Skip to main content

Advertisement

SpringerLink
Log in

Migraine

  • Primer
  • Published:

From Nature Reviews Disease Primers

View current issue Sign up to alerts

Abstract

Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT1B/1D receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1F receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Full-blown migraine attack.
Fig. 2: One-year prevalence of migraine.
Fig. 3: Anatomical substrates of migraine.
Fig. 4: Sensitization of neural circuits mediating the headache phase of migraine.
Fig. 5: Pathogenesis of familial hemiplegic migraine.

Similar content being viewed by others

References

  1. Goadsby, P. J., Lipton, R. B. & Ferrari, M. D. Migraine–current understanding and treatment. N. Engl. J. Med. 346, 257–270 (2002).

    CAS  PubMed  Google Scholar 

  2. Terwindt, G. M. et al. The impact of migraine on quality of life in the general population: the GEM study. Neurology 55, 624–629 (2000).

    CAS  PubMed  Google Scholar 

  3. Jensen, R. & Stovner, L. J. Epidemiology and comorbidity of headache. Lancet Neurol. 7, 354–361 (2008).

    PubMed  Google Scholar 

  4. Stovner, L. J. et al. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 17, 954–976 (2018).

    Google Scholar 

  5. [No authors listed] Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd Edition. Cephalalgia 38, 1–211 (2018).

    Google Scholar 

  6. Ashina, M. Migraine. N. Engl. J. Med. 383, 1866–1876 (2020).

    CAS  PubMed  Google Scholar 

  7. Steiner, T. J. et al. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J. Headache Pain. 21, 137 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Launer, L. J., Terwindt, G. M. & Ferrari, M. D. The prevalence and characteristics of migraine in a population-based cohort: the GEM study. Neurology 53, 537–542 (1999).

    CAS  PubMed  Google Scholar 

  9. Salomon, J. A. et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010. Lancet 380, 2129–2143 (2012).

    PubMed  Google Scholar 

  10. Hansen, J. M., Goadsby, P. J. & Charles, A. C. Variability of clinical features in attacks of migraine with aura. Cephalalgia 36, 216–224 (2015).

    PubMed  Google Scholar 

  11. Giffin, N. J. et al. Premonitory symptoms in migraine: an electronic diary study. Neurology 60, 935–940 (2003).

    CAS  PubMed  Google Scholar 

  12. Schoonman, G. G., Evers, D. J., Terwindt, G. M., van Dijk, J. G. & Ferrari, M. D. The prevalence of premonitory symptoms in migraine: a questionnaire study in 461 patients. Cephalalgia 26, 1209–1213 (2006).

    CAS  PubMed  Google Scholar 

  13. Karsan, N. & Goadsby, P. J. Biological insights from the premonitory symptoms of migraine. Nat. Rev. Neurol. 14, 699–710 (2018).

    PubMed  Google Scholar 

  14. Giffin, N. J., Lipton, R. B., Silberstein, S. D., Olesen, J. & Goadsby, P. J. The migraine postdrome. Neurology 87, 309–313 (2016).

    PubMed  PubMed Central  Google Scholar 

  15. Ferrari, M. D., Klever, R. R., Terwindt, G. M., Ayata, C. & van den Maagdenberg, A. M. J. M. Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol. 14, 65–80 (2015).

    CAS  PubMed  Google Scholar 

  16. van Oosterhout, W. P. J. et al. Female sex hormones in men with migraine. Neurology 91, e374–e381 (2018).

    PubMed  Google Scholar 

  17. Stewart, W. F., Wood, C., Reed, M. L., Roy, J. & Lipton, R. B. Cumulative lifetime migraine incidence in women and men. Cephalalgia 28, 1170–1178 (2008).

    CAS  PubMed  Google Scholar 

  18. Bigal, M. E. & Lipton, R. B. The epidemiology, burden, and comorbidities of migraine. Neurol. Clin. 27, 321–334 (2009).

    PubMed  Google Scholar 

  19. Merikangas, K. R. Contributions of epidemiology to our understanding of migraine. Headache 53, 230–246 (2013).

    PubMed  Google Scholar 

  20. Stovner, L. J. et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27, 193–210 (2007).

    PubMed  Google Scholar 

  21. Ashina, M., Hansen, J. M. & Olesen, J. Pearls and pitfalls in human pharmacological models of migraine: 30 years’ experience. Cephalalgia 33, 540–553 (2013).

    PubMed  Google Scholar 

  22. Diener, H.-C. et al. Chronic migraine–classification, characteristics and treatment. Nat. Rev. Neurol. 8, 162–171 (2012).

    CAS  PubMed  Google Scholar 

  23. Sun-Edelstein, C., Rapoport, A. M., Rattanawong, W. & Srikiatkhachorn, A. The evolution of medication overuse headache: history, pathophysiology and clinical update. CNS Drugs 35, 545–565 (2021).

    PubMed  Google Scholar 

  24. Louter, M. A. et al. Cutaneous allodynia as a predictor of migraine chronification. Brain 136, 3489–3496 (2013).

    PubMed  Google Scholar 

  25. Ottman, R. & Lipton, R. B. Is the comorbidity of epilepsy and migraine due to a shared genetic susceptibility? Neurology 47, 918–924 (1996).

    CAS  PubMed  Google Scholar 

  26. Bauer, P. Headache in people with epilepsy. Nat. Rev. Neurol. 17, 529–544 (2021).

    PubMed  Google Scholar 

  27. Modgill, G., Jette, N., Wang, J. L., Becker, W. J. & Patten, S. B. A population-based longitudinal community study of major depression and migraine. Headache 52, 422–432 (2011).

    PubMed  Google Scholar 

  28. Breslau, N., Lipton, R. B., Stewart, W. F., Schultz, L. R. & Welch, K. M. A. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology 60, 1308–1312 (2003).

    CAS  PubMed  Google Scholar 

  29. The Brainstorm Consortium. et al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018).

    PubMed Central  Google Scholar 

  30. Tietjen, G. E. et al. High prevalence of somatic symptoms and depression in women with disabling chronic headache. Neurology 68, 134–140 (2007).

    CAS  PubMed  Google Scholar 

  31. Sacco, S. & Kurth, T. Migraine and the risk for stroke and cardiovascular disease. Curr. Cardiol. Rep. 16, 524 (2014).

    PubMed  Google Scholar 

  32. Etminan, M. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 330, 60–63 (2005).

    Google Scholar 

  33. Schürks, M. et al. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ 339, b3914 (2009).

    PubMed  PubMed Central  Google Scholar 

  34. Spector, J. T. et al. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am. J. Med. 123, 612–624 (2010).

    PubMed  PubMed Central  Google Scholar 

  35. Kurth, T., Chabriat, H. & Bousser, M.-G. Migraine and stroke: a complex association with clinical implications. Lancet Neurol. 11, 92–100 (2012).

    PubMed  Google Scholar 

  36. Kurth, T. et al. Association of migraine with aura and other risk factors with incident cardiovascular disease in women. JAMA 323, 2281–2289 (2020).

    PubMed  PubMed Central  Google Scholar 

  37. Gudmundsson, L. S. et al. Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study. BMJ 341, c3966 (2010).

    PubMed  PubMed Central  Google Scholar 

  38. Peng, K.-P., Chen, Y.-T., Fuh, J.-L., Tang, C.-H. & Wang, S.-J. Migraine and incidence of ischemic stroke: a nationwide population-based study. Cephalalgia 37, 327–335 (2016).

    PubMed  Google Scholar 

  39. Martinez‐Majander, N. et al. Association between migraine and cryptogenic ischemic stroke in young adults. Ann. Neurol. 89, 242–253 (2021).

    PubMed  Google Scholar 

  40. Li, L., Schulz, U. G., Kuker, W. & Rothwell, P. M. Age-specific association of migraine with cryptogenic TIA and stroke. Neurology 85, 1444–1451 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Monteith, T. S., Gardener, H., Rundek, T., Elkind, M. S. V. & Sacco, R. L. Migraine and risk of stroke in older adults. Neurology 85, 715–721 (2015).

    PubMed  PubMed Central  Google Scholar 

  42. Tzourio, C. et al. Migraine and risk of ischaemic stroke: a case-control study. BMJ 307, 289–292 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Tzourio, C. et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ 310, 830–833 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sacco, S., Ornello, R., Ripa, P., Pistoia, F. & Carolei, A. Migraine and hemorrhagic stroke: a meta-analysis. Stroke 44, 3032–3038 (2013).

    PubMed  Google Scholar 

  45. Adelborg, K. et al. Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ 360, k96 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. Kruit, M. C. Migraine as a risk factor for subclinical brain lesions. JAMA 291, 427–434 (2004).

    CAS  PubMed  Google Scholar 

  47. Kruit, M. C., Launer, L. J., Ferrari, M. D. & van Buchem, M. A. Brain stem and cerebellar hyperintense lesions in migraine. Stroke 37, 1109–1112 (2006).

    PubMed  Google Scholar 

  48. Kurth, T. et al. Headache, migraine, and structural brain lesions and function: population based epidemiology of vascular ageing-MRI study. BMJ 342, c7357 (2011).

    PubMed  PubMed Central  Google Scholar 

  49. Scher, A. I. Migraine headache in middle age and late-life brain infarcts. JAMA 301, 2563–2570 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Palm-Meinders, I. H. et al. Structural brain changes in migraine. JAMA 308, 1889–1897 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Gaist, D. et al. Migraine with aura and risk of silent brain infarcts and white matter hyperintensities: an MRI study. Brain 139, 2015–2023 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Benedittis, G., Lorenzetti, A., Sina, C. & Bernasconi, V. Magnetic resonance imaging in migraine and tension-type headache. Headache 35, 264–268 (1995).

    PubMed  Google Scholar 

  53. Takagi, H. & Umemoto, T., ALICE (All-Literature Investigation of Cardiovascular Evidence) Group. A meta-analysis of case-control studies of the association of migraine and patent foramen ovale. J. Cardiol. 67, 493–503 (2016).

    PubMed  Google Scholar 

  54. West, B. H. et al. Frequency of patent foramen ovale and migraine in patients with cryptogenic stroke. Stroke 49, 1123–1128 (2018).

    PubMed  PubMed Central  Google Scholar 

  55. Sen, S. et al. Migraine with visual aura is a risk factor for incident atrial fibrillation: a cohort study. Neurology 91, e2202–e2210 (2018).

    PubMed  PubMed Central  Google Scholar 

  56. Scher, A. I. et al. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 64, 614–620 (2005).

    CAS  PubMed  Google Scholar 

  57. Kurth, T. et al. Migraine and risk of cardiovascular disease in women. JAMA 296, 283–291 (2006).

    CAS  PubMed  Google Scholar 

  58. Kurth, T. Migraine and risk of cardiovascular disease in men. Arch. Intern. Med. 167, 795–801 (2007).

    PubMed  Google Scholar 

  59. Bigal, M. E. et al. Migraine and cardiovascular disease: a population-based study. Neurology 74, 628–635 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sacco, S. et al. Migraine and risk of ischaemic heart disease: a systematic review and meta-analysis of observational studies. Eur. J. Neurol. 22, 1001–1011 (2015).

    CAS  PubMed  Google Scholar 

  61. Bushnell, C. D., Jamison, M. & James, A. H. Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study. BMJ 338, b664 (2009).

    PubMed  PubMed Central  Google Scholar 

  62. Schürks, M., Winter, A., Berger, K. & Kurth, T. Migraine and restless legs syndrome: a systematic review. Cephalalgia 34, 777–794 (2014).

    PubMed  Google Scholar 

  63. Scher, A. I., Stewart, W. F. & Lipton, R. B. The comorbidity of headache with other pain syndromes. Headache 46, 1416–1423 (2006).

    PubMed  Google Scholar 

  64. Tietjen, G. E. et al. Allodynia in migraine: association with comorbid pain conditions. Headache 49, 1333–1344 (2009).

    PubMed  Google Scholar 

  65. Fagherazzi, G. et al. Associations between migraine and type 2 diabetes in women: findings from the E3N cohort study. JAMA Neurol. 76, 257–263 (2019).

    PubMed  Google Scholar 

  66. Ashina, M., Hansen, J. M., Á Dunga, B. O. & Olesen, J. Human models of migraine – short-term pain for long-term gain. Nat. Rev. Neurol. 13, 713–724 (2017).

    PubMed  Google Scholar 

  67. Lashley, K. S. Patterns of cerebral integration indicated by the scotomas of migraine. Arch. Neurol. Psychiatry 46, 331–339 (1941).

    Google Scholar 

  68. Hansen, J. M., Baca, S. M., VanValkenburgh, P. & Charles, A. Distinctive anatomical and physiological features of migraine aura revealed by 18 years of recording. Brain 136, 3589–3595 (2013).

    PubMed  Google Scholar 

  69. Charles, A. C. & Baca, S. M. Cortical spreading depression and migraine. Nat. Rev. Neurol. 9, 637–644 (2013).

    PubMed  Google Scholar 

  70. Dreier, J. P. et al. Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: review and recommendations of the COSBID research group. J. Cereb. Blood Flow. Metab. 37, 1595–1625 (2017).

    PubMed  Google Scholar 

  71. Ayata, C. & Lauritzen, M. Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol. Rev. 95, 953–993 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Parker, P. D. et al. Non-canonical glutamate signaling in a genetic model of migraine with aura. Neuron 109, 611–628.e8 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Eikermann-Haerter, K. Neuronal plumes initiate spreading depolarization, the electrophysiologic event driving migraine and stroke. Neuron 109, 563–565 (2021).

    CAS  PubMed  Google Scholar 

  74. Hadjikhani, N. et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc. Natl Acad. Sci. USA 98, 4687–4692 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Arngrim, N. et al. Heterogenous migraine aura symptoms correlate with visual cortex functional magnetic resonance imaging responses. Ann. Neurol. 82, 925–939 (2017).

    PubMed  Google Scholar 

  76. Ashina, M. et al. Migraine and the trigeminovascular system–40 years and counting. Lancet Neurol. 18, 795–804 (2019).

    PubMed  PubMed Central  Google Scholar 

  77. Goadsby, P. J. et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol. Rev. 97, 553–622 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. Burstein, R. & Jakubowski, M. Unitary hypothesis for multiple triggers of the pain and strain of migraine. J. Comp. Neurol. 493, 9–14 (2005).

    PubMed  Google Scholar 

  79. Maniyar, F. H., Sprenger, T., Monteith, T., Schankin, C. & Goadsby, P. J. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 137, 232–241 (2013).

    PubMed  Google Scholar 

  80. Noseda, R., Jakubowski, M., Kainz, V., Borsook, D. & Burstein, R. Cortical projections of functionally identified thalamic trigeminovascular neurons: implications for migraine headache and its associated symptoms. J. Neurosci. 31, 14204–14217 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhang, X. et al. Activation of central trigeminovascular neurons by cortical spreading depression. Ann. Neurol. 69, 855–865 (2011).

    PubMed  PubMed Central  Google Scholar 

  82. Zhang, X. et al. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J. Neurosci. 30, 8807–8814 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Noseda, R., Constandil, L., Bourgeais, L., Chalus, M. & Villanueva, L. Changes of meningeal excitability mediated by corticotrigeminal networks: a link for the endogenous modulation of migraine pain. J. Neurosci. 30, 14420–14429 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Schain, A. J. et al. Activation of pial and dural macrophages and dendritic cells by cortical spreading depression. Ann. Neurol. 83, 508–521 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Schain, A. J., Melo-Carrillo, A., Strassman, A. M. & Burstein, R. Cortical spreading depression closes paravascular space and impairs glymphatic flow: implications for migraine headache. J. Neurosci. 37, 2904–2915 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Karatas, H. et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339, 1092–1095 (2013).

    CAS  PubMed  Google Scholar 

  87. Ayata, C. Cortical spreading depression triggers migraine attack: pro. Headache 50, 725–730 (2010).

    PubMed  Google Scholar 

  88. Charles, A. Does cortical spreading depression initiate a migraine attack? Maybe not. Headache 50, 731–733 (2010).

    PubMed  Google Scholar 

  89. Ayata, C., Jin, H., Kudo, C., Dalkara, T. & Moskowitz, M. A. Suppression of cortical spreading depression in migraine prophylaxis. Ann. Neurol. 59, 652–661 (2006).

    CAS  PubMed  Google Scholar 

  90. Bogdanov, V. B. et al. Migraine preventive drugs differentially affect cortical spreading depression in rat. Neurobiol. Dis. 41, 430–435 (2011).

    CAS  PubMed  Google Scholar 

  91. Ayata, C. Spreading depression: from serendipity to targeted therapy in migraine prophylaxis. Cephalalgia 29, 1095–1114 (2009).

    CAS  PubMed  Google Scholar 

  92. Edvinsson, L., Haanes, K. A., Warfvinge, K. & Krause, D. N. CGRP as the target of new migraine therapies–successful translation from bench to clinic. Nat. Rev. Neurol. 14, 338–350 (2018).

    CAS  PubMed  Google Scholar 

  93. Knight, Y. E., Edvinsson, L. & Goadsby, P. J. 4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT(1B/1D) receptor agonist activity? Neuropharmacology 40, 520–525 (2001).

    CAS  PubMed  Google Scholar 

  94. Goadsby, P. J., Edvinsson, L. & Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 (1990).

    CAS  PubMed  Google Scholar 

  95. Goadsby, P. J. & Edvinsson, L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann. Neurol. 33, 48–56 (1993).

    CAS  PubMed  Google Scholar 

  96. Olesen, J. et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N. Engl. J. Med. 350, 1104–1110 (2004).

    CAS  PubMed  Google Scholar 

  97. Tvedskov, J. F. et al. No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann. Neurol. 58, 561–568 (2005).

    CAS  PubMed  Google Scholar 

  98. Melo-Carrillo, A. et al. Fremanezumab — a humanized monoclonal anti-CGRP antibody — inhibits thinly myelinated (Aδ) but not unmyelinated (C) meningeal nociceptors. J. Neurosci. 37, 10587–10596 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Melo-Carrillo, A. et al. Selective inhibition of trigeminovascular neurons by fremanezumab: a humanized monoclonal anti-CGRP antibody. J. Neurosci. 37, 7149–7163 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Strassman, A. M., Raymond, S. A. & Burstein, R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384, 560–564 (1996).

    CAS  PubMed  Google Scholar 

  101. Burstein, R., Yamamura, H., Malick, A. & Strassman, A. M. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J. Neurophysiol. 79, 964–982 (1998).

    CAS  PubMed  Google Scholar 

  102. Burstein, R., Yarnitsky, D., Goor-Aryeh, I., Ransil, B. J. & Bajwa, Z. H. An association between migraine and cutaneous allodynia. Ann. Neurol. 47, 614–624 (2000).

    CAS  PubMed  Google Scholar 

  103. Burstein, R. The development of cutaneous allodynia during a migraine attack: clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 123, 1703–1709 (2000).

    PubMed  Google Scholar 

  104. Akerman, S., Holland, P. R. & Goadsby, P. J. Diencephalic and brainstem mechanisms in migraine. Nat. Rev. Neurosci. 12, 570–584 (2011).

    CAS  PubMed  Google Scholar 

  105. Schulte, L. H., Mehnert, J. & May, A. Longitudinal neuroimaging over 30 days: temporal characteristics of migraine. Ann. Neurol. 87, 646–651 (2020).

    PubMed  Google Scholar 

  106. Schulte, L. H. & May, A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139, 1987–1993 (2016).

    PubMed  Google Scholar 

  107. Weiller, C. et al. Brain stem activation in spontaneous human migraine attacks. Nat. Med. 1, 658–660 (1995).

    CAS  PubMed  Google Scholar 

  108. Goadsby, P. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain 120, 193–209 (1997).

    PubMed  Google Scholar 

  109. Sprenger, T. & Goadsby, P. J. What has functional neuroimaging done for primary headache and for the clinical neurologist? J. Clin. Neurosci. 17, 547–553 (2010).

    PubMed  Google Scholar 

  110. Andreou, A. P., Summ, O., Charbit, A. R., Romero-Reyes, M. & Goadsby, P. J. Animal models of headache: from bedside to bench and back to bedside. Expert Rev. Neurother. 10, 389–411 (2010).

    PubMed  Google Scholar 

  111. Knight, Y. E., Bartsch, T., Kaube, H. & Goadsby, P. J. P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J. Neurosci. 22, RC213 (2002).

    PubMed  PubMed Central  Google Scholar 

  112. Bartsch, T., Knight, Y. E. & Goadsby, P. J. Activation of 5-HT1B/1D receptor in the periaqueductal gray inhibits nociception. Ann. Neurol. 56, 371–381 (2004).

    CAS  PubMed  Google Scholar 

  113. Bergerot, A., Storer, R. J. & Goadsby, P. J. Dopamine inhibits trigeminovascular transmission in the rat. Ann. Neurol. 61, 251–262 (2007).

    CAS  PubMed  Google Scholar 

  114. Charbit, A. R., Akerman, S. & Goadsby, P. J. Trigeminocervical complex responses after lesioning dopaminergic A11 nucleus are modified by dopamine and serotonin mechanisms. Pain 152, 2365–2376 (2011).

    CAS  PubMed  Google Scholar 

  115. Lauritzen, M. & Olesen, J. E. S. Regional cerebral blood flow during migraine attacks by xenon-133 inhalation and emission tomography. Brain 107, 447–461 (1984).

    PubMed  Google Scholar 

  116. Olesen, J., Burstein, R., Ashina, M. & Tfelt-Hansen, P. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol. 8, 679–690 (2009).

    PubMed  Google Scholar 

  117. Charles, A. Vasodilation out of the picture as a cause of migraine headache. Lancet Neurol. 12, 419–420 (2013).

    PubMed  Google Scholar 

  118. Schoonman, G. G. et al. Migraine headache is not associated with cerebral or meningeal vasodilatation–a 3T magnetic resonance angiography study. Brain 131, 2192–2200 (2008).

    CAS  PubMed  Google Scholar 

  119. Amin, F. M. et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 12, 454–461 (2013).

    PubMed  Google Scholar 

  120. Khan, S. et al. Meningeal contribution to migraine pain: a magnetic resonance angiography study. Brain 142, 93–102 (2019).

    PubMed  Google Scholar 

  121. Christensen, C. E. et al. Intradural artery dilation during experimentally induced migraine attacks. Pain 162, 176–183 (2021).

    CAS  PubMed  Google Scholar 

  122. May, A. New insights into headache: an update on functional and structural imaging findings. Nat. Rev. Neurol. 5, 199–209 (2009).

    PubMed  Google Scholar 

  123. Zielman, R. et al. Cortical glutamate in migraine. Brain 140, 1859–1871 (2017).

    PubMed  Google Scholar 

  124. Russell, M. B. & Olesen, J. Increased familial risk and evidence of genetic factor in migraine. BMJ 311, 541–544 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Ulrich, V., Gervil, M., Fenger, K., Olesen, J. & Russell, M. B. The prevalence and characteristics of migraine in twins from the general population. Headache 39, 173–180 (1999).

    CAS  PubMed  Google Scholar 

  126. Gormley, P. et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat. Genet. 48, 856–866 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. de Vries, B. et al. Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set. Cephalalgia 36, 604–614 (2015).

    PubMed  Google Scholar 

  128. Gormley, P. et al. Common variant burden contributes to the familial aggregation of migraine in 1,589 families. Neuron 98, 743–753.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Oexle, K. & Winkelmann, J. Common grounds for family maladies. Neuron 98, 671–672 (2018).

    CAS  PubMed  Google Scholar 

  130. Joutel, A. et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383, 707–710 (1996).

    CAS  PubMed  Google Scholar 

  131. Chabriat, H. et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet 346, 934–939 (1995).

    CAS  PubMed  Google Scholar 

  132. Richards, A. et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat. Genet. 39, 1068–1070 (2007).

    CAS  PubMed  Google Scholar 

  133. Stam, A. H. et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain 139, 2909–2922 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. Terwindt, G. Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud’s phenomenon. Brain 121, 303–316 (1998).

    PubMed  Google Scholar 

  135. Pelzer, N. et al. Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease. J. Intern. Med. 285, 317–332 (2019).

    CAS  PubMed  Google Scholar 

  136. Xu, Y. et al. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644 (2005).

    CAS  PubMed  Google Scholar 

  137. Brennan, K. C. et al. Casein kinase I mutations in familial migraine and advanced sleep phase. Sci. Transl. Med. 5, 183ra56 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Russell, M. B. & Ducros, A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol. 10, 457–470 (2011).

    PubMed  Google Scholar 

  139. Zhao, H. et al. Gene-based pleiotropy across migraine with aura and migraine without aura patient groups. Cephalalgia 36, 648–657 (2015).

    PubMed  PubMed Central  Google Scholar 

  140. Pelzer, N., Stam, A. H., Haan, J., Ferrari, M. D. & Terwindt, G. M. Familial and sporadic hemiplegic migraine: diagnosis and treatment. Curr. Treat. Options Neurol. 15, 13–27 (2013).

    PubMed  Google Scholar 

  141. Ophoff, R. A. et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543–552 (1996).

    CAS  PubMed  Google Scholar 

  142. Fusco, M. D. et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump α2 subunit associated with familial hemiplegic migraine type 2. Nat. Genet. 33, 192–196 (2003).

    PubMed  Google Scholar 

  143. Vanmolkot, K. R. J. et al. Novel mutations in the Na+,K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann. Neurol. 54, 360–366 (2003).

    CAS  PubMed  Google Scholar 

  144. Dichgans, M. et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366, 371–377 (2005).

    CAS  PubMed  Google Scholar 

  145. Pietrobon, D. Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine. J. Physiol. 588, 1871–1878 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kahlig, K. M. et al. Divergent sodium channel defects in familial hemiplegic migraine. Proc. Natl Acad. Sci. USA 105, 9799–9804 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Cestele, S., Schiavon, E., Rusconi, R., Franceschetti, S. & Mantegazza, M. Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects. Proc. Natl Acad. Sci. USA 110, 17546–17551 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. van den Maagdenberg, A. M. J. M. et al. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41, 701–710 (2004).

    PubMed  Google Scholar 

  149. van den Maagdenberg, A. M. J. M. et al. High cortical spreading depression susceptibility and migraine-associated symptoms in Cav2.1 S218L mice. Ann. Neurol. 67, 85–98 (2010).

    PubMed  Google Scholar 

  150. Leo, L. et al. Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet. 7, e1002129 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Eikermann-Haerter, K. et al. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J. Clin. Invest. 119, 99–109 (2009).

    CAS  PubMed  Google Scholar 

  152. Eikermann-Haerter, K. et al. Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice. Ann. Neurol. 66, 564–568 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Eikermann-Haerter, K. et al. Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice. J. Neurosci. 31, 5755–5763 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Tottene, A. et al. Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in CaV2.1 knockin migraine mice. Neuron 61, 762–773 (2009).

    CAS  PubMed  Google Scholar 

  155. Capuani, C. et al. Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2. EMBO Mol. Med. 8, 967–986 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Chanda, M. L. et al. Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice. Pain 154, 1254–1262 (2013).

    PubMed  Google Scholar 

  157. Langford, D. J. et al. Coding of facial expressions of pain in the laboratory mouse. Nat. Methods 7, 447–449 (2010).

    CAS  PubMed  Google Scholar 

  158. van Oosterhout, F. et al. Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice: circadian phase resetting. Ann. Neurol. 64, 315–324 (2008).

    PubMed  Google Scholar 

  159. Eikermann-Haerter, K. et al. Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations. Circulation 125, 335–345 (2011).

    PubMed  PubMed Central  Google Scholar 

  160. Gao, Z. et al. Cerebellar ataxia by enhanced CaV2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1aS218L mutant mice. J. Neurosci. 32, 15533–15546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Pelzer, N. et al. Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation. Neurology 90, e575–e582 (2018).

    PubMed  Google Scholar 

  162. Hiekkala, M. E. et al. The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: a clinical and genetic study in Finnish migraine families. Cephalalgia 38, 1849–1863 (2018).

    PubMed  Google Scholar 

  163. Riant, F. et al. PRRT2 mutations cause hemiplegic migraine. Neurology 79, 2122–2124 (2012).

    CAS  PubMed  Google Scholar 

  164. Pelzer, N. et al. PRRT2 and hemiplegic migraine: a complex association. Neurology 83, 288–290 (2014).

    PubMed  Google Scholar 

  165. Bendtsen, L. et al. Guideline on the use of onabotulinumtoxinA in chronic migraine: a consensus statement from the European Headache Federation. J. Headache Pain. 19, 91 (2018).

    PubMed  PubMed Central  Google Scholar 

  166. Hoffmann, J. & Recober, A. Migraine and triggers: post hoc ergo propter hoc? Curr. Pain. Headache Rep. 17, 370 (2013).

    PubMed  Google Scholar 

  167. Lipton, R. B., Pavlovic, J. M., Haut, S. R., Grosberg, B. M. & Buse, D. C. Methodological issues in studying trigger factors and premonitory features of migraine. Headache 54, 1661–1669 (2014).

    PubMed  Google Scholar 

  168. Pavlovic, J. M., Buse, D. C., Sollars, C. M., Haut, S. & Lipton, R. B. Trigger factors and premonitory features of migraine attacks: summary of studies. Headache 54, 1670–1679 (2014).

    PubMed  Google Scholar 

  169. Vollesen, A. L. H. et al. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial. JAMA Neurol. 75, 1187–1197 (2018).

    PubMed  PubMed Central  Google Scholar 

  170. Vollesen, A. L. H. et al. The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache. Cephalalgia 40, 1474–1488 (2020).

    PubMed  Google Scholar 

  171. Chaitman, B. R. et al. A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina. Clin. Pharmacol. Ther. 91, 459–466 (2012).

    CAS  PubMed  Google Scholar 

  172. Brennan, K. C., Romero Reyes, M., López Valdés, H. E., Arnold, A. P. & Charles, A. C. Reduced threshold for cortical spreading depression in female mice. Ann. Neurol. 61, 603–606 (2007).

    PubMed  Google Scholar 

  173. Lipton, R. B. et al. Reduction in perceived stress as a migraine trigger: testing the ‘let-down headache’ hypothesis. Neurology 82, 1395–1401 (2014).

    PubMed  PubMed Central  Google Scholar 

  174. Kelman, L. The triggers or precipitants of the acute migraine attack. Cephalalgia 27, 394–402 (2007).

    CAS  PubMed  Google Scholar 

  175. Bigal, M. E. & Lipton, R. B. Modifiable risk factors for migraine progression. Headache 46, 1334–1343 (2006).

    PubMed  Google Scholar 

  176. Schoonman, G. G. et al. Is stress a trigger factor for migraine? Psychoneuroendocrinology 32, 532–538 (2007).

    CAS  PubMed  Google Scholar 

  177. Schulte, L. H., Menz, M. M., Haaker, J. & May, A. The migraineur’s brain networks: continuous resting state fMRI over 30 days. Cephalalgia 40, 1614–1621 (2020).

    PubMed  Google Scholar 

  178. Borsook, D., Maleki, N., Becerra, L. & McEwen, B. Understanding migraine through the lens of maladaptive stress responses: a model disease of allostatic load. Neuron 73, 219–234 (2012).

    CAS  PubMed  Google Scholar 

  179. Land, B. B. et al. The dysphoric component of stress is encoded by activation of the dynorphin κ-opioid system. J. Neurosci. 28, 407–414 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Bruchas, M. R., Land, B. B. & Chavkin, C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 1314, 44–55 (2010).

    CAS  PubMed  Google Scholar 

  181. Russell, M. B., Rasmussen, B. K., Fenger, K. & Olesen, J. 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 16, 239–245 (1996).

    CAS  PubMed  Google Scholar 

  182. Russell, M. B. & Olesen, J. A nosographic analysis of the migraine aura in a general population. Brain 119, 355–361 (1996).

    PubMed  Google Scholar 

  183. Schott, G. D. Exploring the visual hallucinations of migraine aura: the tacit contribution of illustration. Brain 130, 1690–1703 (2007).

    CAS  PubMed  Google Scholar 

  184. Yamani, N., Chalmer, M. A. & Olesen, J. Migraine with brainstem aura: defining the core syndrome. Brain 142, 3868–3875 (2019).

    PubMed  Google Scholar 

  185. Do, T. P. et al. Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list. Neurology 92, 134–144 (2019).

    PubMed  PubMed Central  Google Scholar 

  186. Dodick, D. Pearls: headache. Semin. Neurol. 30, 74–81 (2010).

    PubMed  Google Scholar 

  187. Vongvaivanich, K., Lertakyamanee, P., Silberstein, S. D. & Dodick, D. W. Late-life migraine accompaniments: a narrative review. Cephalalgia 35, 894–911 (2014).

    PubMed  Google Scholar 

  188. Worthington, I. et al. Canadian Headache Society guideline: acute drug therapy for migraine headache. Can. J. Neurol. Sci. 40, S1–S3 (2013).

    PubMed  Google Scholar 

  189. Roon, K. I. et al. No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic inflammation: results of two randomized, double-blind, placebo-controlled clinical trials. Ann. Neurol. 47, 238–241 (2000).

    CAS  PubMed  Google Scholar 

  190. Levy, D., Jakubowski, M. & Burstein, R. Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT1B/1D receptor agonists. Proc. Natl Acad. Sci. USA 101, 4274–4279 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Ferrari, M. D., Goadsby, P. J., Roon, K. I. & Lipton, R. B. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 22, 633–658 (2002).

    CAS  PubMed  Google Scholar 

  192. Ferrari, M. D., Roon, K. I., Lipton, R. B. & Goadsby, P. J. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 358, 1668–1675 (2001).

    CAS  PubMed  Google Scholar 

  193. Subcutaneous Sumatriptan International Study Group Treatment of migraine attacks with sumatriptan. N. Engl. J. Med. 325, 316–321 (1991).

    Google Scholar 

  194. Thorlund, K. et al. Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment comparison meta-analysis. Cephalalgia 34, 258–267 (2013).

    PubMed  Google Scholar 

  195. Brandes, J. L. et al. Sumatriptan-naproxen for acute treatment of migraine. JAMA 297, 1443–1454 (2007).

    CAS  PubMed  Google Scholar 

  196. Lipton, R. B. et al. Stratified care vs step care strategies for migraine: the Disability in Strategies of Care (DISC) Study: a randomized trial. JAMA 284, 2599–2605 (2000).

    CAS  PubMed  Google Scholar 

  197. Pilgrim, A. J. Methodology of clinical trials of sumatriptan in migraine and cluster headache. Eur. Neurol. 31, 295–299 (1991).

    CAS  PubMed  Google Scholar 

  198. Ferrari, M. D. Should we advise patients to treat migraine attacks early: methodologic issues. Eur. Neurol. 53, 17–21 (2005).

    PubMed  Google Scholar 

  199. Bates, D. et al. Subcutaneous sumatriptan during the migraine aura. Neurology 44, 1587–1587 (1994).

    CAS  PubMed  Google Scholar 

  200. Roberto, G. et al. Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: systematic review of observational studies. Cephalalgia 35, 118–131 (2015).

    CAS  PubMed  Google Scholar 

  201. Dodick, D. et al. Consensus statement: cardiovascular safety profile of triptans (5-HT1B/1D agonists) in the acute treatment of migraine. Headache 44, 414–425 (2004).

    PubMed  Google Scholar 

  202. Roberto, G., Piccinni, C., D’Alessandro, R. & Poluzzi, E. Triptans and serious adverse vascular events: data mining of the FDA Adverse Event Reporting System database. Cephalalgia 34, 5–13 (2014).

    PubMed  Google Scholar 

  203. Wammes-van der Heijden, E. A., Rahimtoola, H., Leufkens, H. G. M., Tijssen, C. C. & Egberts, A. C. G. Risk of ischemic complications related to the intensity of triptan and ergotamine use. Neurology 67, 1128–1134 (2006).

    CAS  PubMed  Google Scholar 

  204. Ephross, S. A. & Sinclair, S. M. Final results from the 16-year sumatriptan, naratriptan, and treximet pregnancy registry. Headache 54, 1158–1172 (2014).

    PubMed  Google Scholar 

  205. Orlova, Y., Rizzoli, P. & Loder, E. Association of coprescription of triptan antimigraine drugs and selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor antidepressants with serotonin syndrome. JAMA Neurol. 75, 566–572 (2018).

    PubMed  PubMed Central  Google Scholar 

  206. Tfelt-Hansen, P. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123, 9–18 (2000).

    PubMed  Google Scholar 

  207. Marmura, M. J., Silberstein, S. D. & Schwedt, T. J. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache 55, 3–20 (2015).

    PubMed  Google Scholar 

  208. Rubio-Beltrán, E., Labastida-Ramírez, A., Villalón, C. M. & MaassenVanDenBrink, A. Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy? Pharmacol. Ther. 186, 88–97 (2018).

    PubMed  Google Scholar 

  209. Lipton, R. B. et al. Effect of ubrogepant vs placebo on pain and the most bothersome associated symptom in the acute treatment of migraine: the ACHIEVE II randomized clinical trial. JAMA 322, 1887–1898 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Lipton, R. B. et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N. Engl. J. Med. 381, 142–149 (2019).

    CAS  PubMed  Google Scholar 

  211. Kuca, B. et al. Lasmiditan is an effective acute treatment for migraine: a phase 3 randomized study. Neurology 91, e2222–e2232 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Goadsby, P. J. et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain 142, 1894–1904 (2019).

    PubMed  PubMed Central  Google Scholar 

  213. Saengjaroentham, C. et al. Differential medication overuse risk of novel anti-migraine therapeutics. Brain 143, 2681–2688 (2020).

    PubMed  PubMed Central  Google Scholar 

  214. Chou, D. E. et al. Acute migraine therapy with external trigeminal neurostimulation (ACME): a randomized controlled trial. Cephalalgia 39, 3–14 (2019).

    PubMed  Google Scholar 

  215. Schoenen, J. et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 80, 697–704 (2013).

    PubMed  Google Scholar 

  216. Stanak, M., Wolf, S., Jagoš, H. & Zebenholzer, K. The impact of external trigeminal nerve stimulator (e-TNS) on prevention and acute treatment of episodic and chronic migraine: a systematic review. J. Neurol. Sci. 412, 116725 (2020).

    CAS  PubMed  Google Scholar 

  217. Lipton, R. B. et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 9, 373–380 (2010).

    PubMed  Google Scholar 

  218. Tassorelli, C. et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology 91, e364–e373 (2018).

    PubMed  PubMed Central  Google Scholar 

  219. Silberstein, S. D. et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: the EVENT study. Neurology 87, 529–538 (2016).

    PubMed  PubMed Central  Google Scholar 

  220. Andreou, A. P. et al. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain 139, 2002–2014 (2016).

    PubMed  PubMed Central  Google Scholar 

  221. Chen, S.-P. et al. Vagus nerve stimulation inhibits cortical spreading depression. Pain 157, 797–805 (2016).

    PubMed  PubMed Central  Google Scholar 

  222. Yarnitsky, D. et al. Nonpainful remote electrical stimulation alleviates episodic migraine pain. Neurology 88, 1250–1255 (2017).

    PubMed  Google Scholar 

  223. Evers, S. et al. EFNS guideline on the drug treatment of migraine – revised report of an EFNS task force. Eur. J. Neurol. 16, 968–981 (2009).

    CAS  PubMed  Google Scholar 

  224. Pringsheim, T. et al. Canadian Headache Society guideline for migraine prophylaxis. Can. J. Neurol. Sci. 39, S1–S59 (2012).

    PubMed  Google Scholar 

  225. Silberstein, S. D. et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78, 1337–1345 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Russell, F. A., King, R., Smillie, S.-J., Kodji, X. & Brain, S. D. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94, 1099–1142 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Forbes, R. B., McCarron, M. & Cardwell, C. R. Efficacy and contextual (placebo) effects of CGRP antibodies for migraine: systematic review and meta-analysis. Headache 60, 1542–1557 (2020).

    PubMed  Google Scholar 

  228. Drellia, K., Kokoti, L., Deligianni, C. I., Papadopoulos, D. & Mitsikostas, D. D. Anti-CGRP monoclonal antibodies for migraine prevention: a systematic review and likelihood to help or harm analysis. Cephalalgia 41, 851–864 (2021).

    PubMed  Google Scholar 

  229. Reuter, U. et al. Erenumab versus topiramate for the prevention of migraine – a randomised, double-blind, active-controlled phase 4 trial. SSRN Electron. J. https://doi.org/10.2139/ssrn.3791424 (2021).

    Article  Google Scholar 

  230. Reuter, U. et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet 392, 2280–2287 (2018).

    CAS  PubMed  Google Scholar 

  231. Ferrari, M. D. et al. Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. Lancet 394, 1030–1040 (2019).

    CAS  PubMed  Google Scholar 

  232. Mulleners, W. M. et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 19, 814–825 (2020).

    CAS  PubMed  Google Scholar 

  233. Goadsby, P. J. et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol. 19, 727–737 (2020).

    CAS  PubMed  Google Scholar 

  234. Croop, R. et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet 397, 51–60 (2021).

    CAS  PubMed  Google Scholar 

  235. MaassenVanDenBrink, A., Meijer, J., Villalón, C. M. & Ferrari, M. D. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol. Sci. 37, 779–788 (2016).

    CAS  PubMed  Google Scholar 

  236. Vos, T. et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2163–2196 (2012).

    PubMed  PubMed Central  Google Scholar 

  237. Depre, C. et al. A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. Headache 58, 715–723 (2018).

    PubMed  PubMed Central  Google Scholar 

  238. Ho, T. W. et al. Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache 52, 224–235 (2012).

    PubMed  Google Scholar 

  239. Maassen van den Brink, A., Rubio-Beltrán, E., Duncker, D. & Villalón, C. M. Is CGRP receptor blockade cardiovascularly safe? Appropriate studies are needed. Headache 58, 1257–1258 (2018).

    CAS  PubMed  Google Scholar 

  240. Ashina, M. et al. Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: a pooled analysis of four placebo-controlled trials with long-term extensions. Cephalalgia 39, 1798–1808 (2019).

    PubMed  Google Scholar 

  241. Holroyd, K. A. et al. Effect of preventive (β blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ 341, c4871 (2010).

    PubMed  PubMed Central  Google Scholar 

  242. Carlsen, L. N. et al. Comparison of 3 treatment strategies for medication overuse headache: a randomized clinical trial. JAMA Neurol. 77, 1069–1078 (2020).

    PubMed  Google Scholar 

  243. Evers, S. & Jensen, R. Treatment of medication overuse headache – guideline of the EFNS headache panel. Eur. J. Neurol. 18, 1115–1121 (2011).

    CAS  PubMed  Google Scholar 

  244. Pijpers, J. A. et al. Acute withdrawal and botulinum toxin A in chronic migraine with medication overuse: a double-blind randomized controlled trial. Brain 142, 1203–1214 (2019).

    PubMed  PubMed Central  Google Scholar 

  245. Diener, H.-C. et al. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 27, 814–823 (2007).

    PubMed  Google Scholar 

  246. Dodick, D. W. et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache 50, 921–936 (2010).

    PubMed  Google Scholar 

  247. Chiang, C.-C., Schwedt, T. J., Wang, S.-J. & Dodick, D. W. Treatment of medication-overuse headache: a systematic review. Cephalalgia 36, 371–386 (2015).

    PubMed  Google Scholar 

  248. Charles, A. & Pozo-Rosich, P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet 394, 1765–1774 (2019).

    CAS  PubMed  Google Scholar 

  249. Ailani, J. et al. Positive response to galcanezumab following treatment failure to onabotulinumtoxinA in patients with migraine: post hoc analyses of three randomized double‐blind studies. Eur. J. Neurol. 27, 542–549 (2020).

    CAS  PubMed  Google Scholar 

  250. Afridi, S. K., Giffin, N. J., Kaube, H. & Goadsby, P. J. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology 80, 642–647 (2013).

    CAS  PubMed  Google Scholar 

  251. Vos, T. et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396, 1204–1222 (2020).

    Google Scholar 

  252. Linde, M. et al. The cost of headache disorders in Europe: the Eurolight project. Eur. J. Neurol. 19, 703–711 (2012).

    CAS  PubMed  Google Scholar 

  253. Lancaster University Management School. Migraine costs EU economy €95bn per year (2019).

  254. Burstein, R., Noseda, R. & Borsook, D. Migraine: multiple processes, complex pathophysiology. J. Neurosci. 35, 6619–6629 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. Lauritzen, M. et al. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J. Cereb. Blood Flow. Metab. 31, 17–35 (2010).

    PubMed  PubMed Central  Google Scholar 

  256. Gupta, R. M. et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170, 522–533.e15 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Tzourio, C. et al. Migraine and the risk of cervical artery dissection: a case-control study. Neurology 59, 435–437 (2002).

    CAS  PubMed  Google Scholar 

  258. Rist, P. M., Diener, H.-C., Kurth, T. & Schürks, M. Migraine, migraine aura, and cervical artery dissection: a systematic review and meta-analysis. Cephalalgia 31, 886–896 (2011).

    PubMed  PubMed Central  Google Scholar 

  259. Tfelt-Hansen, P. C. & Tfelt-Hansen, J. Nitroglycerin headache and nitroglycerin-induced primary headaches from 1846 and onwards: a historical overview and an update. Headache 49, 445–456 (2009).

    PubMed  Google Scholar 

  260. Kruuse, C., Thomsen, L. L., Birk, S. & Olesen, J. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 126, 241–247 (2003).

    PubMed  Google Scholar 

  261. Asghar, M. S. et al. Evidence for a vascular factor in migraine. Ann. Neurol. 69, 635–645 (2011).

    PubMed  Google Scholar 

  262. Amin, F. M. et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 137, 779–794 (2014).

    PubMed  Google Scholar 

  263. Dickson, L., Aramori, I., McCulloch, J., Sharkey, J. & Finlayson, K. A systematic comparison of intracellular cyclic AMP and calcium signalling highlights complexities in human VPAC/PAC receptor pharmacology. Neuropharmacology 51, 1086–1098 (2006).

    CAS  PubMed  Google Scholar 

  264. Guo, S., Olesen, J. & Ashina, M. Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 137, 2951–2959 (2014).

    PubMed  Google Scholar 

  265. Al-Karagholi, M. A.-M., Hansen, J. M., Guo, S., Olesen, J. & Ashina, M. Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine. Brain 142, 2644–2654 (2019).

    PubMed  Google Scholar 

  266. Ashina, M. et al. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet 397, 1496–1504 (2021).

    CAS  PubMed  Google Scholar 

  267. Nieswand, V., Richter, M. & Gossrau, G. Epidemiology of headache in children and adolescents–another type of pandemia. Curr. Pain. Headache Rep. 24, 62 (2020).

    PubMed  PubMed Central  Google Scholar 

  268. Karsan, N., Prabhakar, P. & Goadsby, P. J. Characterising the premonitory stage of migraine in children: a clinic-based study of 100 patients in a specialist headache service. J. Headache Pain. 17, 94 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Gelfand, A. A., Reider, A. C. & Goadsby, P. J. Cranial autonomic symptoms in pediatric migraine are the rule, not the exception. Neurology 81, 431–436 (2013).

    PubMed  PubMed Central  Google Scholar 

  270. Gelfand, A. A. & Goadsby, P. J. Treatment of pediatric migraine in the emergency room. Pediatr. Neurol. 47, 233–241 (2012).

    PubMed  PubMed Central  Google Scholar 

  271. Gelfand, A. A. Pediatric and adolescent headache. Continuum 24, 1108–1136 (2018).

    PubMed  Google Scholar 

  272. Gelfand, A. A., Thomas, K. C. & Goadsby, P. J. Before the headache: Infant colic as an early life expression of migraine. Neurology 79, 1392–1396 (2012).

    PubMed  PubMed Central  Google Scholar 

  273. Goadsby, P. J. in Oxford Textbook of Medicine 5th edn Ch. 24.8 (eds Warrell, D. A., Cox. T. M. & Firth, J. D.) (Oxford Univ. Press, 2018).

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands

    Michel D. Ferrari & Arn M. J. M. van den Maagdenberg

  2. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Peter J. Goadsby & Andrew Charles

  3. Department of Anaesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Centre, Boston, MA, USA

    Peter J. Goadsby & Rami Burstein

  4. NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK

    Peter J. Goadsby

  5. Harvard Medical School, Boston, MA, USA

    Rami Burstein

  6. Institute of Public Health, Charité — Universitätsmedizin Berlin, Berlin, Germany

    Tobias Kurth

  7. Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Cenk Ayata

  8. Stroke Service, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Cenk Ayata

  9. Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Messoud Ashina

  10. Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Messoud Ashina

  11. Department of Human Genetics, Leiden University Medical Centre, Leiden, Netherlands

    Arn M. J. M. van den Maagdenberg

  12. Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA

    David W. Dodick

Authors
  1. Michel D. Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Goadsby
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rami Burstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tobias Kurth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cenk Ayata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew Charles
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Messoud Ashina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arn M. J. M. van den Maagdenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David W. Dodick
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (M.D.F., D.W.D. and P.J.G.); Epidemiology (T.K. and M.D.F.); Pathophysiology (C.A., M.A., R.B., A.C., P.J.G., M.D.F. and A.M.J.M.v.d.M.); Diagnosis, screening and prevention (D.W.D. and M.D.F.); Management (D.W.D., P.J.G. and M.D.F.); Quality of Life (T.K.); Outlook (A.C., P.J.G., D.W.D. and M.D.F.); Overview of the Primer (all authors).

Corresponding author

Correspondence to Michel D. Ferrari.

Ethics declarations

Competing interests

D.W.D. reports the following conflicts: consulting: AEON, Amgen, Clexio, Cerecin, Cooltech, Ctrl M, Allergan, Alder, Biohaven, GSK, Linpharma, Lundbeck, Promius, Eli Lilly, eNeura, Novartis, Impel, Satsuma, Theranica, WL Gore, Nocira, XoC, Zosano, Upjohn (Division of Pfizer), Pieris, Praxis, Revance, Equinox; honoraria: 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, Southern Headache Society (MAHEC), WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press; research support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI); stock options/shareholder/patents/boards of directors: Ctrl M (options), Aural Analytics (options), ExSano (options), Palion (options), Healint (options), Theranica (options), Second Opinion/Mobile Health (options), Epien (options/Board), Nocira (options), Matterhorn (shares/Board), Ontologics (shares/Board), King-Devick Technologies (options/Board), Precon Health (options/Board); patent 17189376.1-1466:v (title: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis). M.A. is a consultant or scientific advisor for AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis and Teva; a primary investigator for ongoing Amgen, AbbVie/Allergan and Lundbeck trials; and has received grants from Lundbeck Foundation, Novo Nordisk Foundation and a research grant from Novartis. T.K. reports having contributed to an advisory board of CoLucid and a research project funded by Amgen, for which the Charité–Universitätsmedizin Berlin received an unrestricted compensation; he further reports having received honoraria from Lilly, Newsenselab, and Total for providing methodological advice, from Novartis and from Daiichi Sankyo for providing a lecture on neuroepidemiology and research methods, and from the BMJ for editorial services. P.J.G. reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, a grant from Celgene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, Lundbeck, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics, Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees for advice through Gerson Lehrman Group, and Guidepoint, fees for educational materials from Massachusetts Medical Society, Medery, Medlink, PrimeEd, UptoDate, WebMD, and publishing royalties from Oxford University Press, and Wolters Kluwer, and for medicolegal advice in headache, and a patent magnetic stimulation for headache (no. WO2016090333 A1) assigned to eNeura without fee. M.D.F. reports grants and consultancy or industry support from Electrocore, Medtronic, Eli Lilly, Amgen, Novartis, Satsuma, Lundbeck, and TEVA, and independent support from The Netherlands Organisation for Scientific Research (NWO), The Netherlands Organisation for Health Research and Development (ZonMW), The Dutch Brain Foundation, The Dutch Heart Foundation, The Dutch Ministry of Health, and The NutsOhra Foundation from the Dutch Insurance Companies. A.C. is a compensated consultant for Amgen, Biohaven, Eli Lilly, Lundbeck, and Satsuma; he is on the executive board of the American Headache Society. R.B. is the John Hedley-Whyte Professor of Anaesthesia and Neuroscience at the Beth Israel Deaconess Medical Center and Harvard Medical School; he has received research support from the NIH (R01 NS094198-01A1, R37 NS079678, R01NS095655, R01 NS104296, R21 NS106345), Allergan, Teva, Dr. Ready, Eli Lilly, Trigemina and the Migraine Research Foundation; he is a reviewer for NINDS; he holds stock options in AllayLamp, Theranica and Percept; he serves as consultant, advisory board member, or has received honoraria from: Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Biohaven, Dr. Reddy’s Laboratory, electroCore, Eli Lilly, GlaxoSmithKline, Merck, Pernix, Theranica, Teva, and Trigemina; and has reveived CME fees from Healthlogix, Medlogix, WebMD/Medscape. A.M.J.M.v.d.M. reports grants and or industry support from Precision Medicine and Schedule 1 Therapeutics and independent support from The Netherlands Organisation for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW). C.A. declares no competing interests.

Additional information

Peer review information

Nature Reviews Disease Primers thanks Hartmut Göbel, Andrew Hershey, Michel Lanteri-Minet, Cristina Tassorelli and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ferrari, M.D., Goadsby, P.J., Burstein, R. et al. Migraine. Nat Rev Dis Primers 8, 2 (2022). https://doi.org/10.1038/s41572-021-00328-4

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-021-00328-4

  • Springer Nature Limited

This article is cited by

Search

Navigation