It 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-HT1B/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 ‘premonitorylike’, given they can start before or during pain. Symptoms starting after pain resolution (postdromal symptoms) will not be covered here.
Migraine, premonitory, prodrome, functional imaging
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.
March 12, 2017 Accepted
April 25, 2017
Peter J Goadsby, Wellcome Foundation Building, King’s College Hospital, London, UK. E: firstname.lastname@example.org
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.
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 nonpainful 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
1. Gowers W, A Manual of Diseases of the Nervous System, 2nd ed. Vol. II. Philadelphia: P. Blakiston, Son & Co, 1886;777–84.
2. Blau JN, Resolution of migraine attacks: sleep and the recovery phase, J Neurol Neurosurg, 1982;45:223–6.
3. Blau JN, Migraine prodromes separated from the aura: complete migraine, Br Med J, 1980;281:658–60.
4. Lance JW, What is a migraine?, Adv Neurol, 1982;33:21–6.
5. Kelman L, The postdrome of the acute migraine attack, Cephalalgia, 2006;26:214–20.
6. Schulte LH, Jurgens TP, May A, Photo-, osmo- and phonophobia in the premonitory phase of migraine: mistaking symptoms for triggers?, J Headache Pain, 2015;16:14.
7. Pavlovic JM, Buse DC, Sollars CM, et al., Trigger factors and premonitory features of migraine attacks: summary of studies, Headache, 2014;54:1670–9.
8. Drummond PD, Lance JW, Neurovascular disturbances in headache patients, Clin Exp Neurol, 1984;20:93–9.
9. Amery WK, Waelkens J, Vandenbergh V, Migraine warnings, Headache, 1986;26:60–6.
10. Russell MB, Rasmussen BK, Fenger K, et al., Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population, Cephalalgia, 1996;16:239–45.
11. Rasmussen BK, Olesen J, Migraine with aura and migraine without aura: an epidemiological study, Cephalalgia, 1992;12:221–8; discussion 186.
12. Waelkens J, Warning symptoms in migraine: characteristics and therapeutic implications, Cephalalgia, 1985;5:223–8.
13. Schoonman GG, Evers DJ, Terwindt GM, et al., The prevalence of premonitory symptoms in migraine: a questionnaire study in 461 patients, Cephalalgia, 2006;26:1209–13.
14. Kelman L, The premonitory symptoms (prodrome): a tertiary care study of 893 migraineurs, Headache, 2004;44:865–72.
15. Quintela E, Castillo J, Munoz P, et al., Premonitory and resolution symptoms in migraine: a prospective study in 100 unselected patients, Cephalalgia, 2006;26:1051–60.
16. Giffin NJ, Ruggiero L, Lipton RB, et al., Premonitory symptoms in migraine: an electronic diary study, Neurology, 2003;60:935–40.
17. Karsan N, Prabhakar P, Goadsby PJ, Characterising the premonitory stage of migraine in children: a clinic-based study of 100 patients in a specialist headache service, J Headache Pain, 2016;17:94.
18. Cuvellier JC, Mars A, Vallee L, The prevalence of premonitory symptoms in paediatric migraine: a questionnaire study in 103 children and adolescents, Cephalalgia, 2009;29:1197–201.
19. Akerman S, Holland PR, Goadsby PJ, Diencephalic and brainstem mechanisms in migraine, Nat Rev Neurol, 2011;12:570–84.
20. Afridi SK, Giffin NJ, Kaube H, et al., A positron emission tomographic study in spontaneous migraine, Arch Neurol, 2005;62:1270–5.
21. Afridi SK, Matharu MS, Lee L, et al., A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate, Brain, 2005;128:932–9.
22. Bahra A, Matharu MS, Buchel C, et al., Brainstem activation specific to migraine headache, Lancet, 2001;357:1016–7.
23. Schulte LH, May A, The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks, Brain, 2016;139:1987–93.
24. Schulte LH, Sprenger C, May A, Physiological brainstem mechanisms of trigeminal nociception: an fMRI study at 3T, NeuroImage, 2016;124:518–25.
25. Lemaire JJ, Frew AJ, McArthur D, et al., White matter connectivity of human hypothalamus, Brain Res, 2011;1371: 43–64.
26. Argiolas A, Melis MR, The neuropharmacology of yawning, Eur J Pharmacol, 1998;343:1–16.
27. Knight YE, Bartsch T, Kaube H, et al., P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine?, J Neurosci, 2002;22:RC213.
28. Goadsby PJ, Lambert GA, Lance JW, Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation, Brain Res, 1982;249:247–54.
29. Maniyar FH, Sprenger T, Schankin C, et al., The origin of nausea in migraine–a PET study, J Headache Pain, 2014;15:84.
30. Maniyar FH, Sprenger T, Monteith T, et al., Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks, Brain, 2014;137:232–41.
31. Maniyar FH, Sprenger T, Schankin C, Goadsby PJ, Photic hypersensitivity in the premonitory phase of migraine: a positron emission topography study, Eur J Neur, 2014;21:1178–83.
32. Waelkens J, Dopamine blockade with domperidone: bridge between prophylactic and abortive treatment of migraine? A dose-finding study, Cephalalgia, 1984;4:85–90.
33. Waelkens J, Domperidone in the prevention of complete classical migraine, Br Med J (Clin Res Ed), 1982;284:944.
34. Afridi SK, Kaube H, Goadsby PJ, Glyceryl trinitrate triggers premonitory symptoms in migraineurs, Pain, 2004;110:675–80.
35. Guo S, Vollesen AL, Olesen J, et al., Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine, Pain, 2016;157:2773–81.
36. Iversen HK, Olesen J, Headache induced by a nitric oxide donor (nitroglycerin) responds to sumatriptan. A human model for development of migraine drugs, Cephalalgia, 1996;16:412–8.
37. Zagami AS, Edvinsson L, Goadsby PJ, Pituitary adenylate cyclase activating polypeptide and migraine, Ann Clin Transl Neurol, 2014;1:1036–40.
38. Schytz HW, Birk S, Wienecke T, et al., PACAP38 induces migraine-like attacks in patients with migraine without aura, Brain, 2009;132:16–25.
39. Goadsby PJ, Bench to bedside advances in the 21st century for primary headache disorders: migraine treatments for migraine patients, Brain, 2016;139:2571–7.
Migraine, premonitory, prodrome, functional imaging