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Management of Trigeminal Autonomic Cephalalgias Including Chronic ClusterA Review

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Importance  Trigeminal autonomic cephalalgias (TACs) comprise a unique collection of primary headache disorders characterized by moderate or severe unilateral pain, localized in in the area of distribution of the first branch of the trigeminal nerve, accompanied by cranial autonomic symptoms and signs. Most TACs are rare diseases, which hampers the possibility of performing randomized clinical trials and large studies. Therefore, knowledge of treatment efficacy must be based only on observational studies, rare disease registries, and case reports, where real-world data and evidence play an important role in health care decisions.

Observations  Chronic cluster headache is the most common of these disorders, and the literature offers some evidence from randomized clinical trials to support the use of pharmacologic and neurostimulation treatments. Galcanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide, was not effective at 3 months in a randomized clinical trial but showed efficacy at 12 months in a large case series. For the other TACs (ie, paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms), only case reports and case series are available to guide physicians in everyday management.

Conclusions and Relevance  The accumulation of epidemiologic, pathophysiologic, natural history knowledge, and data from case series and small controlled trials, especially over the past 20 years from investigators around the world, has added to the previously limited evidence and has helped advance and inform the treatment approach to rare TACs, which can be extremely challenging for clinicians.

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Article Information

Accepted for Publication: November 3, 2022.

Published Online: January 17, 2023. doi:10.1001/jamaneurol.2022.4804

Corresponding Author: Hans Christoph Diener, MD, Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), Department of Neuroepidemiology, University Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany (hans.diener@uk-essen.de).

Conflict of Interest Disclosures: Dr Diener reported personal fees from Eli Lilly and Company, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; other support from WebMD as author; grants from the German Research Council, German Ministry of Education and Research, and the European Union during the conduct of the study; serves on the editorial board of Cephalalgia, Lancet Neurology, and Drugs; and is a member of the clinical trials committee of the International Headache Society. Dr Tassorelli reported personal fees from AbbVie, Eli Lilly and Company, Novartis, Teva Pharmaceuticals, Lundbeck, Dompé, and WebMD; grants from AbbVie during the conduct of the study; is principal investigator or collaborator in clinical trials sponsored by Alder, Eli Lilly and Company, IBSA, Novartis, and Teva Pharmaceuticals; grants from the European Commission, the Italian Ministry of Health, the Italian Ministry of University, and the Migraine Research Foundation; is president of and serves on the clinical trials committee for the International Headache Society; and serves on the editorial boards of Cephalalgia and The Journal of Headache and Pain. Dr Dodick reported personal fees from AbbVie, Acorda, AEON, Alcobra, Alder, Allergan, American Academy of Neurology, Amgen, Arteaus, Atria Health, Autonomic Technologies, Axsome, Biocentric, Biohaven, Boston Scientific, Bristol Myers Squibb, CapiThera, CC Ford West Group, Cerecin, Ceruvia, Charleston Laboratories, Colucid, CoolTech Medical, CTRLM, Decision Resources, Dr Reddy’s–Promius Pharma, electroCore, Eli Lilly and Company, eNeura, Equinox, Ethicon, Foresight, Genentech, GSK, Impax, Impel, Insys, IntraMed, Ispen, Labrys, Linpharma, Lundbeck, Magellan, MAP BioPharma, Medtronic, Merck, Neurolief, Nocira, Novartis, NuPathe, Oxford University Press, Perfood, Pfizer, Pieris, Praxis, Revance, SAGE Publishing, Salvia, Satsuma, St Jude, Supernus, Teva Pharmaceuticals, Theranica, Tonix, UpToDate, Vedanta, Wiley Blackwell, WL Gore, Wolters Kluwer Health, Xenon, Xoc Pharmaceuticals, Zogenix, Zosano, and ZP Opco; grants and personal fees from Cefaly, electroCore, Eli Lilly and Company, Novartis, Merz Pharma, Teva Pharmaceuticals, Specifar, Amgen, Biogen, and Genesis Pharma; personal fees and nonfinancial support from West Virginia University Foundation, Canadian Headache Society, Healthlogix, Universal Meeting Management, WebMD/Medscape, Oregon Health Science Center, Albert Einstein University, University of Toronto, Synergy, MedNet, Peer View Institute for Medical Education, Medicom, Medlogix, Chameleon Communications, Academy for Continued Healthcare Learning, Haymarket Medical Education, Global Scientific Communications, Miller Medical, MeetingLogiX, University of British Columbia, University of Southern California, University of California (Los Angeles), American Academy of Neurology, and Canadian Headache Society outside the submitted work; nonfinancial support from Starr Clinical, International Headache Society, American Headache Society, American Brain Foundation, and American Migraine Foundation; a patent for Wolters Kluwer with royalties paid, for Oxford University Press with royalties paid, Cambridge University Press with royalties paid, for botulinum toxin dosage regimen for chronic migraine prophylaxis (nonroyalty bearing) issued, and for Synaquell (Precon Health) pending; research support from Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, and Patient-Centered Outcomes Research Institute; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from American Migraine Foundation, American Brain Foundation, International Headache Society Global Patient Advocacy Coalition; stock options/shareholder/patents/board of directors from Aural Analytics, Axon Therapeutics, ExSano, Man and Science, Healint, Theranica, Second Opinion/Mobile Health, Epien, Nocira, Matterhorn, Ontologics, King-Devick Technologies, Precon Health, AYYA Biosciences, and Atria Health; payment or honoraria for lectures, presentations, and educational events from Amgen, Novartis, Eli Lilly and Company, Teva Pharmaceuticals, Allergan, AbbVie, Lundbeck, Biohaven, and Pfizer; and honoraria from Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, MJH Lifesciences, Miller Medical Communications, and WebMD Health/Medscape.

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