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Review Headache Premonitory-like Symptomatology in Migraine Nazia Karsan 1 and Peter J Goadsby 2 1. Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK; 2. NIHR and Wellcome Trust King’s Clinical Research Facility, King’s College Hospital, London, UK I t has been historically accepted that migraine involves symptomatology outside of head pain. These symptoms can be as equally disabling as the pain, and can include tiredness, concentration impairment, memory impairment and mood change. The symptoms may start before the onset of pain and can persist throughout the headache phase, and even after effective headache treatment into the postdrome. Despite knowledge of these symptoms, their neurobiologic basis and relationship to migraine pain is poorly understood. The fact that these symptoms start early, up to hours to days before the onset of headache, and are so symptomatically heterogeneous, suggests that the neurobiology of migraine extends beyond conventionally accepted anatomical pain areas within the brain – what has been known as the pain matrix or network. In a research area where no effective acute abortive drugs have gained a license for migraine since the triptans (serotonin 5-HT 1B/1D receptor agonists), in the 1990s, further understanding of such symptomatology will allow therapeutic advances for treatments that may work before the onset of migraine pain and thus prevent it. This review will outline our current understanding about the phenotype and neurobiology of the premonitory (prodromal) symptoms, which for the purpose of this review will be called ‘premonitory- like’, given they can start before or during pain. Symptoms starting after pain resolution (postdromal symptoms) will not be covered here. Keywords Migraine, premonitory, prodrome, functional imaging Disclosure: Nazia Karsan is an Association of British Neurologists/Guarantors of Brain Clinical Research Training Fellow. Peter J Goadsby reports personal fees from Allergan, Amgen, and Eli-Lilly and Company; and personal fees from Akita Biomedical, Alder Biopharmaceuticals, Autonomic Technologies Inc., Avanir Pharma, Cipla Ltd, CoLucid Pharmaceuticals Inc., Dr Reddy’s Laboratories, eNeura, ElectroCore LLC, Novartis, Pfizer Inc., Promius Pharma, Quest Diagnostics, Scion, Teva Pharmaceuticals, Trigemina Inc., Scion; and personal fees from MedicoLegal work, Journal Watch, Up-to-Date, Oxford University Press; in addition, Peter J Goadsby has a magnetic stimulation for headache patent pending assigned to eNeura. No funding was received for the publication of this article. Peter J Goadsby is a member of the European Neurological Review Editorial Board. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: 12 March 2017 Accepted: 25 April 2017 Citation: European Neurological Review, 2017;12(1):28–30 Corresponding Author: Peter J Goadsby, Wellcome Foundation Building, King’s College Hospital, London, UK. E: firstname.lastname@example.org It has been recognised for centuries that symptoms outside of pain are reported with migraine. 1 Symptoms prior to the onset of migraine headache have been called premonitory or prodromal symptoms and the symptoms after headache resolution have been called postdromal or resolution symptoms in the literature. 2–4 These symptoms are likely to be a continuum, starting before the onset of headache, and persisting throughout the headache phase, perhaps becoming less noticeable in the presence of moderate-to-severe pain. They can also persist after the resolution of pain before return to normal function, and studies have shown similarities in the phenotype of premonitory and postdromal symptoms. 5 These non-painful cognitive, homeostatic and sensory sensitivity symptoms can be disabling and prevent normal function, adding to the morbidity associated with a migraine attack. It is therefore important to recognise their phenotype and relationship to headache, and further to understand their neurobiology. Most research in this field has focused on symptoms displayed before the onset of moderate–severe migraine headache. However, for the purpose of this review we call the symptoms ‘premonitory-like’ as we have observed that they can start at the same time as pain, or occur during the pain itself. Whether symptoms start before or during pain, they are likely to be biologically mediated the same way, regardless of their onset within the migraine timeline; hence the use of this definition here. For the purpose of this review, premonitory-like symptoms will be defined as any non- painful symptom associated with the migraine attack, possibly predictive of impending headache and starting before the onset of pain, or non-migraine-defining symptoms occurring during the pain itself. Postdrome or resolution symptoms are neurobiologically poorly understood at the moment, and phenotypically not well reported in the literature and will therefore not be included in this review. It should also be noted that premonitory-like symptoms are often mistaken as migraine triggers; for example, a craving for chocolate may be a premonitory symptom, but patients are likely to interpret this as chocolate often triggering a migraine headache in them. 6 Increasingly, the evidence suggests that many of the triggers reported by patients are not reproducible in experimental research, and may actually represent the manifestation of premonitory-like symptomatology. 6,7 Therefore, there is an increasing need to understand the mediation of such symptoms, and their differentiation from migraine triggers, to allow patients to understand their condition better and effectively manage their lifestyles accordingly. Prevalence of premonitory-like symptoms in migraine The true prevalence of premonitory symptoms among migraineurs is unknown, as most of the studies are retrospective and the numbers reported vary greatly across different studies. 8–13 In addition, the majority of the studies performed so far have only looked at symptoms starting before the 28 TOU C H ME D ICA L ME D IA