Faculty Disclosures. Learning Objectives

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1 Pathophysiology Content developed by: Andrew C. Charles, MD, FAHS, Peter J. Goadsby, MD, PhD, FAHS Donna Gutterman, PharmD Faculty Disclosures ANDREW C. CHARLES, MD, FAHS Dr. Charles has received consulting fees and/orhonoraria from Amgen, eneura and AGA Medical. PETER J. GOADSBY, MD, PHD, FAHS Dr. Goadsby has received consulting fees and/or honoraria from Pfizer, Zogenix, Nevrocorp, Impax, Dr. Reddy, Zosano and Amgen. He is on the Speaker s Bureau of Allergan, Inc., and Pfizer, Inc. He has received other financial benefit, as an expert witness from for Journal Watch Neurology (manuscript preparation), Medico (Legal advice, patient advice). Dr. Goadsby's institution has received grants from ENeura, Amgen and Allergan, Inc. DONNA GUTTERMAN, PHARMD Dr. Gutterman has received consulting fees and/or honoraria from NuPathe, Teva Pharmaceuticals, Dr. Reddy Pharmaceuticals. Learning Objectives At the conclusion of this talk, participants will be able to: Recognize that episodic and chronic migraine involve overlapping trigeminovascular mechanisms Know the role of allodynia and central sensitization in chronic migraine Explain how activation of brain regions are involved in the pathophysiology of migraine Identify new treatment mechanisms in migraine 1

2 FHM CACNA1A ATP1A2 SCN1A FAMILIAL MIGRAINE TRESK CK1δ SUSCEPTIBILITY LOCI PRDM16 TRPM8 LRP1 ZNF555 ADARB2 GRM7 HTR7 MEF2D TGFBR2 PHACTR1 ASTN2 TIMELINE OF A MIGRAINE Premonitory Aura Headache Postdrome Yawning Polyuria Neck Pain Fatigue Mood change Light sensitivity Sound sensitivity Nausea Visual symptoms Sensory symptoms Language symptoms Cognitive symptoms Headache Cutaneous allodynia Hypothalamus Brainstem Cortex Cortex Brainstem Thalamus Hypothalamus Cortex Thalamus Hypothalamus Vascular theory of migraine- R.I.P. Theory Aura is caused by cerebral vasoconstriction Pain is due to reflex vasodilation Acute treatments work by vasoconstriction But Cerebral and meningeal blood vessels are not dilated during migraine induced by: Nitroglycerin 1 Sildenafil 1 Some drugs that induce significant cerebral vasodilation do not cause migraine Vasoactive intestinal peptide 3 Graham & Wolff Arch Neurol 1938;39: Schoonman et al., Brain. 2008;131: Nagata et al., Intern Med 2009;48: Rahmann et al., Cephalalgia. 2008;28:226 2

3 Nineteen patients with spontaneous migraine No extracranial artery dilation during attack Slight intracranial artery dilation during attack Effective treatment with sumatriptan caused no intracranial vasoconstriction Amin et al., Lancet Neurology 2013;12:454 Clinical Features of Chronic Migraine Often evolves from episodic migraine Has overlapping phenotypic features Allodynia Risk factor for progression Persists interictally May be difficult to reverse Overlapping Mechanisms of EM and CM Shared pathways Trigeminovascular system Involved in episodic and chronic migraine More easily activated in chronic dura mater V ganglion Trigeminal cervical complex Thalamus Sensory Cortex First-order Second-order Third-order 3

4 Migraine and the Neck- Referred pain in the TCC Thalamus dura mater A V ganglion Neurons in the cervicomedullary junction and the dorsal horn of the spinal cord trigeminal nucleus B Cervical input C 1 C 2 *Trigemino-Cervical Complex Thalamic Sensitization in Migraine with Extended Allodynia dura mater V ganglion First-order Ipsilateral Trigeminal cervical complex Second-order Thalamus Third-order Contralateral Sensory Cortex Sensitization Meningeal blood vessel Sensitized peripheral (trigeminal ganglion) Dura Pain perception Activated central (Thalamus) Cutaneous allodynia Throbbing pain Sensitized central (trigemino-cervical complex) Muscle tenderness 4

5 Cutaneous Allodynia in Episodic and Chronic Migraine Non-nociceptive stimuli are painful Region of spontaneous pain: sensitization of V1 Expanded regions: trigeminocervical complex s Contralateral and ipsilateral: sensitization of thalamic s Presumed mechanism of allodynia is sensitization Allodynia is more common in CM than EM Pathophysiology ARS Question 1 The transition from episodic to CM involves which of the following? a) central sensitization b) abnormal pain modulation by brainstem nuclei c) white matter lesions d) large patent foramen ovale (PFO) e) frequent use of over the counter NSAIDs A. All the above B. a and b only C. c and d only D. e only E. none of the above Role of the Brainstem May play a key role in development of chronic migraine Neurotransmitters are similar in CM and EM Iron deposition in PAG related to frequency of attacks Pontine lesions cause CM-like headache 5

6 ACTIVATION OF BRAINSTEM DURING ACUTE MIGRAINE ATTACKS Weiller et al, Nat Med. 1: ; 1995 Afridi, S. K. et al. Brain : ; Bahra, et al., Lancet 357: Periaqueductal Gray Matter (PAG) Opioids, Ergots, Triptan, CGRP and P/Q Ca 2+ channel actions converge Triptans Ergots Goadsby & Knight Cephalalgia 1997;17:153 Ann Neurol 1991;21:91-94 Mean±SEM change in TNC Aδ activity after PAG agatoxin, n=18 WDR, n=16; NS, n=2 % change P/Q Blockade agatoxin Agatoxin time in minutes Pozo-Rosich Knight et al., et J al., Neurosci Cephalalgia 2002; 2009;29 (RC213):1-6 CORTICAL WAVES IN MIGRAINE WITH AURA Olesen, et al Hadjikhani et al., 2001 and without aura Cao et al., 1999 Woods et al.,

7 Activation of Hypothalamus in Migraine IN PREMONITORY PHASE Maniyar et al., Brain 2014;137:232) DURING AND AFTER HEADACHE (Denuelle et al., Headache 2007;47:1418) Areas of Reduced Brain Volume in Chronic Migraine Valfrè W et al. Headache. 2008;48:109 Rocca MA et al. Stroke. 2006;37:1765 Grey Matter Reduction in Chronic Post-Traumatic Headache Reduced grey matter at three months in patients with post-traumatic headache that has recovered at one year Anterior cingulate cortex Dorsolateral prefrontal cortex Obermann et al., Neurology 2009; 73:978 7

8 MRI Lesions in Migraine CAMERA -2 FOLLOW-UP 8.5 ( ) years Controls (n=83/140) Migraine with Aura (114/162) Migraine without Aura (89/134) Slight increased risk of progression of deep white matter lesions in women only with migraine without aura Palm-Meinders et al., JAMA. 2012;308:1889 MRI Lesions in Migraine CAMERA -2 FOLLOW-UP 8.5 ( ) years Controls (n=83/140) Migraine with Aura (114/162) Migraine without Aura (89/134) Slight increased risk of progression of deep white matter lesions in women only with migraine without aura No increase in progression of brainstem hyperintensities in patients with migraine compared with controls Palm-Meinders et al., JAMA. 2012;308:1889 MRI Lesions in Migraine CAMERA -2 FOLLOW-UP 8.5 ( ) years Controls (n=83/140) Migraine with Aura (114/162) Migraine without Aura (89/134) Slight increased risk of progression of deep white matter lesions in women only with migraine without aura No increase in progression of brainstem hyperintensities in patients with migraine compared with controls No increased risk of posterior posterior circulation infarcts in patients with migraine compared with controls No difference in cognitive function in patients with white matter lesions compared with controls Palm-Meinders et al., JAMA. 2012;308:1889 8

9 CGRP (Calcitonin Gene Related Peptide) IN MIGRAINE CGRP is elevated in the cranial circulation in severe, acute migraine 1 CGRP infusion triggers migraine 2 CGRP receptor antagonists abort acute migraine 3 CGRP levels are elevated in chronic migraine 4 1. Goadsby et al., Ann Neurol 1990;28: Lassen et al., Cephalalgia. 2002;22:54 3. Olesen et al., N Engl J Med. 2004;350: Cernuda-Morollon et al., Neurology. 2013;81:1191 Biologic Approaches to Migraine Prevention Amgen AMG Human monoclonal IgG1 receptor CLR/RAMP1 Phase II- episodic & chronic Migraine Alder Biopharmaceuticals- ALD Humanized CGRP peptide antibody Phase II: episodic migraine Arteaus Therapeutics/Lilly- LY Humanized CGRP peptide antibody Phase II: episodic migraine Labrys/Tev- LBR Humanized CGRP peptide antibody Phase II: episodic & chronic migraine 1. Shi et al., Headache 2014;54: Dodick et al., Lancet Neurol 2014;13:in press 3. Dodick et al., Lancet Neurol 2014;13: Garzone et al., Cephalalgia 2013;33:966 Lutterotti & Martin Lancet Neurol 2008;7:538 Summary Although there is much to still address regarding migraine mechanisms and the brain, selected studies suggest: Migraine mechanisms involve the trigeminovascular system which can be sensitized Brainstem activation is involved in the mechanisms of episodic and chronic migraine Chronic migraine can produce structural brain changes over time that may be reversible Calcitonin gene-related peptide (CGRP) mechanisms are promising targets for anti-migraine therapeutics 9

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