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

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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  5 

BRAINSTEMANDCEREBELLARHYPERINTENSE

LESIONSINMIGRAINE

MarkC.Kruit

DepartmentofRadiology,LUMC



LenoreJ.Launer

LaboratoryofEpidemiology,DemographyandBiometry,

NationalInstituteonAging,NIH,Bethesda



MichelD.Ferrari

DepartmentofNeurology,LUMC



MarkA.vanBuchem

DepartmentofRadiology,LUMC























 Stroke2006;37:11091112

A B S T R A C T 

Background and Purpose Migraineurs are at increased risk of cerebellar infarcts and

supratentorial white matter lesions. The prevalence, frequency, and distribution of

infratentorialhyperintenselesionsinmigraineareunknown.

Methods Migraineurs with aura (n=161), without aura (n=134), and controls (n=140)

from a populationbased sample of adults (30 to 60 years of age) were evaluated with

MRI.

ResultInfratentorialhyperintensitieswereidentifiedin13of295(4.4%)migraineursand

in1of140(0.7%)controls(P=.04).Twelvecaseshadhyperintensities,mostlybilaterally,

in the dorsal basis pontis. Those with infratentorial hyperintensities also had supraten

torialwhitematterlesionsmoreoften.

ConclusionWefoundanincreasedprevalenceofinfratentorial(mostlypontine)hyperin

tensitiesinmigraineursfromthegeneralpopulation.Thisextendstheknowledgeabout

vulnerablebrainregionsandtypeoflesionsinmigrainebrains.Ahemodynamicischemic

pathogenesisislikely,butfurtherresearchisneeded.





INTRODUCTION

We showed in a populationbased MRI

study that migraineurs with aura (MA)

havea12foldincreasedriskofcerebellar

infarcts,andthatfemalemigraineurshad

more supratentorial deep white matter

lesions (DWMLs)than nonmigraineurs.⁷¹ The risk of lesions increased with attack

frequency,independentofcardiovascular

risk factors. Based on the same popula

tionbased study, we now describe the

prevalence, distribution pattern, and as

sociated neuroimaging characteristics of

infratentorialhyperintenselesions(IHLs).

METHODS

The Dutch populationbased Genetic

Epidemiology of Migraine (GEM) and its

substudy, the Cerebral Abnormalities in

Migraine, an Epidemiological Risk Analy

sis (CAMERA) MRI Study have been

described previously.^7;71 In brief, 863

migraineurs and 5628 controls were

identified in the GEM study according to

the IHS criteria.³ From those 30 to 60

years of age, we randomly selected for

the MRI study 134 migraineurs without

aura (MO), 161 MA, and 140 controls

frequency matched by sex, 5year age

TABLECaseSummaryofParticipantswithInfratentorialHyperintenseLesions

 Migrainecharacteristics Brainlesions†

Cases Age/sexRiskfactors* Diagnosis Ageof

onsetend

Average

attacks/yr

Infratentorial hyperintensity

DWML score‡

PVWML

score‡ Infarcts

1 41/F ht,hcr MA 33 18  Pons(3) 1 1 

2 42/F ht MO 11 7  Cerebellum(1) 1 2 

3 43/F ht MA 14 43  Cerebellum(3) 0 0 

4 52/M ht MA 32 14  Pons(5) 1 2 

5 52/F ht MO 3351 12  Cerebellum (3)

Pons(3)

7§ 4§ 1temporallobe

(10mm)

6 52/F ht MO 25 6  Pons(5) 11§ 2 

7 55/M ht MA 25 6  Pons(5) 0 1 

8 56/M ht,hcr MO 20 15  Pons(5) 9§ 5§ 

9 60/F  MO 1454 12  Pons(5) 6§ 2 

10 61/M ht MA 7 3  Pons(5) 3 0 1cor.radiata(4mm)

11 61/F ht MA 20 6  Pons(5) 13§ 3§ 

12 61/F ht MA 1556 32  Pons(5) 10§ 2 

13 61/F hcr Co    Pons(5) 17§¶ 4§ 2capsulainterna

(both3mm);

1thalamus(2mm)

14 63/F ht,hcr MA 30 30  Pons(5) 6 3§ 

* htindicateshypertension;hcr,highcholesterolratio

† location(Scheltensscore/size);‡Scheltensscore

§ Alsoclassifiedashaving‘highDWMLload’or‘highPVWMLload’

¶ Largeconfluentwhitematterlesion

strata, and place of residence. Neither

cases and controls nor responders (69%)

and nonresponders differed by age, sex,

andcardiovascularriskfactors.

Threemillimeter axial slicesof brain MRI

were acquired with proton density (PD),

T2weighted, and fluidattenuated inver

sion recovery (FLAIR) sequences. Blinded

to clinical status, 1 neuroradiologist read

all images and recorded topographic

details of observed abnormalities. IHLs

were hyperintense on PD and T2 images

and were not hypointense on FLAIR

images.^172175 Periventricular white mat

ter lesions (PVWMLs) and DWMLs (sub

cortical) were scored with semiquantita

tive scales with known reliability and

validity.¹¹⁸ In addition, the white matter

lesion Scheltens score was calculated.¹¹⁷ PVWMLscores>3(of15)andthehighest

20% volumes of total DWML load were

classifiedintheanalysesashighload.

RESULTS

IHLs were identified in 1 of 140 controls

(0.7%) and 13 of 295^migraineurs (4.4%;

P=.04), slightly more in MA (8 of 161;

5.0%)^thaninMO(5of134;3.7%;TABLE).

Allsubjectshadanormal^standardneuro

logical examination and no history of

transient^ischemicattackorstroke.^ Of the 14 cases with IHLs, 3 had 1

smalltomediumsize(2to^5mm)lesions

FIG1T2andFLAIRimagesof2caseswithcerebellarhyperintenselesions.



in the deep cerebellar white matter that

were^hyperintenseonallpulsesequences

(FIGURE 1) and confined^to the posterior

inferiorcerebellararteryterritory.

Twelve^caseshadIHLslocatedinthe

pons (pontine hyperintense lesions^ [PHLs]):1of140controls(0.7%),7of161

MA (4.3%;P=.05^vs. controls), and 4 of

134 MO (3.0%). PHLs were visible^on 2,

toamaximumof6,slices.Allwereinthe

dorsal basis pontis, adjacent to the teg

mentum, at the level of, and slightly

cranial to, the entry zone of the trigemi

nal nerve (FIGURE 2). None reached the

surface. In 4 cases, the lesions extended

to the midline. In 11 of 12 cases, PHLs

were bilateral and more or less symmet

rical. Lesions seem to involve the ponto

cerebellar fibers, the pontine nuclei, or

the nucleus reticularis tegmenti pontis,

and, in some cases, parts of the cortico

pontine (pyramidal tract) or medial

lemniscus fibers. PHLs were in the terri

tories supplied by the anteromedial and

anterolateral groups arising from the

basilarartery.

Comparedwiththosewithout,those

with IHLs significantly more often had

high PVWML load (8% vs. 31%; P<.005)

and high DWML load (19% vs. 43%;

P<.05), but there were no significant

differences in infarct prevalence (7% vs.

18%) or, more specifically, in cerebellar

infarct prevalence (4% vs. 0%). Migraine

caseswithandwithoutIHLsweresimilar

with respect to migraine type, attack

frequency, age at onset, or treatment

status.

DISCUSSION

Populationbased migraineurs had IHLs

more often than controls. IHLs were

associated with PVWML and DWML but

FIG 2T2andPDimagesatthemidpontinelevelshowingPHLsin4cases.Conspicuityof

thelesionsdifferedbetweenT2andPDweightedimagesfromcasetocase.



not with cerebellar infarcts, as described

previouslyinmigraineurs.⁷¹Inthemajor

ity of cases (86%), hyperintensities were

located in the midpontine parenchyma

(PHLs). The brain stem is involved in

migraine pathophysiology, and specific

activation of the dorsal rostral pons and

periaqueductal gray matter have been

reportedduringmigraine.¹⁷However,the

specific ‘migraine areas’ were not in

volvedinourcases.

In cerebral autosomal dominant ar

teriopathy with subcortical infarcts and

leukoencephalopathy (CADASIL), a disor

der in which MA often is the presenting

symptom, similar brain stem hyperinten

sities are frequent.¹⁷⁴ In CADASIL, de

creased cerebral perfusion secondary to

changes in the wall of cerebral arteries

leads to early damage of the periven

tricular and deep supratentorial white

matter.Thoseregionsareirrigatedbythe

longest perforating arteries and are thus

the most vulnerable to hypoperfusion.

Thisisparticularlythecaseforthecentral

part of the pons. Repeated or prolonged

reduced perfusion has been described in

migraine attacks, although not specifi

callyinthepons.¹²⁷Thereisevidencefor

impairedadaptivecerebralhemodynamic

mechanisms in the posterior circulation

ofmigrainepatients.¹⁶²

WearenotawareofreportsonPHLs

in migraine. Most reports on PHLs de

scribe an association with an increased

cardiovascular burden,172;173;175

 leuko

araiosis, lacunar infarcts,¹⁷³ and poor

clinical outcome.¹⁷⁵ A histopathological

study reported a good correlation be

tween PHLs and MRI changes.¹⁷² Sym

metrical PHLs (histologically correspond

ingtomyelinpallorandreactiveastrocy

tosis) have a comparable pathophysiol

ogy as lesions in subcortical arterioscle

roticencephalopathy,ie,ischemiasecon

dary to smallartery sclerosis. Small

vessel disease or repetitive perfusion

deficits are likely to be common patho

physiological mechanisms for PHLs,

DWMLsandPVWMLs,andlacunarinfarc

tion.^172;173

The origin of PHLs is not known. A

number of specific relatively infrequent

clinicalentities,includingmultiplesclero

sis, encephalitis, Behçet disease, osmotic

myelinolysis, hypertensive encephalopa

thy,neoplasm,chemotherapy,andradia

tion, have been implicated but were

excluded in our sample. Similarly, en

larged perivascular spaces or brain stem

infarcts as a cause for pontine T2 hyper

intensitieswere excluded because of the

absence of concomitant hypointense

changesonT1orFLAIRimages.¹¹⁴

In summary, we found an increased

prevalence of infratentorial (mostly

pontine) hyperintensities in migraineurs

from the general population. This ex

tends the knowledge about vulnerable

brain regions and type of lesions in mi

graine brains. The etiology of these

lesions in migraine is unknown but likely

attributable to smallvessel disease

(arteriosclerosis), repetitive perfusion

deficits, or both; further research is

needed.