MIGRAINE AURAMIGRAINE AURANEW INSIGHTS NEW INSIGHTS

ANDAND PERSISTENT QUESTIONSPERSISTENT QUESTIONS

Andrew Charles, M.D.Andrew Charles, M.D.ProfessorProfessor

Director, Headache Research and Treatment ProgramDirector, Headache Research and Treatment ProgramDavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA

MIGRAINE – A MULTISYMPTOM COMPLEXMIGRAINE – A MULTISYMPTOM COMPLEX

PATHOPHYSIOLOGICALPATHOPHYSIOLOGICALMECHANISMSMECHANISMS

AURA

LANGUAGE SYMPTOMSLANGUAGE SYMPTOMS

MOTOR MOTOR DYSFUNCTIONDYSFUNCTION

YAWNING,YAWNING,POLYURIAPOLYURIA

ICHD Classification of Migraine ICHD Classification of Migraine With AuraWith Aura

A. At least 2 attacks fulfilling criteria B–DA. At least 2 attacks fulfilling criteria B–D

B. Aura consisting of at least one of the following, B. Aura consisting of at least one of the following, but no motor but no motor weakness:weakness:

1. 1. fully reversible visual symptomsfully reversible visual symptoms including positive features (eg, including positive features (eg, flickering lights, spots or lines) and/or negative features (ie, loss of flickering lights, spots or lines) and/or negative features (ie, loss of vision)vision)

2. 2. fully reversible sensory symptomsfully reversible sensory symptoms including positive features (ie, including positive features (ie, pins and needles) and/or negative features (ie, numbness)pins and needles) and/or negative features (ie, numbness)

3. 3. fully reversible dysphasic speech disturbancefully reversible dysphasic speech disturbance

C. At least two of the following:C. At least two of the following:

1. 1. homonymous visual symptomshomonymous visual symptoms and/or and/or unilateral sensory symptomsunilateral sensory symptoms

2. 2. at least one aura symptom develops gradually over ≥5 minutes at least one aura symptom develops gradually over ≥5 minutes and/or different aura symptoms and/or different aura symptoms occur in succession over ≥5 occur in succession over ≥5 minutesminutes

3. each symptom 3. each symptom lasts ≥5 and <60 minuteslasts ≥5 and <60 minutes

D. Headache fulfilling criteria B–D for 1.1 Migraine without aura D. Headache fulfilling criteria B–D for 1.1 Migraine without aura begins begins during the aura or follows aura within 60 minutesduring the aura or follows aura within 60 minutes

E. Not attributed to another disorderE. Not attributed to another disorder

DIFFERENT CLINCIAL FEATURES DIFFERENT CLINCIAL FEATURES OF MIGRAINE WITH VS. WITHOUT OF MIGRAINE WITH VS. WITHOUT

AURAAURA• Different patterns of inheritanceDifferent patterns of inheritance• Different occurrence relative to Different occurrence relative to

menstrual cyclemenstrual cycle• Higher incidence of allodynia in Higher incidence of allodynia in

patients with aurapatients with aura• Vibeke et al., Evidence of a genetic factor in migraine with aura: A population-based Vibeke et al., Evidence of a genetic factor in migraine with aura: A population-based

Danish twin study. Annals of Neurology. 1999;45:242-6.Danish twin study. Annals of Neurology. 1999;45:242-6.• MacGregor E. Oestrogen and attacks of migraine with and without aura. The Lancet MacGregor E. Oestrogen and attacks of migraine with and without aura. The Lancet

Neurology. 2004;3:354-61.Neurology. 2004;3:354-61.• Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous

allodynia in the migraine population. Ann Neurol. 2008;63:148-58.allodynia in the migraine population. Ann Neurol. 2008;63:148-58.

MIGRAINE WITH AURA HAS MIGRAINE WITH AURA HAS GREATER ASSOCIATION GREATER ASSOCIATION

WITH:WITH:• STROKESTROKE• PATENT FORAMEN OVALEPATENT FORAMEN OVALE• CARDIOVASCULAR DISEASE IN WOMENCARDIOVASCULAR DISEASE IN WOMEN• DEPRESSIONDEPRESSION• ANXIETY, PANIC, PHOBIAS, SUICIDAL ANXIETY, PANIC, PHOBIAS, SUICIDAL

IDEATIONIDEATIONSchwedt TJ, Demaerschalk BM, Dodick DW. Cephalalgia. 2008;28:531-40.Schwedt TJ, Demaerschalk BM, Dodick DW. Cephalalgia. 2008;28:531-40.

Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Jama. 2006;296:283-91.Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Jama. 2006;296:283-91.

Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al. Neurology. 2005;64:1020-6.Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al. Neurology. 2005;64:1020-6.

Samaan Z, Farmer A, Craddock N, Jones L, Korszun A, Owen M, McGuffin P. The British Journal of Psychiatry. Samaan Z, Farmer A, Craddock N, Jones L, Korszun A, Owen M, McGuffin P. The British Journal of Psychiatry. 2009;194:350-4.2009;194:350-4.

HOWEVER….HOWEVER….• VERY FEW MA PATIENTS HAVE AURA VERY FEW MA PATIENTS HAVE AURA

WITH 100% OF THEIR ATTACKSWITH 100% OF THEIR ATTACKS• MANY PATIENTS CLASSIFIED AS HAVING MANY PATIENTS CLASSIFIED AS HAVING

MIGRAINE WITHOUT AURA HAVE HAD 1 MIGRAINE WITHOUT AURA HAVE HAD 1 or 2 EPISODES WITH TYPICAL AURAor 2 EPISODES WITH TYPICAL AURA

• CLINICAL SYMPTOMS MAY NOT MEET CLINICAL SYMPTOMS MAY NOT MEET DEFINITION OF AURA (e.g. cognitive DEFINITION OF AURA (e.g. cognitive symptoms, timing relative to symptoms, timing relative to headache,)headache,)

Olesen, et al. 1981 Hadjikhani et al., 2001

Cao et al., 1999

CORTICAL “WAVES” IN MIGRAINE WITH AURA

Bereczki et al., 2008

PET STUDY SHOWS SPREADING PET STUDY SHOWS SPREADING OLIGEMIA IN MIGRAINE PATIENT OLIGEMIA IN MIGRAINE PATIENT

WITHOUT AURAWITHOUT AURA

Woods RP, Iacoboni M, Mazziotta JC.. N Engl J Med. 1994;331:1689-92.

Woods et al., 1994

Chalaupka, 2008

Denuelle et al., 2008

Before sumatriptan2 to 4 h after the attack onset

After sumatriptan4 to 6 h after the attack onset

…AND MIGRAINE WITHOUT AURA

• UNDERLYING PATHOPHYSIOLOGICAL UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF AURA MAY BE MECHANISMS OF AURA MAY BE CLINICALLY SILENTCLINICALLY SILENT

• ABSENCE OF AURA SYMPTOMS, ABSENCE OF AURA SYMPTOMS, PARTICULARLY THOSE STRICTLY PARTICULARLY THOSE STRICTLY DEFINED BY ICHD CRITERIA, DOES DEFINED BY ICHD CRITERIA, DOES NOT MEAN THAT CORTICAL NOT MEAN THAT CORTICAL PHENOMENA ARE NOT OCCURRINGPHENOMENA ARE NOT OCCURRING

Afridi, S. K. et al. Brain 2005 128:932-939;

Activation of the ipsilateral pons in patients with right-sided attacks (n = 8, A) and left-sided attacks (n = 8, B)

Hypothalamic Activation in Migraine (Denuelle et al., Headache, 2007)

MIGRAINE – A MULTISYMPTOM COMPLEXMIGRAINE – A MULTISYMPTOM COMPLEX

AURA

LANGUAGE SYMPTOMSLANGUAGE SYMPTOMS

MOTOR MOTOR DYSFUNCTIONDYSFUNCTION

YAWNING,YAWNING,POLYURIAPOLYURIA

Cortical Cortical ActivationActivation

BrainstemBrainstemActivationActivation

HypothalamicHypothalamicActivationActivation

OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSIONOPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION• Allows visualization of parenchymal and vascular signalsAllows visualization of parenchymal and vascular signals over large area with local electrophysiological recordingover large area with local electrophysiological recording• Induction thresholds can be reliably established Induction thresholds can be reliably established

CSD evoked by KCl pulse --- rat cortex. 5 minute recording

OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION -- OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION -- DIGITAL SUBTRACTION IMAGEDIGITAL SUBTRACTION IMAGEK.C. BrennanK.C. Brennan

CSD evoked by KCl pulse --- mouse cortex. 5 minute recording

Fabricius, M. et al. Brain 2006 129:778-790;.

Recording of CSD in the injured human cortex over a period of 40 min

SPREADING DEPRESSION IN HUMANS WITH BRAIN INJURY PLAYS A ROLE IN PROGRESSION OF INJURY

ISSUES WITH CLASSICAL CORTICAL ISSUES WITH CLASSICAL CORTICAL SPREADING DEPRESSION IN MIGRAINESPREADING DEPRESSION IN MIGRAINE

• CLASSIC EEG FINDINGS OF CORTICAL SPREADING CLASSIC EEG FINDINGS OF CORTICAL SPREADING HAVE NOT BEEN OBSERVED IN MIGRAINE HAVE NOT BEEN OBSERVED IN MIGRAINE PATIENTSPATIENTS

• MOST PATIENTS DO NOT HAVE THE PROFOUND MOST PATIENTS DO NOT HAVE THE PROFOUND NEUROLOGICAL IMPAIRMENT ONE WOULD NEUROLOGICAL IMPAIRMENT ONE WOULD EXPECT WITH CLASSICAL CSDEXPECT WITH CLASSICAL CSD

• MIGRAINE MAY INVOLVE CORTICAL WAVES THAT MIGRAINE MAY INVOLVE CORTICAL WAVES THAT ARE RELATED TO, BUT NOT IDENTICAL TO CSD ARE RELATED TO, BUT NOT IDENTICAL TO CSD OBSERVED IN ANIMAL MODELSOBSERVED IN ANIMAL MODELS

• DIFFERENT TYPES OF CORTICAL WAVES MAY DIFFERENT TYPES OF CORTICAL WAVES MAY INVOLVE DISTINCT CELLULAR MECHANISMSINVOLVE DISTINCT CELLULAR MECHANISMS

VASCULAR EVENTS IN VASCULAR EVENTS IN CORTICAL ARTERIOLES WITH CORTICAL ARTERIOLES WITH

CSDCSD– INITIAL DILATIONINITIAL DILATION

• Conducted With Intrinsic Velocity Conducted With Intrinsic Velocity Ahead of CSDAhead of CSD

–SUBSEQUENT CONSTRICTIONSUBSEQUENT CONSTRICTION–EVENTUAL DILATION OR EVENTUAL DILATION OR

SUSTAINED CONSTRICTION – MAY SUSTAINED CONSTRICTION – MAY DEPEND ON METABOLIC STATEDEPEND ON METABOLIC STATE

INTRINSIC VASCULAR CONDUCTION WITH CSDINTRINSIC VASCULAR CONDUCTION WITH CSDBrennan et al., J. Neurophys, 2007Brennan et al., J. Neurophys, 2007

CSD evoked by KCl pulse --- mouse cortex. 5 minute recording

VASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERSVASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERSTHAT MAY INFLUENCE ACTIVITY OF NEIGHBORINGTHAT MAY INFLUENCE ACTIVITY OF NEIGHBORING

NEURONS AND GLIAL CELLSNEURONS AND GLIAL CELLS

K.C. BrennanK.C. Brennan

Spontaneous CSD in setting of hypoxia – profound vasoconstriction

ARTERIOLAR DILATION PROPAGATES AHEADARTERIOLAR DILATION PROPAGATES AHEADOF PARENCHYMAL CHANGES OF CSDOF PARENCHYMAL CHANGES OF CSD

COULD VASCULAR SIGNALING PLAY AN ACTIVE ROLE IN COULD VASCULAR SIGNALING PLAY AN ACTIVE ROLE IN CORTICAL WAVES?CORTICAL WAVES?

“It seems well to consider, therefore, that, however brought about, vascular changes may precede and condition the cortical depression”.

Leao, J. Neurophys, 1945

HUMAN ASTROCYTE WITH BLOOD VESSEL AND NEURONSMaiken Nedergaard

Calcium wave evoked by mechanical stimulation in glial culture. Real TimeCalcium wave evoked by mechanical stimulation in glial culture. Real Time

Astrocytes are capable of widespread intercellular Astrocytes are capable of widespread intercellular signaling via propagated waves of increased signaling via propagated waves of increased

intracellular calciumintracellular calcium

ASTROCYTE CALCIUM ASTROCYTE CALCIUM WAVESWAVES

• SLOWLY PROPAGATED WAVES EVOKED BY SLOWLY PROPAGATED WAVES EVOKED BY WIDE VARIETY OF STIMULIWIDE VARIETY OF STIMULI

• ASSOCIATED WITH ASSOCIATED WITH ACTIVEACTIVE RELEASE OF: RELEASE OF:– ATPATP– GLUTAMATEGLUTAMATE– K+K+– LACTATELACTATE– PROSTANOIDSPROSTANOIDS– INTERLEUKINSINTERLEUKINS

• CAPABLE OF CAPABLE OF ACTIVEACTIVE MODULATION OF MODULATION OF NEURONAL AND VASCULAR ACTIVITYNEURONAL AND VASCULAR ACTIVITY

Multifocal Astrocyte Multifocal Astrocyte Calcium Waves in Cortical Calcium Waves in Cortical Slice Slice

Multifocal CSD Evoked by Multifocal CSD Evoked by KCl Crystal In Vivo KCl Crystal In Vivo

CORTICAL WAVES MAY BE REPETITIVE, CORTICAL WAVES MAY BE REPETITIVE, MULTIFOCAL EVENTS MULTIFOCAL EVENTS

Na+/K+ ATPase

P/Q Ca2+ Channel Nav1 Na+ ChannelFHM Mutations

Neurons

Astrocytes

Vascular cells

ATP

Adenosine

GLUTAMATE

Eicosanoids

K+

K+

ATP

Adenosine

Nitric OxideEndothelin

CGRP

PROPENSITY FOR CSD IS PROPENSITY FOR CSD IS INCREASED BY:INCREASED BY:

• GENES -- Transgenic mice expressing GENES -- Transgenic mice expressing FHM1 genes show increased propensity for FHM1 genes show increased propensity for CSDCSD

• GENDER – Female mice have a reduced GENDER – Female mice have a reduced threshold for CSDthreshold for CSD

• HORMONES – Ovarian hormones reduce HORMONES – Ovarian hormones reduce the threshold for CSDthe threshold for CSD

• van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, Kaja S, Broos LAM, Cesetti T, et al. van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, Kaja S, Broos LAM, Cesetti T, et al. Neuron. 2004;41:701-10.Neuron. 2004;41:701-10.

• Brennan KC, Romero-Reyes M, López Valdés HE, Arnold AP, Charles AC. Annals of Neurology. Brennan KC, Romero-Reyes M, López Valdés HE, Arnold AP, Charles AC. Annals of Neurology. 2007;61:603-6.2007;61:603-6.

• Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, et al. J Clin Invest. Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, et al. J Clin Invest. 2009;119:99-109.2009;119:99-109.

MEDICATIONS THAT INHIBIT CORTICAL MEDICATIONS THAT INHIBIT CORTICAL EXCITABILITY PREVENT MIGRAINE EXCITABILITY PREVENT MIGRAINE

WITH AND WITHOUTWITH AND WITHOUT AURA AURA• Ayata et al., Annals of Neurology 2006.Ayata et al., Annals of Neurology 2006.

– Diverse pharmacological agents that are Diverse pharmacological agents that are effective for migraine prevention suppress effective for migraine prevention suppress cortical spreading depression in rat.cortical spreading depression in rat.

• Memantine for migraine prevention??Memantine for migraine prevention??– Identified as an inhibitor of CSDIdentified as an inhibitor of CSD– Initial clinical results encouraging (Charles, et Initial clinical results encouraging (Charles, et

al, Journal of Headache and Pain, 2007). al, Journal of Headache and Pain, 2007). • Specific neuronal, astrocytic, and vascular cortical Specific neuronal, astrocytic, and vascular cortical

mechanisms may represent individual distinct mechanisms may represent individual distinct targets for new acute and preventive therapiestargets for new acute and preventive therapies

MIGRAINE – A MULTISYMPTOM COMPLEXMIGRAINE – A MULTISYMPTOM COMPLEX

AURA

LANGUAGE SYMPTOMSLANGUAGE SYMPTOMS

MOTOR MOTOR DYSFUNCTIONDYSFUNCTION

YAWNING,YAWNING,POLYURIAPOLYURIA

Cortical Cortical ActivationActivation

BrainstemBrainstemActivationActivation

HypothalamicHypothalamicActivationActivation

AcknowledgementsAcknowledgements• UCLA Headache Research and Treatment ProgramUCLA Headache Research and Treatment Program

– K.C. BrennanK.C. Brennan – Marcelo Romero ReyesMarcelo Romero Reyes– Hector Lopez-ValdesHector Lopez-Valdes

• Feldman LabFeldman Lab– Mike BacaMike Baca

• UCSF/HHMIUCSF/HHMI– Louis Ptáček– Ying-Hui FuYing-Hui Fu– Ying XuYing Xu– Archana ShenoyArchana Shenoy

• University of VermontUniversity of Vermont– Robert E. ShapiroRobert E. Shapiro

• Department of Neurology/Brain Mapping CenterDepartment of Neurology/Brain Mapping Center– John MazziottaJohn Mazziotta– Arthur TogaArthur Toga