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1
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
2
(#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.
3
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.
4
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
5
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
6
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
7
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
8
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
9
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.
10
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.
28
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
11
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