Migraine and brain lesions. Data from the population-based CAMERA Study Kruit, Mark Christian

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  9 

SUMMARY&GENERALDISCUSSION

INPARTADAPTEDFROM

Cephalalgia2009,June4

 Thegeneralobjectiveofthisthesiswasto

elucidate whether migraine is a true and

independent risk factor for brain lesions.

Studies performed before the initiation

of the research project described in this

thesis remained with unresolved ques

tions and discrepancies regarding this

issue.Weaimedtofinddefiniteanswers.

Becausestudiesinnonmigrainepatients

have shown that both clinical and sub

clinicalbrainlesionscanleadtonegative

functional (cognitive and physical) se

quellae,^9092;97anincreasedriskofsimilar

lesions in migraineurs, is also likely to

have negative consequences. Because

migraineisaconditionwithahighpreva

lence, this would then apply to large

numbers of patients, and form a large

potentialsourceofneurologicaldeficitin

thegeneralpopulation.

In order to give definite answers, a

populationbased casecontrol MRI study

wasdesigned,in which potentialsources

of bias were minimized, and potential

confounding factors were as much as

possible taken care of.In theparagraphs

below,wesummarizetheprimaryresults

from the CAMERAstudy, as described in

the previous chapters. We finalize with

remarks on the relevance of the findings

presentedinthisthesis,anddescribethe

necessity of future initiatives based on

thecurrentresults.

MIGRAINEASARISKFACTORFOR

WML,SILENTINFARCTAND

STROKE

In theINTRODUCTION the clinical symp

toms of migraine attacks are summa

rized, and the IHS diagnostic criteria are

listed. The strict adherence to these

criteria is in scientific studies a sinequa

non for minimizing potential bias due to

diagnostic misclassification. Epidemi

ologic data illustrate how prevalent

migraineisinthegeneralpopulation,and

how prevalence changes by sex and age.

Several aspects of assumed migraine

pathophysiology are discussed, including

concepts around central pain processing,

brainstem trigeminovascular system

dysfunction and generation of migraine

aurathroughCSD.

InCHAPTER2wegiveanoverviewof

the complex relationship between mi

graine and ischemic stroke, at the mo

ment this research project was initiated.

Although migraine attacks may directly

lead to brain infarction (migrainous

infarction), this occurs with a low inci

dence (1.43.4/100.000) and is probably

an overdiagnosed condition, accounting

for <40% of clinical ischemic stroke in

women with migraine under age 50.

Some disorders (like CADASIL and brain

arteriovenous malformation) can mimic

migraine symptoms, and unrelated to a

migraine attack lead to brain infarction.

Incidentally, migraine symptoms are

secondary to cerebral hypoperfusion or

real ischemia by other causes, like cervi

cal artery dissection. Finally, stroke and

migraine appear often to coexist in indi

viduals without or with other stroke risk

factors (like oral contraception use,

smoking, etc.). Migraine can thus be a

true risk factor for stroke, but other risk

factors have to be considered for their

potentialcontribution.

Although hampered by methodo

logical and diagnostic problems, data

from observational and casecontrol

studiesindicatethatnotablyinwomenin

the childbearing age, migraine is associ

ated with an independently increased

risk of 2.2 (95% CI 1.92.5) for clinical

stroke. Higher risks seem to apply for

female patients with aura, with higher

attack frequency, who smoke, who have

hypertension,orwhouseoralcontracep

tives. Migraine may also be a risk factor

forsilentischemicbrainlesions,butthere

are no previous studies specifically as

sessing the prevalence of silent infarcts.

And although clinicbased MRI studies

found an increased prevalence of cere

bralwhitematterhyperintenselesionsin

migrainepatients(pooledOR3.9,95%CI

2.36.7), the results from several studies

were discrepant, and their data were

likely to be influenced by selection bias

and other methodological limitations (as

discussed).

Because of the methodological limi

tations associated with earlier case

control and clinicbased studies, definite

conclusions as to the relationship be

tween migraine and ischemic brain le

sions could not be drawn.^75;236 Since

migraine is a highly prevalent disorder,

affectingupto15%ofthegeneralpopu

lation,^7;11 and studies in nonmigraine

cases have shown that both clinical and

subclinical brain lesions increase the risk

of (new) clinical stroke events, physical

limitations and cognitive impairment,^90

92;97

establishingwhetherornotmigraine

is a true and independent risk factor for

clinical and subclinical brain lesions may

have important implications for primary

andsecondarypreventionmeasures.

Therefore, as described in

CHAPTER3, we conducted in 1999 and

2000 the CAMERA study, a population

basedcasecontrolMRIstudyinanunbi

ased sample of 295 migraine cases

(n=161MA;n=134MO)and140ageand

sexmatched nonmigraine controls, who

were randomlyselected from a previ

ously diagnosed sample (n=6039) from

the Dutch general population. This epi

demiologic approach minimized the role

of potential selection bias, and a proper,

multistep method to establish the mi

grainediagnosisminimizedthepossibility

of diagnostic misclassification and recall

bias. Sensitive imaging and lesion rating

methods, including full brain covering

thin (3mm) T2 and FLAIR slices, blinded

expert reading, and semiquantitative

lesion volume quantification, minimized

the possibility of lesion misclassification.

The complete description of the cohort,

with several baseline measurements

available from the MORGENstudy, al

lowed to statistically control for relevant

confounders. These rigid measures re

sultedinastudypopulationthatisrepre

sentativeforthegeneralpopulation,and

consists of a group of migraine sufferers

with general migraine symptomatology

and average migraine severity. Through

these guarantees, the acquired results

arerobustandcanbegeneralizedtothe

generalpopulation.

FromtheanalysesoftheMRIimages

inconjunctionwithsocioeconomicdata,

cardiovascular risk factors, and migraine

characteristics, it appeared that brain

infarction in the posterior circulation

territory occurred far more frequently in

migraine cases than expected.⁷¹ Findings

were most pronounced in migraine with

aura: 8% have subclinical cerebellar

infarcts (OR 13.7; 95% CI 1.7112; com

pared to controls, controlled for cardio

vascular risk factors). Female migraine

cases were at increased risk of high

DWMLload (top 20th percentile of the

distributionofDWMLload),independent

of migraine subtype and independent of

the effects of cardiovascular risk factors

(OR 2.0; 95% CI 1.04.2). This risk in

creasedwithattackfrequency(highestin

those with t1 attack/month: OR=2.6;

95% CI 1.26.0), suggestive of a causal

relationship.

These populationbased findings

suggest strongly that migraineurs with

and without aura are at independently

increased risk for subclinical brain le

sions.Weconcludedthat–giventhehigh

prevalence of migraine  these findings

areofpotentialpublichealthimportance

and may have implications for manage

ment guidelines for migraine; further

study into the possible etiologic mecha

nisms, but also into the potential func

tional consequences of brain lesions in

migrainepatientsisnowrequired.

CHAPTER 4 details on the finding of

increasedprevalenceofposteriorcircula

tioninfarctlikelesionsinmigraineurs.Of

all 60 identified brain infarcts, 39 (65%)

wereintheposteriorcirculationterritory,

and a majority of these (85%) were

located in the cerebellum. Lesions were

oftenmultiple,androundorovalshaped,

with a mean size 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%), cases with migraine

without aura (2.2%) and cases with

migrainewithaura(7.5%).Besideshigher

age, cardiovascular risk factors were not

more prevalent in migraineurs with

posterior circulation infarctlike lesions.

Thecombinationofvasculardistribution,

deep border zone location, shape, size

and imaging characteristics on MRI

makes it likely that the lesions have an

infarctiousorigin.

We discussed that the most likely

mechanisms are hypoperfusion and/or

embolism, rather than atherosclerosis or

small vessel disease. During and after

migraine attacks, sluggish low cerebral

flow below an ischemic threshold has

been described.42;127;128;151153

 A decrease

in brain perfusion pressure (e.g. during

migraine) theoretically affects the clear

anceanddestinationofembolicparticles;

narrowing of the arterial lumen and

endothelial abnormalities stimulate

formation of thrombi; occlusive thrombi

further reduce blood flow and brain

perfusion.¹⁴⁸Becausethedeepcerebellar

territorieshaveapatternofprogressively

tapering arteries with only few anasto

moses present, they are likely to be

particularly vulnerable to hypoperfusion

related border zone infarct mecha

nisms.^149;150

No previous study specifically re

ported on cerebellar lesions in migraine.

But interestingly, subclinical cerebellar

dysfunction has been reported in mi

graineurs,^163;164whichraisesthequestion

whether more advanced functional tests

wouldhaveidentifiedcerebellardysfunc

tion in our cases. Common forms of

migraine may share cerebellar abnor

malities to some extent with cases of

familial hemiplegic migraine, and epi

sodic and spinocerebellar ataxia (caused

byCACNA1Agenemutations).122;165171



InCHAPTER5,weevaluatedthepre

valence, frequency and distribution of

infratentorial hyperintense lesions (IHL).

Lesions were identified in 13/295 (4.4%)

migraineurs andin 1/140 (0.7%)controls

(P=.04). Twelve cases had IHLs, mostly

bilaterally, in the dorsal basis pontis,

seeming to notably affect the transverse

fibers on this location. Those with IHL

alsomoreoftenhadsupratentorialWML.

The increased prevalence of IHL in mi

graineurs extends the knowledge about

vulnerable brain regions and type of

lesions in migraine brains. Although the

brainstem is involved in migraine patho

physiology, and activation of the dorsal

rostral pons and periaqueductal gray

matter has been described during at

tacks, these regions seemed not to be

affected by hyperintense signal changes.

Wediscussed,thatthebrainstemlesions

are likely due to smallvessel disease

(arteriosclerosis) and/or repetitive perfu

sion deficits, similar to the proposed

mechanism(s) for the occurrence of

similar lesions in nonmigraine subjects

with pronounced cardiovascular risk

profileorcaseswithCADASIL.Theprecise

etiology of these lesions in migraine and

the reason why migraineurs seem to be

moresusceptibleforthiskindofvasculo

ischemic brain changes remains still

unknown.

Together,theCHAPTERS35describe

in detail the populationbased cross

sectional MRI findings in migraineurs vs.

controls. Based on these data, there is

now strong evidence that migraine is

indeed an independent risk factor for

DWMLs, silent posterior circulation

territory infarcts and IHL, with higher

risks in those with higher attack fre

quency. The earlier medical opinion that

only female migraine patients below age

45 with MA are at increased clinical

stroke risk,^5862 likely underestimates the

real extent of brain injury in migraine

patientsinthegeneralpopulation.

ETIOLOGYOFLESIONS

Several hemodynamic features of mi

graine could contribute to the patho

genesis ofboth hyperintense lesions and

infarcts in migraine, but a combination

with other factors may be necessary to

finallyresultinfocallesions.Anincreased

coagulatory propensity, vasoconstric

tion,^79;129131 local excessive neuronal

activation, neurogenic inflammation,

neuropeptide and cytokine release¹³² or

excitotoxity,¹³³ and cardiac abnormalities

(like a patent foramen ovale, PFO) have

been suggested to act as potential con

tributingorcausalfactors.ReversibleMRI

abnormalities during migraine aura,

including regions of cerebral vasogenic

edema²⁸ and evidence of vasogenic

bloodbrain barrier leakage in prolonged

aura have been reported.^27;237 These

abnormalities were linked to (temporal)

impairment of the bloodbrain barrier

(BBB) integrity and enhanced permeabil

ity of meningeal microvessels.^27;238 There

areargumentsthatCSDcausesdisruption

of the BBB through a matrix metallopro

teinase9 dependent cascade mecha

nism, possibly together also resulting in

localtissuedamage.²⁵Penetrationofany

toxicagentthroughatemporallyreduced

BBB, might be an explanation for the

development of (focal) WML or (silent)

infarcts. From studies in experimental

andhumancerebralischemiaitisknown

that periinfarct CSDlike depolarization

potentiatesinfarctgrowth.²³⁹

The crosssectional approach of our

study does not permit answering patho

physiological questions. With the estab

lishedrelationshipbetweenmigraineand

brainlesions,wenowneedtoplanstud

ies assessing etiology and relevance of

brainlesionsinmigraine.

IRONDEPOSITSINMIGRAINE

In a previous preliminary MRI study,

brain iron levels were found to be in

creased in the periaqueductal grey mat

ter (PAG) of migraine patients attending

an headache clinic.⁷² This was suggested

to reflect an impaired central antino

ciceptive neuronal network in patients

with severe migraine. InCHAPTER 6, we

examined iron concentration in deep

brainnucleiwithMRIinparticipantsfrom

the CAMERA study, and correlated this

with migraine diagnosis and subtype,

number of attacks experienced, and

duration of migraine history. T2 values

derived from dualecho MR images

(1.5T) were measured in seven deep

brain nuclei in migraine cases (n=138)

and controls (n=75). The relationship

betweenironconcentrationandT2value

permits quantitative assessment of

differences in iron concentration in vivo.

We separately analyzed subjects under

(n=112) and above age 50 (n=101), be

cause measurements in older subjects

are increasingly influenced by noniron

related factors. In migraineurs aged <50,

compared to controls, T2values were

lower in the putamen (P=.02), globus

pallidus (P=.03) and red nucleus (P=.03).

Controlling for age (in these younger

migraineurs),thosewithlongermigraine

history had lower T2 values in the puta

men (P=.01), caudate (P=.04) and red

nucleus (P=.001). We found no differ

encesbetweenMAandMO.

The findings suggest that repeated

migraine attacks are associated with

increased iron concentration in multiple

deep brain nuclei that are known to be

involved in central pain processing and

migraine pathophysiology. Accumulation

of iron in migraineurs thus not only

occursintheperiaqueductalgreymatter,

as suggested by the earlier study. It

remains unclear whether the increased

iron concentration is just a physiological

response induced by repeated activation

ofnucleiinvolvedincentralpainprocess

ing, or whether the increased iron con

centration could also damage these

structuressecondarily,e.g.duetoforma

tion of free radicals in oxidative stress.

Theoretically, damage to these pain

processing nuclei might explain the

occurrence of chronification of the dis

ease in a minority of migraine patients.

Recent observations from other MRI

studies also point at disturbances in the

painprocessingnetwork, and support

the concept that changes in a chain of

brainlocationsoccurinmigraineurs.^240;241 Further study into pain mechanisms in

migraine should not be limited to the

brainstem areas, but should cover a

broader scope, and consider the whole

involvedpainnetwork.

SYNCOPE,MIGRAINEANDBRAIN

LESIONS

Many earlier studies evaluated the func

tion of the autonomic nervous system

(ANS) in migraineurs. Studies were

mostly performed interictally in clinic

basedsamples,^715andreportedinconsis

tent findings of either increased or de

creased sympathetic or parasympathetic

function.Becauseofthesediscrepancies,

because several reports suggest that

migraine and syncope cooccur together

more frequently than chance would

predict,andbecausepreviousstudiesdid

not address clinical symptoms of ANS

failure, including syncope, orthostatic

insufficiency (OI) and postural tachycar

dia syndrome (POTS), we assessed in

CHAPTER 7 the prevalence of these enti

tiesinmigraineusingapopulationbased

design.

Migraineurs with and without aura

(n=323) and control subjects (n=153)

from the CAMERA study answered a

systematic questionnaire and underwent

cardiovascular measurements during

rest, while standing and after venipunc

ture, together addressing the prevalence

of syncope, OI, OH and POTS. The data

showed that (compared to controls)

migraineurs had a higher lifetime preva

lence of syncope (46% vs. 31%, P=.001),

frequent syncope (5 attacks; 13% vs.

5%,P=.02)andOI(32%vs.12%,P<.001).

There was no association between ANS

symptomsandtheseverityofmigraineor

migraine subtype. Cardiovascular meas

urements and the prevalence of POTS

and OH did not differ significantly be

tweenmigraineursandcontrols.

Thisfirstpopulationbasedstudyas

sessing clinical presentations of ANS

dysfunctionaswellasBPandHRreflexes

in migraine, showed an increased preva

lence of syncoperelated ANS symptoms

in migraineurs compared to controls.

Because of these findings, but also be

cause we found that migraineurs are at

increased risk of subclinical brain lesions

and clinical stroke (chapters 25), the

purpose of CHAPTER 8 was to assess

whether syncoperelated ANS symptoms

andsignsareriskfactorsforbrainlesions

inbothmigraineursandcontrols.

The multivariate analysis of theMRI

datafromthesameparticipantsrevealed

that frequent syncope and orthostatic

insufficiency were independent risk

factors for highDWMLload in both

controls(infemales:OR=8.8;95%CI:1.4

55)and migraineurs (in females: OR=5.7;

95% CI:2.115). Female migraineurs

without a history of frequent syncope or

OI still remained at a significantly in

creasedriskofhighDWMLload(OR=2.4;

95% CI: 1.15.3). Individuals with OI had

higher prevalence of highPVWMLload

(2% vs. 8%, P=.005), and individualswith

OH had higher prevalence of IHL (2% vs.

9%, P=.005), but not of supratentorial

lesions.SyncopeandOIwerenotrelated

to subclinical infarcts or infratentorial

lesions. POTS was not found to be risk

factorsforbrainlesions.

We identified frequent syncope and

OI as independent risk factors for high

DWMLload in both controls and mi

graineurs. These findings may suggest

that those with impaired control of

cerebral perfusion pressure are at in

creased risk for ischemic white matter

tissue damage, irrespective of migraine

status. In female migraineurs, this adds

to the known increased risk of high

DWMLload (chapter 3), but does not

completely explain it. Impaired sympa

thetic nervous system function may be

considered as a possible key to under

stand the described associations. Addi

tionalstudiesareneededtoconfirmand

explorethesefindings.

SIGNIFICANCEOFBRAINLESIONS

INMIGRAINE

The data from the populationbased

CAMERA study support and extend the

results from earlier studies, and indicate

that migraineis associated with asignifi

cantly increased risk of subclinical and

clinical ischemic brain lesions.⁷¹ The

robustness of the methods and the

validity of the findings have been ac

knowledged.192;235;242

 Supportive evi

dence for the association between mi

graine and increased risk of cardiovascu

lar related events, comes from the US

Women'sHealthStudy(n=27,840),show

ing that active migraine with aura was

associated with increased risk of major

cardiovasculardisease,myocardialinfarc

tion, ischemic stroke, and death due to

ischemic cardiovascular disease, as well

as with coronary revascularization and

angina.²⁴³

A causal relationship between mi

graine attacks and brain lesions and iron

depositionswassuggestedbythefinding

of higher risk of lesions in those with

higher attack frequencies or longer

migraine history. To prove that ongoing

migraine attacks lead to progression of

lesions, we need followup data showing

that there is a higher rate of lesion pro

gression over time in migraine cases,

compared to (e.g. age related) progres

sion of lesions in controls. In addition,

identification of a linear relationship

between migraine severity (e.g. attack

rate)andvolumeoflesions(progression),

will increase the likelihood of a causal

relationship.

Numerous studies in nonmigraine

elderlysubjectsdemonstratedthatsilent

brain infarcts and WML are associated

with increased risk of stroke, dementia,

and cognitive decline.^9092;97 Findings in

several studies also suggest that impair

ment of cortical brain function occurs

more often in clinicbased migraine

patients than in controls,²⁴⁴ and some

authors described significant cognitive

changes during and between migraine

episodes,^245249 but others failed to con

firm these findings.^250253 Differences in

patient population, cognitive test selec

tion,andmethodologiesusedtoconduct

neuropsychological examinations likely

account for dissimilarities in results

across studies. Cerebellar dysfunction in

migraineurshasalsobeensuggestedina

fewstudies,^163;254andisaknownentityin

familial hemiplegic migraine (a rare type

of inherited migraine)^255;256 However,

with respect to migraine patients, it is

still unknown whether brain lesions do

have any negative (longterm) functional

consequences. For these reasons to

gether, it is now essential to measure

cerebral or cerebellar function in mi

graineurs, and correlate the results with

eventual presence and progression of

brainlesions.

Confirmation that recurrence of mi

graine attacks is indeed associated with

an increasing risk of brain lesions and/or

brain dysfunction, will change migraine

from an episodic disorder to a chronic

episodic or chronic progressive disor

der.¹⁹²Suchashiftinconceptualizationof

the disease also will change goals of

treatments, and prevention of migraine

maythenpotentiallyneedtobecomean

important target for secondary preven

tion in the general population. This

should boost the interest of academic

institutes and pharmaceutical companies

to invest in the development of specific,

effective prophylactic (rather than symp

tomatic) migraine agents, which are

currently lacking. Such new therapeutic

strategies, have then to be tested in

randomizedcontrolledtrials.

Identificationof specific factors that

increase the risk of brain lesions in mi

graine patients, such as migraine type,

migraine severity, sympathetic nervous

system dysfunction, cardiovascular risk

factorsandPFO,mayallowidentification

of specific subgroups to be treated. For

instance,demonstrationofanassociation

betweenMRIlesionsandthepresenceof

a PFO would promote the (renewed)

initiation of prospective randomized

clinical trials on the effect of closure of

PFO on migraine severity and associated

brainlesions.

IMPACTOFTHESEFINDINGSFOR

MIGRAINEPATIENTS

TheprimaryresultsoftheCAMERAstudy

included the finding that a highly preva

lentandpreviouslyconsideredharmless

although disabling disorder as migraine

is associated with an up to 14fold in

creased risk of brain lesions. Our first

article captured worldwide media atten

tion, including prime time television and

radio broadcasts, and generated reports

in newspapers and all over the Internet.

The headlines were sometimes over

simplified and frightening: “Migraine

causes permanent brain damage.” “Mi

graine causes holes in your brain.” And,

“Migrainemighthandicapyou.”

Thiswidespreadcoverageprompted

concern and confusion among migraine

patients. Many general practitioners and

neurologists had to answer questions

about what migraineurs should do with

these‘alarming’newfacts.Ourresponse

to thesequestionsis,that becausethere

are not yet data available on the func

tional correlates or on the risk of pro

gressionoflesions,atthismomentthese

findingshavenodirectconsequencesfor

migraine patients and/or the present

lines of migraine management. We

actively propagated this view in a press

release, newspaper articles, and contri

butions to several websites and other

media.

NEURORADIOLOGICAL

CONSIDERATIONS

The knowledge that migraine is an inde

pendent risk factor for highDWMLload

and posterior circulation infarcts can not

be translated directly to an individual

patient or MRI scan. In routine neurora

diological practice, on FLAIR and/or T2

images hyperintenselesions in the white

matter are frequently encountered in

subjects above age 50, but can also

appearinyoungerindividuals.Theclinical

context,thenumber,aspectanddistribu

tionoflesions,andtheageofthepatient

together, enable the neuroradiologist

only in a limited number of cases to

identifyacauseofthelesions,butmostly

lesions remain ‘aspecific’, and/or ‘proba

blybasedonvasculoischemicprocesses’.

Theidentifiedwhitematterhyperintense

lesionsinthemigraineursintheCAMERA

study appeared not to present in a spe

cificpattern,onapreferentiallocationor

after a certain age. Therefore, to our

opinion, WML in individual patients can

not be attributed to migraine directly.

Because data are lacking on functional

consequencesofsuchlesions,theidenti

fication of a limited number of small to

medium sized lesions does not need

further medical attention in general. In

other cases, evaluation of potential

causesoflesionsshouldbeconsidered.

Incidentally, WMLs are observed in

MRI images from relatively young pa

tients (e.g. below age 3540). In such

cases number, location, aspect and

distribution of the lesions have to be

carefully evaluated, and based on the

images and clinical history together,

likelihood of diseases (e.g. multiple

sclerosis, vasculitis, CADASIL, MELAS,

coagulationdisorders,cardiacabnormali

ties, etc) associated with white matter

lesions has to be considered. With the

observations from the CAMERA study,

‘migraine’hastobeaddedtothislist,but

this does not imply that other options

can be disregarded, or that migraine is

‘thecause’ofthelesionsinapatientwith

migraine.

Similarly,theidentificationofoneor

moresilentcerebellarinfarctsonanMRI

scan can not directly be attributed to

‘migraine’, although this findings  with

the data from the CAMERA study, show

ing 8% affected  is not so unusual in

migraine patients with aura. In such

cases, if the observation is incidental, no

direct clinical consequence seems to be

necessary, until data is available regard

ing potential progression or functional

consequencesofsmallcerebellarinfarcts.

Iffutureresearchindicatesthatthereisa

risk of progression of number or size of

lesions or if there are associated func

tional consequences, additional study of

causes and evaluation of usefulness of

preventive therapy has to be initiated.

However,apatientwhopresentswithan

acute cerebellar infarct, irrespective of

the size of the lesion or presence of

migraine, has to be screened for (em

bolic) sources of the infarction, and

treatedaccordingly.

FUTUREPERSPECTIVES

Weshowedthatthe‘averagemigraineur’

from the general population has in

creased risks of cerebral WML and cere

bellar infarcts. As the risk was higher in

those with higher attack frequency, we

hypothesize that migraine attackscauses

(progressive) brain damage in at least

subgroups of patients. To prove this

hypothesis,furtherresearchisnecessary.

In addition, we need to assess whether

the identified brain lesions have any

functionalconsequences.

FOLLOWUPSTUDY:PROGRESSION

&FUNCTIONALCONSEQUENCES?

Whether progression of migraine is

relatedtoprogressionofbrainlesioncan

only be demonstrated in a longitudinal

design. We therefore started in 2008 to

rescan and reevaluate the entire

‘CAMERA’ case and control population

that was originally scanned in 1999 and

2000. We planned to measure the

changeinbrainlesionloadinmigraineurs

vs.controlsafter8years.Becauseofthe

high prevalence of PFO in MA, we in

cluded a cardiac righttoleft shunt

screening with transcranial Doppler, to

assessthecontributionofPFOintherisk

of migrainerelated brain lesions. An

other aim is to study the functional

consequencesofthebrainlesions.

Inthisfollowupstudy,wehypothe

size that migraine patients show attack

frequency dependent (i) progression of

number and volume of brain lesions, (ii)

cognitive impairment and (iii) cerebellar

dysfunction. We hypothesize further,

that the subgroups at highest risks of

brain lesion consist of cases with high

attack frequency, MA, and/or PFO; this

will be particularly strong in female

migrainepatients.

Inthisstudy,wewill:

1. rescan the entire populationbased

CAMERA case and control study

population;

2. assess progression of lesions within

affectedcasesandidentifynewlyaf

fectedcases;

3. assess quantitative measures of

globalandregionalbrainatrophy

4. correlate gender and migraine char

acteristics (aura, attack frequency,

useofmigrainemedication)tocross

sectional and longitudinal differ

encesinMRIfindings;

5. screenforthepresenceofacardiac

righttoleft shunt with transcranial

Doppler indicative for a likely PFO,

and correlate if this with the pres

enceandprogressionofMRIlesions

6. testforimpairedcerebellarfunction

with an eye blink conditioning test

and swaytest and correlate findings

withMRIabnormalitiesandmigraine

characteristics;

7. testcognitivefunctionwithaneuro

psychological test battery similar to

theoriginalCAMERAstudy;compare

results crosssectionally and longitu

dinally with baseline, correlate find

ings to (longitudinal) MRI findings

andmigrainecharacteristics.

ETIOLOGYOFLESIONS

ICTALSCANNING

Another approach to assess whether

migraine attacks change the brain is to

perform MRI scans during migraine

attacks. Several types of MRI data are of

interest,includingstructuralinformation,

(regional) brain perfusion values, perme

ability of BBB, brain activation measures

andpatterns,andconcentrationvaluesof

several metabolites. Ictal scans, prefera

bly also during the initial phase of aura

symptoms (CSD), need then to be corre

lated to either preictal scans, postictal

scans, or ideally both. Because of the

episodic character of the disorder, but

alsobecauseoftheassociatedsymptoms

(nausea, vomiting, and sensitivity to

light/sound/movement), the planning

and execution of such studies is difficult,

butnotimpossible.

OTHERCONTRIBUTORSORCAUSES

Asindicatedintheparagraphsabove(see

‘Etiology of lesions’), a variety of poten

tial other causes or contributors to the

occurrence of brain lesions could play a

role,andneedtobeconsideredasfuture

studyopportunities.

x Brain perfusion changes: may lead to

focal hypoperfusion and ischemia,

and have to be assessed during mi

graine attacks; see ‘Ictal scanning’

(above).

x Presenceandrelevanceofneurogenic

inflammationandneuronalexcitation

may be of value to be assessed also

duringictalevaluationofmigraine.

x There is increasing evidence that

migraine is associated with (acute)

endothelial dysfunction, which may

lead to impaired vasodilatation, im

pairedvascularreactivity,²⁵⁷increased

platelet aggregation,²⁵⁸ and inflam

mation.²⁵⁹ Endothelial dysfunction is

knowntopotentiallyleadtotransient

ischemic attack and stroke.²⁶⁰ Mi

graineprevalenceislikelyincreasedin

personswithpolymorphismslinkedto

endothelial dysfunction.130;261266



 We are currently underway to

evaluate laboratory samples of the

CAMERA study population for evi

dence of endothelial dysfunction. We

aim to determine if endothelial dys

function is associated with migraine,

and in particular, migraine with aura.

Plasma markers of endothelial dys

functionandassociatedfactorswillbe

studied in available specimens. Fur

ther, plasma biomarkers of endothe

lialdysfunctionwillbetestedfortheir

predictive value on the development

ofbrainlesionsovertime.

x Other laboratory analyses can be

considered to evaluate neuropeptide

and cytokine release during migraine

attacks, and other factors that may

play a role in increasing coagulatory

propensity.

BRAINCHANGESBEYONDWML’S

ANDINFARCTS?

In the CAMERA study, we identified

(interictal) MRI visible lesions in mi

graineurs. Diffuse changes in the white

and/or gray matter may remain unde

tected using conventional MRI se

quences, and could be assessed using

other, more sensitive MRI methods, like

magnetizationtransferimaging, diffusion

(tensor) imaging, or imaging at higher

field strengths, with greater anatomical

detail.Similarly,moredetailedimagingof

the brainstemandcerebellum is likely of

additive value. Evaluation ofirondeposi

tion in deep nuclei (and grey matter?) is

alsopossibleinamoresensitivewaythan

wecouldperformintheCAMERAstudy.

CONCLUSION

In this thesis we presented strong evi

denceforthehypothesisthatmigraineis

a true and independent risk factor for

brainlesions,includingDWMLs,IHLsand

posterior circulation infarcts. Some data

suggested a causal relationship between

migraine attacks and lesions, but the

crosssectional approach of the study

does not permit a definite conclusion.

Although syncoperelated autonomic

nervous system symptoms were more

prevalent in migraineurs compared to

controls, and these factors were also

shown to be associated with increased

risk of white matter lesions in mi

graineurs and controls, they did not

explain the increased risk of deep white

matter lesions in female migraineurs.

Repeated migraine attacks were shown

to be associated with increased iron

concentration in multiple deep brain

nuclei.Thisissuggestiveforaconceptin

which a chain of nuclei is involved in

central pain processing in migraine,

rather than only one (or few) brainstem

structure.

Further study is needed to assess

whetherongoingmigraineattacksleadto

progressionoflesions.Atthesametime,

evaluation of potential functional conse

quences of lesion has to be performed.

Several etiologic options have to be

considered for their possible relevance.

We listed a number of future directions

of scientific research in this field. After

demonstrationofaprogressivenatureof

lesions, and/or demonstration of any

negative functional consequences of

lesions,migrainehastobereappraisedas

a chronicepisodic or chronic progressive

disorder, and changes in migraine man

agement aimed at prevention of lesions

havetobeconsidered.