Kruit, Mark Christian
Citation
Kruit, M. C. (2010, January 20). Migraine and brain lesions. Data from the population-based CAMERA Study. Department of Radiology, Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University.
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C H A P T E R 4
INFARCTSINTHEPOSTERIORCIRCULATION
TERRITORYINMIGRAINE
MarkC.Kruit
DepartmentofRadiology,LUMC
LenoreJ.Launer
LaboratoryofEpidemiology,DemographyandBiometry,
NationalInstituteonAging,NIH,Bethesda
MichelD.Ferrari
DepartmentofNeurology,LUMC
MarkA.vanBuchem
DepartmentofRadiology,LUMC
Brain2005;128:20682077
A B S T R A C T
Background and purpose Ina previousstudy, migraine cases from thegeneral population were
foundto be at significantly increased risk for silent infarctlikelesions inthe posteriorcirculation
(PC) territory of the brain, notably in the cerebellum. In this study we describe the clinical and
neuroimagingcharacteristicsofmigrainecaseswithandwithoutauraandcontrolswithPClesions.
Results In total 39 PC infarctlike lesions represent the majority (65%) of all 60 identified brain
infarctlike lesions in the study sample (n=435 subjects with and without migraine). Most lesions
(n=33)werelocatedinthecerebellum,oftenmultiple,androundorovalshaped,withameansize
of 7 mm. The majority (88%) of infratentorial infarctlike lesions had a vascular border zone
location in the cerebellum. Prevalence of these border zone lesions differed between controls
(0.7%),caseswithmigrainewithoutaura(2.2%)andcaseswithmigrainewithaura(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 supratentorial brain changes, such as
whitematterlesions.
Interpretation The combination of vascular distribution, deep border zone location, shape, size
and imaging characteristics on MRI makes it likely that the lesions have an infarctious origin.
Previous investigators attributed cases of similar ‘very small’ cerebellar infarcts in nonmigraine
patientsto a number of differentinfarct mechanisms. Relevance and likelihood of the etiological
options are placed in the context of known migraine pathophysiology. In addition, the specific
involvement of the cerebellum in migraine is discussed. The results suggest a combination of
(possibly migraine attack related) hypoperfusion and embolism is the likeliest mechanism for PC
infarctioninmigraine,andnotatherosclerosisorsmallvesseldisease.
INTRODUCTION
Migraineisaprevalent,chronic,multifac
torial neurovascular disorder, character
ized by recurrent attacks of debilitating
headacheandautonomicnervoussystem
dysfunction(migrainewithoutaura;MO);
up to onethird of patients also have
neurological aura symptoms (migraine
with aura; MA).2;5 Migraine is commonly
thought of tobeacutelydisabling during
attacks,withoutlongtermconsequences
on the brain. However, we found in our
populationbasedCAMERAstudy(n=435)
migraine cases had a significantly higher
prevalenceofwhite matterhyperintense
lesions and cerebellar infarctlike le
sions.71 Traditional cardiovascular risk
factors and specific antimigraine medi
cation did not modify the association
betweenthestructuralbrainchangesand
migraine.
Intotal,8.1%of161caseswithMA,
compared to2.2%of 134caseswithMO
and0.7%of140controls(P=.05),hadone
or more lesions in the cerebellar region
of the posterior circulation (PC) territory
of the brain.71 The highest risk was in
participants with MA with at least 1
attack per month (odds ratio, 15.8; 95%
CI, 1.8140), compared with controls.
These cerebellar lesions appear as in
farcts on MRIs, although none of the
patients had a clinical history of stroke.
Clinical infarcts in patients with migraine
were previously suggested (in some
clinicallybased studies) to be over
represented in the PC territory, notably
in the occipital lobes, but not infraten
torially.4648;77;86;87;126;139;140
Reports that
detaillocation,sizeandregionaldistribu
tion patterns of such infarcts in patients
with migraine are lacking. Also, little is
known about the etiology of these brain
lesions.
Here we describe the clinical and
neuroimaging characteristics of cases
from the CAMERA study with PC lesions,
relatethosetowhatisknownofmigraine
pathophysiology, and provide evidence
for an infarctious origin of the identified
infarctlikelesions.
METHODS
STUDYPOPULATION
A complete description of the study
population and methods has been de
tailed elsewhere.71 In brief, cases and
controls were randomly selected from
the Genetic Epidemiology of Migraine
(GEM) study, a populationbased survey
of 6491 Dutch adults aged 2060 years
living in two representative Dutch mu
nicipalities(MaastrichtandDoetinchem).
With this procedure we identified 863
cases of migraine according to Interna
tional Headache Society criteria; 54% of
the cases had not been previously diag
nosedbyaphysician.7
For the Cerebral Abnormalities in
Migraine, an Epidemiological Risk Analy
sis (CAMERA) Study, two diagnostic
groups (cases with migraine with aura
and without aura) were randomly se
lected from the earlier populationbased
survey cases aged 3060 years; the con
trol group was randomly selected from
the cohort to frequency match the cases
by sex, municipality and 5year age
strata. The study protocol was approved
by the ethics committees of the Leiden
UniversityMedicalCenterandincludeda
structured telephone interview and a
clinic visit for a brain MRI study, blood
drawn and a standard physical and neu
rologicalexamination.
Acompleteprotocolwasperformed
in 435 participants (69% overall re
sponse): 134 MO, 161 MA and 140 con
trols. All participants gave written in
formedconsentandparticipatedwithout
any financial reimbursement. The clinic
visits took place within 10 days of the
telephone interview; patients with mi
graine underwent examinations in a
headache free period (t3 days after a
migraineattack).
CONFOUNDERS,COVARIATESAND
MIGRAINECHARACTERISTICS
Sociodemographic, medical and migraine
characteristics were assessed by inter
view.Educationwascategorizedintolow
(primary school or lower vocational
education)andhigh.Smokinghistorywas
defined as never, former and current,
and for eversmokers, packyears of
exposure. The average alcohol intake in
thepastyearwasbasedonresponsesto
questions on frequency and quantity of
drinks per occasion and categorized into
none, moderate (13 drinks per day) and
high (t3 drinks per day). Women re
ported the number of years they used
oral contraceptives. Selfreported weight
and height were used to calculate body
mass index (weight in kilograms divided
bythesquareofheightinmeters).Blood
pressure was the mean of three meas
urements obtained at 1min intervals in
the upper arm with an electronic oscil
lometric BP monitor (OMRON 711, Om
ron Healthcare Europe, Hoofddorp, the
Netherlands). Hypertension was defined
asasystolicbloodpressureof160mmHg
and higher or a diastolic blood pressure
of95mmHgandhigherorcurrentuseof
antihypertensive drugs. A measure of
total cholesterol was available from the
baseline examination.119 As previously
detailed, migrainecases estimated head
ache and aura attack frequency, and
frequency and amount of specific anti
migraine medication (ergotamines,
triptans)theyusedintheyearstheyhad
migraineattacks.71
MRI
BrainMRIswereacquiredona1.5Tunit
in Maastricht (ACSNT, Philips Medical
Systems, Best, The Netherlands) and a
1.0T unit in Doetinchem (Magnetom
Harmony, Siemens AG, Erlangen, Ger
many).Protocolsinthetwocenterswere
comparable. Whole brain images were
acquired with 48 contiguous 3 mm axial
slices (fieldofview, 22 cm; matrix, 190
205 x 256). Pulse sequences included a
combined proton density and T2weigh
ted fast spinecho sequence (ACSNT:
3000/27120/1/10; Magnetom Harmony:
3000/1485/2/5; relaxation time (ms)/
echo time(ms)/excitations (number)/
echotrain length(number)) and fluid
attenuated inversionrecovery sequence
(FLAIR; ACSNT: 8000/100/ 2000/2/19;
MagnetomHarmony:8000/105/2000/2/
7; relaxation time(ms)/echo time(ms)/
inversiontime(ms)/excitations(number)/
echotrainlength(number)).
One neuroradiologist (M.A.v.B.),
who was blinded to migraine diagnosis
and clinical data, rated white matter
lesions(WMLs)andinfarctlikelesionson
hard copies. A complete description of
the WMLrating methods has been de
scribed previously.71 Infarctlike lesions
were defined as nonmass parenchymal
defects, with a vascular distribution,
isointensetocerebrospinalfluidsignalon
all sequences, and when supratentorial,
surrounded by a hyperintense rim on
fluidattenuated inversionrecovery and
proton density images. In total 60 brain
infarctlike lesions were detected in 31
individuals. Location and size of these
lesions were recorded. Supratentorially,
VirchowRobinspaceswerediscriminated
from infarctlike lesions, based on loca
tion,shape,sizeandabsenceofahyper
intense border on proton density and
FLAIRimages.114;141
The topography and corresponding
dominant arterial territory of the identi
fied infarctlike lesions was determined
according to the maps by Tatu and col
leagues.115;116 The PC territory included
all brainstem and cerebellar branches of
FIG.1Infratentorialposteriorcirculation(PC)infarctlikelesionsinthecerebellum(n=33)
superimposedoverdiagramwitharterialterritoriesindicated
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
ofSCA(lSCA)ortheterritory
of the anterior inferior
cerebellar artery (AICA). Left
sided lesions (red coloured)
are mirrored to the right
hemisphere for presentation
purposes.
lSCA
m SCA AICA lPICA
mPICA
thevertebralandbasilararteries,andthe
posterior cerebral arteries and their
branches. The infratentorial PC infarct
like lesions were further subclassified as
either territorial or junctional (=border
zone) according to previously published
criteria.142145
In the assessment of infratentorial
PC territory lesions the following proce
durewasappliedtominimizeanyformof
potential classification bias. First, the
indications of the arterial (sub)territories
weredefinedinadiagramofthecerebel
lumandbrainstem(FIGURE1,thecolored
areas).115;142 Second, the position, shape
andsizeofaninfratentorialPClesionwas
copied fromhard copy into a diagram of
the cerebellum and brainstem without
thecoloredvascularterritories(FIGURE1,
the black lines). This was repeated for
eachindividuallesioninaseparate(emp
ty)diagram.Inthirdinstance,allseparate
drawings were superimposed over the
previously defined indications of the
arterial(sub)territories(FIGURE1).
Thereafter, each infarctlike lesion
was classified as either territorial or
junctional (=border zone). Territorial
lesions occupied the territory of the
posteriorinferiorcerebellarartery(PICA),
the medial branch of the PICA (m PICA),
thelateralbranchofthePICA(lPICA),the
territoryofthesuperiorcerebellarartery
(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). Junc
tionallesionswerelocatedatthebound
ary region (defined asd5 mm from the
indicated border in the template) be
tweentwoarterialterritories.
STATISTICS
TheF2 test, the unpaired ttests, and
analyses of variance controlling for age
andsexwereusedtotestfordifferences
in the distributions and means of meas
ured characteristics among the study
groups. Analyses were conducted with
SPSS statistical software (version 10.0.5;
SPSSInc.,Chicago,IL).
RESULTS
TABLE 1showsdataonprevalence,char
acteristics and distribution of the 39
infarctlike lesions identified in the PC
territory. These PC infarctlike lesions
represent the majority (65%) of all 60
identifiedinfarctlikelesionsinthewhole
brain in the study sample. Between the
diagnostic groups, the percentage of the
PClesionsdiffered:81%ofallinfarctlike
lesions in MA were in the PC territory,
47%inMOand 44%incontrols.Incases
with migraine, most PC infarctlike le
sions were located infratentorially: 96%
of PC lesions in MA and 89% in MO;
amongthe4controlswithPCinfarctlike
lesions, only 1 subject had an infraten
torial lesion. Of the 39 PC infarctlike
lesions, 33 were located in the cerebel
lum (1 in a control, 8 in 3 MO, 24 in 13
MA), 1 in the pons (in a MA) and five in
the thalamus (3 in 3 controls, 1 in a MO
and 1 in a MA). Besides the thalamic
infarctlike lesions, no other infarctlike
lesionswereidentifiedsupratentoriallyin
the posterior circulation territory. The
mean diameter of the PC infarctlike
lesions was 7.1 mm, ranging between 2
21 mm, and 69% were located on the
rightside.Theaveragenumberoflesions
per subject was 1.8. Lesion sizes and
number of lesions per subject did not
differbetweenthediagnosticgroups.
Infratentorial PC infarctlike lesions
were subclassified as either territorial or
junctional as defined previously. Of the
34 infratentorial PC lesions 30 were
classifiedasjunctional.InMA,92%ofthe TABLE 1 Prevalence and characteristics of posterior circulation (PC) infarctlike lesion
(ILL).
All Controls MO MA
(n=435) (n=140) (n=134) (n=161) Pvalue
PCINFARCTLIKELESIONS
TotalnumberofPCILL(%ofallbrainILL) 39 (65%) 4 (44%) 9 (47%) 26 (81%) <.05
Subjectswitht1PCILL(%ofallpart.) 21 (4.8%) 4 (2.9%) 4 (3.0%) 13 (8.1%) <.05
LOCATIONOFPCINFARCTLIKELESIONS(N=39)
Supratentorial(eg.occipitallobe,thalamus)
Totalnumber(%ofallPCILL) 5 (13%) 3 (75%) 1 (11%) 1 (4%) <.005
Subjectswitht1ILLofthistype 5 (1.1%) 3 (2.1%) 1 (0.7%) 1 (0.6%)
Infratentorial
Totalnumber(%ofallPCILL) 34 (87%) 1 (25%) 8 (89%) 25 (96%) <.005
Subjectswitht1ILLofthistype 17 (3.9%) 1 (0.7%) 3 (2.2%) 13 (8.1%) <.005
LOCATIONOFINFRATENTORIALILL(N=34)
Junctional/Borderzone
Totalnumber(%ofinfratent.ILL) 30 (88%) 1 (100%) 6 (75%) 23 (92%)
Subjectswitht1ILLofthistype 16 (3.7%) 1 (0.7%) 3 (2.2%) 12 (7.5%) <.005
Territorial
Totalnumber(%ofinfratent.ILL) 4 (12%) 2 (25%) 2 (8%)
Subjectswitht1ILLofthistype 3 (0.7%) 1 (0.7%) 2 (1.2%)
LOCATIONOFJUNCTIONALILL(N=30)
lPICAAICAborderzone(%ofjunct.ILL) 4 (13%) 1 (17%) 3 (13%)
lPICAmPICAborderz.(%ofjunct.ILL) 3 (10%) 3 (13%)
lPICAlSCAborderzone(%ofjunct.ILL) 2 (7%) 2 (9%)
mPICAmSCAborderz.(%ofjunct.ILL) 11 (37%) 1 (100%) 2 (33%) 8 (35%)
lSCAmSCAborderzone(%ofjunct.ILL) 10 (33%) 3 (50%) 7 (30%)
Dataarenumberofindividuals(%)andnumberofinfarctlikelesions(%).PvaluesarefromPearsons's2test
(unadjusted).mPICA=medialbranchoftheposteriorinferiorcerebellarartery(PICA);lPICA=lateralbranchof
the PICA; mSCA =medialbranchofthe superior cerebellar artery (SCA); lSCA = lateralbranch of SCA; AICA =
anteriorinferiorcerebellarartery
Unlessstatedotherwise,differenceswerenotstatisticallysignificant
CASE21 CASE18 CASE9 CASE5
FIG. 2 Cerebellar infarctlike lesions. Corresponding T2weighted (left) and fluid
attenuated inversionrecovery images (right) showing (multiple) cerebellar infarctlike
lesions(arrows)infourrepresentativecases(numbersrefertocasenumbersinTable2).
infratentorial lesions were junctional,
75%inMO;theonlyinfratentoriallesion
in the one control was also junctional.
ThemPICAmSCAborderzone(37%ofall
junctional infarctlike lesions; in seven of
16 subjects with junctional infarctlike
lesions)andlSCAmSCAborderzone(33%
of all junctional lesions; in eight of 16
subjects with junctional lesions) were
mostlyinvolved.
These distributions over the sepa
rateborderzonesdidnotdifferbetween
the diagnostic groups. In FIGURE1, all
infratentorial PC infarctlike lesions are
superimposed over the respective arte
rial territories of the cerebellar hemi
spheres.Mostlesionswereroundoroval
shaped,andmoreorlessclusteredinthe
border zones. Orientation of the junc
tional infarctlike lesions was mostly
alongtheborderbetweentherespective
territories. One infarctlike lesion in
volved a part of the local cerebellar
cortex,butallotherlesionswerelocated
in the deep cerebellar regions.FIGURE 2 shows four examples of representative
cases with infratentorial PC (cerebellar)
infarctlikelesions.
TABLE 2 lists sociodemographic and
migraine characteristics and other struc
tural brain damage variables of the sub
jectswithPCinfarctlikelesions.Informa
tion is provided on the size, side and
location of the separate infarctlike
lesions, as well as on concurrent infarct
like lesions located outside the PC terri
tory (e.g. anterior/carotid circulation).
The presence of a high load of periven
tricular white matter lesions (high
PVWML load) and/or a high deep white
matter lesion load (high DWML load) is
indicated for each subject. Eleven sub
jects had more than one infarctlike
lesion (‘multiple infarctlike lesions’; 59%
of the migraine cases and 25% of the
controls).MultiplePClesionswereidenti
fiedexclusivelyincaseswithmigraine;in
these seven cases, more than one sepa
rate border zone was involved. Although
theprevalenceofahighDWMLloadwas
higher in subjects with PC lesions, this
difference was not confirmed in subana
lysisformigrainepatientsseparately.
SubjectswithinfarctlikelesionsinthePC
territoryweresignificantlyolder,andhad
significantly 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 significant in the
subanalysis among the cases with mi
graine. Other cardiovascular risk factors
were not more prevalent among those
with PC infarctlike lesions. The number
ofcaseswithPClesionswastoosmallto
compare 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 significantly more
oftenpreviouslyconsultedaphysicianfor
their migraine (TABLE 4). Other migraine
characteristics did not differ between
those with and without PC infarctlike
lesions.
TABLE2Caseswithposteriorcirculationinfarctlikelesions(PCILL).
Migrainecharacteristics PCILL† OtherILL†
Whitematter
lesions
Nr.
Age/
sex Diag.
Age
affected
Attacks /year
Aura
characteristics*
Infratent.
Territorial
Infratentorial
Junctional
Supra
tentorial
(any) Location
PV
WML
(score)
High
DWML
load
1 41/F MA 1351 51 Visual;
30%MA
12 rAICAlPICA
12 rlPICAlSCA
5 rmPICAlPICA
2 no
2 42/F MA 3242 30 Visual 5 l mPICAlPICA 1 no
3 44/M MA 244 35 Visual;
10% MA
age1444
9 l pons
18 rlPICAAICA
12 rmPICAmSCA
8 l mPICAmSCA 21 l mPICAmSCA‡
8 l thal 0 no
4 48/F MA 3847 2 Visual;
always aura w/oheadache
8 rlSCAmSCA
5 rmPICAmSCA
8 l mPICAmSCA
1 no
5 52/F MA 1735 24 Visual/sens 8 rmSCAlSCA
8 l mSCAmPICA
2 yes
6 52/M MA 2151 10 Visual; 80% MA age3551
6 l mPICAmSCA 1 no
7 52/M MA 3651 41 Visual 10 l AICAlPICA 9 l frt lobe
6 rfrtlobe
2 yes
8 55/F MA 2255 6 Visual 3 l lSCA 0 no
9 55/M MA 1855 8 Visual/sens./
aphasia; part.
auraonly
12 rmSCAmPICA 8 l nc.caud. 1 no
10 56/F MA 1753 27 Visual;
70%MA
4 rlSCAmSCA 2 yes
11 57/F MA 4057 3 Visual 5 rlPICAmPICA 0 no
12 57/M MA 3549 9 Visual 6 rmSCAlSCA 0 no
13 57/M MA 2257 30 Visual;
100% MA
age3053
5 rlSCAmSCA
5 rlSCAmSCA
4 rlPICAlSCA‡
4 l lSCAmSCA‡
1 yes
14 58/M Co 5 rthal 5 yes
15 59/F MO 1459 17 9 rlSCAmSCA 1 no
16 60/M MO 2058 24 10 rlSCAmSCA
5 rmPICAmSCA 10 rmPICAmSCA
3 yes
17 61/F Co 2 rthal
3 l caps. int.
3 l caps.int
5 yes
18 61/F Co 3 rmPICAmSCA 1 no
19 61/W MO 2550 12 2 l thal
3 l caps. int.
2 l cor. rad.
2 l cor.rad.
5 yes
20 62/M Co 7 rthal 1 yes
21 63/F MO 3363 51 2 rlPICA§
3 rlPICA§
4 l lSCAmSCA
6 rAICAlPICA
5 l frtlobe 2 no
* Unlessstatedotherwise,MAhadin100%ofattacksaurasymptoms.
† For each individual ILL, its size (maximum diameter in mm), side [left (l) or right (r)] and vascular supply territory (for
territorialILLs)orborderzoneregionbetweenthenotedterritories(forjunctionalILLs)oranatomicallocation(fornonPC
infarctlike lesions) is indicated. Thal = thalamus; frt lobe = frontal lobe; caps. int. = capsula interna; cor. rad. = corona
radiata;nc.caud.=caudatenucleus.
‡ ILLlocated>5mmbut<10mmfromtheindicatedborderzone;treatedasjunctional.
§ ILLpossiblylocatedintheborderzoneregionbetweenlPICAandlSCA;thiscouldnotbedeterminedfromthetemplates.
M=male;F=female;MA= migrainewithaura;MO= migraine withoutaura;Co= control.High DWMLload=highdeep
DISCUSSION
Inapreviouspopulationbasedstudy,we
found migraine to be a significant risk
factor for PC infarctlike lesions, notably
in cases with migraine with aura. In the
current study, the topographic details of
these parenchymal defects were system
atically characterized. All lesions fulfilled
MRIcriteria for infarcts; therefore we
refer to these lesions in the text as ‘in
farctlikelesions’.Mostpronouncedwere
findingsinMA:over80%ofallinfarctlike
lesions were located in the PC territory
areas, and over 90% of these were lo
cated in the (deep) arterial border zone
areas of the cerebellum. All PC lesions
weresmall,andoftenmultiplePCinfarct
like lesions were identified in a single
subject. No previous studies reported on
TABLE 3 Age and sexadjusted characteristics of subjects with and without posterior
circulationinfarctlikelesions(PCILL).
Total Migraineurs Controls
PCILL PCILL PCILL
no yes no yes no yes
Characteristic (n=414) (n=21)
(n=278) (n=17) (n=136) (n=4)
SOCIODEMOGRAPHIC
Age(years)
Mean(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%
Loweducation† 52% 50% 53% 41% 50% 91%
CLINICAL
Body mass index
(kg/m2)
25.0 (0.2) 25.4 (0.9) 25.4 (0.3) 25.5 (1.0) 24.3 (0.3) 25.4 (1.9)
Bloodpressure
Systolic(mmHg) 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(mmHg) 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
(amongsmokers)
10.2 (0.6) 8.4 (2.9) 9.9 (0.8) 5.7 (3.1) 11.0 (1.2) 19.6 (7.0)
Alcoholuse
None 20% 23% 23% 23% 15% 25%
t3units/day 11% 0.4% 8% 2% 16% 0%
OCs use
(womenonly)
t15yearsOCuse 24% 21% 25% 21% 24% 22%
OTHERBRAINDAMAGE
HighPVWMLload 9% 14% 10% 7% 7% 47% †
HighDWMLload 19% 35% 22% 32% 15% 51% *
Dataareestimatedmean(SE)orpercentageofsubjects,basedonunivariateanalysesofvariance,controllingforageandsex.
Unless stated otherwise, differences were not statistically significant. P values are based on tests of the betweensubjects
effect. Loweducation – primary school or lower vocational education; OC = oral contraceptive; DWML = deep white matter
lesions.*P<.05;†P<.005.
prevalence and size of cerebellar infarct
like lesions in migraine, and although a
small number of clinicopathological and
clinicoradiologicalstudiesreportonsmall
cerebellar infarcts, in none of these
studies migraine status was known or
included in the analyses.142147 However,
the ‘very small’ cerebellar lesions identi
fiedinoursamplehavesimilardiameters
(220 mm), shapes and typical border
zone locations as the small cerebellar
infarcts reported in these previous stud
ies.
Border zone infarction is probably
bestexplainedbyinvokingacombination
of low flow and embolism: a decrease in
cerebral perfusion pressure and asso
ciated changes in the cerebral hemody
namicsaffectstheclearanceanddestina
tion of embolic particles; narrowing of
thearteriallumen andintimaland endo
thelial abnormalities stimulate formation
of thrombi; occlusive thrombi further
reducebloodflowandbrainperfusion.148 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 hypoperfusionrelated
border zone infarct mechanisms.149;150 TheprevalentinvolvementofSCAwater
shed zones might be explained by a
longercourseofSCAbranches,compared
toPICAand AICA branches.149 Thishypo
TABLE 4 Migraine characteristics of migraine patients with and without posterior
circulationinfarctlikelesions(PCILL.
PCILL
no yes
Migrainecharacteristic (n=278) (n=17)
Migrainesubtype
Migrainewithoutaura 130 (47%) 4 (24%)
Migrainewithaura 148 (53%) 13 (77%)
Migraineattacks
Mediannumberofattacks 11.0 24.0
2575thpercentile 6.117.4 8.532.4
Frequency<1attack/month 152 (55%) 7 (41%)
Frequencyt1attack/month 126 (45%) 10 (59%)
Age
Atmigraineonset 22.8 (0.7) 22.9 (2.5)
Atlastmigraineattack 46.3 (0.5) 51.9 (1.8)*
Previousphysiciandiagnosisofmigraine 143 (52%) 13 (77%)*
Familyhistoryofmigraine
t 1 family member
(parents,children,siblings)
170 (61%) 9 (53%)
t1parent 112 (40%) 5 (29%)
t1child 22 (8%) 2 (12%)
Data are number of individuals (%) and mean (SE) values. Unless indicated otherwise, differences were not
statisticallysignificant.PvaluesarefromPearsons’s2test(unadjusted)andunpairedttests.*P<.05.
perfusionrelated concept matches the
findings of previous studies in which the
small cerebellar border zone infarcts, in
particular when multiple, were strongly
associated with severe occlusive and/or
(arterytoartery) embolic disease based
on vertebrobasilar atherosclerosis, likely
to result in hypoperfusion and infarc
tion.143145;147
Nonborder zone territorial
infarcts were suggested to result from
coagulopathy, arteritis and microem
bolism,duetoinvolvementofsmalldistal
arteries145. Since we found ‘very small
territorial infarctlike lesions’ (n=3) only
in a minority of cases, this suggests that
focal hypoperfusion rather than micro
embolic occlusion is responsible for the
observedcerebellarlesionsinmigraine.
During and after migraine attacks,
sluggish low cerebral flow below an
ischemic threshold has been de
scribed.42;127;128;151153
Reductions of cere
bral blood flow vary from a 7% to 53%
decrease128;153andpersistfromonehour
tomorethanoneday.127Thisisprobably
the result of the effects of cortical
spreading depression (CSD), which has
been implicated as the generator of
migraineaura.19andcanalsooccurinthe
cerebellum.38 CSD (indirectly) alters
bloodbrain barrier permeability, which
might lead to an exacerbation of local
cellular injury caused by ischemia. To
gether with factors predisposing to
coagulopathy,79;154159andreleaseoflocal
vasoactive neuropeptides,130;160;161
this
could result in further changes of cere
bral hemodynamics, arterial thrombosis
and infarction.86 An impairment in the
adaptive cerebral hemodynamic mecha
nismsinthePCinmigrainepatientswith
aura might be part of the underlying
mechanismsbetweenmigraineandbrain
infarcts.162
Although migrainerelated clinical
strokesarereportedtooccurmostoften
supratentorially, in the occipital lobes,46
48;77;86;87;126;139;140
we did not find any
infarctlike lesions in these areas of the
PC. This difference between on the one
hand clinically manifest supratentorial
infarctsandontheotherhandsubclinical
or silent infratentorial infarcts might be
explainedbyanoveralllowerprevalence
of occipital lobe infarcts compared to
cerebellar infarcts in migraine cases, and
theassumptionthatoccipitalinfarctsare
far less likely to remain clinically silent.
The only supratentorial PC infarctlike
lesions we identified were located in the
thalamus: in three controls and two
patients with migraine (concerning 75%
of all PC infarctlike lesions in controls
and only 5% in patients with migraine).
Dataaboutsubclinicalthalamicinfarctsin
migraine are lacking, but clinically mani
fest thalamic infarcts in migraine have
been reported to be significantly more
prevalent in younger migraine cases
comparedtocontrols(14%vs.6%).86 Results from a number of studies
suggest that the cerebellum plays a role
in migraine pathophysiology. In common
forms of migraine (subclinical) cerebellar
dysfunction has been reported.163;164 Although it remains unknown whether
structural lesions caused the cerebellar
dysfunctioninthesestudies,itraisesthe
question whether more advanced func
tionaltestscouldhaveidentifiedsubclini
cal cerebellar dysfunction in our cases.
Cerebellar abnormalities (such as cere
bellar atrophy, decreased cerebellar
blood flow, and cerebellar dysfunction)
havealsobeendescribedinseveralcases
of familial hemiplegic migraine. Muta
tions of the P/Qtype Ca2+channel 1
subunit gene (CACNA1A) are responsible
for at least 50% of all cases of this un
commonsubtypeofmigraine,121butthey
are involved in the common forms of
migraine, notably in MA.122;165 In other
disorders caused by CACNA1A defects,
such as episodic and spinocerebellar
ataxia, similar structural cerebellar
changeshavebeendescribedasinfamil
ial hemiplegic migraine.166171 However,
the described structural cerebellar
changes in these CACNA1Adisorders did
not comprise infarctlike lesions, but
werelimitedtocerebellaratrophy.
Insummary,wedescribedaspecific
pattern of small cerebellar border zone
infarctlike lesions in migraine patients,
notably in those with aura. A combina
tion of (possibly migrainerelated) hy
poperfusionandembolismisthelikeliest
etiological mechanism, although other
mechanisms could also play a role. Al
though the sample is small, we did not
see an association between PC territory
infarctlikelesionsandtypesofsupraten
torial brain changes, such as DWML or
PVWML. Furthermore there were not
large differences in cardiovascular risk
factors in those with and without PC
territory infarctlike lesions. These two
factors suggest the lesions are not
atherosclerotic in origin or reflect ‘small
vessel disease’. As a limitation of the
currentstudy,wecouldnotassessverte
brobasilar vascular status or cardiac
abnormalities of the participants, and
neither could we specifically assess
prothrombotic conditions, otherwise
than by askingallparticipants forhistory
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 (sub
clinical) dysfunctioning, identification of
specific risk factors for PC infarction in
migrainecasescouldallowforpreventive
measuresinthosemostatrisk.
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 reviewing
MR examinations, to the team of MR
technicians and to the medical students
for their dedication and help. This study
was supported by grant 97.108 from the
Netherlands Heart Foundation. The GEM
study was conducted by the National
Institute of Public Health and the Envi
ronment,DepartmentofChronicDisease
and Environmental Epidemiology, Biltho
ven,TheNetherlands.
