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

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

3. EPIDEMIOLOGY

4. Years Lived With Disability
(#3 in age <50)

5. 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.

6. 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

7. 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

8. 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 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):
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):

9. Louis Ptacek
Migraine Genetics

10. 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

11. 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

12. 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.

13. 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

15. BASIC MECHANISMS

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

18. Dural Stimulation Pain Events
Parenchymal Stimulation Pain Events

19. 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:
Nagata E, et al. The middle meningial artery during a migraine attack: 3T magnetic resonance angiography study. Intern Med. 2009;48:
Some drugs that induce significant cerebral vasodilation do not cause migraine
Vasoactive intestinal peptide

20. 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

21. 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

22. 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):
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):
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

23. 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

24. …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

25. 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, (2005).
2. Bahra, A., Matharu, M.S., Buchel, C., Frackowiak, R.S. & Goadsby, P.J. Brainstem activation specific to migraine headache. Lancet 357, (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, (1995).
Weiller et al, Nat Med. 1: ; 1995
Afridi, S. K. et al. Brain : ;
Bahra, et al.,
Lancet 357:

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

27. 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

28. 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.

29. HUMAN MIGRAINE TRIGGERS:
DELAYED MIGRAINE
Nitroglycerin/ GTN
CGRP
PACAP
Sildenafil
Histamine
Dipyridamole
Prostaglandin I2
Hypoxia
IMMEDIATE MIGRAINE
Prostaglandin E2

30. 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):
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):
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 zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet. 2009;372:

31. 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

32. 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:
Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:
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– Russo AF. Annu Rev Pharmacol Toxicol. 2015;55:533–552.

33. 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:
Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide receptor antagonists. Ther Adv Neurol Disord. 2010;3:
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:
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– Eftekhari S, Edvinsson L. Ther Adv Neurol Disord. 2010;3:369– Raddant AC, Russo AF. Expert Rev Mol Med. 2011;13:e36.

34. 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):

36. 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???