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American Headache Society®

November 16 - 19, 2017JW Marriott Desert Rid ge Resort & SpaP H O E N I X , A R I Z O N A

2017scottsdaleheadache symposium ®

POWEPOINT

2017scottsdaleheadache symposium ®

American Headache Society® November 16 - 19, 2017

JW M arriot t Desert Ridge Resort & Sp aP H O E N I X

A R I Z O N A

Headache 101: Pathophysiology

Todd J. Schwedt, MD FAHS

Professor of Neurology

Mayo Clinic Arizona

American Headache Society®

November 16 - 19, 2017JW Marriott Desert Rid ge Resort & SpaP H O E N I X , A R I Z O N A

2017scottsdaleheadache symposium ®

Disclosures

• Consulting: Allergan, Amgen, ATI, Avanir, Dr. Reddy’s, Ipsen Bioscience, Nocira, Novartis, Teva

• Options: Nocira, Second Opinion

• Research Funding: US Department of Defense, NIH, Patient-Centered Outcomes Research Institute (PCORI), American Migraine Foundation, Mayo Clinic, Arizona State University

Learning Objectives

At the conclusion of this lecture, attendees will be better able

to discuss the pathophysiology underlying:

– migraine headache

– other phases of the migraine attack

– cluster headache and associated features

Phases of a Migraine Attack

Premonitory

Aura

Headache

Postdrome

• Hypothalamus • Dopamine

• CSD • Trigeminocervical Complex • Pain Matrix • CGRP • Abnormal Sensory Processing

Attack Generation

Pons Hypothalamus

Trigeminal Nucleus

Migraine Generation

fMRI – 13 migraineurs during spontaneous migraine attacks.

PET – spontaneous migraine attack successfully treated with sumatriptan. Brainstem region persists with increased rCBF.

May A. Cephalalgia 2013;33:554-565. Weiller C et. al. Nature Medicine 1995;7:658-60.

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Migraine Generation

PET – spontaneous migraine attacks. Increased rCBF in brainstem and hypothalamus.

Persistent increases in rCBF to brainstem and hypothalamus following treatment.

Denuelle M et. al. Headache 2007;47:1418.

Migraine Generation • N=1; EM without aura

• Trigeminal nociceptive stim via intranasal ammonia

• Approaching next migraine, increased activation:

– Hypothalamus

– Trigeminal nucleus

– Middle pons

– Visual cortex

• Hypothalamic functional coupling altered prior to and during migraine attack

– Pre-Ictal: stronger hypothalamus-spinal trigeminal nuclei

– Ictal: stronger hypothalamus-dorsal rostral pons Schulte L. Brain. 2016;139(7):1987-1993.

Migraine Premonitory Phase

• Up to 80% of individuals

• Can start hours prior to headache

– Drowsiness, Irritability, Difficulty concentrating, Yawning, Nausea, Stiff neck, Change in

appetite, Sensory Hypersensitivities

• Dopamine involvement

– Receptor agonists produce similar symptoms (yawning, nausea, drowsiness, lightheaded) • Migraineurs might have dopamine hypersensitivity (e.g. more susceptible to side effects of dopamine agonists)

– Receptor antagonists during premonitory phase can abort migraine attacks

– Other antagonists (e.g. metoclopramide, prochlorperazine, haloperidol) can abort attacks

Migraine Premonitory Phase

Hypothalamus – Mood

– Appetite

– Energy

– Thirst

– Sleep

(Releases dopamine as

well)

Increased rCBF to: • Hypothalamus • Periaqueductal gray • Dorsal pons

Maniyar FH, et. al. Brain 2014;137:232-241.

Early Premonitory vs. Interictal

Migraine Aura

• Approximately 1/3 of people with migraine

• Visual: spreading fortifications followed by scotoma

• Sensory: Paresthesias

• Cortical spreading depression – Depolarization of neurons and glial cells followed by neuronal silence

• Spreads across the cortex at 2-3 mm/min • Transient increases in extracellular potassium, nitric oxide and glutamate.

– Hyperemia followed by decrease in cerebral blood flow (spreading oligemia).

MRI-BOLD functional

imaging in patient with visual

aura: depolarization and

following hyperpolarization

with secondary changes in

blood flow. (3mm/min)

Hadjikhani N et. al. Proc Natl Acad Sci USA 2001

Migraine Headache Phase

Trigeminocervical/Trigeminovascular Complex

•Trigeminal Nucleus Caudalis

• Pontine level to C2

•Trigeminal nerve

• From trigeminal ganglion

•Major intracranial arteries

•Thalamus

•Cortex

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The Pain Experience

May A. J Headache Pain 2006; Bingel and Tracy 2008.

Migraine Headache Phase

Role of CGRP

Iyengar S et. al. Pain 2017.

Potent vasodilator

Modulation of

neuronal sensitization

Facilitates nociceptive transmission

Increased serum

CGRP during migraine

Infusing CGRP in

migraineurs provokes migraine

Blocking CGRP

treats migraine

Sensitization and Allodynia

• Synaptic strength is not fixed. – Amplitude of synaptic contact between neurons may increase or decrease (plasticity).

• Central sensitization

– Activity dependent increase in the excitability and synaptic strength of neurons

• Effects of nociceptive stimulus are sustained after end of stimulation

Longer lasting pain

• Amplified effects of nociceptive stimuli

More severe pain

Sensitization and Allodynia

Burstein R. Neurophysiol 1998;79:964. Woolf CJ. J Neurosci 1990;10:2717.

• Low level of nociceptive input required to sustain effects of nociceptive stimulus

Lower thresholds for pain maintenance

• Activation of nociceptors with typically non-nociceptive input

Non-painful stimuli are perceived as painful

• Cutaneous Allodynia – Reduced effectiveness of migraine treatment – Increased risk of developing more frequent headaches – Alters brain structure and function

Abnormal Sensory Processing Greater Pain Facilitation and Less Pain Inhibition

• Painful heat stimulation during fMRI

• Migraine – greater activation of pain-facilitating regions and less activation of pain inhibiting regions

Moulton EA et. al. PLoS ONE 2008;3:e3799. Schwedt Cephalalgia 2014. 2008;3:e3799.

Abnormal Sensory Processing Increased Responsiveness to Visual Stimuli

Datta R, et. al. Cephalalgia 2013;33:365-374.

Migraine vs. Healthy Controls

Schwedt TJ et. al., Lancet Neurology 2015;14:81-91.

Migraine with Aura vs. Healthy Controls

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Cluster Headache

A. At least 5 attacks fulfilling criteria B-D B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180

min (when untreated) C. Either or both of the following:

1. 1 of the following ipsilateral symptoms or signs: a) conjunctival injection and/or lacrimation; b) nasal congestion and/or rhinorrhoea; c) eyelid oedema; d) fore-head and facial sweating; e) forehead and facial flushing; f) sensation of fullness in the ear; g) miosis and/or ptosis

2. a sense of restlessness or agitation

D. Frequency from 1/2 d to 8/d for > half the time when active

Cluster Headache and the Hypothalamus

• Suprachiasmatic nucleus of hypothalamus = “autonomous circadian clock”

– circadian and circannual temporal rhythmicity

• Stimulation of post hypothalamus results in restlessness and desire to move

• DBS in region of post hypothalamus can be effective treatment

Cluster Headache and the Hypothalamus

Ipsilateral inferior hypothalamus activation during pain state

May A et. al. Lancet 1998;352:275. Goadsby PJ et. al. Neurology 1999;52:1522.

PET study of nitroglycerin-induced cluster attacks

Cluster Headache: Trigeminal-Parasympathetic Pathway

Leone M et. al. Exp Rev Neurother 2016. Barloese M. Clin Aut Res 2017.

• Afferent Loop: • Trigeminal nerve • Trigeminal ganglion • TNC

• Efferent Loop:

• Superior salivatory nucleus • SPG • gives rise to innervation of

the vasculature by vasomotor neurons and innervation of the lacrimal and nasal mucosa glands by secromotor neurons

Brain Structure and Function are Dynamic

• Multiple phases of episodic cluster make it more complicated to study

– In bout during attack

– In bout between attacks

– Between bouts

Yang F-C. Cephalalgia 2017. Naegel S et. al. Neuroimage: Clinical 2014;6:415. Chou F-C et. al. Cephalalgia 2016;epub ahead of print.

Open Questions • Mechanisms responsible for transitioning from one phase to the next

– Are the phases of migraine attack truly distinct

– Aura phase to headache (some animal studies suggest CSD can trigger trigeminal system and cause headache)

– How does migraine attack stop

– Cluster out-of-bout to in-bout and vice-versa

• How similar/different are the mechanisms for different headache types?

• How do headache triggers initiate a headache/migraine attack?

• Central vs. Peripheral nervous system mechanisms