (kg/m
2
) 25.0 (0.2) 25.4 (0.9) 25.4 (0.3) 25.5 (1.0) 24.3 (0.3) 25.4 (1.9)
Blood pressure
Systolic (mm Hg) 134.5 (0.8) 130.1 (3.6) 134.3 (1.0) 131.3 (3.9) 135.0 (1.4) 129.5 (8.8)
Diastolic (mm Hg) 91.2 (0.5) 90.6 (2.2) 91.3 (0.6) 91.8 (2.4) 90.9 (0.8) 85.3 (4.9)
Hypertension 38% 39% 41% 45% 33% 15%
Cholesterol (mmol/l) 5.3 (0.04) 5.7 (0.2)
*
5.3 (0.1) 5.6 (0.2) 5.2 (0.1) 6.3 (0.4)
*
Diabetes 2.0% 2.9% 1.5% 0% 2.9% 28%
*
Smoking
Never 36% 37% 37% 40% 35% 27%
Pack years (among smokers) 10.2 (0.6) 8.4 (2.9) 9.9 (0.8) 5.7 (3.1) 11.0 (1.2) 19.6 (7.0)
Alcohol use
None 20% 23% 23% 23% 15% 25%
3 units/day 11% 0.4% 8% 2% 16% 0%
Oral contraceptive use (women only)
15 years OC use 24% 21% 25% 21% 24% 22%
Other brain damage
High PVWML load 9% 14% 10% 7% 7% 47%

High DWML load 19% 35% 22% 32% 15% 51%

*
Data are estimated mean (SE) or percentage of subjects, based on univariate analyses of variance, controlling for age and sex. Unless
stated otherwise, differences were not statistically signicant. P values are based on tests of the between-subjects effect. Low education =
primary school or lower vocational education; OC = oral contraceptive; DWML = deep white matter lesion; PVWML = periventricular
white matter lesion.
*
P < 0.05;

P < 0.005.
2074 Brain (2005), 128, 20682077 M. C. Kruit et al.

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et al., 1998; Cutrer et al., 1998; Sanchez del Rio et al., 1999).
Reductions of cerebral blood ow vary from a 7% to a 53%
decrease (Cutrer et al., 1998; Sanchez del Rio et al., 1999) and
persist from 1 h to more than 1 day (Bednarczyk et al., 1998).
This is probably the result of the effects of cortical spreading
depression, which has been implicated as the generator of
migraine aura (Moskowitz et al., 2004), and can also occur
in the cerebellum (Ebner and Chen, 2003). Cortical spreading
depression (indirectly) alters bloodbrain barrier permeabil-
ity, which might lead to exacerbation of local cellular injury
caused by ischaemia. Together with factors predisposing to
coagulopathy (Couch and Hassanein, 1977; Silvestrini et al.,
1994; Cesar et al., 1995; DAndrea et al., 1995; Tozzi-
Ciancarelli et al., 1997; Tietjen et al., 2001; Salobir et al.,
2002) and release of local vasoactive neuropeptides
(Edvinsson and Goadsby, 1995; Hargreaves and Shepheard,
1999; Tzourio et al., 2001), this could result in further changes
in cerebral haemodynamics, arterial thrombosis and infarc-
tion (Milhaud et al., 2001). An impairment in the adaptive
cerebral haemodynamic mechanisms in the posterior circu-
lation in migraine patients with aura might be part of the
underlying mechanisms between migraine and brain infarcts
(Silvestrini et al., 2004).
Although migraine-related clinical strokes are reported
to occur most often supratentorially, in the occipital lobes
(Featherstone, 1986; Broderick and Swanson, 1987;
Bogousslavsky et al., 1988; Rothrock et al., 1988; Shuaib and
Lee, 1988; Sacquegna et al., 1989; Caplan, 1991; Hoekstra-van
Dalen et al., 1996; Milhaud et al., 2001), we did not nd any
infarct-like lesions in these areas of the posterior circulation.
This difference between clinically manifest supratentorial
infarcts and subclinical or silent infratentorial infarcts might
be explained by an overall lower prevalence of occipital lobe
infarcts compared with cerebellar infarcts in migraine cases,
and the assumption that occipital infarcts are far less likely to
remain clinically silent. The only supratentorial PC infarct-
like lesions we identied were located in the thalamus: in three
controls and two patients with migraine (concerning 75% of
all PC infarct-like lesions in controls and only 5% in patients
with migraine). Data about subclinical thalamic infarcts in
migraine are lacking, but clinically manifest thalamic infarcts
in migraine have been reported to be signicantly more pre-
valent in younger migraine cases compared with controls
(14 versus 6%) (Milhaud et al., 2001).
Results from a number of studies suggest that the cerebel-
lum plays a role in migraine pathophysiology. In common
forms of migraine, (subclinical) cerebellar dysfunction has
been reported (Sandor et al., 2001; Harno et al., 2003).
Although it remains unknown whether structural lesions
caused the cerebellar dysfunction in these studies, it raises
the question of whether more advanced functional tests
could have identied subclinical cerebellar dysfunction in
our cases. Cerebellar abnormalities (such as cerebellar
atrophy, decreased cerebellar blood ow, and cerebellar dys-
function) have also been described in several cases of familial
hemiplegic migraine. Mutations of the P/Q-type Ca
2+
channel
a1 subunit gene (CACNA1A) responsible for at least 50%of all
cases of this uncommon subtype of migraine (Ducros et al.,
2001), but they are involved in the common forms of
migraine, notably in MA (Ophoff et al., 1996; Terwindt
et al., 2001). In other disorders caused by CACNA1A defects,
such as episodic and spinocerebellar ataxia, structural cere-
bellar changes have been described similar as in familial hemi-
plegic migraine (De Michele et al., 1998; Klockgether et al.,
1998; Murata et al., 1998; Melberg et al., 1999; Stevanin et al.,
1999; Tournier-Lasserve, 1999). However, the described
structural cerebellar changes in these CACNA1A-disorders
did not comprise infarct-like lesions, but were limited to
cerebellar atrophy.
In summary, we described a specic pattern of small cere-
bellar border zone infarct-like lesions in migraine patients,
notably in those with aura. A combination of (possibly
migraine-related) hypoperfusion and embolism is the likeliest
aetiological mechanism, although other mechanisms could
also play a role. Although the sample is small, we did not
see an association between PC territory infarct-like lesions
and types of supratentorial brain changes, such as deep
white matter lesions or periventricular white matter lesions.
Furthermore, there were not large differences in cardiovascu-
lar risk factors in those with and without PC territory infarct-
like lesions. These two factors suggest that the lesions are not
atherosclerotic in origin or reect small-vessel disease. As
a limitation of the current study, we could not assess verte-
brobasilar vascular status or cardiac abnormalities of the
Table 4 Migraine characteristics of migraine patients
with and without posterior circulation infarct-like lesions
(PC ILL): the CAMERA study
Migraine characteristic PC ILL
No Yes
(n = 278) (n = 17)
Migraine subtype
Migraine without aura 130 (47%) 4 (24%)
Migraine with aura 148 (53%) 13 (77%)
Migraine attacks
Median number of attacks 11.0 24.0
2575th percentile 6.117.4 8.532.4
Frequency <1 attack/month 152 (55%) 7 (41%)
Frequency 1 attack/month 126 (45%) 10 (59%)
Age (yrs)
At migraine onset 22.8 (0.7) 22.9 (2.5)
At last migraine attack 46.3 (0.5) 51.9 (1.8)
*
Previous physician diagnosis of migraine 143 (52%) 13 (77%)
*
Family history of migraine
1 family member
(parents, children, siblings)
170 (61%) 9 (53%)
1 parent 112 (40%) 5 (29%)
1 child 22 (8%) 2 (12%)
Data are number of individuals (%) and mean (SE) values. Unless
indicated otherwise, differences were not statistically signicant.
P values are from Pearsons x
2
test (unadjusted) and unpaired
t-tests.
*
P < 0.05.
Posterior circulation lesions in migraine Brain (2005), 128, 20682077 2075

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participants, and neither could we specically assess
prothrombotic conditions other than by asking all parti-
cipants for a history of thrombosis or (inherited) coagulo-
pathies, which was absent in all cases. Since silent PC
infarction might not be negligible and might be related to
(subclinical) dysfunctioning, identication of specic risk
factors for PC infarction in migraine cases could allow pre-
ventive measures in those most at risk.
Acknowledgements
We are indebted to J. T. Wilmink P. A. M. Hofman,
J. T. N. Bakkers and J. K. Krabbe for their support and
help in clinically reviewing the MRI examinations, to the
team of MRI technicians in both research centres and to
the medical students for their dedication and help. This study
was supported by a grant from the Netherlands Heart
Foundation (grant 97.108). The Genetic Epidemiology of
Migraine study was conducted by the National Institute of
Public Health and the Environment, Department of Chronic
Disease and Environmental Epidemiology, Bilthoven,
The Netherlands.
References
Amarenco P. The spectrum of cerebellar infarctions. Neurology 1991; 41:
9739.
Amarenco P, Hauw JJ, Gautier JC. Arterial pathology in cerebellar infarction.
Stroke 1990; 21: 1299305.
Amarenco P, Kase CS, Rosengart A, Pessin MS, Bousser MG, Caplan LR. Very
small (border zone) cerebellar infarcts. Distribution, causes, mechanisms
and clinical features. Brain 1993; 116: 16186.
Amarenco P, Levy C, Cohen A, Touboul PJ, Roullet E, Bousser MG. Causes
and mechanisms of territorial and nonterritorial cerebellar infarcts in 115
consecutive patients. Stroke 1994; 25: 10512.
Barth A, Bogousslavsky J, Regli F. The clinical and topographic spectrum of
cerebellar infarcts: a clinical-magnetic resonance imaging correlation study.
Ann Neurol 1993; 33: 4516.
Bednarczyk EM, Remler B, Weikart C, Nelson AD, Reed RC. Global cerebral
blood ow, blood volume, and oxygen metabolism in patients with
migraine headache. Neurology 1998; 50: 173640.
Boer JM, Feskens EJ, Schouten EG, Havekes LM, Seidell JC, Kromhout D.
Lipid proles reecting high and low risk for coronary heart disease: con-
tribution of apolipoprotein E polymorphism and lifestyle. Atherosclerosis
1998; 136: 395402.
Bogousslavsky J, Regli F, Van Melle G, Payot M, Uske A. Migraine stroke.
Neurology 1988; 38: 2237.
Bokura H, Kobayashi S, Yamaguchi S. Distinguishing silent lacunar infarction
from enlarged Virchow-Robin spaces: a magnetic resonance imaging and
pathological study. J Neurol 1998; 245: 11622.
Broderick JP, Swanson JW. Migraine-related strokes. Clinical prole and
prognosis in 20 patients. Arch Neurol 1987; 44: 86871.
Canaple S, Bogousslavsky J. Multiple large and small cerebellar infarcts. J
Neurol Neurosurg Psychiatry 1999; 66: 73945.
Caplan LR. Migraine and vertebrobasilar ischemia. Neurology 1991; 41:
5561.
Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an
important link between hypoperfusion, embolism, and ischemic stroke.
Arch Neurol 1998; 55: 147582.
Cesar JM, Garcia-Avello A, Vecino AM, Sastre JL, Alvarez-Cermeno JC.
Increased levels of plasma von Willebrand factor in migraine crisis. Acta
Neurol Scand 1995; 91: 4123.
Couch JR, Hassanein RS. Platelet aggregability in migraine. Neurology 1977;
27: 8438.
Cutrer FM, Sorensen AG, Weisskoff RM, Ostergaard L, Sanchez DR, Lee EJ,
et al. Perfusion-weighted imaging defects during spontaneous migrainous
aura. Ann Neurol 1998; 43: 2531.
DAndrea G, Cananzi AR, Perini F, Hasselmark L. Platelet models and their
possible usefulness in the study of migraine pathogenesis. Cephalalgia 1995;
15: 26571.
De Michele G, Mainenti PP, Soricelli A, Di Salle F, Salvatore E, Longobardi
MR, et al. Cerebral blood ow in spinocerebellar degenerations: a single
photon emission tomography study in 28 patients. J Neurol 1998; 245:
6038.
Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, et al.
The clinical spectrum of familial hemiplegic migraine associated with
mutations in a neuronal calcium channel. N Engl J Med 2001; 345: 1724.
Duvernoy H, Delon S, Vannson JL. The vascularization of the human
cerebellar cortex. Brain Res Bull 1983; 11: 41980.
Ebner TJ, Chen G. Spreading acidication and depression in the cerebellar
cortex. Neuroscientist 2003; 9: 3745.
Edvinsson L, Goadsby PJ. Neuropeptides in the cerebral circulation: relevance
to headache. Cephalalgia 1995; 15: 2726.
Featherstone HJ. Clinical features of stroke in migraine: a review. Headache
1986; 26: 12833.
Ferrari MD. Migraine. Lancet 1998; 351: 104351.
Fessatidis IT, Thomas VL, Shore DF, Hunt RH, Weller RO, Goodland F, et al.
Assessment of neurological injury due to circulatory arrest during
profound hypothermia. An experimental study in vertebrates. Eur J
Cardiothorac Surg 1993; 7: 46572.
Friberg L, Olesen J, Lassen NA, Olsen TS, Karle A. Cerebral oxygen extraction,
oxygen consumption, and regional cerebral blood ow during the aura
phase of migraine. Stroke 1994; 25: 9749.
Hargreaves RJ, Shepheard SL. Pathophysiology of migrainenew insights.
Can J Neurol Sci 1999; 26 Suppl 3: S129.
Harno H, Hirvonen T, Kaunisto MA, Aalto H, Levo H, Isotalo E, et al.
Subclinical vestibulocerebellar dysfunction in migraine with and without
aura. Neurology 2003; 61: 174852.
Headache Classication Committee of the International Headache Society.
Classication and diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalalgia 1988; 8 Suppl 7: 196.
Hoekstra-van Dalen RA, Cillessen JP, Kappelle LJ, van Gijn J. Cerebral infarcts
associated with migraine: clinical features, risk factors and follow-up.
J Neurol 1996; 243: 5115.
Klockgether T, Skalej M, Wedekind D, Luft AR, Welte D, Schulz JB, et al.
Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of
posterior fossa structures and basal ganglia in spinocerebellar ataxia
types 1, 2 and 3. Brain 1998; 121: 168793.
Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari
MD, et al. Migraine as a risk factor for subclinical brain lesions. JAMA
2004; 291: 42734.
Launer LJ, Terwindt GM, Ferrari MD. The prevalence and characteristics of
migraine in a population-based cohort: the GEM study. Neurology 1999;
53: 53742.
Melberg A, Dahl N, Hetta J, Valind S, Nennesmo I, Lundberg PO, et al.
Neuroimaging study in autosomal dominant cerebellar ataxia, deafness,
and narcolepsy. Neurology 1999; 53: 21902.
Milhaud D, Bogousslavsky J, Van Melle G, Liot P. Ischemic stroke and active
migraine. Neurology 2001; 57: 180511.
Moskowitz MA, Bolay H, Dalkara T. Deciphering migraine mechanisms: clues
from familial hemiplegic migraine genotypes. Ann Neurol 2004; 55:
27680.
Murata Y, Kawakami H, Yamaguchi S, Nishimura M, Kohriyama T, Ishizaki
F, et al. Characteristic magnetic resonance imaging ndings in spinocere-
bellar ataxia 6. Arch Neurol 1998; 55: 134852.
Olesen J, Friberg L, Olsen TS, Iversen HK, Lassen NA, Andersen AR, et al.
Timing and topography of cerebral blood ow, aura, and headache during
migraine attacks. Ann Neurol 1990; 28: 7918.
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman,
et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by
mutations in the Ca2+ channel gene CACNL1A4. Cell 1996; 87: 54352.
2076 Brain (2005), 128, 20682077 M. C. Kruit et al.

b
y

g
u
e
s
t

o
n

J
a
n
u
a
r
y

1
3
,

2
0
1
4
h
t
t
p
:
/
/
b
r
a
i
n
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

Rothrock JF, Walicke P, Swenson MR, Lyden PD, Logan WR. Migrainous
stroke. Arch Neurol 1988; 45: 637.
Sacquegna T, Andreoli A, Baldrati A, Lamieri C, Guttmann S, de Carolis P,
et al. Ischemic stroke in young adults: the relevance of migrainous infarc-
tion. Cephalalgia 1989; 9: 2558.
Salobir B, Sabovic M, Peternel P, Stegnar M, Grad A. Classic risk factors,
hypercoagulability and migraine in young women with cerebral lacunar
infarctions. Acta Neurol Scand 2002; 105: 18995.
Sanchez del Rio M, Bakker D, Wu O, Agosti R, Mitsikostas DD, Ostergaard L,
et al. Perfusion weighted imaging during migraine: spontaneous visual aura
and headache. Cephalalgia 1999; 19: 7017.
Sandor PS, Mascia A, Seidel L, de Pasqua V, Schoenen J. Subclinical cerebellar
impairment in the common types of migraine: a three-dimensional analysis
of reaching movements. Ann Neurol 2001; 49: 66872.
Shuaib A, Lee MA. Cerebral infarction in patients with migraine accompani-
ments. Headache 1988; 28: 599601.
Silvestrini M, Matteis M, Troisi E, Cupini LM, Zaccari G, Bernardi G.
Migrainous stroke and the antiphospholipid antibodies. Eur Neurol
1994; 34: 3169.
Silvestrini M, Baruffaldi R, Bartolini M, Vernieri F, Lanciotti C, Matteis M,
et al. Basilar and middle cerebral artery reactivity in patients with migraine.
Headache 2004; 44: 2934.
Song CJ, Kim JH, Kier EL, Bronen RA. MR imaging and histologic features
of subinsular bright spots on T2-weighted MR images: Virchow-Robin
spaces of the extreme capsule and insular cortex. Radiology 2000; 214:
6717.
Stevanin G, Herman A, Brice A, Durr A. Clinical and MRI ndings in
spinocerebellar ataxia type 5. Neurology 1999; 53: 13557.
Tatu L, Moulin T, Bogousslavsky J, Duvernoy H. Arterial territories of human
brain: brainstem and cerebellum. Neurology 1996; 47: 112535.
Tatu L, Moulin T, Bogousslavsky J, Duvernoy H. Arterial territories of the
human brain: cerebral hemispheres. Neurology 1998; 50: 1699708.
Terwindt GM, Ophoff RA, van Eijk R, Vergouwe MN, Haan J, Frants RR, et al.
Involvement of the CACNA1A gene containing region on 19p13 in
migraine with and without aura. Neurology 2001; 56: 102832.
Tietjen GE, Al Qasmi MM, Athanas K, Dafer RM, Khuder SA. Increased von
Willebrand factor in migraine. Neurology 2001; 57: 3346.
Tournier-Lasserve E. CACNA1A mutations: hemiplegic migraine, episodic
ataxia type 2, and the others. Neurology 1999; 53: 34.
Tozzi-Ciancarelli MG, De Matteis G, Di Massimo C, Marini C, Ciancarelli I,
Carolei A. Oxidative stress and platelet responsiveness in migraine.
Cephalalgia 1997; 17: 5804.
Tzourio C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alperovitch A.
Association between migraine and endothelin type A receptor (ETA 231
A/G) gene polymorphism. Neurology 2001; 56: 12737.
Woods RP, Iacoboni M, Mazziotta JC. Brief report: bilateral spreading cereb-
ral hypoperfusion during spontaneous migraine headache. N Engl J Med
1994; 331: 168992.
Posterior circulation lesions in migraine Brain (2005), 128, 20682077 2077

b
y

g
u
e
s
t

o
n

J
a
n
u
a
r
y

1
3
,

2
0
1
4
h
t
t
p
:
/
/
b
r
a
i
n
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m