MIG_01161_Migraine Pathophysiology_DT3 3/28/2016 11:34 AM

Eric J. Eross, D.O.Director, The CORE Institute Center for Headache Medicine

Fellowship‐Trained Headache Medicine Specialist, Mayo ClinicAssociate Clinical Professor, Midwestern University

Founder & President, Glia Sciences, INC.

Financial Disclosures:

Grant / Research Support

Clinical / Research Consultant

Speakers’ Bureau Major Stock Holder/ Investor

Other Financial / Material Support

Allergan YES no YES no no

ATI YES no no no no

Avinir no no YES no no

Depomed no no YES no no

Eli Lilly YES no no no no

Glia Sciences YES YES YES YES YES

Pernix no no YES no no

Teva no no YES no no

Upsher-Smith no YES no no no

Overview of Presentation

Clinical Features

PathophysiologyEffective Treatments

Overview of Presentation

Throbbing / Pounding

Worsening with Activity

Photophobia / Phonophobia

Nausea and Vomiting

Allodynia

Misdiagnosis as Sinus Headache

Misdiagnosis as Tension-Type Headache

Medication Overuse Headache (MOH)

Migraine specific acute treatments- triptans

DHE vs. triptan site(s) of action

Early vs. late treatment

Treatment while experiencing allodynia

Rescue with NSAID’s or steroids

MOA for preventative pharmaceuticals

CLINICAL FEATURES: EFFECTIVE TREATMENT:

Common triggers

Family history

MOA of osteopathic manipulation

New targets- CGRP, Sub P, NKA, etc.

MOA of blocks, stimulators, OT-A, TCMS

Objectives:

List the (ICHD-3 beta) diagnostic criteria for migraine headache and apply them effectively in clinical practice

Briefly explain the pathophysiology behind the main clinical features seen in migraine

Describe the site and mechanism(s) of action of at least three acute and three preventative treatments for migraine

Migraine Prevalence Compared With Other Neurologic Diseases

0.09% 0.71% 0.96% 1%

6.7%

12.1%

0

5

10

15

MS Epilepsy PD+HD Stroke AD Migraine

MS = multiple sclerosis; PD+HD = Parkinson disease + Huntington disease; AD = Alzheimer’s disease.1. Hirtz D. et al. Neurology. 2007;68:326–337. 2. National Institute of Neurological Disorders and Stroke. Available at: www.ninds.nih.gov. Accessed May 17, 2007.

Dis

ease

pre

vale

nce

, % 9.46%1.3x

Migraine: A Disabling Headache Disorder Burden

– Among the world’s 20 most disabling diseases (WHO)– Indirectly costs employers up to $13 billion per year– Direct medical costs exceed $1 billion per year

– “same level of disability as dementia, quadriplegia and acute psychosis”

WHO = World Health Organization.Pietrobon D. Neuroscientist. 2005;11:373–386; Stovner LJ et al. Cephalalgia. 2007;27:193–210.Linde M. Acta Neurol Scand. 2006;114:71–83; ICHD. Cephalalgia. 2004;24 (Suppl 1):9–160.Hu XH. et al Arch Intern Med. 1999;159:813–818.

A Sophisticated Array of Effective Treatment Options

PREVENTATIVE: ABORTIVE:

• Dietary modification• Trigger identification & avoidance• Exercise• Sleep hygiene / improvement• Biofeedback• Stress management & relaxation• Acupuncture• Osteopathic manipulation• Nutraceuticals• Herbal preparations• Pharmaceuticals• Onabotulinum Toxin A injections• Peripheral nerve blockade / stimulation

• Biofeedback and progressive relaxation• Sleep induction• Acupuncture• Osteopathic manipulation• Biofeedback• Nutraceuticals• Herbal preparations• Occipital nerve blocks• Trigeminal nerve blocks• Neurostimulation• Triptans• Ergots & DHE• NSAID’s• Antiemetics• IV infusions

Migraine Without Aura:International Headache Society Criteria

A. At least 5 attacks fulfilling criteria B through D

B. Headache attacks: 4 to 72 hours

C. Headache with at least 2 of the following characteristics1. Unilateral2. Pulsating3. Moderate or severe pain intensity4. Aggravation by or causing avoidance of routine physical activity

D. During headache at least 1 of the following:1. Nausea and/or vomiting2. Photophobia and phonophobia

E. Not attributed to another disorder

Headache Classification Subcommittee of the International Headache Society. Cephalalgia. 2004;24 (suppl 1):1–160.

Migraine With Aura:International Headache Society CriteriaA. At least 2 attacks fulfilling criteria B through D

B. Aura consisting of at least 1 of the following, but no motor weakness1. Fully reversible visual symptoms*2. Fully reversible sensory symptoms*3. Fully reversible dysphasic speech disturbance

C. At least 2 of the following1. Homonymous visual symptoms and/or unilateral sensory symptoms2. ≥1 aura symptom over ≥5 minutes, and/or different aura symptoms in

succession over ≥5 minutes3. Each symptom: ≥5 and ≤60 minutes

D. Headache fulfilling criteria B through D for migraine without aura begins during the aura or follows aura within 60 minutes

E. Not attributed to another disorder

* Including positive features and/or negative features.Headache Classification Subcommittee of the International Headache Society. Cephalalgia. 2004; 24 (suppl 1):1–160.

The Natural Course of a Typical Migraine Attack

Adapted with permission from Linde M. Acta Neurol Scand. 2006;114:71–83.

Premonitory phase

Headachephase

Resolution Postdrome

Headache

Time

Au

ra

12

Theoretical Model of a Migraine Cycle

Adapted from Expert Review Neurother. 4(3) 391–430 (2004) with permission of Future Drugs Ltd.

Initiatingmechanisms

Perpetuatingmechanisms

Resolvingmechanisms

Trigger

Low threshold

13

Migraine Triggers and Precipitants

0

25

50

75

100

Stress

Hormon

es

Not eat

ing

Wea

ther

Sleep

dis

turb

ance

Perfu

me

or o

dor

Neck

pain

Light(s

)

Alcohol

Smoke

Sleep

ing

late

Heat

Food

Exerc

ise

Sexua

l act

ivity

Fre

qu

enc

y (%

)

Adapted with permission from Kelman L. Cephalalgia. 2007; 27:394–402.

N=1,207 patients with migraine 75.9% reported triggers

– 40.4% infrequently– 26.7% frequently– 8.8% very frequently

14

Migraine Pathophysiology:Proposed Mechanisms

TVS = trigeminovascular system.Adapted with permission from Pietrobon D. Neuroscientist. 2005;11:373–386.

Aura CSD

Cortical neuronal hyperexcitability

Activation and peripheral sensitization of TGVS

Neurogenicinflammation

Centralsensitization

HEADACHE

?

+

+

Genetic predisposition

Migraine initiation

Pain generation/

perpetuation

Abnormal brainstem function

15

Low threshold to abnormal cortical activity

TGVS = trigeminovascular system.

Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386–398; Pietrobon D. Neuroscientist. 2005;11:373–386.

The “vascular theory” not supported by experimental evidence: → migraine does not start in the blood vessels

Cortical Spreading Depression (?)

The Primary Cause of the Migraine Headache Lies in the Brain

Cortical neuronal hyperexcitability and/orbrainstem dysfunction

Activation & sensitization of the TGVS

Prolonged headache pain of migraine

Genetic predisposition in some patients

Trigger

16

Dura

Migraine Pathophysiology: Central Role of the Trigeminovascular System

Trigeminal nerves

TNC

CSD = cortical spreading depression; TNC = trigeminal nucleus caudalis.

Pietrobon D et al. Nat Rev Neuro. 2003;4:386–398.

PAIN

CSD

TGVS activated

17

Parasympathetic Contribution to Migraine Pathophysiology

Adapted with permission from Goadsby PJ et al. N Engl J Med. 2002;346:257–270.Pietrobon D et al. Nat Rev Neuro. 2003;4:386–398.

18

FHM: a rare inherited form of migraine

Genetically heterogenous autosomal dominant

Genetic Predisposition:Familial Hemiplegic Migraine

FHM = familial hemiplegic migraine. 1. Sanchez del-Rio M et al. Curr Opin Neurol. 2006;19:294–298. 2. Pietrobon D. Neurotherapeutics. 2007;4:274–284.

Gene Protein Consequence

FHM-1 CACNA1A P/Q Ca2+

channels↑ presynaptic Ca2+

FHM-2 ATP1A2 Na+/K+-ATPase

↓ K+ and glutamate clearance

FHM-3 SCN1A Na+

channelPersistent Na+ influx

19

Familial Hemiplegic Migraine:Functional Implications of Gene Mutations

Adapted with permission from Sanchez del-Rio M et al. Curr Opin Neurol. 2006;19:294–298.

FHM-1CACNA1A gene

Cav2.1 Ca2+

Gain of function

FHM-2ATP1A2 gene

α2-subunitNa+/K+ ATPase pump

Loss of function

FHM-3SCN1A gene

Nav1.1Sodium channel

Gain of function

↑Glu/↑K+

CSD

Synapticmetabolism

(including glucose uptake)

20

Cortical Neuronal Hyperexcitability:Multiple Mechanisms

Enhanced release of excitatory neurotransmitters– For example, elevated plasma glutamate concentration

in patients with migraine– Identified genetic mutations in FHM

Reduced intracortical inhibition

Low brain Mg2+

Altered brain energy metabolism

NMDA = N-methyl-D-aspartate.Pietrobon D. et al. Nat Rev Neurosci. 2003;4:386–398.

21

Initiating Mechanisms of Headache Pain: Cortical Spreading Depression

Wave of intense cortical neuron activity– ↑ rCBF

Followed by neuronal suppression – ↓ rCBF– Often coincides with

headache onset

Velocity: 2–3 mm/min

Underlies visual aura

Occurs in clinically silent areas of the cortex?– Migraine without aura

rCBF = regional cerebral blood flow.

Adapted with permission from Hadjikhani N, Sanchez del-Rio M, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687-4692. Copyright 2001 National Academy of Sciences, U.S.A.

Pietrobon D. Neuroscientist. 2005;11:373–386; Goadsby PJ et al. N Engl J Med. 2002;346:257–270.

Time(s)

Blood oxygenation1 min

Occipital cortex

22

Initiating Mechanisms of Migraine: Brainstem Dysfunction

Dysfunction in areas involved in central control of nociception– PAG

Induces migraine?– Brainstem generator

Facilitates activation and sensitization of TNC neurons?– Decreased descending

inhibition during a migraine attack

PAG = periaqueductal gray regionAdapted with permission from Pietrobon D. Nat Rev Neurosci. 2003;4:386–398.

PAG

TGVS activation

HEADACHE

Substance P

23

Activation of the Trigeminovascular System and Pain Generation

Adapted with permission from Iadecola C. Nat Med. 2002;8:110–112.Bolay H. et al. Nat Med. 2002;8:136–142.

24

Activation of the Trigeminovascular System: Physiologic ImpactMeningealevents• Inflammation• Peripheral sensitization

Vasodilation of cerebral vessels

Adapted with permission from Durham PL. N Engl J Med. 2004;350:1073–1075.

Brainstemevents• Pain signal to CNS

• Central sensitization

• Allodynia

25

CGRP and substance P activate mast cells

Mast cell degranulation– Histamine– NGF– Serotonin– Proinflammatory

cytokines TNF, IL-1, IL-6

Neurogenic InflammationMeninges

Longoni M, Ferrarese C. 2006;27 (Suppl 2):S107–110; Pietrobon D. Neuroscientist. 2005;11:373–386.Durham PL N Engl J Med. 2004;350:1073–1075. Edvinsson L, Uddman R. Brain Res Rev. 2005;48:438–456.Theoharides TC. et al. Brain Res Rev. 2005;49:65–76; Goadsby PJ. Trends Mol Med. 2007;13:39–44.Levy D. et al. Headache. 2006;46 (suppl 1):S13–S18; Levy D. et al. Pain. 2007; April 23; [Epub ahead of print].

26

Vasodilation of Cerebral Vessels

NO

Adapted with permission from Durham PL. N Engl J Med. 2004;350:1073–1075.

27

5-HT receptors activated

CGRP releaseinhibited

During headache pain:Trigeminal nociceptors

become activated

Hypothesis: Serotonin Presynaptically Inhibits CGRP Release in Active Trigeminal Nociceptors

Serotonin

5-HT1D 5-HT1F

CGRP

Ahn AH et al. J Neurosci. 2006;26:8332–8338.

Serotonin receptor

28

Pain Signaling to CNS

Adapted with permission from Durham PL. N Engl J Med. 2004;350:1073–1075.

Ramadan NM et al. Pharmacol Ther. 2006;112:199–212; Storer BJ et al. Neuroscience. 1999;90:1371–1376; Edvinsson I. et al. Brain Res Rev. 2005;48:438–456; Pietrobon D. Neuroscientist. 2005;11:373–386; Geppetti P et al. J Headache Pain. 2005;6:61–70; Dodick D et al. Headache. 2006;46 (suppl 4):S182–S191; Buldyrev J et al. J Neurochem. 2006;99:1338–1350; Storer RJ. et al. Br J Pharmacol. 2004;142:1171–1181.

29

TNC

PAIN

Neuronal Sensitization and Migraine

TGVS Activation

Dodick D et al. Headache. 2006;46 (suppl 4):S182–S191.Durham PL et al. [Abstract]; 2007. American Headache Society.

Central Sensitization

Peripheral Sensitization

Meninges

Ganglion

30

Peripheral sensitizationResponse threshold of meningeal TGVS nociceptors

Response amplitude

Peripheral Sensitization and Migraine

Neurogenic inflammation

• Early: within ~ 20 min of the onset of pain

• Can last for up to 2 hours

• Throbbing pain • Worsened by

movement

• Drives central sensitization

Pietrobon D et al. Nat Rev Neurosci. 2003;4:386–398; Dodick D et al. Headache. 2006;46 (suppl 4):S182–S191.

31

Central sensitizationNeuronal hyperexcitability in the TNC

Possibly due to: CGRP Ca2+ glutamate (NMDA)

Central Sensitization and Migraine

Peripheral sensitizationincoming stimulation from the

trigeminal nerve

•Later: within ~60 min of the onset of pain

•Can last up to 10 hours

•Allodynia•Prolongation of the attack

•Drives sensitization of higher-order neurons

Dodick D, Silberstein S. Headache. 2006;46(suppl 4):S182–S191.

32

Measurable Neuropeptide Levels in the External Jugular Vein During Migraine Attacks

± 0 = no change from before headache.↑ = significant increase in neuropeptide level.Adapted with permission from Edvinsson L, Uddman R. Brain Res Rev. 2005;48:438–456.

VIP Substance P CGRP

Migraine without aura ± 0 ± 0 ↑

Migraine with aura ± 0 ± 0 ↑

Trigeminal neuralgia ± 0 ± 0 ↑

Cluster headache ↑ ± 0 ↑

Chronic paroxysmal headache

↑ ± 0 ↑

33

Activation of the Trigeminovascular System:Primary Neuromediators in Migraine

Origin of ReleaseSuggested

Meningeal ActionsBrain-stem

TGVSNerves

ParasympNerves Vasodilation

Mast Cell Degranulation

Plasma Extravasation

Neuro-peptides

CGRP Substance P

VIP Small Molecules

NO Glutamate

CGRP = calcitonin gene–related peptide; VIP = vasoactive intestinal peptide.Pietrobon D. Neuroscientist. 2005;11:373–386; Edvinsson L. et al. Brain Res Rev. 2005;48:438–456;Ramadan NM et al. Pharmacol Ther. 2006;112:199–212; Storer RJ et al. Neuroscience. 1999;90:1371–1376.Theoharides TC et al. Brain Res Rev. 2005;49:65–76; Goadsby PJ. Trends Mol Med. 2007;13:39–44.Storer RJ et al. Br J Pharmacol. 2004;142:1171–1181.

34

CGRP: Central Role in Migraine

Main neuropeptide released by activated TGVS neurons in migraine– Major neuropeptide of the TGVS

Infusion in susceptible individual induces migraine

During migraine: increased in jugular venous blood, cerebrospinal fluid, saliva– Also elevated in blood between attacks

Physiologic actions:– Vasodilation– Meningeal mast cell degranulation– Activation of second-order neurons in the TNC

Goadsby PJ, Edvinsson L. Ann Neurol. 1993;33:48–56.66; Gulbenkian S. et al. Peptides. 2001;22:995–1007.Edvinsson L, Uddman R. Brain Res Rev. 2005;48:438–456; Lassen LH et al. Cephalalgia. 2002;22:54–61.Edvinsson L. Headache. 2006;46:1088–1094; Sarchielli P. et al. Neurology. 2001;57:132–134.Bellamy JL. et al. Headache. 2006;46:24–33; Ashina M. et al. Pain. 2000;86:133–138.Pietrobon D. Neuroscientist. 2005;11:373–386; Theoharides TC. et al. Brain Res Rev. 2005;49:65–76. Storer RJ. et al. Br J Pharmacol. 2004;142:1171–1181.

35

Calcitonin receptor–like receptor

CGRP Receptor

Adapted with permission from Brain SD, Grant AD. Physiol Rev. 2004;84:903–934.

CLRCGRP

binding

36

Substance P:Role in Migraine? Member of the tachykinin neuropeptide family

– Substance P– Neurokinin A

Coexpressed and coreleased with CGRP– Less abundant than CGRP in trigeminal neurons

Role in migraine—if any—poorly understood – Substance P blood levels not increased

during headache phase– Substance P does not appear involved

in vascular nociception– Substance P mediates dural plasma extravasation

Edvinsson L. et al. Brain Res Rev. 2005;48:438–456; Geppetti P et al. J Headache Pain. 2005;6:61–70.

37

Substance P Receptors

Khedkar SA et al. Internet Elec J Molec Design. 2004;3:1–11.

Substance Pbinding

38

Glutamate: Central Role in Migraine Increased brain levels of glutamate may underlie cortical

hyperexcitability in patients with migraine

CSD– Is propagated by glutamate– Can be induced by NMDA and Mg2+ depletion (which releases NMDA

receptors)

Trigeminovascular activation– Glutamate-positive neurons found in all migraine pain-relay centers– All glutamate receptor subtypes expressed on the trigeminal system

Pain signaling to CNS and central sensitization– Involves glutamate

Ramadan NM. CNS Spectr. 2003;8:446–449. Longoni M et al. Neurol Sci. 2006;27 (suppl 2):S107–S110.

39

Nitric Oxide and Migraine Potent vasodilator

NO donors induce migraine in susceptible humans

NOS-containing fibers found around cranial blood vessels– Parasympathetic fibers– Trigeminal sensory fibers

May contribute to vasodilation and activation of the TGVS nociceptive nerve terminals

Role as a neurotransmitter– NOS expressed in trigeminal nerve cell bodies– May be involved in the activation and/or sensitization of TNC neurons

NOS = nitric oxide synthase.Edvinsson L et al. Brain Res Rev. 2005;48:438–456;Ramadan NM et all. Pharmacol Ther. 2006;112:199–212;Pietrobon D. et al. Nat Rev Neurosci. 2003;4:386–398.

40

Neurogenicinflammation

Migraine Pathophysiology:Summary

Cortical neuronal hyperexcitability

Abnormal brainstem function

Activation of TGVSNeuromediator release

(CGRP, glutamate)HEADACHE

+

+

Genetic predisposition

Initiation

Pain generation/perpetuation

TGVS = trigeminovascular system.

Adapted with permission from Pietrobon D. Neuroscientist. 2005;11:373–386.

Centralsensitization

Peripheralsensitization

+

(?)

(?)