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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)

Years Lived With Disability

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.

Migraine and Right-to-left Shunt

Migraine with aura associated with patent foramen

ovale

Migraine with aura associated with pulmonary right to

left shunt in hereditary hemorrhagic telangiectasia

Multiple negative studies of PFO closure for migraine with and without aura

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West, et al. The frequency of patent foramen ovale and migraine in patients

with cryptogenic stroke. Stroke In Press, 2018

UCLA Stroke Database Review

• PFO and migraine with frequent aura overrepresented in

cryptogenic stroke

• Migrainous infarction very uncommon

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.

Migraine Genetics

Louis Ptacek

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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 CDASIL – Notch 3 Gene

Retinal vasculopathy with cerebral leukodystrophyRCVL - TREX1 gene

Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy COL4A1 gene

Families with identified single gene mutations

TRESK – 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

Familial Hemiplegic Migraine

FHM-1 – Mutations in CACNA1A – gene encoding

p/q type calcium channel (involved in neurotransmitter release)

FHM-2 – Mutations in ATP1A2 – gene encoding Na+/K+ pump (ATPase) that controls levels of

extracellular K+

FHM-3 – Mutations in SCN1A –gene encoding

neuronal Na+ channel

??FHM-4 – Mutations in gene encoding PRRT2 ---

gene associated with PKD and infantile seizures

Familial Migraine (genes identified in

isolated families)

TRESK – Potassium channel --- single

family

Casein Kinase 1 delta – Enzyme that

phosphorylates multiple proteins

including “clock” proteins in

hypothalamus. Also causes advanced

sleep phase syndrome --- reported in 2

families by may be more common.

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Monogenetic vasculopathies with

migraine as part of phenotype

Cerebral autosomal dominant arteriopathy with

subcortical infarcts and leukoencephalopathy CADASIL – Notch 3 Gene

Retinal vasculopathy with cerebral leukodystrophyRCVL - TREX1 gene

Hereditary infantile hemiparesis, retinal arteriolar

tortuosity, and leukoencephalopathy COL4A1 gene

BASIC MECHANISMS

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Dura

Thalamus

Trigeminal ganglion

Meningealblood vessel

Trigeminal cervical complex

Sensor y cortex and“Pain Matrix”

Upper cervical nerveroots

Peri-aqueductalgray

PAIN PATHWAYS IN MIGRAINE

Ray BS, Wolff HG. Experimental studies in headache: Pain-sensitive structures of the head and their significance in headache. Arch Surg. 1940;41:813-856.

Dural Stimulation Pain Events Parenchymal Stimulation Pain Events

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DILATION OF BLOOD VESSELS IS NEITHER NECESSARY

NOR SUFFICIENT FOR CAUSING MIGRAINE PAIN

Cerebral and meningeal blood vessels are

not dilated during spontaneous migraine or migraine induced by:

– Nitroglycerin

– SildenafilSchoonman GG, et al., Migraine headache is not associated with cerebral or meningealvasodilatation--a 3T magnetic resonance angiography study. Brain. 2008;131:2192-200.

Nagata E, et al. The middle meningial artery during a migraine attack: 3T magnetic resonance

angiography study. Intern Med. 2009;48:2133-5.

Some drugs that induce significant cerebral

vasodilation do not cause migraine

– Vasoactive intestinal peptide

19 patients with spontaneous migraine

No extracranial artery dilation during attack

Slight intracranial artery dilation during attack

Effective treatment with sumatriptan caused no intracranial vasoconstriction

Premonitory Aura PostdromeHeadache

Yawning

Polyuria

Neck Pain

FatigueMood change Light sensitivitySound sensitivity

Visual symptomsSensory symptoms

Language symptomsCognitive symptoms

Nausea

Headache

Cutaneous allodynia

Hypothalamus

Brainstem

Cortex

Cortex Brainstem

Thalamus

Hypothalamus

Cortex

Thalamus

Hypothalamus

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

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

Cao et al., 1999

CORTICAL “WAVES” IN MIGRAINE WITH AURA

Bereczki et al., 2008

Woods et al., 1994

Chalaupka, 2008

Denuelle et al., 2008

Before sumatriptan

2 to 4 h after the attack onset

After sumatriptan

4 to 6 h after the attack onset

…AND MIGRAINE WITHOUT AURA

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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 DURING

ACUTE MIGRAINE ATTACKS

Ipsilateral Contralateral

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

AURA

LANGUAGE SYMPTOMS

MOTOR

DYSFUNCTION

YAWNING,

POLYURIA

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Migraine Biomarkers?• Elevated CSF levels of:

• Glutamate

• CGRP

• NGF

• Elevated blood levels of

• Glutamate

• CGRP

• Decreased CSF and blood levels of

• Beta-endorphin

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

HUMAN MIGRAINE TRIGGERS:

DELAYED MIGRAINE

Nitroglycerin/ GTN

CGRP

PACAP

Sildenafil

Histamine

Dipyridamole

Prostaglandin I2

Hypoxia

IMMEDIATE MIGRAINE

Prostaglandin E2

CGRP (Calcitonin Gene Related Peptide)

IN MIGRAINE

CGRP is released into the jugular venous system

during a migraine attack

CGRP infusion evokes migraine

CGRP receptor antagonists effectively abort

migraine attacks

Serum CGRP levels elevated in chronic migraine

1Goadsby PJ, Edv insson 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, Edv insson L. Human in v ivo ev idence 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 Migraine. 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

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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.

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 activ ity-

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 receptors are present in multiple central and peripheral locations

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CGRP receptors are located on both sides of the blood–brain barrier*1,2

CGRP receptors are found

in multiple areas:2,3

• Trigeminal ganglion

• Dura vasculature

• Brainstem, eg, TNC

• Brain, eg, thalamus

CGRP receptors

are expressed on

numerous cell types:2,3

• Vascular smooth muscle cells

• Neurons

• Glial cells

• Mast cells

CLRRAMP1

CGRP receptor complex1,3

Thalamus

CGRP receptors are localized at several sites within the trigeminal pathway and brain2

*CGRP receptor localization data are based on ev idence of co-localization of the receptor components (RAMP1, CLR) and binding of

CGRP receptor antagonists.2 CGRP may be expressed in additional brain regions in which CGRP receptor localization has not been

established.4

1. Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533–552. 2. Eftekhari S, Edv insson L. Ther Adv Neurol Disord. 2010;3:369–378.

3. Raddant AC, Russo AF. Expert Rev Mol Med. 2011;13:e36.

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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

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???

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