HEADACHE PATHOPHYSIOLOGY

Transcription

1 HEADACHE PATHOPHYSIOLOGY Andrew Charles, M.D. Professor Director, UCLA Goldberg Migraine Program Meyer and Renee Luskin Chair in Migraine and Headache Studies Director, Headache Research and Treatment Program David Geffen School of Medicine at UCLA

2 Disclosures Amgen Consultant for educational material Eli Lilly Global scientific advisory board eneura Medical Advisory Board St. Jude Medical Clinical trial steering committee Takeda Pharmceuticals Grant support for laboratory research

3 50 year old woman Audrey Episodic attacks for last 20 years, occurring twice per month Her partner knows attack is beginning when she becomes negative about everything and irritable Patients reports that she feels tired and yawns, then develops mild nausea and difficulty focusing vision. Develops moderate neck pain eventually spreading to retro-orbital region bilaterally Has difficulty speaking and concentrating Each episode lasts for hours, and she feels like she has to go to sleep. Cognitive dysfunction and fatigue are most disabling symptoms Identifies bright light and strong smells as triggers

4 What Is the Diagnosis? Chronic fatigue syndrome Chronic Lyme disease Hypothyroidism Migraine with aura

5 Premonitory Aura Headache Postdrome Yawning, Polyuria Timeline of a Migraine Attack Neck Pain, Fatigue, Mood change Light sensitivity, Sound sensitivity 4-72 hours Predisposing Factors Genes Hormones Metabolism Environment Medications Symptoms Nausea Visual changes Numbness/tingling Language dysfunction Cognitive dysfunction Brainstem symptoms Headache Cutaneous allodynia Brain Activation Hypothalamus, Brainstem Cortex Cortex Brainstem Thalamus Hypothalamus Cortex Thalamus Hypothalamus Neurophysiology Thalamocortical circuit changes Pain/emotion network changes Neurochemistry Dopamine? Hypothalamic peptides? Glutamate?, PACAP Release

6 Patient scanned daily with fmri for 30 days 3 migraine attacks captured Interictal and ictal periods captured

7 Sensory Sensitization Before Headache

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

9 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

10 DEFAULT MODE NETWORK

11 Abnormal Functional Connectivity in Migraine Chronic migraine associated with altered connectivity of anterior insula, amygdala, pulvinar, mediodorsal thalamus, middle temporal cortex, and periaqueductal gray UPDATED FIGURES AND REFERENCES TO BE INSERTED

12 45 year old woman Clinical Case Constant neck tightness Daily moderate headache that is bilateral, constant, sometimes associated with light sensitivity 8 attacks per month of markedly worse neck pain and headache. Neck pain worsens before and after headache. Some response of both to sumatriptan Normal neurological exam, diffuse cervical paraspinous muscle tenderness

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14 What is the diagnosis? A. Chronic migraine B. Cervicogenic headache C. Intracranial hypertension due to cervical stenosis D. Vertebral artery dissection

15 Neck Pain and Migraine Neck pain is a common symptom of migraine May occur as part of premonitory phase or postdrome in addition to attack phase Neck related disability scores high in migraine patients

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17 Cervical nerves and headache

18 Advances in Migraine Genetics

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20 Migraine Biomarkers? Elevated CSF levels of: Glutamate NGF Elevated blood levels of Glutamate 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.

21 Does blood brain barrier open in migraine? Likely not much.

22 (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: Receptor

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24 in Migraine and Cluster Headache is released into the circulation during a migraine or cluster headache attack 1,2 infusion evokes migraine 3 Serum levels may be elevated in chronic migraine 4 receptor antagonists effectively abort migraine attacks 5,6 1. 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. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117 ( Pt 3): Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia : 2010; 30(10): Cernuda-Morollon E, Larrosa D, Ramon C, Vega J, Martinez-Camblor P, Pascual J. Interictal increase of levels in peripheral blood as a biomarker for chronic migraine. Neurology 2013; 81(14): 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 receptor antagonist, MK-0974, in acute treatment of migraine. Neurology. 2008;70:

25 Release in Migraine Attacks but not neuropeptide Y, VIP, or substance P released in migraine with and without aura Elevated levels observed in jugular but not antecubital venous blood on same side as pain Greater elevation in observed in migraine with aura 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):

26 Release in Cluster Headache Attacks levels elevated in jugular blood ipsilateral to side of cluster headache VIP levels also elevated but not neuropeptide Y or substance P Treatment with oxygen or sumatriptan normalized levels, but opioid had no effect. Nesbitt A D, and Goadsby P J BMJ 2012;344:bmj.e2407 Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994;

27 MONOCLONAL ANTIBODIES Variable Antigen binding region Mouse -omab Chimeric Variable region mouse -ximab Constant Fc Heavy Chain Light Chain Humanized Antigen binding region mouse -zumab Human 100% human -umab

28 AMY1 RECEPTORS RECEPTORS

29 AMY1 RECEPTORS RECEPTORS

30 Summary New therapeutic targets based on: Better understanding of migraine anatomy targets for neuromodulation approaches Study of mechanisms of migraine occurring before headache Increased understanding of role of brain networks and brain rhythms Better understanding of mechanisms of current migraine medications New antibody approaches to specifically targeting migraine mechanisms