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PathophysiologyContent developed by:

Andrew C. Charles, MD, FAHS,

Peter J. Goadsby, MD, PhD, FAHSDonna Gutterman, PharmD

Faculty Disclosures

ANDREW C. CHARLES, MD, FAHSDr. Charles has received consulting fees and/orhonoraria from Amgen,

eNeura and AGA Medical.

PETER J. GOADSBY, MD, PHD, FAHS Dr. Goadsby has received consulting fees and/or honoraria from Pfizer,

Zogenix, Nevrocorp, Impax, Dr. Reddy, Zosano and Amgen. He is on theSpeaker’s Bureau of Allergan, Inc., and Pfizer, Inc. He has received other

financial benefit, as an expert witness from for Journal Watch Neurology (manuscript preparation), Medico (Legal advice, patient advice). Dr.

Goadsby's institution has received grants from ENeura, Amgen and Allergan, Inc.

DONNA GUTTERMAN, PHARMD

Dr. Gutterman has received consulting fees and/or honoraria from NuPathe, Teva Pharmaceuticals, Dr. Reddy Pharmaceuticals.

Learning Objectives

At the conclusion of this talk, participants will be able to:

• Recognize that episodic and chronic migraine involve overlapping trigeminovascular mechanisms

• Know the role of allodynia and central sensitization in chronic migraine

• Explain how activation of brain regions are involved in the pathophysiology of migraine

• Identify new treatment mechanisms in migraine

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PRDM16TRPM8

LRP1ZNF555

ADARB2GRM7

HTR7MEF2D

TGFBR2PHACTR1

ASTN2

SUSCEPTIBILITY LOCI

FHM

FAMILIAL MIGRAINE

CACNA1AATP1A2

SCN1A

TRESK

CK1δ

PremonitoryPremonitory AuraAura PostdromePostdromeHeadacheHeadache

YawningPolyuria

Neck PainFatigue

Mood change Light sensitivitySound sensitivity

Visual symptomsSensory symptomsLanguage symptomsCognitive symptoms

Nausea

Headache

Cutaneous allodynia

HypothalamusBrainstemCortex

Cortex BrainstemThalamusHypothalamus

CortexThalamusHypothalamus

TIMELINE OF A MIGRAINE

Vascular theory of migraine- R.I.P.

Theory• Aura is caused by cerebral vasoconstriction

• Pain is due to reflex vasodilation• Acute treatments work by vasoconstriction

But

• Cerebral and meningeal blood vessels are not dilatedduring migraine induced by:

–Nitroglycerin1

–Sildenafil1

• Some drugs that induce significant cerebral vasodilationdo not cause migraine

–Vasoactive intestinal peptide3

Graham & WolffArch Neurol 1938;39:737

1. Schoonman et al., Brain. 2008;131:21922. Nagata et al., Intern Med 2009;48:21333. Rahmann et al., Cephalalgia. 2008;28:226

3

• Nineteen patients with spontaneous migraine

• No extracranial artery dilation during attack

• Slight intracranial artery dilation during attack

• Effective treatment with sumatriptan caused

no intracranial vasoconstriction

Amin et al., Lancet Neurology 2013;12:454

Clinical Features of Chronic Migraine Clinical Features of Chronic Migraine

Often evolves from episodic migraine

Has overlapping phenotypic features

AllodyniaRisk factor for progression

Persists interictally

May be difficult to reverse

Overlapping Mechanisms of EM and CM

Trigeminovascular system

• Involved in episodic and chronic migraine

• More easily activated in chronic

dura mater

V ganglion

Trigeminalcervical

complexSensory Cortex

First-order neuron

Second-order neuron

Third-order neuron

Thalamus

Shared pathways

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dura mater

V ganglion

trigeminal

nucleus

C2

C1

Cervical input

*Trigemino-Cervical Complex

Migraine and the Neck- Referred pain in the TCC

Thalamus

Neurons in the cervicomedullary junction

and the dorsal horn of the spinal cord

A

B

Thalamic Sensitization in Migraine with Extended Allodynia

dura mater

V ganglion

Trigeminalcervical

complex Sensory Cortex

First-order neuron

Second-order neuron

Third-order neuron

Thalamus

Ipsilateral Contralateral

Dura

Cutaneousallodynia

Throbbingpain

Muscle tenderness

Activated central neuron(Thalamus)

Sensitized peripheral neuron

(trigeminal ganglion)

Meningealblood vessel

Sensitizedcentral neuron

(trigemino-cervical

complex)

Pain Pain perceptionperception

Sensitization

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Cutaneous Allodynia in Episodic and Chronic Migraine

• Non-nociceptive stimuli are painful

–Region of spontaneous pain: sensitization of V1

–Expanded regions: trigeminocervical complex neurons

–Contralateral and ipsilateral: sensitization of thalamic neurons

• Presumed mechanism of allodynia is sensitization

• Allodynia is more common in CM than EM

Pathophysiology ARS Question 1

The transition from episodic to CM involves which of the following?

a) central sensitization

b) abnormal pain modulation by brainstem nuclei

c) white matter lesions

d) large patent foramen ovale (PFO)

e) frequent use of over the counter NSAIDs

A. All the above

B. a and b only

C. c and d only

D. e only

E. none of the above

Role of the BrainstemRole of the Brainstem

May play a key role in development of chronic migraine

• Neurotransmitters are similar in CM and EM

• Iron deposition in PAG related to frequency of

attacks

• Pontine lesions cause CM-like headache

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

Bahra, et al., Lancet 357:1016-1017 2001

Weiller et al, Nat Med. 1:658-660; 1995

ACTIVATION OF BRAINSTEM DURINGACUTE MIGRAINE ATTACKS

Periaqueductal Gray Matter (PAG)Opioids, Ergots, Triptan, CGRP and P/Q Ca2+ channel actions converge

Pozo-Rosich et al., Cephalalgia 2009;29

Mean±SEM change in TNC Aδ activity after PAG agatoxin, n=18WDR, n=16; NS, n=2

time in minutes

-10 0 10 20 30 40 50 60

% c

hang

e

100

110

120

130

140

150

agatoxin

Knight et al., J Neurosci 2002; (RC213):1-6

P/Q BlockadeAgatoxin

Goadsby & KnightCephalalgia 1997;17:153

Triptans

Ann Neurol 1991;21:91-94

Ergots

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

Cao et al., 1999

CORTICAL “WAVES” IN MIGRAINE WITH AURA

Woods et al., 1994

…and without aura

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Activation of Hypothalamus in Migraine

DURING AND AFTER HEADACHE

IN PREMONITORY PHASE

(Denuelle et al., Headache 2007;47:1418)

Maniyar et al., Brain 2014;137:232)

Areas of Reduced Brain Volume in Chronic Migraine

Valfrè W et al. Headache. 2008;48:109

Rocca MA et al. Stroke. 2006;37:1765

Grey Matter Reduction in Chronic Post-Traumatic Headache

Obermann et al., Neurology 2009; 73:978

Reduced grey matter at three months in patients with post-traumatic headachethat has recovered at one year

Anterior cingulate cortex Dorsolateral prefrontal cortex

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MRI Lesions in Migraine

• CAMERA -2 FOLLOW-UP

– 8.5 (7.9-9.2) years

– Controls (n=83/140)

– Migraine with Aura (114/162)

– Migraine without Aura (89/134)

� Slight increased risk of progression of deep white matter lesions in women only with migraine without

aura

Palm-Meinders et al., JAMA. 2012;308:1889

MRI Lesions in Migraine

• CAMERA -2 FOLLOW-UP

– 8.5 (7.9-9.2) years

– Controls (n=83/140)

– Migraine with Aura (114/162)

– Migraine without Aura (89/134)

• Slight increased risk of progression of deep white matter lesions in women only with migraine without aura

� No increase in progression of brainstem

hyperintensities in patients with migraine compared

with controls

Palm-Meinders et al., JAMA. 2012;308:1889

MRI Lesions in Migraine

• CAMERA -2 FOLLOW-UP

– 8.5 (7.9-9.2) years

– Controls (n=83/140)

– Migraine with Aura (114/162)

– Migraine without Aura (89/134)

• Slight increased risk of progression of deep white matter lesions in women only with migraine without aura

• No increase in progression of brainstem

hyperintensities in patients with migraine compared

with controls

� No increased risk of posterior posterior circulation

infarcts in patients with migraine compared with controls

• No difference in cognitive function in patients with white

matter lesions compared with controls

Palm-Meinders et al., JAMA. 2012;308:1889

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CGRP (Calcitonin Gene Related Peptide)

IN MIGRAINE

• CGRP is elevated in the cranial circulation in severe, acute migraine1

• CGRP infusion triggers migraine2

• CGRP receptor antagonists abort acute migraine3

• CGRP levels are elevated in chronic migraine4

1. Goadsby et al., Ann Neurol 1990;28:1832. Lassen et al., Cephalalgia. 2002;22:54

3. Olesen et al., N Engl J Med. 2004;350:11044. Cernuda-Morollon et al., Neurology. 2013;81:1191

Biologic Approaches to Migraine Prevention

• Amgen AMG 3341

– Human monoclonal IgG1 receptor CLR/RAMP1

– Phase II- episodic & chronic Migraine

� Alder Biopharmaceuticals- ALD 4032

– Humanized CGRP peptide antibody

– Phase II: episodic migraine

� Arteaus Therapeutics/Lilly- LY29517423

– Humanized CGRP peptide antibody

– Phase II: episodic migraine

• Labrys/Tev- LBR-1014

– Humanized CGRP peptide antibody

– Phase II: episodic & chronic migraine

1. Shi et al., Headache 2014;54:14172. Dodick et al., Lancet Neurol 2014;13:in press3. Dodick et al., Lancet Neurol 2014;13:8854. Garzone et al., Cephalalgia 2013;33:966

Lutterotti & Martin Lancet Neurol 2008;7:538

Summary

Although there is much to still address regarding migraine mechanisms and the brain, selected

studies suggest:

• Migraine mechanisms involve the trigeminovascularsystem which can be sensitized

• Brainstem activation is involved in the mechanisms of episodic and chronic migraine

• Chronic migraine can produce structural brain changes over time that may be reversible

• Calcitonin gene-related peptide (CGRP) mechanisms are promising targets for anti-migraine therapeutics

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