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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
3
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.
5
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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