UPDATE ON MIGRAINE UPDATE ON MIGRAINE EPIDEMIOLOGY, GENETICS, AND EPIDEMIOLOGY, GENETICS, AND 

BASIC MECHANISMSBASIC MECHANISMSBASIC MECHANISMSBASIC MECHANISMSAndrew Charles, M.D.Andrew Charles, M.D.Professor of NeurologyProfessor of Neurology

Director, Director, UCLA Goldberg Migraine ProgramUCLA Goldberg Migraine ProgramMeyer and Renee Luskin Chair in Migraine and Headache StudiesMeyer and Renee Luskin Chair in Migraine and Headache Studiesy gy g

David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA

DISCLOSURESDISCLOSURESDISCLOSURESDISCLOSURES

Grant SupportGrant SupportGrant Support Grant Support TakedaTakeda

ConsultantConsultantConsultantConsultantAmgen*, Eli Lilly*, Amgen*, Eli Lilly*, eNeuraeNeura, Trevena, Trevena

Clinic Trial Steering CommitteeClinic Trial Steering CommitteeSt. JudeSt. Jude

*Will discuss products from these companies*Will discuss products from these companies

EPIDEMIOLOGYEPIDEMIOLOGY

Migraine and StrokeMigraine and StrokeMetaMeta‐‐analyses indicate that migraine with aura analyses indicate that migraine with aura is associated with approximately 2is associated with approximately 2‐‐fold relative fold relative risk of risk of  ischemic stroke, although significant ischemic stroke, although significant variability between studiesvariability between studiesHigh frequency of attacks and recent onset of High frequency of attacks and recent onset of migraine may be associated with increased riskmigraine may be associated with increased riskMigraine associated with 1.5 fold risk of Migraine associated with 1.5 fold risk of intracranial hemorrhage (both intracerebral andintracranial hemorrhage (both intracerebral andintracranial hemorrhage (both intracerebral and intracranial hemorrhage (both intracerebral and subarachnoid)subarachnoid)

Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ. 15.Schürks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ. 2009;339:b3914.Spector JT, Kahn SR, Jones MR, Jayakumar M, Dalal D, Nazarian S. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med.

Northern Manhattan StudyNorthern Manhattan StudyRacially, ethnically diverse cohortRacially, ethnically diverse cohort1292 participants1292 participantsp pp pMean age 68Mean age 68Patients followed prospectively over 11 yearsPatients followed prospectively over 11 yearsPatients followed prospectively over 11 yearsPatients followed prospectively over 11 yearsMigraine prevalence 20% women, 6% menMigraine prevalence 20% women, 6% men

NO INCREASED STROKE RISK IN NONNO INCREASED STROKE RISK IN NON‐‐SMOKERSSMOKERS1.83 HAZARD RATIO IN SMOKERS1.83 HAZARD RATIO IN SMOKERS

Monteith TS, Gardener H, Rundek T, Elkind MS, Sacco RL. Migraine and risk , , , , gof stroke in older adults: Northern Manhattan Study. Neurology 2015; 85(8): 715-21.

Migraine and Cardiovascular Migraine and Cardiovascular DiseaseDisease

Conflicting evidenceConflicting evidenceSome metaSome meta‐‐analysis indicate 1.3 fold risk of MI analysis indicate 1.3 fold risk of MI in patients with migrainein patients with migraineAssociation between migraine and Association between migraine and ggcardiovascular disease is less that that cardiovascular disease is less that that between migraine and strokebetween migraine and strokegg

Other Migraine AssociationsOther Migraine Associationski ’ di ?ki ’ di ?Parkinson’s disease?Parkinson’s disease?ScherScher, , et al. Midlife migraine and lateet al. Midlife migraine and late‐‐life parkinsonism: AGESlife parkinsonism: AGES‐‐Reykjavik study. Reykjavik study. Neurology. 2014;83(14):1246Neurology. 2014;83(14):1246‐‐5252..WangWang HI Ho YC Huang YP Pan SL Migraine is related to an increased risk ofHI Ho YC Huang YP Pan SL Migraine is related to an increased risk ofWang Wang HI, Ho YC, Huang YP, Pan SL. Migraine is related to an increased risk of HI, Ho YC, Huang YP, Pan SL. Migraine is related to an increased risk of Parkinson's disease: A populationParkinson's disease: A population‐‐based, propensity scorebased, propensity score‐‐matched, matched, longitudinal followlongitudinal follow‐‐up study. up study. CephalalgiaCephalalgia 2016.2016.

Restless legs syndromeRestless legs syndromeRestless legs syndromeRestless legs syndromeSchurksSchurks M, Winter A, Berger K, M, Winter A, Berger K, KurthKurth T. Migraine and restless legs syndrome: a T. Migraine and restless legs syndrome: a systematic review. systematic review. CephalalgiaCephalalgia. 2014;34(10):777. 2014;34(10):777‐‐94.94.

ExtracranialExtracranial artery dissection (MO)artery dissection (MO)MetsoMetso TM, et al. Migraine in cervical artery dissection and ischemic stroke TM, et al. Migraine in cervical artery dissection and ischemic stroke patients. Neurology. 2012;78(16):1221patients. Neurology. 2012;78(16):1221‐‐8.8.

Patent foramen Patent foramen ovaleovale (MA)(MA)Schwedt Schwedt TJ, TJ, et al. Patent et al. Patent foramen foramen ovaleovale and migraine: a quantitative and migraine: a quantitative systematic review. systematic review. CephalalgiaCephalalgia. 2008;28(5):531. 2008;28(5):531‐‐4040..

DepressionDepressionBuseBuse DC, DC,  et al. Psychiatric et al. Psychiatric comorbidities of episodic and chronic migraine. comorbidities of episodic and chronic migraine. NeurologyNeurology. 2013; 260(8): 1960. 2013; 260(8): 1960‐‐9.9.

Louis Ptacek

Advances in Migraine Genetics

FHMCACNA1AATP1A2ATP1A2SCN1APRRT-2 ??

FAMILIAL MIGRAINETRESKCK1

PRDM16 TRPM8LRP1 ZNF555

SUSCEPTIBILITY LOCI

ADARB2 GRM7HTR7 MEF2DTGFBR2 PHACTR1ASTN2 ….And more than 30 MORE!!!

Familial Hemiplegic MigraineFamilial Hemiplegic MigraineFamilial Hemiplegic MigraineFamilial Hemiplegic MigraineFHMFHM‐‐11 –– Mutations in CACNA1A Mutations in CACNA1A –– gene gene encoding p/q type calcium channel (involved in encoding p/q type calcium channel (involved in neurotransmitter release)neurotransmitter release)FHMFHM‐‐22 –– Mutations in ATP1A2 Mutations in ATP1A2 –– gene encoding gene encoding Na+/K+ pump (ATPase) that controls levels of Na+/K+ pump (ATPase) that controls levels of extracellular K+extracellular K+FHMFHM‐‐33 –– Mutations in SCN1A Mutations in SCN1A ––gene encoding gene encoding g gg gneuronal Na+ channelneuronal Na+ channel??FHM??FHM‐‐44 –– Mutations in gene encoding PRRT2Mutations in gene encoding PRRT2 ‐‐‐‐??FHM??FHM‐‐4 4  Mutations in gene encoding PRRT2 Mutations in gene encoding PRRT2 ‐‐‐‐‐‐gene associated with PKD and infantile seizuresgene associated with PKD and infantile seizures

Familial Migraine (genes identified Familial Migraine (genes identified in isolated families)in isolated families)

TRESKTRESK P i h lP i h l i l f ili l f ilTRESK TRESK –– Potassium channel Potassium channel ‐‐‐‐‐‐ single familysingle familyCasein Kinase 1 delta Casein Kinase 1 delta –– Enzyme that Enzyme that phosphorylates multiple proteins including phosphorylates multiple proteins including “clock” proteins in hypothalamus. Also causes “clock” proteins in hypothalamus. Also causes advanced sleep phase syndrome advanced sleep phase syndrome ‐‐‐‐‐‐ reported reported in 2 families by may be more common. in 2 families by may be more common. 

S C C S SBASIC MECHANISMS

Animal Models of MigraineAnimal Models of MigraineAnimal Models of MigraineAnimal Models of Migraine

Cortical spreading depressionCortical spreading depressionCortical spreading depressionCortical spreading depressionDural stimulationDural stimulation

El t i l ti l tiEl t i l ti l tiElectrical stimulationElectrical stimulationInflammatory stimulationInflammatory stimulation

Systemic administration of known human Systemic administration of known human migraine triggersmigraine triggers

NitroglycerinNitroglycerin‐‐evoked evoked hyperalgesiahyperalgesia

Headache Anatomy/Physiology: Headache Anatomy/Physiology: Th S h l ti G liTh S h l ti G liThe Sphenopalatine GanglionThe Sphenopalatine Ganglion

Primary path for cranialPrimary path for cranialPrimary path for cranial Primary path for cranial parasympathetic outflowparasympathetic outflowNeurons of SPG release Neurons of SPG release acetylcholine vasoactiveacetylcholine vasoactive

Orbital branch

acetylcholine, vasoactive acetylcholine, vasoactive intestinal peptide (VIP), intestinal peptide (VIP), nitric oxidenitric oxideStimulation of SPG evokesStimulation of SPG evokesStimulation of SPG evokes Stimulation of SPG evokes cerebral vasodilation  cerebral vasodilation  

Robbins MS, Robertson CE, Kaplan E, et al. The Sphenopalatine Ganglion: Anatomy, Pathophysiology, and Therapeutic Targeting in Headache. Headache 2015.

HUMANMIGRAINE TRIGGERS:HUMANMIGRAINE TRIGGERS:HUMAN MIGRAINE TRIGGERS:HUMAN MIGRAINE TRIGGERS:

DELAYED MIGRAINEDELAYED MIGRAINEDELAYED MIGRAINEDELAYED MIGRAINENitroglycerin/ GTNNitroglycerin/ GTNCGRPCGRPPACAPPACAPSildenafilSildenafilHistamineHistamineDipyridamoleDipyridamoleP t l di I2P t l di I2Prostaglandin I2Prostaglandin I2

IMMEDIATE MIGRAINEIMMEDIATE MIGRAINEP t l di E2P t l di E2Prostaglandin E2Prostaglandin E2

CGRP (calcitonin geneCGRP (calcitonin gene--related related peptide) peptide) --------What is it?What is it?

•• Peptide produced in neural cells Peptide produced in neural cells •• Peptide produced in neural cells Peptide produced in neural cells throughout the body, involved in:throughout the body, involved in:

Pain transmissionPain transmission–– Pain transmissionPain transmission–– VasodilationVasodilation

I fl tiI fl ti–– InflammationInflammation–– Regeneration of motor neuronsRegeneration of motor neurons

CGRPReceptor

CGRP IN MIGRAINECGRP IN MIGRAINECGRP IN MIGRAINECGRP IN MIGRAINE•• CGRP is released into the circulation during CGRP is released into the circulation during

a migraine attacka migraine attack•• CGRP infusion evokes migraineCGRP infusion evokes migraine•• Serum CGRP levels may be elevated in Serum CGRP levels may be elevated in

chronic migrainechronic migraine•• CGRP receptor antagonists effectively abort CGRP receptor antagonists effectively abort

migraine attacksmigraine attacksLassen L, Lassen L, HaderslevHaderslev P, Jacobsen V et al. CGRP may play a causative role in migraine . P, Jacobsen V et al. CGRP may play a causative role in migraine . CephalalgiaCephalalgia. 2002;22:54. 2002;22:54--6161

Goadsby PJ, Goadsby PJ, EdvinssonEdvinsson L. Human in vivo evidence for L. Human in vivo evidence for trigeminovasculartrigeminovascular activation in cluster headache. activation in cluster headache. NeuropeptideNeuropeptide changes changes and effects of acute attacks therapies. Brain. 1994;117 ( Pt 3):427and effects of acute attacks therapies. Brain. 1994;117 ( Pt 3):427--434434

OlesenOlesen J, J, DienerDiener HH--C, C, HusstedtHusstedt IW et al. IW et al. CalcitoninCalcitonin GeneGene--Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine. N Treatment of Migraine. N EnglEngl J Med. 2004;350:1104J Med. 2004;350:1104--11101110

Ho TW, Ho TW, MannixMannix LK, Fan X et al. Randomized controlled trial of an oral CGRP receptor antagonist, MKLK, Fan X et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK--0974, in acute treatment of 0974, in acute treatment of ,, , p g ,, p g , ,,migraine. Neurology. 2008;70:1304migraine. Neurology. 2008;70:1304--13121312

Ho TW, Ferrari MD, Dodick DW et al. Efficacy and tolerability of MKHo TW, Ferrari MD, Dodick DW et al. Efficacy and tolerability of MK--0974 (0974 (telcagepanttelcagepant), a new oral antagonist of ), a new oral antagonist of calcitonincalcitonin genegene--related peptide receptor, compared with related peptide receptor, compared with zolmitriptanzolmitriptan for acute migraine: a for acute migraine: a randomisedrandomised, placebo, placebo--controlled, parallelcontrolled, parallel--treatment trial. Lancet. 2009;372:2115treatment trial. Lancet. 2009;372:2115--21232123

“The“The cerebrovascularcerebrovascular trigeminal neuronal system in which CGRP is thetrigeminal neuronal system in which CGRP is the

Chronic division of trigeminal nerve prolongs recovery from vasoconstrictionChronic division of trigeminal nerve prolongs recovery from vasoconstriction

The The cerebrovascularcerebrovascular trigeminal neuronal system, in which CGRP is thetrigeminal neuronal system, in which CGRP is themost potent most potent vasoactivevasoactive constituent, may participate in a reflex or local constituent, may participate in a reflex or local response to excessive cerebral vasoconstriction that restores normal response to excessive cerebral vasoconstriction that restores normal vascular diameter.”vascular diameter.”

MigraineMigraine‐‐related Regions in Which CGRP and its related Regions in Which CGRP and its Receptor are ExpressedReceptor are ExpressedReceptor are ExpressedReceptor are Expressed

Trigeminal nociceptive neuronsTrigeminal nociceptive neuronsDural mast cellsDural mast cellsTrigeminal nucleus Trigeminal nucleus caudaliscaudalisDorsolateral pons/midbrainDorsolateral pons/midbrainThalamusThalamusHypothalamusHypothalamusCortexCortexCerebellumCerebellumAmygdalaAmygdalaVestibular nucleiVestibular nuclei

Small molecule CGRP Small molecule CGRP iireceptor antagonistsreceptor antagonists

MONOCLONAL ANTIBODIESMONOCLONAL ANTIBODIES

Mouse“-omab”

VariableChimericVariable region mouse

Antigen bindingregion

Constant

Variable Variable region mouse“-ximab”

HumanizedLight ChainFc Humanized

Antigen binding region mouse“-zumab”

g

H Ch iHeavy ChainHuman100% human“-umab”

CGRPCGRPCGRPCGRP

CGRPCGRP

CGRPCGRPCGRPCGRP

CGRPCGRP CGRPCGRPCGRPCGRP

CGRPCGRPCGRPCGRP

CGRPCGRPCGRPCGRP

CGRP RECEPTORSCGRP RECEPTORS

CGRPCGRPCGRPCGRP

CGRPCGRP

CGRPCGRPCGRPCGRP

CGRPCGRP

CGRPCGRP CGRPCGRP CGRPCGRP

CGRPCGRPCGRPCGRPCGRPCGRP

CGRP RECEPTORSCGRP RECEPTORS

MULTIPLE CGRP RECEPTORS?MULTIPLE CGRP RECEPTORS?

PACAP (Pituitary adenylate cyclase activating PACAP (Pituitary adenylate cyclase activating id ) A h P i l Th i Tid ) A h P i l Th i Tpeptide): Another Potential Therapeutic Targetpeptide): Another Potential Therapeutic Target

f i f i i i i iblf i f i i i i iblInfusion of PACAP triggers migraine in susceptible Infusion of PACAP triggers migraine in susceptible individualsindividualsPACAP l l l t d i i l ti i i i dPACAP l l l t d i i l ti i i i dPACAP levels elevated in circulation in migraine and PACAP levels elevated in circulation in migraine and cluster headache attackscluster headache attacksCoCo localized with CGRP in many anatomical regionslocalized with CGRP in many anatomical regionsCoCo‐‐localized with CGRP in many anatomical regionslocalized with CGRP in many anatomical regionsShares an accessory protein with CGRP (RampShares an accessory protein with CGRP (Ramp‐‐1)1)M k i ti ll ith CGRP ibl ithM k i ti ll ith CGRP ibl ithMay work synergistically with CGRP or possibly with May work synergistically with CGRP or possibly with distinct sites of action???distinct sites of action???

Migraine Biomarkers?Migraine Biomarkers?Elevated CSF levels of:Elevated CSF levels of:

GlutamateGlutamateCGRPCGRPNGFNGFNGFNGF

Elevated blood levels of Elevated blood levels of GlutamateGlutamateGlutamateGlutamateCGRPCGRP

D d CSF d bl d l l fD d CSF d bl d l l fDecreased CSF and blood levels ofDecreased CSF and blood levels ofBetaBeta‐‐endorphinendorphin

van Dongen RM, et al. Migraine biomarkers in cerebrospinal fluid: A systematic review and meta-analysis. Cephalalgia 2016.

FUNCTIONAL IMAGING STUDIES SHOW FUNCTIONAL IMAGING STUDIES SHOW CHANGES IN THE ACTIVITY OF MULTIPLE BRAIN CHANGES IN THE ACTIVITY OF MULTIPLE BRAIN 

REGIONS DURING A MIGRAINE ATTACKREGIONS DURING A MIGRAINE ATTACK•• CortexCortexCortexCortex

•• Waves of change in blood flow and metabolismWaves of change in blood flow and metabolism•• Increased responses to light in occipital cortexIncreased responses to light in occipital cortex•• Sustained Sustained hypoperfusionhypoperfusion

•• BrainstemBrainstem•• Increased blood flow in Increased blood flow in dorsolateraldorsolateral ponspons/midbrain/midbrain

•• HypothalamusHypothalamusI d bl d fl i d i it hI d bl d fl i d i it h•• Increased blood flow in during premonitory phase, Increased blood flow in during premonitory phase, headache, and headache, and postdromepostdrome

•• ThalamusThalamus•• Increased functional response correlated with somatic Increased functional response correlated with somatic allodyniaallodynia

THE PREMONITORY PHASE OF MIGRAINE: ACTIVATION OF THE HYPOTHALAMUS AND OTHER BRAIN REGIONS

Maniyar FH Sprenger T Monteith T Schankin C Goadsby PJ BrainManiyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 2014; 137(Pt 1): 232-41.

Sprenger T, Maniyar FH, Monteith TS, Schankin C, Goadsby PJ. Midbrain Activation in the Premonitory Phase of Migraine: A H215O-Positron emission tomography study. Headache 2012; 52: 863-4.

BRAIN ACTIVATION CORRELATES WITH MIGRAINE SYMPTOMS

NauseaNausea

PhotophobiaPhotophobia

A PET study of photophobia during spontaneous migraineA PET study of photophobia during spontaneous migraine attacksattacks

Maniyar FH Sprenger T Schankin

A PET study of photophobia during spontaneous migraine A PET study of photophobia during spontaneous migraine attacksattacksDenuelleDenuelle, M; , M; BoullocheBoulloche, N; , N; PayouxPayoux, P; MD, PhD; Fabre, N; Trotter, , P; MD, PhD; Fabre, N; Trotter, Y; Y; GeraudGeraud, , G NeurologyG Neurology. 76(3):213. 76(3):213--218, 218, 2011.2011.

Maniyar FH, Sprenger T, SchankinC, Goadsby PJ. The origin of nausea in migraine-a PET study. J Headache Pain 2014; 15: 84.

Clinical Clinical NeurophysiologicalNeurophysiological StudiesStudiesof Migraineof Migraine

Visual, auditory, and Visual, auditory, and somatosensorysomatosensory evoked evoked potential recordings may show reduced potential recordings may show reduced habituation between attackshabituation between attacksHabituation is normalized immediately Habituation is normalized immediately preceding and during headachepreceding and during headachep g gp g gHabituation may be normalized by therapy Habituation may be normalized by therapy with migraine preventive medicationswith migraine preventive medicationswith migraine preventive medicationswith migraine preventive medications

These studies are consistent with alterations in These studies are consistent with alterations in the excitability of cortical thalamic andthe excitability of cortical thalamic andthe excitability of cortical, thalamic, and the excitability of cortical, thalamic, and brainstem circuits in migraine brainstem circuits in migraine 

Somatosenory evoked potential high frequency oscillations are reduced in migraine patients indicating

alterations in thalamocortical circuitsalterations in thalamocortical circuits

Illustrative a traces of a (A) broad-band SSEPs, (B) HFO SSEPs and (C) three-dimensional short-time f OFourier transform spectrum in a healthy volunteer, a MO and a MA patient.

Coppola G et al. Brain 2005;128:98-103Brain Vol. 128 No. 1 © Guarantors of Brain 2004; all rights reserved

CORTICAL WAVESCORTICAL WAVESCSDAstrocyte wavesVascular waves

AURAVisual SensoryCognitive

BBB Permeability

MODULATINGFACTORS

G

DYSREGULATION OF CORTICAL

Cognitive

NOCICEPTIVE ACTIVATIONVasoconstrictionGenes

Gender/HormonesIonic/MetabolicDrugsEnvironment

OF CORTICAL BRAINSTEM, HYPOTHALAMIC,THALAMICEXCITABILITY

HEADACHEVasoconstrictionVascular/metabolic uncouplingRelease of CGRP, PACAP, NO, ATPVasodilation

BRAINSTEM /HYPOTHALAMIC/ THALAMIC ACTIVATION AND SENSITIZATION

SENSORY SENSITIVITYPhoto/phonophobiaCutaneous allodyniaNAUSEAVERTIGO

Trigeminal nucleus caudalisPeriaqueductal grayOther brainstem nuclei

FATIGUEMOOD CHANGE

PREMONITORY SYMPTOMSYawningYawningPolyuriaNeck pain

AURALANGUAGE SYMPTOMSLANGUAGE SYMPTOMS

MOTORMOTOR DYSFUNCTION

YAWNING,POLYURIA