Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Headache in people with epilepsy

Nature Reviews Neurology volume 17, pages 529–544 (2021)Cite this article

Subjects

Abstract

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.

Key points

  • The lifetime prevalence of migraine is 52% greater in individuals with epilepsy than in individuals without epilepsy.

  • The symptoms of epilepsy and headache can present diagnostic challenges; a detailed history and EEG recording of the epileptic and/or headache event are important for classification and management.

  • Enhanced neuronal excitability might be the mechanistic link between headaches and seizures.

  • Several genetic mutations can cause epilepsy and migraine, but the genetic association between polygenic forms of epilepsy and migraine remains unclear.

  • Novel therapies include calcitonin gene-related peptide-blocking drugs for migraine and neuromodulative non-pharmacological approaches for migraine and epilepsy; behavioural and self-management approaches are increasing in popularity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: A selection of key publications on headache in epilepsy from before 2015.
Fig. 2: A timeline showing the different types of peri-ictal headaches.
Fig. 3: Putative pathophysiological mechanisms linking seizures and headache.

Similar content being viewed by others

References

  1. Fisher, R. S. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55, 475–482 (2014).

    Article  PubMed  Google Scholar 

  2. GBD 2016 Epilepsy Collaborators. Global, regional, and national burden of epilepsy, 1990 – 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 357–375 (2019).

    Article  Google Scholar 

  3. Scheffer, I. E. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 512–521 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1789–1858 (2018).

    Article  Google Scholar 

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

    Article  Google Scholar 

  6. Goadsby, P. J. Pathophysiology of migraine. Neurol. Clin. 27, 335–360 (2009).

    Article  PubMed  Google Scholar 

  7. Naeije, G., Gaspard, N., Legros, B. & Mavroudakis, N. Transient CNS deficits and migrainous auras in individuals without a history of headache. Headache 54, 493–499 (2014).

    Article  PubMed  Google Scholar 

  8. Keezer, M. R., Bauer, P. R., Ferrari, M. D. & Sander, J. W. The comorbid relationship between migraine and epilepsy: a systematic review and meta-analysis. Eur. J. Neurol. 22, 1038–1047 (2014).

    Article  PubMed  Google Scholar 

  9. Duko, B., Ayalew, M. & Toma, A. The epidemiology of headaches among patients with epilepsy: a systematic review and meta-analysis. J. Headache Pain. 21, 3 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Çilliler, A. E., Güven, H. & Çomoğlu, S. S. Epilepsy and headaches: further evidence of a link. Epilepsy Behav. 70, 161–165 (2017).

    Article  PubMed  Google Scholar 

  11. Hofstra, W., Hageman, G. & de Weerd, A. Periictal and interictal headache including migraine in Dutch patients with epilepsy: a cross-sectional study. Epilepsy Behav. 44, 155–158 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Mutlu, A. Association between epilepsy and headache. Neurol. Sci. 39, 2129–2134 (2018).

    Article  PubMed  Google Scholar 

  13. Seo, J. H., Joo, E. Y., Seo, D. W. & Hong, S. B. Correlation between headaches and affective symptoms in patients with epilepsy. Epilepsy Behav. 60, 204–208 (2016).

    Article  PubMed  Google Scholar 

  14. Whealy, M. A., Myburgh, A., Bredesen, T. J. & Britton, J. W. Headache in epilepsy: a prospective observational study. Epilepsia Open. 4, 593–598 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kim, D. W., Sunwoo, J. S. & Lee, S. K. Headache as an aura of epilepsy: Video-EEG Monitoring Study. Headache 56, 762–768 (2016).

    Article  PubMed  Google Scholar 

  16. Begasse de Dhaem, O. A. J. et al. Migraine comorbidity and cognitive performance in patients with focal epilepsy. Epilepsy Behav. 97, 29–33 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Salma, Z. et al. Headaches and their relationships to epileptic seizures. Epilepsy Behav. 90, 233–237 (2019).

    Article  PubMed  Google Scholar 

  18. Wilner, A. N., Sharma, B. K., Soucy, A., Thompson, A. & Krueger, A. Common comorbidities in women and men with epilepsy and the relationship between number of comorbidities and health plan paid costs in 2010. Epilepsy Behav. 32, 15–20 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Bernasconi, A., Andermann, F., Bernasconi, N., Reutens, D. C. C. & Dubeau, F. Lateralizing value of peri-ictal headache: a study of 100 patients with partial epilepsy. Neurology 56, 130–132 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Belcastro, V., Striano, P. & Parisi, P. “Ictal epileptic headache”: beyond the epidemiological evidence. Epilepsy Behav. 25, 9–10 (2012).

    Article  PubMed  Google Scholar 

  21. Wang, X. Q. et al. Comorbidity between headache and epilepsy in a Chinese epileptic center. Epilepsy Res. 108, 535–541 (2014).

    Article  PubMed  Google Scholar 

  22. Keezer, M. R., Bouma, H. K. & Wolfson, C. The diagnostic accuracy of screening questionnaires for the identification of adults with epilepsy: a systematic review. Epilepsia 55, 1772–1780 (2014).

    Article  PubMed  Google Scholar 

  23. Dugan, P. et al. Auras in generalized epilepsy. Neurology 83, 1444–1449 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Delgado-Rodriguez, M. & Llorca, J. Bias. J. Epidemiol. Community Health. 58, 635–641 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Belcastro, V., Striano, P., Kasteleijn-Nolst Trenité, D. G. A., Villa, M. P. & Parisi, P. Migralepsy, hemicrania epileptica, post-ictal headache and ‘ictal epileptic headache’: a proposal for terminology and classification revision. J. Headache Pain. 12, 289–294 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hofstra, W. A., Hageman, G. & De Weerd, A. W. Headache in epilepsy patients: the (un)awareness of this phenomenon among Dutch neurologists. Seizure 25, 37–39 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Parisi, P. et al. Diagnostic criteria currently proposed for ‘ictal epileptic headache’: perspectives on strengths, weaknesses and pitfalls. Seizure 31, 56–63 (2015).

    Article  PubMed  Google Scholar 

  28. Harnod, T., Wang, Y. C. & Kao, C. H. High risk of developing subsequent epilepsy in young adults with migraine: a nationwide population-based cohort study in Taiwan. QJM 108, 449–455 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Harnod, T., Wang, Y. C. & Tseng, C. H. Male, old age and low income to predispose epilepsy in migraineurs. Eur. J. Clin. Invest. 47, 63–72 (2017).

    Article  PubMed  Google Scholar 

  30. Leniger, T., Isbruch, K., Von Den Driesch, S., Diener, H. C. & Hufnagel, A. Seizure-associated headache in epilepsy. Epilepsia 42, 1176–1179 (2002).

    Article  Google Scholar 

  31. Yankovsky, A. E., Andermann, F. & Bernasconi, A. Characteristics of headache associated with intractable partial epilepsy. Epilepsia 46, 1241–1245 (2005).

    Article  PubMed  Google Scholar 

  32. Förderreuther, S., Henkel, A., Noachtar, S. & Straube, A. Headache associated with epileptic seizures: epidemiology and clinical characteristics. Headache 42, 649–655 (2002).

    Article  PubMed  Google Scholar 

  33. Karaali-Savrun, F., Göksan, B., Naz Yeni, S., Ertan, S. & Uzun, N. Seizure-related headache in patients with epilepsy. Seizure 11, 67–69 (2002).

    Article  PubMed  Google Scholar 

  34. Mainieri, G. et al. Headache in epilepsy: prevalence and clinical features. J. Headache Pain. 16, 556 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Mameniškienė, R., Karmonaitė, I. & Zagorskis, R. The burden of headache in people with epilepsy. Seizure 41, 120–126 (2016).

    Article  PubMed  Google Scholar 

  36. Blume, W. T. et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 42, 1212–1218 (2002).

    Article  Google Scholar 

  37. Lieb, J., Walsh, G., Babb, T., Walter, R. & Crandall, P. A comparison of EEG seizure patterns recorded with surface and depth electrodes in patients with temporal lobe epilepsy. Epilepsia 17, 137–160 (1976).

    Article  CAS  PubMed  Google Scholar 

  38. de Tommaso, M. An update on EEG in migraine. Expert. Rev. Neurother. 19, 729–737 (2019).

    Article  PubMed  CAS  Google Scholar 

  39. Bjork, M., Stovner, L. J., Hagen, K. & Sand, T. What initiates a migraine attack? Conclusions from four longitudinal studies of quantitative EEG and steady-state visual-evoked potentials in migraineurs. Acta Neurol. Scand. 124 (Suppl. 191), 56–63 (2011).

    Article  Google Scholar 

  40. Sand, T. EEG in migraine: a review of the literature. Funct. Neurol. 6, 7–22 (1991).

    CAS  PubMed  Google Scholar 

  41. Sand, T. Electroencephalography in migraine: a review with focus on quantitative electroencephalography and the migraine vs. epilepsy relationship. Cephalalgia 23, 5–11 (2003).

    Article  PubMed  Google Scholar 

  42. Viana, M., Tronvik, E. A., Do, T. P., Zecca, C. & Hougaard, A. Clinical features of visual migraine aura: a systematic review. J. Headache Pain. 20, 64 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Adcock, J. E. & Panayiotopoulos, C. P. Occipital lobe seizures and epilepsies. J. Clin. Neurophysiol. 29, 397–407 (2012).

    Article  PubMed  Google Scholar 

  44. Saitowitz, Z., Flamini, R. & Berenson, F. Ictal epileptic headache: a review of current literature and differentiation from migralepsy and other epilepsies. Headache 54, 1534–1540 (2014).

    Article  PubMed  Google Scholar 

  45. Hartl, E., Angel, J., Rémi, J., Schankin, C. J. & Noachtar, S. Visual auras in epilepsy and migraine – an analysis of clinical characteristics. Headache 57, 908–916 (2017).

    Article  PubMed  Google Scholar 

  46. Verrotti, A. et al. Should “migralepsy” be considered an obsolete concept? A multicenter retrospective clinical/EEG study and review of the literature. Epilepsy Behav. 21, 52–59 (2011).

    Article  PubMed  Google Scholar 

  47. Verrotti, A. et al. Migralepsy and related conditions: advances in pathophysiology and classification. Seizure 20, 271–275 (2011).

    Article  PubMed  Google Scholar 

  48. Hartl, E., Rémi, J. & Noachtar, S. Two patients with visual aura – migraine, epilepsy, or migralepsy? Headache 55, 1148–1151 (2015).

    Article  PubMed  Google Scholar 

  49. Wang, X. Q. et al. High prevalence of headaches in patients with epilepsy. J. Headache Pain. 15, 70 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Fanella, M. et al. A case of ictal epileptic headache in non convulsive status epilepticus: not always, not only, a matter of pain. Headache 59, 1090–1092 (2019).

    Article  PubMed  Google Scholar 

  51. Parisi, P. et al. ‘Ictal epileptic headache’: recent concepts for new classifications criteria. Cephalalgia 32, 723–724 (2012).

    Article  PubMed  Google Scholar 

  52. Parisi, P., Striano, P., Verrotti, A., Villa, M. P. & Belcastro, V. What have we learned about ictal epileptic headache? A review of well-documented cases. Seizure 22, 253–258 (2013).

    Article  PubMed  Google Scholar 

  53. Cianchetti, C., Dainese, F., Ledda, M. G. & Avanzini, G. Epileptic headache: a rare form of painful seizure. Seizure 52, 169–175 (2017).

    Article  PubMed  Google Scholar 

  54. Parisi, P. et al. Ictal epileptic headache: when terminology is not a moot question. Front. Neurol. 10, 785 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Coci, E. G. & Riedel, J. Exploring two novel cases of suspected ictal epileptic headache, a rare form of paediatric epilepsy. Acta Paediatr. 106, 786–790 (2017).

    Article  PubMed  Google Scholar 

  56. Siegel, A. M., Williamson, P. D., Roberts, D. W., Thadani, V. M. & Darcey, T. M. Localized pain associated with seizures originating in the parietal lobe. Epilepsia 40, 845–855 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Fanella, M. et al. Ictal epileptic headache in adult life: electroclinical patterns and spectrum of related syndromes. Epilepsy Behav. 53, 161–165 (2015).

    Article  PubMed  Google Scholar 

  58. Parisi, P., Belcastro, V., Verrotti, A., Striano, P. & Kasteleijn-Nolst Trenitè, D. G. A. “Ictal epileptic headache” and the revised International Headache Classification (ICHD-3) published in Cephalalgia 2018, vol. 38(1) 1–211: not just a matter of definition! Epilepsy Behav. 87, 243–245 (2018).

    Article  PubMed  Google Scholar 

  59. Subota, A. et al. Signs and symptoms of the postictal period in epilepsy: a systematic review and meta-analysis. Epilepsy Behav. 94, 243–251 (2019).

    Article  PubMed  Google Scholar 

  60. Nye, B. L. & Thadani, V. M. Migraine and epilepsy: review of the literature. Headache 55, 359–380 (2015).

    Article  PubMed  Google Scholar 

  61. Bauer, P. R. et al. Headache and epilepsy. Curr. Pain. Headache Rep. 17, 351–360 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Parisi, P. et al. Hypothesis on neurophysiopathological mechanisms linking epilepsy and headache. Med. Hypotheses 70, 1150–1154 (2008).

    Article  PubMed  Google Scholar 

  63. Jefferys, J. G. R. Advances in understanding basic mechanisms of epilepsy and seizures. Seizure 19, 638–646 (2010).

    Article  PubMed  Google Scholar 

  64. Staley, K. Molecular mechanisms of epilepsy. Nat. Neurosci. 18, 367–372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Janigro, D. & Walker, M. C. What non-neuronal mechanisms should be studied to understand epileptic seizures? Adv. Exp. Med. Biol. 813, 253–264 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Spillane, J., Kullmann, D. M. & Hanna, M. G. Genetic neurological channelopathies: molecular genetics and clinical phenotypes. J. Neurol. Neurosurg. Psychiatry 87, 37–48 (2016).

    CAS  PubMed  Google Scholar 

  67. Whittaker, R. G. et al. Epilepsy in adults with mitochondrial disease: a cohort study. Ann. Neurol. 78, 949–957 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Boison, D. & Steinhäuser, C. Epilepsy and astrocyte energy metabolism. Glia 66, 1235–1243 (2018).

    Article  PubMed  Google Scholar 

  69. Kovács, R. et al. Bioenergetic mechanisms of seizure control. Front. Cell. Neurosci. 12, 335 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Carrasco, M. & Stafstrom, C. E. How early can a seizure happen? Pathophysiological considerations of extremely premature infant brain development. Dev. Neurosci. 40, 417–436 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. Magis, D. et al. Pearls and pitfalls: electrophysiology for primary headaches. Cephalalgia 33, 526–539 (2013).

    Article  PubMed  Google Scholar 

  72. Tolner, E. A., Chen, S. P. & Eikermann-Haerter, K. Current understanding of cortical structure and function in migraine. Cephalalgia 39, 1683–1699 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  75. Romero-Reyes, M. & Akerman, S. Update on animal models of migraine. Curr. Pain. Headache Rep. 18, 462 (2014).

    Article  PubMed  Google Scholar 

  76. Brennan, K. C. & Pietrobon, D. A systems neuroscience approach to migraine. Neuron 97, 1004–1021 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mason, B. N. & Russo, A. F. Vascular contributions to migraine: time to revisit? Front. Cell Neurosci. 12, 233 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Schwedt, T. J., Chiang, C. C., Chong, C. D. & Dodick, D. W. Functional MRI of migraine. Lancet Neurol. 14, 81–91 (2015).

    Article  PubMed  Google Scholar 

  84. Schulte, L. H. & May, A. Of generators, networks and migraine attacks. Curr. Opin. Neurol. 30, 241–245 (2017).

    Article  PubMed  Google Scholar 

  85. Chong, C. D., Schwedt, T. J. & Hougaard, A. Brain functional connectivity in headache disorders: a narrative review of MRI investigations. J. Cereb. Blood Flow. Metab. 39, 650–669 (2019).

    Article  PubMed  Google Scholar 

  86. Skorobogatykh, K. et al. Functional connectivity studies in migraine: what have we learned? J. Headache Pain. 20, 108 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Coppola, G. et al. Resting state connectivity between default mode network and insula encodes acute migraine headache. Cephalalgia 38, 846–854 (2018).

    Article  PubMed  Google Scholar 

  88. Amin, F. M. et al. Altered thalamic connectivity during spontaneous attacks of migraine without aura: a resting-state fMRI study. Cephalalgia 38, 1237–1244 (2018).

    Article  PubMed  Google Scholar 

  89. Hougaard, A., Amin, F. M., Larsson, H. B., Rostrup, E. & Ashina, M. Increased intrinsic brain connectivity between pons and somatosensory cortex during attacks of migraine with aura. Hum. Brain Mapp. 38, 2635–2642 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Vecchia, D. & Pietrobon, D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends Neurosci. 35, 507–520 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Myers, C. T. & Mefford, H. C. Advancing epilepsy genetics in the genomic era. Genome Med. 7, 91 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Franceschini, A. et al. TNFα levels and macrophages expression reflect an inflammatory potential of trigeminal ganglia in a mouse model of familial hemiplegic migraine. PLoS ONE 8, e52394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Eising, E. et al. Cortical spreading depression causes unique dysregulation of inflammatory pathways in a transgenic mouse model of migraine. Mol. Neurobiol. 54, 2986–2996 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Borsook, D. et al. Sex and the migraine brain. Neurobiol. Dis. 68, 200–214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  96. Becerra, L. et al. Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas. J. Neurophysiol. 115, 208–217 (2016).

    Article  CAS  PubMed  Google Scholar 

  97. Negro, A. et al. Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization. J. Headache Pain. 21, 86 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kilic, K. et al. Inadequate brain glycogen or sleep increases spreading depression susceptibility. Ann. Neurol. 83, 61–73 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Martins-Oliveira, M. et al. Neuroendocrine signaling modulates specific neural networks relevant to migraine. Neurobiol. Dis. 101, 16–26 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. van Casteren, D. S., Verhagen, I. E., Onderwater, G. L., MaassenVanDenBrink, A. & Terwindt, G. M. Sex differences in prevalence of migraine trigger factors: A cross-sectional study. Cephalalgia 41, 643–648 (2021).

    Article  PubMed  Google Scholar 

  102. Vezzani, A. Epilepsy and inflammation in the brain: overview and pathophysiology. Epilepsy Curr. 14, 3–7 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Fan, S., Xiao, Z., Zhu, F., He, X. & Lu, Z. A new comorbidity model and the common pathological mechanisms of migraine and epilepsy. Am. J. Transl Res. 9, 2286–2295 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Ravizza, T. et al. High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy. Brain. Behav. Immun. 72, 14–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  105. Nagai, Y. Modulation of autonomic activity in neurological conditions: epilepsy and Tourette syndrome. Front. Neurosci. 9, 278 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Bartolomei, F. et al. Pre-ictal synchronicity in limbic networks of mesial temporal lobe epilepsy. Epilepsy Res. 61, 89–104 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Krüger, H. et al. Repetitive spreading depression causes selective suppression of GABAergic function. Neuroreport 7, 2733–2736 (1996).

    Article  PubMed  Google Scholar 

  108. Gorji, A. & Speckmann, E. J. Spreading depression enhances the spontaneous epileptiform activity in human neocortical tissues. Eur. J. Neurosci. 19, 3371–3374 (2004).

    Article  PubMed  Google Scholar 

  109. Berger, M., Speckmann, E. J., Pape, H. C. & Gorji, A. Spreading depression enhances human neocortical excitability in vitro. Cephalalgia 28, 558–562 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Eickhoff, M. et al. Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues. Exp. Neurol. 253, 1–15 (2014).

    Article  PubMed  Google Scholar 

  111. Zakharov, A., Chernova, K., Burkhanova, G., Holmes, G. L. & Khazipov, R. Segregation of seizures and spreading depolarization across cortical layers. Epilepsia 60, 2386–2397 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sklerov, M., Dayan, E. & Browner, N. Functional neuroimaging of the central autonomic network: recent developments and clinical implications. Clin. Auton. Res. 29, 555–566 (2019).

    Article  PubMed  Google Scholar 

  113. Beissner, F., Meissner, K., Bär, K. J. & Napadow, V. The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function. J. Neurosci. 33, 10503–10511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mazzola, L., Isnard, J., Peyron, R. & Mauguire, F. Stimulation of the human cortex and the experience of pain: Wilder Penfield’s observations revisited. Brain 135, 631–640 (2012).

    Article  PubMed  Google Scholar 

  115. Montavont, A. et al. On the origin of painful somatosensory seizures. Neurology 84, 594–601 (2015).

    Article  PubMed  Google Scholar 

  116. 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).

    Article  PubMed  Google Scholar 

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

    Article  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).

    Article  CAS  PubMed  Google Scholar 

  119. Koroleva, V. I. & Bures, J. Cortical penicillin focus as a generator of repetitive spike-triggered waves of spreading depression in rats. Exp. Brain Res. 51, 291–297 (1983).

    Article  CAS  PubMed  Google Scholar 

  120. Mody, I., Lambert, J. D. & Heinemann, U. Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J. Neurophysiol. 57, 869–888 (1987).

    Article  CAS  PubMed  Google Scholar 

  121. Vinogradova, L. V. Comparative potency of sensory-induced brainstem activation to trigger spreading depression and seizures in the cortex of awake rats: implications for the pathophysiology of migraine aura. Cephalalgia 35, 979–986 (2015).

    Article  PubMed  Google Scholar 

  122. Haglund, M. M. & Schwartzkroin, P. A. Role of Na-K pump potassium regulation and IPSPs in seizures and spreading depression in immature rabbit hippocampal slices. J. Neurophysiol. 63, 225–239 (1990).

    Article  CAS  PubMed  Google Scholar 

  123. Dreier, J. P. et al. Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain 135, 259–275 (2012).

    Article  PubMed  Google Scholar 

  124. Fabricius, M. et al. Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain. Clin. Neurophysiol. 119, 1973–1984 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Kandel, E. R. & Spencer, W. A. Excitation and inhibition of single pyramidal cells during hippocampal seizure. Exp. Neurol. 4, 162–179 (1961).

    Article  CAS  PubMed  Google Scholar 

  126. Bauer, P. R. et al. Dynamics of convulsive seizure termination and postictal generalized EEG suppression. Brain 140, 655–668 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. Pottkämper, J. C. M., Hofmeijer, J., van Waarde, J. A. & van Putten, M. J. A. M. The postictal state – what do we know? Epilepsia 61, 1045–1061 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Boison, D. Adenosine and seizure termination: endogenous mechanisms. Epilepsy Curr. 13, 35–37 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Fleidervish, I. A., Gebhardt, C., Astman, N., Gutnick, M. J. & Heinemann, U. Enhanced spontaneous transmitter release is the earliest consequence of neocortical hypoxia that can explain the disruption of normal circuit function. J. Neurosci. 21, 4600–4608 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. During, M. J. & Spencer, D. D. Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Ann. Neurol. 32, 618–624 (1992).

    Article  CAS  PubMed  Google Scholar 

  131. Kennedy, J. D. & Seyal, M. Respiratory pathophysiology with seizures and implications for sudden unexpected death in epilepsy. J. Clin. Neurophysiol. 32, 10–13 (2015).

    Article  PubMed  Google Scholar 

  132. Nass, R. D., Zur, B., Elger, C. E., Holdenrieder, S. & Surges, R. Acute metabolic effects of tonic‐clonic seizures. Epilepsia Open. 4, 599–608 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Fisher, R. S. & Schachter, S. C. The postictal state: a neglected entity in the management of epilepsy. Epilepsy Behav. 1, 52–59 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Kohling, R. et al. Differential sensitivity to induction of spreading depression by partial disinhibition in chronically epileptic human and rat as compared to native rat neocortical tissue. Brain Res. 975, 129–134 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Tozzi, A. et al. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc. Natl Acad. Sci. U S A 109, 18985–18990 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Raimondo, J. V., Burman, R. J., Katz, A. A. & Akerman, C. J. Ion dynamics during seizures. Front. Cell Neurosci. 9, 419 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Barbarosie, M., Louvel, J., Kurcewicz, I. & Avoli, M. CA3-released entorhinal seizures disclose dentate gyrus epileptogenicity and unmask a temporoammonic pathway. J. Neurophysiol. 83, 1115–1124 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Farrell, J. S. et al. Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent. eLife 5, e19352 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Weinand, M. E. et al. Cerebral blood flow and temporal lobe epileptogenicity. J. Neurosurg. 86, 226–232 (1997).

    Article  CAS  PubMed  Google Scholar 

  140. Phillips, T. J., Gom, R. C., Wolff, M. D. & Teskey, G. C. Caffeine exacerbates postictal hypoxia. Neuroscience 422, 32–43 (2019).

    Article  CAS  PubMed  Google Scholar 

  141. Arngrim, N. et al. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain 139, 723–737 (2016).

    Article  PubMed  Google Scholar 

  142. Myers, K. A., Johnstone, D. L. & Dyment, D. A. Epilepsy genetics: current knowledge, applications, and future directions. Clin. Genet. 95, 95–111 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Noebels, J. L. Single-gene models of epilepsy. Adv. Neurol. 79, 227–238 (1999).

    CAS  PubMed  Google Scholar 

  144. Dedei Daryan, M. et al. Prevalence and clinical characteristics of headache in juvenile myoclonic epilepsy: experience from a tertiary epilepsy center. Neurol. Sci. 39, 519–525 (2018).

    Article  PubMed  Google Scholar 

  145. Prontera, P. et al. Epilepsy in hemiplegic migraine: genetic mutations and clinical implications. Cephalalgia 38, 361–373 (2018).

    Article  CAS  PubMed  Google Scholar 

  146. Haan, J., van den Maagdenberg, A. M., Brouwer, O. F. & Ferrari, M. D. Migraine and epilepsy: genetically linked? Expert. Rev. Neurother. 8, 1307–1311 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  148. Ophoff, R. 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).

    Article  CAS  PubMed  Google Scholar 

  149. De Fusco, M. 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).

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  151. Vanmolkot, K. R. 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).

    Article  CAS  PubMed  Google Scholar 

  152. Stam, A. H. et al. Early seizures and cerebral oedema after trivial head trauma associated with the CACNA1A S218L mutation. J. Neurol. Neurosurg. Psychiatry 80, 1125–1129 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. Chirchiglia, D. et al. Hemiplegic migraine and late-onset photosensitive epileptic seizures. Neurol. Sci. 37, 2009–2011 (2016).

    Article  PubMed  Google Scholar 

  154. Castro, M. J. et al. First mutation in the voltage-gated Nav1.1 subunit gene SCN1A with co-occurring familial hemiplegic migraine and epilepsy. Cephalalgia 29, 308–313 (2009).

    Article  PubMed  Google Scholar 

  155. Chen, S. P., Tolner, E. A. & Eikermann-Haerter, K. Animal models of monogenic migraine. Cephalalgia 36, 704–721 (2016).

    Article  PubMed  Google Scholar 

  156. 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).

    Article  CAS  PubMed  Google Scholar 

  157. Bianchin, M. M., Londero, R. G., Lima, J. E. & Bigal, M. E. Migraine and epilepsy: a focus on overlapping clinical, pathophysiological, molecular, and therapeutic aspects. Curr. Pain. Headache Rep. 14, 276–283 (2010).

    Article  PubMed  Google Scholar 

  158. Rogawski, M. A. Migraine and epilepsy — shared mechanisms within the family of episodic disorders. in Jasper’s Basic Mechanisms of the Epilepsies (eds. Noebels, J. L., Avoli, M., Rogawski, M. A., Olsen, R. W. & Delgado-Escueta, A. V.) (National Center for Biotechnology Information, 2012).

  159. 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 

  160. van den Maagdenberg, A. M. J. M. et al. High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann. Neurol. 67, 85–98 (2010).

    Article  PubMed  CAS  Google Scholar 

  161. Vecchia, D., Tottene, A., van den Maagdenberg, A. M. & Pietrobon, D. Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice. Neurobiol. Dis. 69, 225–234 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Vecchia, D., Tottene, A., van den Maagdenberg, A. M. & Pietrobon, D. Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans. Front. Cell Neurosci. 9, 8 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Bertelli, S., Barbieri, R., Pusch, M. & Gavazzo, P. Gain of function of sporadic/familial hemiplegic migraine-causing SCN1A mutations: use of an optimized cDNA. Cephalalgia 39, 477–488 (2019).

    Article  PubMed  Google Scholar 

  165. Yu, F. H. et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat. Neurosci. 9, 1142–1149 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Wei, Y., Ullah, G. & Schiff, S. J. Unification of neuronal spikes, seizures, and spreading depression. J. Neurosci. 34, 11733–11743 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Riant, F. et al. De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology 75, 967–972 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Meneret, A. et al. PRRT2 mutations and paroxysmal disorders. Eur. J. Neurol. 20, 872–878 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Jen, J. C., Wan, J., Palos, T. P., Howard, B. D. & Baloh, R. W. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 65, 529–534 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Tzoulis, C. et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 129, 1685–1692 (2006).

    Article  PubMed  Google Scholar 

  171. Lonnqvist, T., Paetau, A., Valanne, L. & Pihko, H. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 132, 1553–1562 (2009).

    Article  PubMed  Google Scholar 

  172. Kuwajima, M. et al. MELAS syndrome with m.4450 G > A mutation in mitochondrial tRNAMet gene. Brain Dev. 41, 465–469 (2019).

    Article  PubMed  Google Scholar 

  173. El-Hattab, A. W., Adesina, A. M., Jones, J. & Scaglia, F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol. Genet. Metab. 116, 4–12 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Winawer, M. R. & Connors, R., EPGP Investigators. Evidence for a shared genetic susceptibility to migraine and epilepsy. Epilepsia 54, 288–295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed Central  CAS  Google Scholar 

  176. Zaccara, G. & Perucca, E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord. 16, 409–431 (2014).

    Article  PubMed  Google Scholar 

  177. Patsalos, P. N. & Perucca, E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2, 473–481 (2003).

    Article  CAS  PubMed  Google Scholar 

  178. Marmura, M. J. & Kumpinsky, A. S. Refining the benefit/risk profile of anti-epileptic drugs in headache disorders. CNS Drugs 32, 735–746 (2018).

    Article  PubMed  Google Scholar 

  179. European Medicines Agency. Valproate and related substances. https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0 (2018).

  180. European Medicines Agency. Topamax. European Medicines Agency https://www.ema.europa.eu/en/medicines/human/referrals/topamax (2009).

  181. Tomson, T. et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia 56, 1006–1019 (2015).

    Article  CAS  PubMed  Google Scholar 

  182. Hernandez-Diaz, S. et al. Topiramate use early in pregnancy and the risk of oral clefts. Neurology 90, e342–e351 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Vatzaki, E. et al. Latest clinical recommendations on valproate use for migraine prophylaxis in women of childbearing age: overview from European Medicines Agency and European Headache Federation. J. Headache Pain. 19, 68 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Buch, D. & Chabriat, H. Lamotrigine in the prevention of migraine with aura: a narrative review. Headache 59, 1187–1197 (2019).

    Article  PubMed  Google Scholar 

  185. Nevitt, S., Sudell, M., Weston, J., Tudur Smith, C. & Marson, A. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst. Rev. 6, CD011412 (2017).

    PubMed  Google Scholar 

  186. Romoli, M. et al. Antiepileptic drugs in migraine and epilepsy: who is at increased risk of adverse events? Cephalalgia 38, 274–282 (2018).

    Article  PubMed  Google Scholar 

  187. Jobst, B. C. & Cascino, G. D. Resective epilepsy surgery for drug-resistant focal epilepsy. JAMA 313, 285–293 (2015).

    Article  PubMed  Google Scholar 

  188. Kaur, A., Selwa, L., Fromes, G. & Ross, D. A. Persistent headache after supratentorial craniotomy. Neurosurgery 47, 633–636 (2000).

    CAS  PubMed  Google Scholar 

  189. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Haanes, K. A. & Edvinsson, L. Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs 33, 525–537 (2019).

    Article  CAS  PubMed  Google Scholar 

  191. 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).

    Article  CAS  PubMed  Google Scholar 

  192. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  194. Deng, P.-Y. & Li, Y.-J. Calcitonin gene-related peptide and hypertension. Peptides 26, 1676–1685 (2005).

    Article  CAS  PubMed  Google Scholar 

  195. Deen, M. et al. Blocking CGRP in migraine patients – a review of pros and cons. J. Headache Pain. 18, 1–9 (2017).

    Article  CAS  Google Scholar 

  196. Tringali, G., Currò, D. & Navarra, P. Perampanel inhibits calcitonin gene-related peptide release from rat brainstem in vitro. J. Headache Pain 19, 107 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Gupta, S. How Medical Marijuana Changed Charlotte Figi’s Daily Life. CNN https://edition.cnn.com/videos/bestoftv/2014/08/01/robin-hoods-of-marijuana.cnn (2014).

  198. Kollewe, J. Cannabis-based drug for childhood epilepsy approved for use in UK. The Guardian https://www.theguardian.com/business/2019/sep/23/cannabis-based-drug-for-childhood-epilepsy-epidyolex-approved-for-use-in-uk (2019).

  199. Velasquez-Manoff, M. Can CBD really do all that? How one molecule from the cannabis plant came to be seen as a therapeutic cure-all. The New York Times Magazine https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html (2019).

  200. Maa, E. & Figi, P. The case for medical marijuana in epilepsy. Epilepsia 55, 783–786 (2014).

    Article  PubMed  Google Scholar 

  201. Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 376, 2011–2020 (2017).

    Article  CAS  PubMed  Google Scholar 

  202. Devinsky, O. et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 90, e1204–e1211 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Devinsky, O. et al. Long‐term cannabidiol treatment in patients with Dravet syndrome: an open‐label extension trial. Epilepsia 60, 294–302 (2019).

    Article  CAS  PubMed  Google Scholar 

  204. Thiele, E. et al. Cannabidiol in patients with Lennox–Gastaut syndrome: interim analysis of an open-label extension study. Epilepsia 60, 419–428 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Devinsky, O. et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N. Engl. J. Med. 378, 1888–1897 (2018).

    Article  CAS  PubMed  Google Scholar 

  206. O’Connell, B. K., Gloss, D. & Devinsky, O. Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav. 70, 341–348 (2017).

    Article  PubMed  Google Scholar 

  207. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03676049 (2020).

  208. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03196934 (2019).

  209. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02397863 (2015).

  210. Food and Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. FDA https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms (2018).

  211. European Medicines Agency. Epidyolex. European Medicines Agency https://www.ema.europa.eu/en/medicines/human/EPAR/epidyolex (2021).

  212. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04360044 (2021).

  213. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03972124 (2021).

  214. Cooper, Y. A. et al. Repetitive transcranial magnetic stimulation for the treatment of drug-resistant epilepsy: a systematic review and individual participant data meta-analysis of real-world evidence. Epilepsia Open 3, 55–65 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Stilling, J. M., Monchi, O., Amoozegar, F. & Debert, C. T. Transcranial magnetic and direct current stimulation (TMS/tDCS) for the treatment of headache: a systematic review. Headache 59, 339–357 (2019).

    Article  PubMed  Google Scholar 

  216. 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).

    Article  PubMed  Google Scholar 

  217. Starling, A. J. et al. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE study). Cephalalgia 38, 1038–1048 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Lan, L., Zhang, X., Li, X., Rong, X. & Peng, Y. The efficacy of transcranial magnetic stimulation on migraine: a meta-analysis of randomized controlled trails. J. Headache Pain 18, 86 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Food and Drug Administration. Transcranial Magnetic Stimulator AC Adapter. 510(k) Notification K140094. accessdata.fda.gov https://www.accessdata.fda.gov/cdrh_docs/pdf14/K140094.pdf (2014).

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  223. Tassorelli, C. et al. Noninvasive vagus nerve stimulation as acute therapy for migraine. Neurology 91, e364–e373 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  225. Aihua, L. et al. A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy. Epilepsy Behav. 39, 105–110 (2014).

    Article  PubMed  Google Scholar 

  226. Rong, P. et al. Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin. Sci. https://doi.org/10.1042/CS20130518 (2014).

    Article  Google Scholar 

  227. Bauer, S. et al. Transcutaneous vagus nerve stimulation (tVNS) for treatment of drug-resistant epilepsy: a randomized, double-blind clinical trial (cMPsE02). Brain Stimul. 9, 356–363 (2016).

    Article  CAS  PubMed  Google Scholar 

  228. Lee, H. J., Lee, J. H., Cho, E. Y., Kim, S. M. & Yoon, S. Efficacy of psychological treatment for headache disorder: a systematic review and meta-analysis. J. Headache Pain. 20, 17 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Probyn, K. et al. Non-pharmacological self-management for people living with migraine or tension-type headache: a systematic review including analysis of intervention components. BMJ Open 7, 1–12 (2017).

    Article  Google Scholar 

  230. Simshäuser, K., Lüking, M., Kaube, H., Schultz, C. & Schmidt, S. Is mindfulness-based stress reduction a promising and feasible intervention for patients suffering from migraine? A randomized controlled pilot trial. Complement. Med. Res. 27, 19–30 (2020).

    Article  PubMed  Google Scholar 

  231. Seng, E. K. et al. Does mindfulness‐based cognitive therapy for migraine reduce migraine‐related disability in people with episodic and chronic migraine? A phase 2b pilot randomized clinical trial. Headache 59, 1448–1467 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Wells, R. E., Beuthin, J. & Granetzke, L. Complementary and integrative medicine for episodic migraine: an update of evidence from the last 3 years. Curr. Pain. Headache Rep. 23, 10 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Michaelis, R. et al. Psychological treatments for adults and children with epilepsy: evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia 59, 1282–1302 (2018).

    Article  PubMed  Google Scholar 

  234. Haut, S. R. et al. Behavioral interventions as a treatment for epilepsy. Neurology 90, e963–e970 (2018).

    Article  PubMed  Google Scholar 

  235. Hesdorffer, D. C. Comorbidity between neurological illness and psychiatric disorders. CNS Spectr. 21, 230–238 (2016).

    Article  PubMed  Google Scholar 

  236. Boison, D. & Aronica, E. Comorbidities in neurology: is adenosine the common link? Neuropharmacology 97, 18–34 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Kros, L., Lykke-Hartmann, K. & Khodakhah, K. Increased susceptibility to cortical spreading depression and epileptiform activity in a mouse model for FHM2. Sci. Rep. 8, 16959 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Jackson, H. Hospital for the epileptic and paralysed: case illustrating the relation betwixt certain cases of migraine and epilepsy. Lancet 106, 244–245 (1875).

    Article  Google Scholar 

  239. Gowers, W. R. Clinical lectures on the borderland of epilepsy. III–Migraine. Br. Med. J. 2, 1617–1622 (1906).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Lennox W. G., Lennox M. A. Epilepsy and Related Disorders (Little, Brown and Company, 1960).

  241. Laplante, P., Saint-Hilaire, J. M. & Bouvier, G. Headache as an epileptic manifestation. Neurology 33, 1493–1493 (1983).

    Article  CAS  PubMed  Google Scholar 

  242. Andermann, F. Migraine-epilepsy relationships. Epilepsy Res. l, 213–226 (1987).

    Article  Google Scholar 

  243. Schon, F. & Blau, J. N. Post-epileptic headache and migraine. J. Neurol. Neurosurg. Psychiatry. 50, 1148–1152 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Hablitz, J. J. & Heinemann, U. Alterations in the microenvironment during spreading depression associated with epileptiform activity in the immature neocortex. Brain Res. Dev. Brain Res. 46, 243–252 (1989).

    Article  CAS  PubMed  Google Scholar 

  245. Ottman, R. & Lipton, R. B. Comorbidity of migraine and epilepsy. Neurology 44, 2105–2110 (1994).

    Article  CAS  PubMed  Google Scholar 

  246. Herreras, O., Largo, C., Ibarz, J. M., Somjen, G. G. & Martín del Río, R. Role of neuronal synchronizing mechanisms in the propagation of spreading depression in the in vivo hippocampus. J. Neurosci. 14, 7087–7098 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Panayiotopoulos, C. P. Visual phenomena and headache in occipital epilepsy: a review, a systematic study and differentiation from migraine. Epileptic Disord. 1, 205–216 (1999).

    CAS  PubMed  Google Scholar 

  248. Gorji, A. et al. Spreading depression in human neocortical slices. Brain Res. 6, 74–83 (2001).

    Article  Google Scholar 

  249. Leniger, T., von den Driesch, S., Isbruch, K., Diener, H. C. & Hufnagel, A. Clinical characteristics of patients with comorbidity of migraine and epilepsy. Headache 43, 672–677 (2003).

    Article  PubMed  Google Scholar 

  250. Rogawski, M. A. & Löscher, W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat. Med. 10, 685–692 (2004).

    Article  CAS  PubMed  Google Scholar 

  251. Welch, K. M. Brain hyperexcitability: the basis for antiepileptic drugs in migraine prevention. Headache 45, S25–S32 (2005).

    Article  PubMed  Google Scholar 

  252. Haut, S. R., Bigal, M. E. & Lipton, R. B. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol. 5, 148–157 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Cai, S., Hamiwka, L. D. & Wirrell, E. C. Peri-ictal headache in children: prevalence and character. Pediatr. Neurol. 39, 91–96 (2008).

    Article  PubMed  Google Scholar 

  254. Somjen, G. G. Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol. Rev. 81, 1065–1096 (2001).

    Article  CAS  PubMed  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 (2011).

    Article  PubMed  Google Scholar 

  256. Enger, R. et al. Dynamics of ionic shifts in cortical spreading depression. Cereb. Cortex 25, 4469–4476 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  257. Kramer, D. R., Fujii, T., Ohiorhenuan, I. & Liu, C. Y. Interplay between cortical spreading depolarization and seizures. Stereotact. Funct. Neurosurg. 95, 1–5 (2017).

    Article  PubMed  Google Scholar 

  258. So, N. K. & Blume, W. T. The postictal EEG. Epilepsy Behav. 19, 121–126 (2010).

    Article  PubMed  Google Scholar 

  259. Lhatoo, S. D. et al. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann. Neurol. 68, 787–796 (2010).

    Article  PubMed  Google Scholar 

  260. Surges, R., Strzelczyk, A., Scott, C. A., Walker, M. C. & Sander, J. W. Postictal generalized electroencephalographic suppression is associated with generalized seizures. Epilepsy Behav. 21, 271–274 (2011).

    Article  PubMed  Google Scholar 

  261. Sarkis, R. A. et al. Autonomic changes following generalized tonic clonic seizures: an analysis of adult and pediatric patients with epilepsy. Epilepsy Res. 115, 113–118 (2015).

    Article  PubMed  Google Scholar 

  262. Bolay, H. et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8, 136–142 (2002).

    Article  CAS  PubMed  Google Scholar 

  263. Dreier, J. P. & Reiffurth, C. The stroke-migraine depolarization continuum. Neuron 86, 902–922 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

P.R.B. is funded by the Berta Ottenstein program of the University of Freiburg, Germany. This work was partly undertaken at NIHR University College London Hospitals Comprehensive Bio-Medical Research Centre, which received a proportion of funding from the Department of Health’s Research Centres funding scheme. M.D.F. receives research support from the Lifetime Scientific Achievement Spinoza Award from the Netherlands Organisation for Scientific Research (NWO). E.A.T. receives research support from a grant from the Netherlands Organisation for Scientific Research (NWO-ZonMW, project “Brain@home”). J.W.S. receives research support from the Dr. Marvin Weil Epilepsy Research Fund and the UK Epilepsy Society.

Author information

Authors and Affiliations

  1. Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany

    Prisca R. Bauer

  2. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

    Else A. Tolner & Michel D. Ferrari

  3. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands

    Else A. Tolner

  4. Research Centre of the Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada

    Mark R. Keezer

  5. School of Public Health, Université de Montréal, Montreal, Quebec, Canada

    Mark R. Keezer

  6. Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands

    Mark R. Keezer & Josemir W. Sander

  7. NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London, UK

    Josemir W. Sander

  8. Chalfont Centre for Epilepsy, Chalfont St Peter, UK

    Josemir W. Sander

Authors
  1. Prisca R. Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Else A. Tolner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark R. Keezer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michel D. Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Josemir W. Sander
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

P.R.B., E.A.T and M.R.K. researched data for the article, made a substantial contribution to the discussion of article content, wrote the article, and reviewed and/or edited the manuscript before submission. M.D.F. and J.W.S. made a substantial contribution to the discussion of article content, wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Prisca R. Bauer.

Ethics declarations

Competing interests

J.W.S. received consultancies from UCB and Arvelle; grants from UCB; and payment for serving on speakers’ bureaus from Eisai, UCB, Novartis, GW and Zogenix. M.R.K. received unrestricted educational grants from UCB; and research grants from UCB and Eisai. P.R.B. has received speaker fees from Novocure. The other authors declare no competing interests.

Additional information

Informed consent

The authors affirm that human research participants provided informed consent for publication of the video in Supplementary Video 1.

Peer review information

Nature Reviews Neurology thanks V. Belcastro, P. Parisi, S. Rheims 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.

Review criteria

We searched PubMed for articles with the MeSH terms and keywords ‘headache’, ‘migraine’, ‘epilepsy’ and ‘treatment’ in the title, abstract or keywords. The search focused on primary studies published in the past 5 years (April 2015–April 2020). Additional articles were identified from the authors’ own files and from chosen bibliographies. The articles in this Review were included at the authors’ discretion on the basis of originality and relevance. Selected key works from before 2015 are shown in Fig. 1.

Supplementary information

Supplementary video 1

Video-EEG recording of an individual with ictal epileptic headache

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bauer, P.R., Tolner, E.A., Keezer, M.R. et al. Headache in people with epilepsy. Nat Rev Neurol 17, 529–544 (2021). https://doi.org/10.1038/s41582-021-00516-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-021-00516-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing