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  7 

SYNCOPEINMIGRAINE

RolandD.Thijs^*

DepartmentofNeurologyandClinicalNeurophysiology,LUMC



MarkC.Kruit^*

DepartmentofRadiology,LUMC



MarkA.vanBuchem

DepartmentofRadiology,LUMC



MichelD.Ferrari

DepartmentofNeurology,LUMC



LenoreJ.Launer

LaboratoryofEpidemiology,DemographyandBiometry,

NationalInstituteonAging,NIH,Bethesda



J.GertvanDijk

DepartmentofNeurologyandClinicalNeurophysiology,LUMC





*Bothauthorscontributedequally.











Neurology2006;66:10341037

A B S T R A C T 

ObjectiveToexaminetheassociationbetweenmigraineandsyncoperelatedautonomicnervous

system(ANS)symptoms.

MethodsApopulationbasedstudyamongmigraineurswithandwithoutaura(n=323)andcontrol

subjects (n=153) was conducted. A systematic questionnaire and cardiovascular measurements

during rest, while standing, and after venipuncture addressed the prevalence of syncope,

orthostatic intolerance, orthostatic hypotension (OH), and the postural tachycardia syndrome

(POTS)inmigraineursandcontrolsubjects.

ResultsThelifetimeprevalenceofsyncopeinallparticipantswas41%,moreofteninwomen(45

vs.32%;P=.02).Comparedwithcontrolsubjects,migraineurshada higherlifetimeprevalenceof

syncope (46 vs. 31%; P=.001), frequent syncope (five or more attacks) (13 vs. 5%; P=.02), and

orthostatic intolerance (32 vs. 12%; P<.001). There was no association between ANS symptoms

and the severity of migraine or migraine subtype. Cardiovascular measurements and the

prevalenceofPOTSandOHdidnotdiffersignificantlybetweenmigraineursandcontrolsubjects.

ConclusionThis populationbased study demonstrated an elevated prevalence of syncope and

orthostatic intolerance in migraineurs without clear interictal signs of autonomic nervous system

dysfunction.

Migraine is an episodic multifactorial

neurovascular disorder characterized by

recurrent attacks of disabling headache,

autonomicdysfunction(migrainewithout

aura [MO]), and focal neurologic aura

symptoms (migraine with aura [MA]).^3;4 Syncope is a paroxysmal symptom con

sisting of a brief, selflimiting transient

loss of consciousness due to global cere

bral hypoperfusion.²⁰³ The prevalence of

bothsyncopeandmigraineishighinthe

general population.^7;203 Several reports

suggest that both conditions cooccur

together more frequently than chance

wouldpredict.

Fainting spells occurred more often

among women with ‘migrainous head

ache’(11%)comparedwithcontrols(2%;

P<.001) in a populationbased study.²⁰⁴ Syncope has also been reported to fre

quently occur during migraine attacks.²⁰⁵ However, neither study used standard

ized and validated methodsfor the diag

nosisofmigraine³andsyncope.²⁰³ The autonomic nervous system

(ANS) has been studied extensively in

migraineurs, mostly in clinicbased sam

ples and for cardiovascular reflex re

sponses mostly in between attacks.^206214 Results were conflicting in that both

sympathetic hypofunction^207213 and

hyperfunction²¹⁴ and both parasympa

thetic hypofunction^207;208 and hyperfunc

tion²¹⁴ have been reported. In the only

populationbased study to date, mi

graineurs with disabling attacks were

more prone to ANS dysfunction than

those with nondisabling attacks.²⁰⁶ This

underscorestheimportanceofapopula

tionbased approach to avoid bias in

assessing the relationship between

migraineandANSdysfunction.

Previous studies did not address

clinical symptoms of ANS failure, includ

ing syncope, orthostatic intolerance, and

the postural orthostatic tachycardia

syndrome (POTS). Here, we assessed the

prevalenceofsyncopeandrelatedsymp

toms in migraine using a population

baseddesign.

METHODS

A complete description of the Cerebral

Abnormalities in Migraine, an Epidemi

ologic Risk Analysis (CAMERA) study

population and methods has been de

tailed elsewhere.⁷¹ In brief, cases and

controls were randomly selected from

the Genetic Epidemiology of Migraine

study, a populationbased survey of

6,491 Dutch adults aged 20 to 60 years

living in two representative Dutch mu

nicipalities (Maastricht and Doet

inchem).⁷Eighthundredsixtythreecases

of migraine were identified according to

International Headache Society criteria³;

54%ofthecaseshadnotbeenpreviously

diagnosed by a physician. We randomly

selected both MA and MO patients as

well as a control group that frequency

matched the cases by sex, municipality,

and 5year age strata. Controls were

selected from those who had indicated

thattheyhadnosevereheadachesinter

fering with daily activities and who had

ratedanyheadachestheyhadas0onthe

pain scale. This effectively excluded

people with chronic daily headache and

cluster headache. We invited 631 indi

viduals; 476 participated in the current

study (80% of migraineurs, 67% of con

trols). Of the remainder, 114 actively

declined participation, 36 could not

participate for various logistic reasons,

and 5 individuals (4 migraineurs, 1 con

trol) were excluded as they had not

completed the syncope questionnaire.

There were no significant differences

between responders and nonresponders

or between nonresponding cases and

nonresponding controls concerning the

following items: age, sex, cardiovascular

risk factors (i.e., body mass index [BMI],

smoking, cholesterol, blood pressure

[BP], diabetes, and oral contraceptive

[OC] use). There was a trend for re

sponders having had more years of

schooling than nonresponders (P=.07).

The study protocol was approved by the

ethics committees of the cooperating

institutions. All participants gave written

informed consent and participated with

outanyfinancialreimbursement.

Thestudy protocolincludeda struc

tured telephone interview, a clinic visit

for a standard physical and neurologic

examination, blood draw, and a brain

MRI study. The telephone interview was

carriedoutbyoneofthreetrainedinter

viewers, who used a computerized,

structured interview,with relevantques

tions presented on the computer screen

that had to be read aloud literally. The

hospitalvisittookplacewithin10daysof

thetelephoneinterview.

Sociodemographic and medical

characteristics were assessed by inter

viewandphysicalexamination.Education

wascategorizedintolow(primaryschool

or lower vocational education) and high.

The average alcohol intake in the last

year was based on responses to ques

tionsonfrequencyandquantityofdrinks

per occasion and categorized into none,

moderate (1 to 3 drinks/day), and high

(3drinks/day).Selfreportedweightand

height were used to calculate BMI

(weight [kg]/height²[m]). A structured

telephonequestionnaireinvestigatedthe

prevalence of syncope and the occur

rence of symptoms (syncope, near syn

cope, or avoidance) during prolonged

standing (queues, during receptions),

during a long hot shower, after a heavy

meal, after exercise, or at the sight of

blood or during a venipuncture. These

circumstances are known syncope trig

gers for patients with autonomic failure,

vasovagalsyncope,ororthostaticintoler

ance, with as exceptions that venipunc

ture acts as a syncope trigger only for

patients with vasovagal syncope and a

heavy meal only for patients with auto

nomicfailure.^203;215

In the interview,syncope (‘fainting’)

wasexplained,toallparticipantswiththe

same standard text, as a brief loss of

consciousnessthatmightbeprovokedby

thesightofbloodorwhilestandingfora

longtimeintheheatbutthatcouldoccur

without a clear provocation. Loss of

consciousness due to head injury or an

epileptic seizure was excluded as syn

cope. ‘Near syncope’ was defined as the

symptoms that usually precede a faint

butcanalsooccurseparatelyandconsist

of dizziness, lightheadedness, loss of

concentration, ringing in the ears, or

darkening of sight. The occurrence of

syncope was defined twice, first as at

least one attack (‘syncope ever’) and

secondas‘frequentsyncope’,thatis,five

syncopalattacksormore.

Diabetes mellitus, history of myo

cardial infarction, BMI, high alcohol

intake,anduseofantihypertensiveswere

examined as potential risk factors for

syncope.²¹⁶ At the clinic visit, BP and

heart rate (HR) were measured with an

electronic oscillometric BP monitor

(OMRON 711; OMRON Matsusaka Co,

Japan).

Twoautonomicreactivitytestswere

performed: the orthostatic change of BP

and HR and the difference after veni

puncture.BPandHRmeasurementswere

made with the subject sitting, after 5

minutes’supinerest,during1,2,3,and4

minutes standing, and directly after

venipuncture. The average of the meas

urements while standing was defined as

‘standing BP’ or ‘standing HR.’ The maxi

mal decrease while standing was calcu

lated by subtracting the lowest BP value

while standing from the resting BP.

Similarly, the resting HR value was sub

tractedfromthehighestHRwhilestand

ing to calculate the maximal increase

while standing. The difference after

venipuncturewascalculatedbysubtract

ingthevalueaftervenipuncturefromthe

resting value. Orthostatic changes of BP

and HR were measured in all but 34

participants (23 migraineurs, 11 con

trols). Migraine cases underwent all

examinations in a headachefree period

(3daysafteramigraineattack).

COMBINEDENDPOINTS

Orthostatichypotensionwasdefinedasa

fallin BP of atleast20 mmHg systolic or

10mmHgdiastolicwithin3minutesafter

standingup.²¹⁷

Orthostatic intolerance was defined

as the provocation of syncope or near

syncope(dizziness,lightheadedness,loss

of concentration, ringing in the ears, or

darkening of sight) upon standing or the

avoidanceofprolongedstanding.

POTS was defined as orthostatic in

toleranceaccompaniedbyanHRincrease

of >30 beats/min or by an HR >120

beats/min within 5 minutes of stand

ing.²¹⁸

Hypertension was defined as a sys

tolic BP of 160 mmHg and higher or a

diastolic BP of 95 mmHg and higher or

current use of antihypertensive drugs.

For this definition, BP was the mean of

three supine BP measurements obtained

at1minuteintervals.

Data of control subjects and mi

graineurswerecomparedwiththe2test

for the comparison of proportions, the

twosided Student t test for normally

distributedcontinuousvariables,andthe

nonparametric Mann–Whitney U testfor

continuous variables without a normal

distribution. Linear regression analysis

was used to explore the relation of two

continuousvariables.Significancewasset

atthe5%level.

RESULTS

POPULATION

Migraineurs(n=323)andcontrols(n=153)

participatedinthestudy.Comparedwith

controlsubjects,fewermigraineurshada

high alcohol intake (TABLE 1). No other

significant differences were found in

baseline population characteristics be

tweenbothgroups.

SYNCOPEQUESTIONNAIRE

The lifetime prevalence of one or more

syncopal events in all participants was

41%.Afemalepreponderancewasfound

forsyncope(45vs.32%;P=.02).

Noneofthepotentialriskfactorsfor

syncope (diabetes mellitus, history of

myocardial infarction, BMI, high alcohol

intake,anduseofantihypertensives)had

a significant association with the preva

lenceofsyncope.

Comparedwithcontrolsubjects,mi

graineurs had a significantly higher life

time prevalence of both syncope and

frequent syncope (Table 2). Migraineurs

reported symptoms (syncope/near syn

cope/avoidance)duringprolongedstand

ing, during a long hot shower, or after

exercise significantly more often than

controlsubjects.

TABLE1Characteristicsofstudyparticipants

All

      

Migraineurs

(n=323)

Controls

(n=153)

Male/Femaleratio,%  32  38

Age,y   48 (8)   48(8)

Bodymassindex  25 (4)  24(4)

Medicalhistory(%present)

 Diabetesmellitus



 4 (1)



 6(4)

 Myocardialinfarction  1 (0.3)  

 Currentlyusesantihypertensivemedication  40(12)   12(8)

 Highalcoholuse(t3drinks/d)  23(7)*   23(15)*

Loweducation†

Migrainewithaura

 171(53)

 174(54) 

 81(53)

 

1migraineattack/mo  156(48)  

Valuesareexpressedasnumber(%)orasmean(SD)

* P<.01²testforthecomparisonofproportions.

† Loweducationindicatesprimaryschoolorlowervocationaleducation.

BPANDHRMEASUREMENTS

The BP and HR measurements supine,

while standing, and after venipuncture

did not differ significantly within both

groups (TABLE 3). There was no signifi

cantdifferenceintheprevalenceofPOTS

and OH between the groups. Neither

migrainetypenorattackfrequency(<1or

t1 attack per month) was associated

withthepresenceofsyncope,orthostatic

intolerance, OH, or POTS (TABLE 4). No

correlation was found between the total

numberofmigraineattacksandsyncopal

spellswithinthemigraineurs.

DISCUSSION

Inthispopulationbasedstudy,weexam

ined clinical presentations of ANS dys

functionaswellasBPandHRreflextests

inmigraine.

The lifetime prevalence of syncope

we found in control subjects is in accor

dance with previous studies in air force

personnel and medical students.^219;220 The populationbased Framingham study

of adults aged 30 to 62 years reported a

lower lifetime prevalence of syncope

(3.0% for men, 3.5% for women).²²¹ However, it seems plausible that these

TABLE2Syncopequestionnaire

 Migraineurs

(n=323)

Controls

(n=153) pValue

SYNCOPEEVER,%

 Women

 Male

 46 

 50

 35

 31 

 32

 26

.001



FREQUENT(t5X)^SYNCOPE

 Women

 Male

 13 

 17

 1

 5 

 6

 5

.02

FAINTERS

 Ageatfirstfaint,y



 21r13



 23r13

 .3

 Ageatlastfaint,y  30r14  29r13 .6

 Faintedpreviousyear,%  12  9 .5

 Totalno.offaints  6r16   6r14  .005

SYMPTOMS,%

 Prolongedstanding



 32 



 12 



<.001

 Longhotshower  11   2  .001

 Afteraheavymeal  4  3 .4

 Afterexercise  23   5  <.001

 Atthesightofblood  9  7 .6

OH,%  16  14 .7

POTS,%  3  2 .5

Valuesareexpressedasproportionorasmean±SD

* SignificanceP<.05²test(proportions)orMannWhitneyUtest(continuousvariables)

OH=orthostatichypotensionPOTS=posturaltachycardiasyndrome

datareferredtotheincidenceofsyncope

during the 26year period of surveil

lance.²¹⁹ Moreover, syncope was not

strictlydefinedintheFraminghamstudy,

resultingininclusionofepilepsyandeven

strokeorTIAasformsofsyncope.²²²This

may explain why risk factors for syncope

identified in the Framingham study

lacked significance in our study. Given

the high prevalence of vasovagal syn

cope,triggersforthistypeofsyncopeare

more likely to affect estimates of the

prevalenceofsyncope.^203;220

We found a higher lifetime preva

lence of syncope and frequent syncope

among migraineurs. The reported symp

toms of migraineurs during prolonged

standing, a warm shower, exercise, and

intheabsenceofcomplaintsatvenipunc

tureorafteraheavymealarebestinter

pretedasorthostaticintolerance.²¹⁵ It is unclear why migraineurs have

an increased tendency toward syncope

and orthostatic intolerance. Our cardio

vascular measurements underline that

there is no gross abnormality of the ANS

inmigraine.However,wecannotexclude

a slight sympathetic dysfunction as our

studylacked a continuousBPmonitoring

upon standing and therefore did not

address the initial orthostatic response.

Arguments favoring a slight sympathetic

dysfunction in migraineurs are the re

ducedplasmanoradrenalinelevelsand

adrenergic hypersensitivity.²²³ Alterna

tively, syncope and orthostatic intoler

ance may occur as paroxysmal abnor

malities without clear interictal signs of

TABLE3Orthostatictest

 Migraineurs

(n=300)

Controls

(n=142)

SBP,MMHG

Supine 



133.3(20.2)



133.0(20.0)

Standing 133.8(17.4) 134.8(17.7)

Max.standing  6.6(10.9)  5.3(11.2)

aftervenipuncture  0.7(10.7)  1.6(11.2) DBP,MMHG

Supine



 85.5(10.8)



 83.8(11.2)

Standing  92.7(10.4)  92.3(9.5)

Max.standing  2.8(7.3)  3.7(7.3)

aftervenipuncture  4.0(7.4)  5.4(8.9)

HR,BEATS/MIN

Supine



 68.1(10.6)



 67.6(11.2)

Standing  78.6(11.7)  78.8(11.6)

Max. standing

aftervenipuncture

 14.5(7.7)

 4.2(6.9)

 14.8(7.2)

 4.2(6.8)

Valuesareexpressedasmeans(SD)

SBP=systolicbloodpressure;DBP=diastolicblood

pressure;HR=heartrate.

TABLE4Syncopequestionnairebymigrainesubtype



n

Syncope

ever,%

Frequent

syncope,%

Orthostatic

intolerance,% POTS,% OH,%

Migraineoverall 323 46 13 32 3 16

Migrainewithaura 174 43 11 32 3 14

Migrainewithoutaura 149 50 15 32 4 17

1migraineattack/mo 156 44 14 37 3 16

<1migraineattack/mo 167 49 12 28 4 15

POTS=posturaltachycardiasyndrome;OH=orthostatichypotension

ANS dysfunction; if so, this parallels

migraine itself, also characterized by

largelynormalinterictalfunctions.

ACKNOWLEDGEMENTS

Thisstudywassupportedbyagrantfrom

the NetherlandsHeart Foundation (grant

97.108) and in part by the Intramural

Research Program, NIA. 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,

theNetherlands.