DISCLOSURES UPDATE ON MIGRAINE EPIDEMIOLOGY, GENETICS, AND BASIC MECHANISMS. Grant Support Takeda

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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 1

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. 2

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 patients Migraine with aura 6.3/1000 patients PFO and Migraine PFO-Migraine Odds Ratios Migraine 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 disease Scher, et al. Midlife migraine and late-life parkinsonism: AGES-Reykjavik study. Neurology. 2014;83(14): Wang HI, Ho YC, Huang YP, Pan SL. Migraine is related to an increased risk of Parkinson's disease: A populationbased, propensity score-matched, longitudinal follow-up study. Cephalalgia Restless legs syndrome Lin 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): Extracranial artery dissection (MO) Metso TM, et al. Migraine in cervical artery dissection and ischemic stroke patients. Neurology. 2012;78(16): Depression Buse DC, et al. Psychiatric comorbidities of episodic and chronic migraine. Neurology. 2013; 260(8):

4 Louis Ptacek Migraine Genetics Migraine Genetics Familial Hemiplegic Migraine FHM1 CACNA1A P/Q type calcium channel FHM2 ATP1A2 Na+/K+ ATPase FHM3 SCN1A Voltage gated sodium channel? PRRT2 Proline rich transmembrane protein 2 Families with identified single gene mutations TRESK K+ channel Casein Kinase 1 delta Kinase associated with advanced sleep phase syndrome Monogenetic vasculopathies with migraine as part of phenotype Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL Notch 3 Gene Gene polymorphisms associated with either increased or decreased risk of migraine based on population (GWAS) studies Retinal vasculopathy with cerebral leukodystrophy RCVL - TREX1 gene Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy COL4A1 gene 4

5 BASIC MECHANISMS TIMELINE OF A MIGRAINE ATTACK 4-72 hours Premonitory Aura Headache Postdrome Yawning Polyuria Neck Pain Fatigue Mood change Light sensitivity Sound sensitivity Nausea Visual symptoms Sensory symptoms Language symptoms Cognitive symptoms Headache Cutaneous allodynia Hypothalamus Brainstem Cortex Cortex Brainstem Thalamus Hypothalamus Cortex Thalamus Hypothalamus 5

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): Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. The origin of nausea in migraine-a PET study. J Headache Pain. 2014;15: 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): 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 6

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 7

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 8

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 For excellent reviews, see: 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: 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 trigeminovascularsystem. Ann Neurol 1988; 23(2): Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascularactivation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117 ( Pt 3): 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: 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: 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 zolmitriptanfor acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet. 2009;372: 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 For review, see Kaiser EA, Russo AF. Neuropeptides 2013; 47: CGRP Receptor 9

10 CGRP and its receptor are part of the calcitonin family of peptides and receptors Ligand CGRP Adrenomedullin Amylin Receptor composition 1, 2 CLR+ RAMP1 CLR+ RAMP2 CLR+ RAMP3 CTR+ RAMP1 CTR+ RAMP2 CTR+ RAMP3 Receptor CGRP ADM1 ADM2 AMY1 AMY2 AMY3 [name] 1 Structure 1 28 The CGRP receptor is a complex that requires both RAMP1 and CLR 1 RAMP1 and CLR are also components of other calcitonin receptors 1,2 Ligands cross-interact with other receptors in the family 1,2 Only the CGRP receptor has been implicated in migraine pathophysiology 2 ADM, adrenomedullin; AMY, amylin; CLR, calcitonin receptor-like receptor; CTR, calcitonin receptor; RAMP, receptor activitymodifying protein. 1. Walker CS, Hay DL. Br J Pharmacol. 2013;170: Russo AF. Annu Rev Pharmacol Toxicol. 2015;55: CGRP Release in Migraine Attacks 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 Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28: 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):

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 11

12 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 12