Abstract
The initiation of migraine may be a central or peripheral process. In favor of a peripheral process are the discovery of neuronal pathways from scalp to dura and meninges to cortex, the inhibition in rats of cortical activation by botulinum toxin via Transient Receptor Potential Vanilloid type 1 (TRPV1) and Transient Receptor Potential cation channel, subfamily A, member 1 (TRPA1) receptors, and the profoundly effective migraine prevention seen rapidly with anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mABs), which do not cross the blood–brain barrier and therefore have only initial peripheral effects. In favor of a central process are the activation of central neuromodulatory pathways and nuclei, specifically in the dorsal pons. The genesis of aura is activation of N-methyl-D-aspartate receptor (NMDA) glutamate receptors and cortical spreading depression (CSD). The ability to suppress CSD is associated with acute and preventive effects by drugs and neuromodulation devices, but whether this suppression alone is sufficient for either clinical effect is unresolved. Migraine pain is due to both meningeal vasodilation and neurogenic inflammation. Presynaptic release of CGRP, vasoactive intestinal peptide (VIP), substance P (SP), neurokinin A, and likely, pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) results in these processes. Triptans and ergots prevent release of CGRP, reverse CGRP-induced vasodilation, and interfere with return of the pain signal from periphery to brainstem. Anti-CGRP drugs and biologics can terminate migraine acutely (gepants) or prevent migraine (monoclonal antibodies). A trigemino-parasympathetic or trigeminal autonomic reflex arc involves efferents from the superior salivatory nucleus (SSN) synapsing in the sphenopalatine ganglion (SPG), and then post-synaptic neurons proceeding to sinus, ocular, and nasal organs. Activation of this reflex, which involves VIP, results in sinus-like symptoms or cranial autonomic symptoms and signs in migraine, and nociceptive afferents return signals to the brain via the first division of the trigeminal nerve or ophthalmic nerve. The exit of parasympathetic efferents via the SPG allows for targeting of this ganglion for acute and preventive treatment of migraine via blocks, ablation, or neuromodulation.
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Edvinsson L. Role of VIP/PACAP in primary headaches. Cephalalgia. 2013;33:1070–2.
Amin F, Hougaard A, Schytz H, Asghar M, Lundholm E, Parvaiz A, de Koning PJ, Andersen MR, Larsson HB, Fahrenkrug J, Olesen J, Ashina M. Investigation of the pathophysiological mechanisms of migraine attacks induced by PACAP38. Brain. 2014;137(Pt 3):779–94.
Goadsby PJ, Zagami AS. Stimulation of the superior sagittal sinus increases metabolic activity and blood flow in certain regions of the brainstem and upper cervical spinal cord of the cat. Brain. 1991;114:1001–11.
Goadsby PJ, Hoskin KL, Knight YE. Stimulation of the greater occipital nerve increases metabolic activity in the trigeminal nucleus caudalis and cervical dorsal horn of the cat. Pain. 1997;73:23–8.
Burstein R, Levy D, Jakubowski M. Effects of sensitization of trigeminovascular neurons to triptan therapy during migraine. Rev Neurol (Paris). 2005;161(6–7):658–60.
Cady R, Saper J, Dexter K, Manley HR. A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with Tx360 as acute treatment for chronic migraine. Headache. 2015;55:101–16.
Jakubowski M, Levy D, Goor-Aryeh I, Collins B, Bajwa Z, Burstein R. Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors. Headache. 2005;45:850–61.
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183–7.
Arulmani U, MaassenVanDenBrink A, Villalon CM, Saxena PR. Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol. 2004;500:315–30.
Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132:16–25.
Edvinsson L, Elsa St, Suzuki N, et al. Origin and co-localization of nitric oxide synthase, CGRP, PACAP, and VIP in the cerebral circulation of the rat. Microsc Res Tech. 2001;53:221–8.
Csati A, Tajti J, Tuka B, et al. Calcitonin gene-related peptide and its receptor components in the human sphenopalatine ganglion—interaction with the sensory system. Brain Res. 2012;1435:29–39.
Tuka B, Helyes Z, Markovics A, Bagoly T, Szolcsányi J, Szabó N, Tóth E, Kincses ZT, Vécsei L, Tajti J. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia. 2013;33:1085–95.
Vécsei L, Tuka B, Tajti J. Role of PACAP in migraine headaches. Brain. 2014;137:646–53.
Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM. BIBN 4096 BS clinical proof of concept study group. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350:1104–10.
Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, Fei K, Assaid C, Lines C, Ho TW. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73:970–7.
Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2011;31:573–84.
Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman R, Taraborelli D, Fan X, Assaid C, Lines C, Ho TW. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cephalalgia. 2011;31:712–22.
Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34:114–25.
Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, Assaid C, Aurora SK, Michelson D. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36:887–98.
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885–92.
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, Wilks K, Kudrow D, Kroll R, Kohrman B, Bargar R, Hirman J, Smith J. ALD403 study investigators. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13:1100–7.
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings EL, Diener HC, Burstein R, Loupe PS, Ma Y, Yang R, Silberstein SD. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14:1091–100.
Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Lenz R. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:382–90.
Goldberg SW, Silberstein SD. Targeting CGRP: a new era for migraine treatment. CNS Drugs. 2015;29:443–52.
Silberstein S, Lenz R, Xu C. Therapeutic monoclonal antibodies: what headache specialists need to know. Headache. 2015;55:1171–82.
Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version. Cephalalgia. 2013;33:629–808.
Lashley K. Patterns of cerebral integration indicated by scotomas of migraine. Arch Neurol Psychiatry. 1941;46:331–9.
Hubel DH, Wiesel TN. Receptive fields of single neurones in the cat’s striate cortex. J Physiol. 1959;148:574–91.
Leao AAAP. Spreading depression of activation in the cerebral cortex. J Neurophysiol. 1944;7:359–90.
Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687–92.
Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain. 1994;117(Pt 1):199–210.
Woods RP, Iacoboni M, Mazziotta JC. Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. 1994;331:1689–92.
Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J. Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study. Lancet Neurol. 2009;8:718–23.
Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006;59:652–61.
Noruzzadeh R, Modabbernia A, Aghamollaii V, Ghaffarpour M, Harirchian MH, Salahi S, Nikbakht N, Noruzi N, Tafakhori A. Memantine for prophylactic treatment of migraine without aura: a randomized double-blind placebo-controlled study. Headache. 2016;56:95–103.
Tepper SJ. Nutraceutical and other modalities for the treatment of headache. Continuum (Minneap Minn). 2015;21:1018–31.
Durham PL. CGRP-receptor antagonists–a fresh approach to migraine therapy? N Engl J Med. 2004;350:1073–5.
Tepper SJ, Stillman MJ. Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine. Headache. 2008;48:1259–68.
Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154(Suppl 1):S44–53.
Zhang X, Strassman AM, Novack V, Brin MF, Burstein R. Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: are we getting closer to solving this puzzle? Cephalalgia. 2016;36:875–86.
Weiller C, May A, Limmroth V, Jüptner M, Kaube H, Schayck RV, Coenen HH, Diener HC. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:658–60.
Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RS, Goadsby PJ. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain. 2005;128(Pt 4):932–9.
Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003;4:386–98.
Bigal ME, Dodick DW, Krymchantowski AV, VanderPluym JH, Tepper SJ, Aycardi E, Loupe PS, Ma Y, Goadsby PJ. TEV-48125 for the preventive treatment of chronic migraine: Efficacy at early time points. Neurology. 2016;87:41–8.
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Tepper, S.J. (2017). Anatomy and Pathophysiology of Migraine. In: Mehle, M. (eds) Sinus Headache, Migraine, and the Otolaryngologist. Springer, Cham. https://doi.org/10.1007/978-3-319-50376-9_2
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