Migraine in Women

Rebecca Burch, MD

John R. Graham Headache CenterDepartment of NeurologyBrigham and Women’s Faulkner Hospitals

Objectives• Discussepidemiologyofmigraineinwomen

• Reviewhormonalcontributionstothepresentationofmigraineinwomen

• Discussheadachemanagementinsituationsspecifictowomen

“The Femaleness of Migraine…is Inescapable.”~KMAWelch

Prevalence of Migraine

• Peakprevalenceisinwomenofchildbearingage• Subgroupsofmigrainealsomorecommoninwomen

FemalesMales

Age (in years)20 30 40 50 60 70 80 100

0

5

10

15

20

25

30

Mig

rain

e Pr

eval

ence

(%)

Lipton R, et al. The American Migraine II Study.

Cumulative incidence of migraine in females (44%)

Stewart W et al. Cephalalgia 2008;28:1170-1178

Cumulative incidence of migraine in males (18%)

Stewart W et al. Cephalalgia 2008;28:1170-1178

Hormonal epochs• Menarche/Puberty

• Menses

• Pregnancy

• Perimenopause

• Menopause/andropause

• Incidencerisesingirls

• Triggerforindividualattacks

• Highlevelsofestrogenchangeexpression

• Worsen,improve,nochange

• Excessriskinwomenisreducedbutpersists

How is migraine different in women?

•Diagnosticcriteriaformenandwomenareidentical

• Theclinicalprofilesofmenwithmigrainedifferfromthoseofwomen

•Womenmorelikelytoexperience• Migraineaccompanyingsymptoms• Disability

Buse D et al Headache June 2013

Population based telephone survey, ages 12-29 with migraine in the last 4 weeks

05

101520253035

Headache Frequency >/= 3

Per Month

Recent Headache Pain >/= 8

Missed Work or School

11

21 2023

29 31

Male

Female

Perc

ent

Associated symptoms in migraine by sex

Buse D et al Headache June 2013

How is migraine different in women?

•Migrainewithauramorecommoninwomen

Buse D et al Headache June 2013

Migraine with aura associated with increased risk of stroke• RRforstrokeisaboutdoubleinwomenwithmigrainewithaura

• Riskgreatestforwomenunder50andwithoutothercardiovascularriskfactors

• Increasedfrequencyofattacksandrecentonsetassociatedwithincreasedrisk

Sacco and Kurth Curr Cardiol Rep 2014

Migraine with aura associated with increased risk of stroke• Typesofstroke:ischemicandhemorrhagicstroke

• Cryptogenicstroke• Possiblylacunarstroke• Probablynotsubarachnoidhemorrhage

• Moststrokesrelatedtomigrainehavegoodfunctionaloutcome

• MAalsoariskfactorforrecurrentvasculareventsandrecurrentischemicstroke

Risk factors for stroke are multiplicative

• Relativerisksforstrokeinwomen<45• Withaura:2• Withauraandsmoking:3-9• Withauraandcombinedoralcontraceptives:4-8• Withauraandsmokingandcombinedoralcontraceptiveuse:10

• Absoluteriskremainslow• 5to11.3per100,000woman-years

White matter lesions and migraine

• Migraineurs haveahigherburdenofasymptomaticwhitematterbrainlesionsandinfarct-likelesions• Linkstrongerinfemales

• Riskincreasedwithattackfrequency• Linkisstrongerformigrainewithaurathanmigrainewithoutaura

• Donotseemtohaveanyprognosticmeaning• Noassociationwithlaterinlifecognitiveimpairment

CAMERA study, EVA study

Migraine associated with complications of pregnancy• Stroke(OR15.05,95%CI8.26to27.4)

• MI(OR2.11,95%CI1.76to2.54)

• PE/VTE(OR3.23,95%CI2.06to7.07)

• Gestationalhypertension/pre-eclampsia (OR2.29,95%CI2.13to2.46)(Furtherstudysuggeststhismaybedrivenbymigrainewithaura)

• Migrainewithauraisasubgrouplesslikelytoimproveduringpregnancy

Bushnell CD et al BMJ 2009

Why do women have more migraine?

• Hormonalfactorsmayaccountfordifferences

• 2wayssexhormonesmightact:Developmentaleffects takeplaceduringacriticalperiodandputapermanentstamponthenervoussystem

Developmental effects: Evidence from the Group Health Study• 3,000boysandgirlsage11to17->telephoneinterview

• Pubertalstageassessedin100%ofheadachesufferersanda10%randomsampleofcontrols

• Pubertalstagewaspredictiveofrapidriseinprevalenceinfemales• Notsignificantlyassociatedwithriseinmalesafteradjustingforage

• Maycontributetoshiftingsexprofileinadolescence• Suggeststhatfemaleandnotmalehormonalchangesmatter

LeResche et al. (2009)

Imaging studies• Femalemigraineurs havemoredisorganizationoftherestingstatenetwork

• Connectivitybetweenthedefaultmodenetworkandexecutivecontrolnetworkismodulatedbyphaseofthemenstrualcycle,andbyOCPuse

• Precuneous (partoftheDMN)thicknessincreasedinfemalemigraineurs

• Whitematterhyperintensities increasedinfemalemigraineurs butnotmales

Pavlovic JM et al J Neurosci Res. 2017 Jan 2;95(1-2):587-593

Animal models• Femalemicehavelowerpainthresholdstothermal,chemical,andmechanicalpainfulstimuli

• Estrogenlowers,testosteroneraisesthethresholdforprovokedcorticalspreadingdepression• Femalemicehave50%lowerCSDthresholdregardlessofestrousphase

• Femalemicehavedifferentneurotransmitterprofiles• IncreasedCGRPexpression

Pavlovic JM et al J Neurosci Res. 2017 Jan 2;95(1-2):587-593

Why do women have more migraine?

• Hormonalfactorsmayaccountfordifferences

• 2wayssexhormonesmightact:Developmentaleffects takeplaceduringacriticalperiodandputapermanentstamponthenervoussystem

Activational effectsarethedirectinfluencesofcirculatinghormonesthatappearwhenhormonallevelsrise,andwanewhenhormonallevelsdrop.

Menses is a powerful trigger factor for migraine in females not present in males

MacGregor E A et al. Neurology 2006;67:2154-2158

©2006 by Lippincott Williams & Wilkins

Theories behind hormonal effects on migraines• NeurotransmitterImbalanceTheory• NeuropeptideTheory• CorticalSpreadingDepressionTheory

• Decliningestrogenà increasesinducedCSD• Womenwithmigrainehavefasterdeclineofestradiolpriortomenses

Martin V. Headache 2006; 46: 3-23.

Welch K. Neurol Sci 2006; 27: S190-192

Eikermann-Haerter K. Headache 2007; 47: S79-85

Pavlovic JM, 2016. Neurology 87:49–56.

Environmental factors that may increase expression of migraine• Adversechildhoodexperiences• IntimatePartnerViolence• Dailyhasslesandstress• Affectivedisorders(Depression,anxiety)

• Allmorecommoninfemales• Riskfactorsforchronicheadaches

• Allpatientsshouldbescreened

Among women in a headache clinic

• 28.3%positiveforPTSD• 9.8%and36.9%endorsedrecentandlifetimeintimatepartnerviolence.

• PTSDstronglyassociatedwithheadacheseverity• ThosewithIPVhadaverageof9additionaldaysofdisabilityper3months.

Gerber MR, Fried LE, Pineles SL, Shipherd JC, Bernstein CA. Posttraumatic stress disorder and intimate partner violence in a women's headache center. Women Health.2012 Jul;52(5):454-71.

Kaplan–Meier curve for the cumulative percentage with adult-onset headache by age for persons with none, one, and two or more childhood family adversities.

Lee S et al. BJP 2009;194:111-116

©2009 by The Royal College of Psychiatrists

Kaplan–Meier curve for adult-onset headache by age for persons with v. without early-onset depression/anxiety disorders.

Lee S et al. BJP 2009;194:111-116

©2009 by The Royal College of Psychiatrists

In the clinic• A28yearoldwomanconsultsyouwithrecurrent,disabling,throbbingheadachesoccurringintermittentlyfor8years.Recentlyincreasinginfrequency,now8days/month.

• Headachesoccurwithmenstrualperiodsandatothertimesofthemonth,last48hours,areassociatedwithvomitingandphotoandphonophobia.

• Benignpastmedicalhistory• Herneurologicexaminationisnormal

ICHD Diagnostic Criteria For Migraine Without Aura• Lasting4to72hours• Twoofthefollowing

• Unilaterallocation• Pulsatingquality• Moderateorsevereintensity• Aggravationbyorcausesavoidanceofroutinephysicalactivity

• Atleastoneofthefollowing:• Nauseaand/orvomiting• Photophobiaandphonophobia

• Atleastfiveattacksfulfillingthethreebulletpointsabove

• Noevidenceoforganicdisease

Our patient• “Iseezig-zaglinesrightbeforemostofmyheadaches.Theygetlargeroverthenext10minutesandthenfadeaway.SometimesIhaveablankspotinmyvision.”

• “Thewholethinglastsabout40minutesandisfollowedbymytypicalbadheadache.”

Aura

• Focal neurologic event(s)…visual, sensory, motor, dysphasic, brainstem?

• Usually precedes headache…but not always• Positive, negative, spreading and reversible

Ø Blurry vision is not auraØ Prodromal fatigue, mood changes, cravings are not

aura

Testing• Primaryheadacheisaclinicaldiagnosis• Testingisusefultoruleoutotherdisorders• Lookfor“redflags”

• Elderly/children• Unusualpattern• Worseningovertime• Abnormalexamination• Noresponsetotreatment

• NoroleforEEG• LPandneuroimagingmostuseful– usuallyMRI,vesselimaging

Managing headaches: no major sex-specific differences

• Abortivetreatment• Virtuallyallpatientsrequire

• Preventivetreatment• Onlyasubsetofpatientswithmigraineandtensiontypeheadache

• Offerforheadachesmorethanonceperweek,acutetreatmentsineffective/overused/contraindicated,specialcircumstances

• Anunderusedintervention!

• Lifestylemodification

Reasonable lifestyle modifications

• Regularmeals

• Adequatesleep;Standardizedsleepandwaketimes

• Regularexerciseandmaintenanceofnormalweight

• Limitoravoidcaffeine,watchalcohol

• Nogoodevidenceforotherdietaryrestrictions– lotsofanecdote

Options for acute therapy

Disorder• Tension-typeHA

• Migraine

Commontreatments• NSAIDs,mildanalgesics

• NSAIDs,mildanalgesics• Triptans• Ergotderivatives• (barbiturates,narcotics)

General principles of abortive therapy

•Useadequatedose•Useearly/atmildstageofheadache•Monitorresponseandadjusttherapyaccordingly(eg combinations)• Triptan +antiemetic• Triptan +NSAID• Triptan +antiemetic+NSAID

A few words on triptans• Therearesevenofthem

• Allavailableorally(2asorallydisintegratingtablets)• Resultsaresimilarwhencomparabledosesareused

• Nonetheless,patientsusuallyhaveafavorite• Twoavailableasnasalsprays,oneasSQandabreathpoweredpowder

• GenericversionsofmostareavailableintheUS

• Sumatriptan alreadyavailablewithoutprescriptioninsomecountries

Loder E . Triptan therapy in migraine. N Engl J Med 2010;363:63-70

Sumatriptan

Zolmitriptan

Naratriptan

Rizatriptan

Almotriptan

Eletriptan

Frovatriptan

Common Triptan Side Effects• Tingling• Warmth• Flushing• Chestdiscomfort• Dizziness

Triptans: Contraindications• Ischemicheartdisease

• Anginapectoris• Historyofmyocardialinfarction• Documentedsilentischemia

• Coronaryvasospasm(includingPrinzmetal’s angina)• Poorlycontrolledhypertension• Multipleriskfactorsforcoronaryarterydisease,unlessworkupisfullynegative

• Pregnancynotnecessarilyacontraindication• SSRI/SNRIusenotahardcontraindication

Classes of Migraine Preventives

• Antiepilepticdrugs• Antidepressants• Beta-adrenergicblockers• Calciumchannelantagonists• Serotonin(5-HT)antagonists• Neurotoxins(eg,onabotulinumtoxinA)• ACEI/ARBs• Vitamins,herbs,minerals

Suppression of cortical spreading depression in migraine prophylaxis

Annals of NeurologyVolume 59, Issue 4, pages 652-661, 31 JAN 2006 DOI: 10.1002/ana.20778http://onlinelibrary.wiley.com/doi/10.1002/ana.20778/full#fig1

CSDs after KCl administration

Common Preventive MedicationsEvidence Level

Medicationü = FDA Indication

Usual Daily Dose

Comments

B Atenolol 50-100 mgA Propranolol ü 80-240 mgA Metoprolol 50-150 mgU Verapamil 180-480 mg Downgraded, favorable AE profile

A Divalproexsodiumü

250-1500 mg FDA pregnancy category X

U Gabapentin 300-1800 mg Downgraded, favorable AE profile

A Topiramateü 25-150 mg FDA pregnancy category DB Amitriptyline 10-150 mg Downgraded but strong clinical

impression of benefitB Venlafaxine 37.5-150 mg Well tolerated, not sedatingC Cyproheptadine 2-8 mg Pediatric population, sedating

Rizzoli, P. Acute and Preventive Treatment of Migraine, Continuum Neurol 2012;18(4):764-82

Another case

• A19yearoldwomanpresentsforevaluationofmigraineswithoutaura

• Headachesoccurwitheverymonthlyperiod,• usually1daypriortostartofmenstruationandcontinuingfor2-3days

• Migrainesmayoccuratothertimesofthemonth,butrarely,andtheyarelesssevere

• Takessumatriptan everymorningbutheadachealwayscomesback

• Wantstoknowwhattreatmentoptionsareavailable

ICHD-3 beta• Puremenstrualmigrainewithoutaura:appendix• Menstrually-relatedmigrainewithoutaura:appendix• Estrogenwithdrawalheadache• Exogenoushormone-inducedheadache

The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl 1:9-160.

Pure menstrual migraine without aura

• Diagnosticcriteria• Attacks,inamenstruatingwomanfulfillingcriteriaformigrainewithoutaura

• Attacksoccurondays-2to+3 ofmenstruation• Inatleast2outof3menstrualcycles• AtNO othertimesofthecycle

+3+2+1-1-2

ICHD-3b DEFINITION

Menstrually-related migraine without aura

•Diagnosticcriteria• Attacks,inamenstruatingwomanfulfillingcriteriaformigrainewithoutaura

• Attacksoccurondays-2to+3ofmenstruation• Inatleast2outof3menstrualcycles• Andadditionallyatothertimesofthecycle

Odds Ratio for Headache Attacks by Type and Time in Cycle

0

1

2

Days 7 to 3before

Days 2 to 1Before

Days 0 to 1 Days 3 to 5after

Ovulation

Time in Cycle

Odd

s R

atio

MWAMw/oATension

Stewart, Lipton et al, Neurology, 2003

Menstrual migraine prevalence• Population-basedNorwegiansurvey:selfreport

• Prevalenceofpuremenstrualmigraine7.7%(6.9-8.7)=2.7%offemalepopulation

• Prevalenceofmenstrually relatedmigraine13.2%(12.1-14.3)=4.6%offemalepopulation

• BUT:• Culturalfactorsmayplayarole• Menstruationisa“magnet”explanationforsymptomsthatmayoccurduetorandomchance

• Prospectivedailydiariesforatleast2monthstheonlywaytoproperlydiagnose

Vetvik, et al. Headache 2010;11(2):87-92. Marcus et al. Headache 1010;50(4):539-550.

Are menstrually related migraines different?• Prospectivediarystudyof81womenwithselfreportedmigrainein>50%ofmenstrualperiods• About2/3hadmenstrually relatedmigraine• Menstrualmigraineswerelongerandassociatedwithmorenausea

• NodifferencesinheadachephenotypeinwomenwithoutICHD-IIdefinedmenstrualmigraine

• Diarystudyof64womenreferredtoatertiaryheadachecenterwithmenstrually relatedmigraine• Menstrualheadacheslonger,moredisabling• Lessresponsivetoacutetreatments

Vetvik KG et al, Cephalalgia 2015, Vol. 35(14) 1261–1268Granella F et al, Cephalalgia 2004, Sep;24(9):707-16.

Is MM treatment response different?

• Sustainedpainfreedom5-7%forMMvs 24%nonMM(diarystudy)

• Painfreedom6.7%MMvs 13.4%nonMM(diary)• Relieffromsumatriptan 100mg33%MMvs 79%nonMM(questionnaire)

• Eletriptan 2hr responsenotdifferentinpooledresultsfrom5trials,buthigherrecurrenceandnauseainMM

• Almotriptan equallyeffectiveinMMandnonMM,posthocanalysis(AEGISstudy)

• Rizatriptan 10mgequallyeffectiveinprospectivesubgroupanalysis(TAMEstudy)

Maasumi K et al. Headache Volume 57, Issue 2, February 2017, Pages 194–208

Estrogen withdrawal headache• Samepatientasbefore,butgetsheadachesonlyduringtheplaceboweekofcombinedoralcontraceptives(COCs)

• DiagnosticcriteriaA.HeadacheormigrainefulfillingcriteriaCandDB.Dailyuseofexogenousestrogenfor>3weeks,

whichisinterruptedC.Headacheormigrainedevelopswithin5daysafterlastuseofestrogen

D.Headacheormigraineresolveswithin3days

Edlow AG, Bartz D. Rev Obstet Gynecol Spring 2010

Treatment options for menstrual headaches• Treatmentasfornon-menstrualmigraine

• Triptans• Prevention• Focusingonlyonhormonaltreatmentsisapitfall!

• Shorttermprophylaxis• Continuousmonophasicoralcontraceptivepills• Additionalestradiol

• Manyofthehormonalstrategiesareofverymodestbenefitcomparedtoplaceboortreatmentasusual.

Triptans in MRM Mini-Prophylaxis

• 2012AAN/AHSguidelines• Frovatriptan classA

• Dosed2.5mgBIDordailyfor2daysbeforemenses,totalof6days• Reducedfrequencyofheadacheandheadachefreemenstrualperiods• Mayjustdelayonsetofheadache,sonotFDAapprovedforMRMppx

• Naratriptan andzolmitriptan classB• Naratriptan 1mgBID2daysbeforemenses,totalof5days• Zolmitriptan 2.5mgBID/TID

• Considerneedtotreatbreakthroughheadache

Silberstein et al. Neurology 2012

Other preventative regimens• NSAIDs

• NaproxenTID– onesmallpositivetrial,onenegative• Mefanamic acid500mgTIDatonsetofMRM&continuedfordurationofmenses– onepositivetrial

• Magnesium– insufficientevidence• Phytoestrogens– insufficientevidence• Transdermalestradiol1.5mg,started2daysbeforeexpectedonsetofheadacheandcontinuedfor7days– twopositivetrials

Pringsheim T et al. Neurology 2008;70:1555-1563

Hormonal prophylaxis• Effectofhormonalcontraceptivesonmigraineisvariable

• FirstgenerationCOCstendedtoworsenmigraine• Secondandthirdgenerationeffectunpredictable• NostudyofindividualOCPshavecarefullycollectedheadachedata

• Considereliminationofplaceboweek• Threeconsecutivepillpacksfollowedbyoneweekofplacebo• Onetrialshowedmodestreductioninheadacheburden

• Progesteroneonlypills• Onesmallpositivetrial,2smalldiarystudies

Coffee et al J Womens Health (Larchmt). 2014;23:310-317Nappi RE et al, J Headache Pain. 2013 Aug 1;14:66

Migraine and menopause• Improvementinmigrainein2/3post-menopausalwomen

• Fluctuatingestrogenlevelsduringperimenopausemayexacerbatemigraine• 1.4foldincreaseinhighfrequencyepisodicmigraine

• Effectofhormonereplacementtherapyonmigraineisunclear• Transdermalpreferable• IncreasedriskforstrokesimilartoCOCs

• RoleforSSRIs/SNRIs?Brandes JL Continuum 2012, Neri I, Maturitas 1993. Facchinetti F, Headache 2002

Martin V, Headache 2016

Migraine after menopause• Notallwomenseeimprovement• Treatmentasforregularmigraine• Intheolderpatient:

• Evaluatecardiacriskfactorsiftriptansused• LongtermAEDuseisariskfactorforosteoporosis• OlderpatientsmaybemoresensitivetoTCAsideeffects• CognitiveeffectsfromAEDsmaybemorebothersome

Brandes JL Continuum 2012, Neri I, Maturitas 1993. Facchinetti F, Headache 2002

Consultation rates and gender assumptions• Womenmorelikelytoconsultthanmenformigraine

• Assumptionthatfemalesconsultforalowlevelofsymptomseveritymayaffectdiagnosisandtreatmentapproach.

• Videostudy:female‘patients’• Askedfewerquestionsbydoctors• Fewerdiagnostictestsrecommended• Doctorsweremorelikelyto‘tuneintopsychologicalcuesandsearchforpsychologicalexplanationsforsymptoms’

Hunt K et al J Health Serv Res Policy. 2011 Apr;16(2):108-17. AdamsA, et al. Sociol Health Illn 2008;30:1–18; ArberS, et al. Br J Gen Pract 2004;54:673–8

Summary• Migraineismorecommonandmoreburdensomeinwomen

• Migrainehasanepidemiologicprofileconsistentwith• Enduringhormonaleffectsondiseaserisk• Short-termeffectsofwithdrawalonattacks

• Societalandculturalfactorsmayalsocontribute• Treatmentsforhormonalheadachedon’thavetobehormonal

• Overemphasisonthesex-specificaspectsoftheseheadachesisapitfallthatcanlimitthinking

Thank you!rburch@partners.org