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 Consultant Clinic Trial Steering Committee Takeda Consultant Alder, Amgen, Biohaven, Eli Lilly, eNeura, Clinic Trial Steering Committee St. Jude

EPIDEMIOLOGY

Years Lived With Disability (#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.

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

UCLA Stroke Database Review 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 disease Scher, 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 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):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. Depression Buse DC, et al. Psychiatric comorbidities of episodic and chronic migraine. Neurology. 2013; 260(8): 1960-9.

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 Monogenetic vasculopathies with migraine as part of phenotype Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CDASIL – 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 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.

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 leukodystrophy RCVL - TREX1 gene Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy COL4A1 gene

BASIC MECHANISMS

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

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 Sildenafil Schoonman GG, et al., Migraine headache is not associated with cerebral or meningeal vasodilatation--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

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

Premonitory Phase 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. 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

CORTICAL “WAVES” IN MIGRAINE WITH AURA Olesen, et al. 1981 Hadjikhani et al., 2001 So by now we see that events c temporal, spatial, blood flow characteristics of CSD appear to occur in migraine pts, correlate with aura sx. Bereczki et al., 2008 Cao et al., 1999

…AND MIGRAINE WITHOUT AURA Woods et al., 1994 Denuelle et al., 2008 Before sumatriptan 2 to 4 h after the attack onset After sumatriptan 4 to 6 h after the attack onset Chalaupka, 2008

ACTIVATION OF BRAINSTEM DURING ACUTE MIGRAINE ATTACKS Several studies have shown activation of the brainstem during a migraine attack 1. Afridi, S.K. et al. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128, 932-9 (2005). 2. Bahra, A., Matharu, M.S., Buchel, C., Frackowiak, R.S. & Goadsby, P.J. Brainstem activation specific to migraine headache. Lancet 357, 1016-7 (2001). 3. Cao, Y., Aurora, S.K., Nagesh, V., Patel, S.C. & Welch, K.M. Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology 59, 72-8 (2002). 4. Weiller, C. et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1, 658-60 (1995). Weiller et al, Nat Med. 1:658-660; 1995 Afridi, S. K. et al. Brain 2005 128:932-939; Bahra, et al., Lancet 357:1016-1017 2001

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

HEADACHE AURA VISUAL SYMPTOMS SENSORY SYMPTOMS LANGUAGE SYMPTOMS MOTOR DYSFUNCTION VISUAL SYMPTOMS COGNITIVE FATIGUE, MOOD CHANGE YAWNING, POLYURIA NAUSEA, VOMITING HEADACHE DIZZINESS, VERTIGO Light, sound smell sensitivity Cutaneous Allodynia

Migraine Biomarkers? Elevated CSF levels of: Elevated blood levels of Glutamate CGRP NGF Elevated blood levels of 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, 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 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

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; 47:451-461. CGRP Receptor

CGRP and its receptor are part of the calcitonin family of peptides and receptors Ligand CGRP Adrenomedullin Amylin Receptor composition1,2 CLR+ RAMP1 RAMP2 RAMP3 CTR+ Receptor [name]1 ADM1 ADM2 AMY1 AMY2 AMY3 Structure1 CGRP and its receptor are part of the calcitonin family, along with adrenomedullin and amylin. The CGRP receptor is a complex that comprises the calcitonin receptor-like receptor (CLR) together with the receptor activity-modifying protein RAMP1. Other receptors in the calcitonin family also include these components, and there is cross-binding of ligands to other calcitonin receptors. However, only the CGRP receptor has been implicated in the pathophysiology of migraine.1,2 Walker CS, Hay DL. CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? Br J Pharmacol. 2013;170:1293-1307. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552. 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.

CGRP receptors are present in multiple central and peripheral locations 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 CGRP receptor complex1,3 CLR RAMP1 Thalamus CGRP receptors are located in both central and peripheral locations, and are expressed on a variety of cell types. Particularly relevant to the pathogenesis of migraine is the presence of CGRP receptors at sites in the trigeminal pathway and brain.4 Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552. Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther Adv Neurol Disord. 2010;3:369-378. Raddant AC, Russo AF. Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med. 2011;13:e36. Tozzi A, de Iure A, Di Filippo M, et al. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci U S A. 2012;109:18985-18990. CGRP receptors are localized at several sites within the trigeminal pathway and brain2 *CGRP receptor localization data are based on evidence 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, Edvinsson L. Ther Adv Neurol Disord. 2010;3:369–378. 3. Raddant AC, Russo AF. Expert Rev Mol Med. 2011;13:e36.

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: 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.

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???