Migraine Pathophysiology. Robert E. Shapiro, MD, PhD

Transcription

1 Migraine Pathophysiology Robert E. Shapiro, MD, PhD

2 Disclosures Eli Lilly Member, Clinical Trials Data Monitoring Committee

3 Learning Objectives By the end of this course participants will be able to describe: the role of cortical spreading depression in migraine aura. the role of the trigeminovascular system in migraine headache the current state of genetic findings for migraine susceptibility. the current state of neuroimaging for migraine.

4 Migraine is NOT Headache Migraine is an episodic state of the nervous system. Headache is one, among many, potential symptoms of the migraine state. migraine symptom patterns idiosyncratic stereotypic evolving migraine susceptibility heritable 50% expressivity chronobiologic hormonal, diurnal, circadian, etc. stimulus-bound chemical, weather, stress

5 Migraine Attacks Premonitory phase: ~ one third of patients, ~ hours to days Aura phase: (~ 25 % of patients): < 60 min symptoms: visual, paresthesias, cognitive, behavioral, perceptual sensory > motor, positive > negative, dynamic > static Headache phase: pain: sensitivities: autonomic: ~4 hours to 3 days unilateral, throbbing, moderate to severe light, sound, odor, touch (allodynia), movement (vertigo) nausea (~90%), vomiting, gastric atony, sinus congestion Recovery phase

6 Phases of a Migraine Attack Mild Moderate to Severe Premonitory/ Prodrome Aura Headache Postdrome Time Adapted from Cady RK. Clin Cornerstone;1: (1999) & Blau JN Lancet; 339:1203 (1992)

7 Probability of Phosphene Magnetic Stimulus Intensity (%) Aurora SK et al. Cephalalgia. 2003;23: The visual cortex of migraineurs is intrinsically hyperexcitable

8 Chronobiology of Migraine 18 seconds 1 day 1 week 1 month 1 year 2 years Lifetime Fox and Davis, Headache 38: 436 (1998) Cugini Chronobiol Internat. 7:467 (1990). Victor et al. Cephalalgia 30:1065 (2010) Mo et al Pain 2013;154:1150 Lipton et al 2014 AHS

9 fmri of Spontaneous Migraine Roles of Left-Pain Right-Pain Hypothalamus Dorsal Pons Occipital Cortex Trigeminal Nucleus N. Tractus Solitarius Weiller et al Nature Med 1:658 (1995) Afridi et al. Brain 128:932 (2005) Schulte & May, Brain 139:1987 (2016) Maniyar et al Headache 55:609 (2015)

10 Stimulus-induced fmri: ictal vs interictal migraineurs No areas have less activity during a migraine attack than in the interictal period. Schewdt et al Lancet Neurol 2015; 14: 81

11 What Causes Aura in Migraine? Sacks Migraine rev. ed. (1999)

12 Migraine Aura and Spreading Depression Lashley s aura (194I) Inferred propagation: 2 4 mm / min Leão s Spreading Depression (1944) Observed Propagation: 2 4 mm / min Human Perception Rabbit Cortex Lashley Arch Neurol Psych 46:333 (1941) Leao J Neurophysiol 7:359 (1944) Silberstein et al. Headache in Clinical Practice 2 nd ed. (2002)

13 Cortical Spreading Depression Spreading Depression? Massive wave of depolarization, propagating at 2 to 4 mm/min, followed by suppressed cortical activity Fluxes in extracellular glutamate and K + Blood oxygenation level-dependent (BOLD) functional MR imaging Hadjikhani et al. PNAS. 98:4687 (2001) Changes in vascular tone

14 The Search for Migraine Genes Louis Ptáček

15 Search for Migraine Genes Twins studies: 30 to 60% heritable Tolner et al, Pain 156:S64 S74 (2015)

16 Search for Migraine Genes Tolner et al, Pain 156:S64 S74 (2015)

17 Channels Implicated in Migraine Voltage-gated C ++ Channel CACNL14 FHM1 Voltage-gated Na + Channel SCN1A FHM3 Na + /K + ATPase Pump ATP1A2 - FHM2 Glutamate Transporter SLC1A3 Episodic Ataxia type 6 Voltage-gated Two-Pore Domain K + Channel TRESK K2P channel Na + /HCO 3- Co-transporter NBCe1 glaucoma, RTA Connexin CX43 CK1δ FASPS? Pannexin Panx1? None of these genotypes have been associated with prevalent forms of migraine

18 FHM1 Mutation Promotes CSD Increased CSD Propagation Velocity Lowered CSD Triggering Threshold van den Maagdenberg et al, Neuron 41: (2004)

19 FHM Mutation Functional Convergence Loss of Function: Na + /K + transport Loss of Function: Na + channel recovery Gain of Function: Ca ++ influx NMDA Modified from Ferrari et al Lancet Neurol 2015;14:65 EA-6 Loss of Function: glutamate transport

20 FHM Mutation Functional Convergence EA-6 SLC1A3 EAAT1 glutamate transporter Modified from van der Ven et al, Arch Neurol 64:643 (2007)

21 What Causes Headache in Migraine? Anguish - George Dergalis

22 Wolff s Observations Only some Intracranial structures Are pain sensitive: Some regions of Dura mater Meningeal vessels, large cerebral vessels & sinuses Muscles of scalp, head and neck Nerves: 5 th, 7 th, 9 th, 10 th, C1, C2 Wolff Headache 1 st ed (1948)

23 Throbbing

24 Wolff s Theory: Lack of Support Cerebral vessel dilation (by vasoactive intestinal polypeptide) does not induce migraine Induction of migraine attacks (by nitroglycerin or sildenafil) does not dilate cerebral / meningeal vessels MR angiogram during spontaneous migraine: No proximal extracranial vessel dilation 10% intracranial vessel dilation Successful sumatriptan treatment, but no intracranial vasoconstriction Schoonman et al Brain. 2008;131:2192 Kruuse et al Brain 2003;126: 241 Rahmann et al Cephalalgia 2008; 28: 226 Amin et Lancet Neurol 2013; 12:454

25 Wolff s Theory: On the other hand Many migraine drugs do not cross the blood-brain barrier (eg. sumatriptan, DHE, anti-cgrp mabs) Expression of high frequency / low risk migraine susceptibility genes is enriched in arterial tissue. Migraine shares polygenic risk with CAD and stroke. Example: PHACTR1 locus is associated with migraine, CAD, cervical artery dissection Distal external carotid diameter has not been studied with fmri during migraine attacks. Gormley et al Nat Genet. 2016; 48:856.

26 Migraine Headache PACAP Pietrobon et al Nat Rev Neurosci 4:386 (2003)

27 CGRP Roles of CGRP and PACAP in Migraine PACAP CGRP Edvinsson & Goadsby Cephalalgia 1994; 14:320 Zagami et al ACTN 2014; CGRP & PACAP are elevated in human serum during migraine CGRP CGRP & PACAP are elevated in cat serum following SSS stimulation PACAP

28 CGRP and PACAP in Migraine CGRP 37 amino acid peptide Widely expressed in neurons Infusion provokes migraine Implicated in pain, vasodilation, inflammation PACAP 38 amino acid peptide May be co-expressed with CGRP Infusion provokes migraine Implicated in pain, circadian rhythms, development, etc. Receptor antagonists block migraine

29 Trigeminovascular System: Migraine Pathways Proposed mechanisms of CSD-mediated brainstem activation, dural vasodilation, & sterile inflammation Bolay et al. Nat Med. 8:136 (2002) Zhang et al Ann Neurol. 2011;69:855 Karatas et al Science 2013;339, 1092 Tolner et al, Pain 156:S64 S74 (2015) TNC SSN

30 Serotonin in Migraine In migraine attacks, blood levels of serotonin drop and urine levels of serotonin metabolites rise. Drugs which deplete platelet serotonin (e.g. reserpine) may trigger migraine-like attacks. Intravenous serotonin relieves migraine. Serotonin is implicated in mechanisms for many conditions comorbid with migraine (e.g. depression, sleep, etc.). Anthony et al Arch Neurol 16:544 (1967) Sicuteri Headache 6:109 (1966) Kimball et al Neurol Minneap 10:107 (1960)

31 Serotonin (5-HT) Receptors and Migraine Therapies Serotonin (5HT) camp PI Na + K + Ca 2+ camp camp camp camp 5HT 1 5HT 2 5HT 3 5HT 4 5HT 5 5HT 6 5HT 7 5-HT 1A 5-HT 1B 5-HT 1D 5-HT 1E 5-HT 1F 5-HT 2A 5-HT 2B 5-HT 2C 5-HT 5A 5-HT 5B Agonists block acute migraine (e.g. triptans) Antagonists prevent migraine (e.g. methysergide) Antagonists prevent nausea (e.g. ondansetron) Adapted from: The Triptans. 2001

32 Trigeminovascular System PAIN Nucleus Caudalis CORTEX THALAMUS Superior Salivatory Nucleus D 5-HT 1D Receptors D Neuropeptide Release Trigeminal Ganglion 5-HT 1D Receptors Trigeminal Inhibition CGRP D SPG B B Vasodilatation 5-HT 1B Receptors (on vascular smooth muscle) Vasoconstriction VIP, NO Recreated from Hargreaves et al. Can J Neurol Sci 1999;26:S12-S19.

33 What Causes Hypersensitivity in Migraine? Migrain Duet - Jeanette Abulafia

34 Nervous System Sensitization in Migraine o o Dural blood vessels Cortex Thalamus Trigeminal ganglia TNC Dorsal root Ganglia (C5/6) Dorsal horn first relay

35 Photophobia in Migraine Noseda & Burstein, Pain 2013;154 Suppl 1:S44

36 Migraine Integration? Abnormal hypothalamus function?? Modified from Pietrobon, Nature Rev Neurosci. 4:386 (2003).