https://doi.org/10.4081/cc.2025.15789

Anti-CGRP monoclonal antibodies and migraine with aura: a narrative review

Vol. 35 No. 2 (2025)
Submitted: 9 July 2025
Accepted: 4 August 2025
Published: 12 September 2025
Migraine, aura, CGRP, cortical spreading depression
Abstract Views: 50
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Authors

Danilo Antonio Montisano
danilo.montisano@gmail.com
Headache Center, Fondazione Istituto Neurologico C. Besta, Milan, Italy.
Marcella De Luca
https://orcid.org/0009-0006-4913-9232
Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Italy.
Sara Giannoni
https://orcid.org/0000-0003-0538-0412
Neurology Unit, Department of Neuroscience, Azienda USL Toscana Centro, San Giuseppe Hospital, Empoli (FI), Italy.
Giada Giuliani
Department of Human Neuroscience, Sapienza University of Rome, Italy.
Marilena Marcosano
Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
Antonio Munafò
https://orcid.org/0000-0003-1370-2880
Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence; Headache Center and Clinical Pharmacology, Careggi Hospital, Florence, Italy.
Daniele Pala
https://orcid.org/0000-0002-3748-8607
Department of Medical Science and Public Health; Department of Biomedical Sciences, University of Cagliari, Italy.
Federica Pes
https://orcid.org/0009-0004-8627-1334
Unit of Clinical Neurology, Neurosciences and Rehabilitation Department, University of Ferrara, Italy.
Marina Romozzi
https://orcid.org/0000-0001-6016-3141
Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome; Neurology Unit, Department of Neuroscience, Sensory Organs and Chest, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
Gabriele Sebastianelli
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Latina, Italy.

Background: Monoclonal antibodies against the calcitonin gene-related peptide (anti-CGRP mAbs) have been a game-changer in migraine treatment over the last decade. However, data regarding the reduction in the frequency of episodes of migraine with aura are limited, as no trials have been specifically designed to evaluate this outcome.

Methods: In this narrative review, we summarized clinical data from both randomized controlled trials (RCTs) and real-world studies (RWSs) on the efficacy and effectiveness of anti-CGRP mAbs in patients with migraine with aura and aura symptoms.

Results: Overall, anti-CGRP mAbs can reduce migraine frequency and burden regardless of the presence of aura, with efficacy and effectiveness in both patients with and without aura. A few studies suggested a potential influence on reducing aura occurrence. However, several limitations affect the available studies and prevent definitive conclusions regarding the effects of anti-CGRP mAbs on aura.

Conclusions: Further studies specifically aimed at assessing the impact of anti-CGRP therapies on the frequency, duration, and characteristics of aura are necessary. Such research could help elucidate the complex relationship between CGRP and aura.

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1. Raggi A, Leonardi M, Arruda M, Caponnetto V, Castaldo M, Coppola G, et al. Hallmarks of primary headache: part 1 – migraine. J Headache Pain 2024;25:189. DOI: https://doi.org/10.1186/s10194-024-01889-x
2. Ashina M, Terwindt GM, Al-Karagholi MAM, de Boer I, Lee MJ, Hay DL, et al. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet 2021;397:1496-504. DOI: https://doi.org/10.1016/S0140-6736(20)32162-0
3. Viana M, Hougaard A, Tronvik E, Winnberg IG, Ambrosini A, Perrotta A, et al. Visual migraine aura iconography: A multicentre, cross-sectional study of individuals with migraine with aura. Cephalalgia 2024;44. DOI: https://doi.org/10.1177/03331024241234809
4. Lauritzen M. Pathophysiology of the migraine aura. Brain 1994;117:199-210. DOI: https://doi.org/10.1093/brain/117.1.199
5. Hadjikhani N, Sanchez del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci 2001;98:4687-92. DOI: https://doi.org/10.1073/pnas.071582498
6. Leao AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944;7:359-90. DOI: https://doi.org/10.1152/jn.1944.7.6.359
7. Tfelt-Hansen P. History of migraine with aura and cortical spreading depression from 1941 and onwards. Cephalalgia 2010;30:780-92. DOI: https://doi.org/10.1111/j.1468-2982.2009.02015.x
8. Ayata C, Lauritzen M. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev 2015;95:953-93. DOI: https://doi.org/10.1152/physrev.00027.2014
9. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rcbf in classic migraine. Ann Neurol 1981;9:344-52. DOI: https://doi.org/10.1002/ana.410090406
10. McLeod GA, Josephson CB, Engbers JDT, Cooke LJ, Wiebe S. Mapping the migraine: Intracranial recording of cortical spreading depression in migraine with aura. Headache 2025;65:658-65. DOI: https://doi.org/10.1111/head.14907
11. Charles AC, Goadsby PJ. The cortical spreading depression/migraine aura hypothesis – Finally some definitive evidence. Headache 2025;65:537-8. DOI: https://doi.org/10.1111/head.14932
12. 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:S44-53. DOI: https://doi.org/10.1016/j.pain.2013.07.021
13. Grangeon L, Lange KS, Waliszewska-Prosół M, Onan D, Marschollek K, Wiels W, et al. Genetics of migraine: where are we now? J Headache Pain 2023;24:12. DOI: https://doi.org/10.1186/s10194-023-01547-8
14. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002;8:136-42. DOI: https://doi.org/10.1038/nm0202-136
15. Kaag Rasmussen M, Møllgård K, Bork PAR, Weikop P, Esmail T, Drici L, et al. Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model. Science 2024;385:80-6. DOI: https://doi.org/10.1126/science.adl0544
16. Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG, Tonabersat TON-01-05 Study Group. Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis. Cephalalgia 2009;29:742-50.
17. Diener HC, Charles A, Goadsby PJ, Holle D. New therapeutic approaches for the prevention and treatment of migraine. Lancet Neurol 2015;14:1010-22. DOI: https://doi.org/10.1016/S1474-4422(15)00198-2
18. Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG. Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study of the Cortical Spreading Depression Inhibiting Agent Tonabersat in Migraine Prophylaxis. Cephalalgia 2009;29:742-50. DOI: https://doi.org/10.1111/j.1468-2982.2008.01804.x
19. 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. DOI: https://doi.org/10.1016/S1474-4422(09)70135-8
20. Silberstein SD, Schoenen J, Göbel H, Diener HC, Elkind AH, Klapper JA, et al. Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraine. Cephalalgia 2009;29:17-27. DOI: https://doi.org/10.1111/j.1468-2982.2009.01974.x
21. Aurora SK, Barrodale PM, McDonald SA, Jakubowski M, Burstein R. Revisiting the Efficacy of Sumatriptan Therapy During the Aura Phase of Migraine. Headache 2009;49:1001-4. DOI: https://doi.org/10.1111/j.1526-4610.2009.01429.x
22. Olesen J, Diener HC, Schoenen J, Hettiarachchi J. No effect of eletriptan administration during the aura phase of migraine. Eur J Neurol 2004;11:671-7. DOI: https://doi.org/10.1111/j.1468-1331.2004.00914.x
23. Bates D, Ashford E, Dawson R, Ensink FB, Gilhus NE, Olesen J, et al. Subcutaneous sumatriptan during the migraine aura. Sumatriptan Aura Study Group. Neurology 1994;44:1587-92. DOI: https://doi.org/10.1212/WNL.44.9.1587
24. Hansen JM, Charles A. Differences in treatment response between migraine with aura and migraine without aura: lessons from clinical practice and RCTs. J Headache Pain 2019;20:96. DOI: https://doi.org/10.1186/s10194-019-1046-4
25. Petrušić I, Goadsby PJ, Tassorelli C, Coppola G. Editorial: Subtypes of typical migraine with aura: exploring markers for subtype classification and treatment response. Front Hum Neurosci 2023;17. DOI: https://doi.org/10.3389/fnhum.2023.1301809
26. Schoenen J, Van Dycke A, Versijpt J, Paemeleire K. Ten open questions in migraine prophylaxis with monoclonal antibodies blocking the calcitonin-gene related peptide pathway: a narrative review. J Headache Pain 2023;24:99. DOI: https://doi.org/10.1186/s10194-023-01637-7
27. Romozzi M, Burgalassi A, Vollono C, Albanese M, Vigani G, De Cesaris F, et al. Prospective evaluation of aura during anti-calcitonin gene-related peptide monoclonal antibody therapy after 52 weeks of treatment. Confinia Cephalal 2024;34. DOI: https://doi.org/10.4081/cc.2024.15762
28. Ashina S, Melo-Carrillo A, Toluwanimi A, Bolo N, Szabo E, Borsook D, et al. Galcanezumab effects on incidence of headache after occurrence of triggers, premonitory symptoms, and aura in responders, non-responders, super-responders, and super non-responders. J Headache Pain 2023;24:26. DOI: https://doi.org/10.1186/s10194-023-01560-x
29. Straube A, Stude P, Gaul C, Schuh K, Koch M. Real-world evidence data on the monoclonal antibody erenumab in migraine prevention: perspectives of treating physicians in Germany. J Headache Pain 2021;22:133. DOI: https://doi.org/10.1186/s10194-021-01344-1
30. Ashina M, Goadsby PJ, Dodick DW, Tepper SJ, Xue F, Zhang F, et al. Assessment of Erenumab Safety and Efficacy in Patients With Migraine With and Without Aura. JAMA Neurol 2022;79:159. DOI: https://doi.org/10.1001/jamaneurol.2021.4678
31. Schoenen J, Timmermans G, Nonis R, Manise M, Fumal A, Gérard P. Erenumab for Migraine Prevention in a 1-Year Compassionate Use Program: Efficacy, Tolerability, and Differences Between Clinical Phenotypes. Front Neurol 2021;12. DOI: https://doi.org/10.3389/fneur.2021.805334
32. Gold L, Back T, Arnold G, Dreier J, Einhäupl KM, Reuter U, et al. Cortical spreading depression-associated hyperemia in rats: involvement of serotonin. Brain Res 1998;783:188-93. DOI: https://doi.org/10.1016/S0006-8993(97)01341-3
33. Wahl M, Schilling L, Parsons AA, Kaumann A. Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression. Brain Res 1994;637:204-10. DOI: https://doi.org/10.1016/0006-8993(94)91234-3
34. Bergerot A, Holland PR, Akerman S, Bartsch T, Ahn AH, MaassenVanDenBrink A, et al. Animal models of migraine: looking at the component parts of a complex disorder. Eur J Neurosci 2006;24:1517-34. DOI: https://doi.org/10.1111/j.1460-9568.2006.05036.x
35. Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S, Pisani A, et al. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci 2012;109:18985-90. DOI: https://doi.org/10.1073/pnas.1215435109
36. Yisarakun W, Chantong C, Supornsilpchai W, Thongtan T, Srikiatkhachorn A, Reuangwechvorachai P, et al. Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model. Neuropeptides 2015;51:9-16. DOI: https://doi.org/10.1016/j.npep.2015.03.008
37. Yao G, Huang Q, Wang M, Yang CL, Liu CF, Yu TM. Behavioral study of a rat model of migraine induced by CGRP. Neurosci Lett 2017;651:134-9. DOI: https://doi.org/10.1016/j.neulet.2017.04.059
38. Close LN, Eftekhari S, Wang M, Charles AC, Russo AF. Cortical spreading depression as a site of origin for migraine: Role of CGRP. Cephalalgia 2019;39:428-34. DOI: https://doi.org/10.1177/0333102418774299
39. Gimeno-Ferrer F, Eitner A, Bauer R, Lehmenkühler A, Edenhofer ML, Kress M, et al. From spreading depolarization to epilepsy with neuroinflammation: The role of CGRP in cortex. Exp Neurol 2022;356:114152. DOI: https://doi.org/10.1016/j.expneurol.2022.114152
40. Hansen JM, Thomsen LL, Olesen J, Ashina M. Calcitonin gene–related peptide does not cause the familial hemiplegic migraine phenotype. Neurology 2008;71:841-7. DOI: https://doi.org/10.1212/01.wnl.0000325482.64106.3f
41. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010;30:1179-86. DOI: https://doi.org/10.1177/0333102410368444
42. Al-Khazali HM, Ashina H, Wiggers A, Rose K, Iljazi A, Christensen RH, et al. Calcitonin gene-related peptide causes migraine aura. J Headache Pain 2023;24:124. DOI: https://doi.org/10.1186/s10194-023-01656-4
43. Dux M, Vogler B, Kuhn A, Mackenzie KD, Stratton J, Messlinger K. The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow. Cells 2022;11:1768. DOI: https://doi.org/10.3390/cells11111768
44. Friedrich N, Németh K, Tanner M, Rosta J, Dobos I, Oszlács O, et al. Anti-CGRP antibody galcanezumab modifies the function of the trigeminovascular nocisensor complex in the rat. J Headache Pain 2024;25:9. DOI: https://doi.org/10.1186/s10194-024-01717-2
45. Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system—40 years and counting. Lancet Neurol 2019;18:795-804. DOI: https://doi.org/10.1016/S1474-4422(19)30185-1
46. Johnson KW, Morin SM, Wroblewski VJ, Johnson MP. Peripheral and central nervous system distribution of the CGRP neutralizing antibody [125I] galcanezumab in male rats. Cephalalgia 2019;39:1241-8. DOI: https://doi.org/10.1177/0333102419844711
47. Iannone LF, De Cesaris F, Ferrari A, Benemei S, Fattori D, Chiarugi A. Effectiveness of anti-CGRP monoclonal antibodies on central symptoms of migraine. Cephalalgia 2022;42:1323-30. DOI: https://doi.org/10.1177/03331024221111526
48. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211. DOI: https://doi.org/10.1177/0333102417738202
49. Ashina M, McAllister P, Cady R, Hirman J, Ettrup A. Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2. Cephalalgia 2022;42:696-704. DOI: https://doi.org/10.1177/03331024221077646
50. Igarashi H, Shibata M, Ozeki A, Matsumura T. Galcanezumab Effects on Migraine Severity and Symptoms in Japanese Patients with Episodic Migraine: Secondary Analysis of a Phase 2 Randomized Trial. Neurol Ther 2023;12:73-87. DOI: https://doi.org/10.1007/s40120-022-00410-3

How to Cite

1.
Montisano DA, De Luca M, Giannoni S, Giuliani G, Marcosano M, Munafò A, et al. Anti-CGRP monoclonal antibodies and migraine with aura: a narrative review. Confinia Cephalal [Internet]. 2025 Sep. 12 [cited 2025 Sep. 15];35(2). Available from: https://www.confiniacephalalgica.com/site/article/view/15789
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