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UPDATE ON MIGRAINE EPIDEMIOLOGY, GENETICS,

AND BASIC MECHANISMS

Andrew Charles, M.D.

Professor of Neurology

Director, UCLA Goldberg Migraine Program

Meyer and Renee Luskin Chair in Migraine and Headache Studies

David Geffen School of Medicine at UCLA

DISCLOSURES

Grant Support

Takeda

Consultant

Alder, Amgen, Biohaven, Eli Lilly, eNeura,

Clinic Trial Steering Committee

St. Jude

EPIDEMIOLOGY

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(#3 in age <50)

Migraine and Stroke

Meta-analyses indicate that migraine with aura is

associated with approximately 2-fold relative risk of

ischemic stroke, although significant variability between studies

High frequency of attacks and recent onset of

migraine may be associated with increased risk

Migraine associated with 1.5 fold risk of intracranial

hemorrhage (both intracerebral and 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.

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Migraine with aura associated with higher risk of peri-operative stroke

• Prospective hospital registry study

• 124,558 patients• Primary outcome ischemic stroke with 30 days of surgery

• Stroke risk

Overall – 2.4/1000 patients

Migraine without aura – 3.9/1000 patientsMigraine with aura – 6.3/1000 patients

PFO and Migraine

PFO-Migraine Odds

RatiosMigraine with aura- 3.4

(p<.00001)

Migraine with or without aura – 2.5

(p=.0001)

Migraine without aura – 1.3

(no statistical significance)

Other Migraine Associations

Parkinson’s diseaseScher, et al. Midlife migraine and late-life parkinsonism: AGES-Reykjavik study. Neurology. 2014;83(14):1246-52.

Wang HI, Ho YC, Huang YP, Pan SL. Migraine is related to an increased risk of Parkinson's disease: A population-

based, propensity score-matched, longitudinal follow-up study. Cephalalgia 2016.

Restless legs syndromeLin GY, Lin YK, Lee JT, Lee MS, Lin CC, Tsai CK, Ting CH, Yang FC. Prevalence of restless legs syndrome in migraine

patients with and without aura: a cross-sectional, case-controlled study. J Headache Pain 2016; 17:97.

Schurks M, Winter A, Berger K, Kurth T. Migraine and restless legs syndrome: a systematic review. Cephalalgia.

2014;34(10):777-94.

Extracranial artery dissection (MO)Metso TM, et al. Migraine in cervical artery dissection and ischemic stroke patients. Neurology. 2012;78(16):1221-8.

DepressionBuse DC, et al. Psychiatric comorbidities of episodic and chronic migraine. Neurology. 2013; 260(8): 1960-9.

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Migraine Genetics

Louis Ptacek

Migraine Genetics

Familial Hemiplegic MigraineFHM1 CACNA1A – P/Q type calcium channel

FHM2 ATP1A2 – Na+/K+ ATPase

FHM3 SCN1A – Voltage gated sodium channel

? PRRT2 Proline rich transmembrane protein 2

Monogenetic vasculopathies with migraine as

part of phenotypeCerebral autosomal dominant arteriopathy with

subcortical infarcts and leukoencephalopathy

CADASIL – Notch 3 Gene

Retinal vasculopathy with cerebral leukodystrophy

RCVL - TREX1 gene

Hereditary infantile hemiparesis, retinal arteriolar

tortuosity, and leukoencephalopathy COL4A1 gene

Families with identified single gene

mutationsTRESK – K+ channel

Casein Kinase 1 delta – Kinase associated with

advanced sleep phase syndrome

Gene polymorphisms associated with

either increased or decreased risk of

migraine based on population (GWAS)

studies

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BASIC MECHANISMS

Premonitory Aura PostdromeHeadache

Yawning

Polyuria

Neck Pain

Fatigue

Mood change

Light sensitivity

Sound sensitivity

Visual symptomsSensory symptomsLanguage symptoms

Cognitive symptoms

Nausea

Headache

Cutaneous allodynia

Hypothalamus

BrainstemCortex

Cortex Brainstem

ThalamusHypothalamus

Cortex

ThalamusHypothalamus

TIMELINE OF A MIGRAINE ATTACK 4-72 hours

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Premonitory Phase

PET studies show brain activation correlated with clinical

Symptoms:

Occipital cortex – Light sensitivity

Rostral doral medulla and PAG - Nausea

Hypothalamus - ? Polyuria, mood change, appetite change

1. Maniyar FH, Sprenger T, Monteith T, Schankin CJ, Goadsby PJ. The premonitory phase

of migraine--what can we learn from it? Headache. 2015;55(5):609-20.

2. Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. The origin of nausea in migraine-a

PET study. J Headache Pain. 2014;15:84.3. Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. Photic hypersensitivity in the

premonitory phase of migraine--a positron emission tomography study. Eur J Neurol. 2014;21(9):1178-

83.

• Patient scanned daily with fMRI

for 30 days

• 3 migraine attacks captured

• Interictal and ictal periods captured

The Hypothalamus as a Therapeutic Target

Hypothalamus has neurons that respond activity to

gluccocorticoids

Hypothalamic neurons release:

Somatostatin

Oxytocin

Orexins

Dopamine

Other substances potentially involved in migraine

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Sensory Sensitization Before Headache

HUMAN MIGRAINE TRIGGERS:

DELAYED MIGRAINE

Nitroglycerin/ GTN

CGRP

PACAP

Sildenafil

Histamine

Dipyridamole

Prostaglandin I2

Hypoxia

IMMEDIATE MIGRAINE

Prostaglandin E2

Ipsilateral Contralateral

Alterations in function and sensitization of the thalamus play a role in migraine

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Measuring Functional Connectivity

with MRI

Based on low frequency (.1 Hz) oscillations in

blood oxygen level dependent (BOLD) MRI

signal

Synchronization of these oscillations in different brain regions is interpreted as functional

connectivity between those regions.

“Resting states” refers to activity in brain regions

that occurs in the absence of external

stimulation

DEFAULT MODE NETWORK

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Abnormal Functional Connectivity

in Migraine

Chronic migraine associated with altered

connectivity of anterior insula, amygdala, pulvinar,

mediodorsal thalamus, middle temporal cortex, periaqueductal gray, and others

Chong CD, Schwedt TJ, Dodick DW. Migraine: What Imaging Reveals. Curr Neurol

Neurosci Rep 2016;16:64.

Schwedt TJ, Chiang CC, Chong CD, et al. Functional MRI of migraine. Lancet

neurology 2015;14:81-91.

For excellent reviews, see:

CGRP (Calcitonin Gene Related Peptide)

IN MIGRAINE

CGRP is released into the jugular venous system during a migraine attak

CGRP infusion evokes migraine

CGRP receptor antagonists effectively abort

migraine attacks

Serum CGRP levels elevated in chronic migraine

1Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 1988; 23(2): 193-6.

Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117 ( Pt 3):427-434

Olesen J, Diener H-C, Husstedt IW et al. Calcitonin Gene-Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of M igraine. N Engl J Med. 2004;350:1104-1110

Ho TW, Mannix LK, Fan X et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70:1304-1312

Ho TW, Ferrari MD, Dodick DW et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet. 2009;372:2115-2123

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

Peptide produced in neural cells throughout the

body, involved in:

Pain transmission

Vasodilation

Inflammation

Regeneration of motor neurons

CGRP Receptor

For review, see Kaiser EA, Russo AF. Neuropeptides 2013; 47:451-461.

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CGRP and its receptor are part of the calcitonin family of

peptides and receptors

• The CGRP receptor is a complex that requires both RAMP1 and CLR1

• RAMP1 and CLR are also components of other calcitonin receptors1,2

• Ligands cross-interact with other receptors in the family1,2

• Only the CGRP receptor has been implicated in migraine pathophysiology2

ADM, adrenomedullin; AMY, amylin; CLR, calcitonin receptor-like receptor; CTR, calcitonin receptor; RAMP, receptor activity-

modifying protein.1. Walker CS, Hay DL. Br J Pharmacol. 2013;170:1293–1307. 2. Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533–552.

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Ligand CGRP Adrenomedullin Amylin

Receptor

composition1,

2

CLR+

RAMP1

CLR+

RAMP2

CLR+

RAMP3

CTR+

RAMP1

CTR+

RAMP2

CTR+

RAMP3

Receptor

[name]1 CGRP ADM1 ADM2 AMY1 AMY2 AMY3

Structure1

CGRP Release in Migraine Attacks

Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral

circulation of humans during migraine headache. Ann Neurol 1990; 28: 183-7.

Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing

cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993;

33(1): 48-56.

• CGRP but not neuropeptide Y, VIP, or

substance P released in migraine with and

without aura

• Elevated CGRP levels observed in jugular

but not antecubital venous blood on same

side as pain

• Greater elevation in CGRP observed in

migraine with aura

• CGRP levels normalize upon treatment with

sumatriptan

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PACAP (Pituitary adenylate cyclase activating

peptide): Another Potential Therapeutic Target

Infusion of PACAP triggers migraine in

susceptible individuals

PACAP levels elevated in circulation in

migraine and cluster headache attacks

Co-localized with CGRP in many anatomical

regions

Shares an accessory protein with CGRP

(Ramp-1)

May work synergistically with CGRP or

possibly with distinct sites of action???

What Do Clinical Trials of

Therapies Tell Us?

Exciting Results with Antibodies

Rapid onset of therapeutic effect (within days)

Sustained duration of therapeutic effect – (3-12 months)

“Super responders” – significant subset of

patients with 75% reduction in migraine days and small subset with 100% reduction in

migraine days

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Conclusions from Data

Specificity of antibodies to targets definitively

proves primary role for CGRP and CGRP

receptor in migraine

Efficacy of antibodies, which presumably do not

cross blood brain barrier, indicates mechanism

of action that is either peripheral, or in brain regions outside of BBB

Lasmiditan

5HT 1F receptor agonist

Receptors are not located on blood vessels

Does not cause vasoconstriction in animal models

Reported efficacy as an acute therapy in migraine

confirms that vasoconstriction is not mechanism of

action of acute migraine therapies

Side effect profile indicates central nervous system

effects – ? Central site of therapeutic action

Conclusions

Migraine is one of the leading causes of disability

worldwide, and overlaps with other major causes of

disability

Advances in the understanding of migraine

pathophysiology are leading to therapies that can be

targeted to specific mechanisms in individual patients

The effects of specific therapies provides important

new insights into fundamental migraine mechanisms