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.
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
Open Access articles citing this article.
The Journal of Headache and Pain Open Access 21 July 2023
Global, regional, and national time trends in incidence for migraine, from 1990 to 2019: an age-period-cohort analysis for the GBD 2019
The Journal of Headache and Pain Open Access 01 July 2023
The Journal of Headache and Pain Open Access 25 May 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Fisher, R. S. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55, 475–482 (2014).
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).
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).
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).
[No authors listed]. Headache Classification Committee of the International Headache Society (IHS): International Classification of Headache Disorders 3rd edn. Cephalalgia 38, 1–211 (2018).
Goadsby, P. J. Pathophysiology of migraine. Neurol. Clin. 27, 335–360 (2009).
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).
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).
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).
Çilliler, A. E., Güven, H. & Çomoğlu, S. S. Epilepsy and headaches: further evidence of a link. Epilepsy Behav. 70, 161–165 (2017).
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).
Mutlu, A. Association between epilepsy and headache. Neurol. Sci. 39, 2129–2134 (2018).
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).
Whealy, M. A., Myburgh, A., Bredesen, T. J. & Britton, J. W. Headache in epilepsy: a prospective observational study. Epilepsia Open. 4, 593–598 (2019).
Kim, D. W., Sunwoo, J. S. & Lee, S. K. Headache as an aura of epilepsy: Video-EEG Monitoring Study. Headache 56, 762–768 (2016).
Begasse de Dhaem, O. A. J. et al. Migraine comorbidity and cognitive performance in patients with focal epilepsy. Epilepsy Behav. 97, 29–33 (2019).
Salma, Z. et al. Headaches and their relationships to epileptic seizures. Epilepsy Behav. 90, 233–237 (2019).
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).
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).
Belcastro, V., Striano, P. & Parisi, P. “Ictal epileptic headache”: beyond the epidemiological evidence. Epilepsy Behav. 25, 9–10 (2012).
Wang, X. Q. et al. Comorbidity between headache and epilepsy in a Chinese epileptic center. Epilepsy Res. 108, 535–541 (2014).
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).
Dugan, P. et al. Auras in generalized epilepsy. Neurology 83, 1444–1449 (2014).
Delgado-Rodriguez, M. & Llorca, J. Bias. J. Epidemiol. Community Health. 58, 635–641 (2004).
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).
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).
Parisi, P. et al. Diagnostic criteria currently proposed for ‘ictal epileptic headache’: perspectives on strengths, weaknesses and pitfalls. Seizure 31, 56–63 (2015).
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).
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).
Leniger, T., Isbruch, K., Von Den Driesch, S., Diener, H. C. & Hufnagel, A. Seizure-associated headache in epilepsy. Epilepsia 42, 1176–1179 (2002).
Yankovsky, A. E., Andermann, F. & Bernasconi, A. Characteristics of headache associated with intractable partial epilepsy. Epilepsia 46, 1241–1245 (2005).
Förderreuther, S., Henkel, A., Noachtar, S. & Straube, A. Headache associated with epileptic seizures: epidemiology and clinical characteristics. Headache 42, 649–655 (2002).
Karaali-Savrun, F., Göksan, B., Naz Yeni, S., Ertan, S. & Uzun, N. Seizure-related headache in patients with epilepsy. Seizure 11, 67–69 (2002).
Mainieri, G. et al. Headache in epilepsy: prevalence and clinical features. J. Headache Pain. 16, 556 (2015).
Mameniškienė, R., Karmonaitė, I. & Zagorskis, R. The burden of headache in people with epilepsy. Seizure 41, 120–126 (2016).
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).
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).
de Tommaso, M. An update on EEG in migraine. Expert. Rev. Neurother. 19, 729–737 (2019).
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).
Sand, T. EEG in migraine: a review of the literature. Funct. Neurol. 6, 7–22 (1991).
Sand, T. Electroencephalography in migraine: a review with focus on quantitative electroencephalography and the migraine vs. epilepsy relationship. Cephalalgia 23, 5–11 (2003).
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).
Adcock, J. E. & Panayiotopoulos, C. P. Occipital lobe seizures and epilepsies. J. Clin. Neurophysiol. 29, 397–407 (2012).
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).
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).
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).
Verrotti, A. et al. Migralepsy and related conditions: advances in pathophysiology and classification. Seizure 20, 271–275 (2011).
Hartl, E., Rémi, J. & Noachtar, S. Two patients with visual aura – migraine, epilepsy, or migralepsy? Headache 55, 1148–1151 (2015).
Wang, X. Q. et al. High prevalence of headaches in patients with epilepsy. J. Headache Pain. 15, 70 (2014).
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).
Parisi, P. et al. ‘Ictal epileptic headache’: recent concepts for new classifications criteria. Cephalalgia 32, 723–724 (2012).
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).
Cianchetti, C., Dainese, F., Ledda, M. G. & Avanzini, G. Epileptic headache: a rare form of painful seizure. Seizure 52, 169–175 (2017).
Parisi, P. et al. Ictal epileptic headache: when terminology is not a moot question. Front. Neurol. 10, 785 (2019).
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).
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).
Fanella, M. et al. Ictal epileptic headache in adult life: electroclinical patterns and spectrum of related syndromes. Epilepsy Behav. 53, 161–165 (2015).
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).
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).
Nye, B. L. & Thadani, V. M. Migraine and epilepsy: review of the literature. Headache 55, 359–380 (2015).
Bauer, P. R. et al. Headache and epilepsy. Curr. Pain. Headache Rep. 17, 351–360 (2013).
Parisi, P. et al. Hypothesis on neurophysiopathological mechanisms linking epilepsy and headache. Med. Hypotheses 70, 1150–1154 (2008).
Jefferys, J. G. R. Advances in understanding basic mechanisms of epilepsy and seizures. Seizure 19, 638–646 (2010).
Staley, K. Molecular mechanisms of epilepsy. Nat. Neurosci. 18, 367–372 (2015).
Janigro, D. & Walker, M. C. What non-neuronal mechanisms should be studied to understand epileptic seizures? Adv. Exp. Med. Biol. 813, 253–264 (2014).
Spillane, J., Kullmann, D. M. & Hanna, M. G. Genetic neurological channelopathies: molecular genetics and clinical phenotypes. J. Neurol. Neurosurg. Psychiatry 87, 37–48 (2016).
Whittaker, R. G. et al. Epilepsy in adults with mitochondrial disease: a cohort study. Ann. Neurol. 78, 949–957 (2015).
Boison, D. & Steinhäuser, C. Epilepsy and astrocyte energy metabolism. Glia 66, 1235–1243 (2018).
Kovács, R. et al. Bioenergetic mechanisms of seizure control. Front. Cell. Neurosci. 12, 335 (2018).
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).
Magis, D. et al. Pearls and pitfalls: electrophysiology for primary headaches. Cephalalgia 33, 526–539 (2013).
Tolner, E. A., Chen, S. P. & Eikermann-Haerter, K. Current understanding of cortical structure and function in migraine. Cephalalgia 39, 1683–1699 (2019).
Burstein, R., Noseda, R. & Borsook, D. Migraine: multiple processes, complex pathophysiology. J. Neurosci. 35, 6619–6629 (2015).
Goadsby, P. J. et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol. Rev. 97, 553–622 (2017).
Romero-Reyes, M. & Akerman, S. Update on animal models of migraine. Curr. Pain. Headache Rep. 18, 462 (2014).
Brennan, K. C. & Pietrobon, D. A systems neuroscience approach to migraine. Neuron 97, 1004–1021 (2018).
Zhang, X. et al. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J. Neurosci. 30, 8807–8814 (2010).
Zhang, X. et al. Activation of central trigeminovascular neurons by cortical spreading depression. Ann. Neurol. 69, 855–865 (2011).
Karatas, H. et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339, 1092–1095 (2013).
Schain, A. J. et al. Activation of pial and dural macrophages and dendritic cells by cortical spreading depression. Ann. Neurol. 83, 508–521 (2018).
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).
Mason, B. N. & Russo, A. F. Vascular contributions to migraine: time to revisit? Front. Cell Neurosci. 12, 233 (2018).
Schwedt, T. J., Chiang, C. C., Chong, C. D. & Dodick, D. W. Functional MRI of migraine. Lancet Neurol. 14, 81–91 (2015).
Schulte, L. H. & May, A. Of generators, networks and migraine attacks. Curr. Opin. Neurol. 30, 241–245 (2017).
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).
Skorobogatykh, K. et al. Functional connectivity studies in migraine: what have we learned? J. Headache Pain. 20, 108 (2019).
Coppola, G. et al. Resting state connectivity between default mode network and insula encodes acute migraine headache. Cephalalgia 38, 846–854 (2018).
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).
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).
Vecchia, D. & Pietrobon, D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends Neurosci. 35, 507–520 (2012).
Myers, C. T. & Mefford, H. C. Advancing epilepsy genetics in the genomic era. Genome Med. 7, 91 (2015).
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).
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).
Borsook, D. et al. Sex and the migraine brain. Neurobiol. Dis. 68, 200–214 (2014).
Lipton, R. B. et al. Reduction in perceived stress as a migraine trigger: testing the ‘let-down headache’ hypothesis. Neurology 82, 1395–1401 (2014).
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).
Negro, A. et al. Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization. J. Headache Pain. 21, 86 (2020).
Kilic, K. et al. Inadequate brain glycogen or sleep increases spreading depression susceptibility. Ann. Neurol. 83, 61–73 (2018).
Martins-Oliveira, M. et al. Neuroendocrine signaling modulates specific neural networks relevant to migraine. Neurobiol. Dis. 101, 16–26 (2017).
Eikermann-Haerter, K. et al. Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice. J. Neurosci. 31, 5755–5763 (2011).
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).
Vezzani, A. Epilepsy and inflammation in the brain: overview and pathophysiology. Epilepsy Curr. 14, 3–7 (2014).
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).
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).
Nagai, Y. Modulation of autonomic activity in neurological conditions: epilepsy and Tourette syndrome. Front. Neurosci. 9, 278 (2015).
Bartolomei, F. et al. Pre-ictal synchronicity in limbic networks of mesial temporal lobe epilepsy. Epilepsy Res. 61, 89–104 (2004).
Krüger, H. et al. Repetitive spreading depression causes selective suppression of GABAergic function. Neuroreport 7, 2733–2736 (1996).
Gorji, A. & Speckmann, E. J. Spreading depression enhances the spontaneous epileptiform activity in human neocortical tissues. Eur. J. Neurosci. 19, 3371–3374 (2004).
Berger, M., Speckmann, E. J., Pape, H. C. & Gorji, A. Spreading depression enhances human neocortical excitability in vitro. Cephalalgia 28, 558–562 (2008).
Eickhoff, M. et al. Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues. Exp. Neurol. 253, 1–15 (2014).
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).
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).
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).
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).
Montavont, A. et al. On the origin of painful somatosensory seizures. Neurology 84, 594–601 (2015).
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).
Khan, S. et al. Meningeal contribution to migraine pain: a magnetic resonance angiography study. Brain 142, 93–102 (2019).
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).
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).
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).
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).
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).
Dreier, J. P. et al. Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain 135, 259–275 (2012).
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).
Kandel, E. R. & Spencer, W. A. Excitation and inhibition of single pyramidal cells during hippocampal seizure. Exp. Neurol. 4, 162–179 (1961).
Bauer, P. R. et al. Dynamics of convulsive seizure termination and postictal generalized EEG suppression. Brain 140, 655–668 (2017).
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).
Boison, D. Adenosine and seizure termination: endogenous mechanisms. Epilepsy Curr. 13, 35–37 (2013).
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).
During, M. J. & Spencer, D. D. Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Ann. Neurol. 32, 618–624 (1992).
Kennedy, J. D. & Seyal, M. Respiratory pathophysiology with seizures and implications for sudden unexpected death in epilepsy. J. Clin. Neurophysiol. 32, 10–13 (2015).
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).
Fisher, R. S. & Schachter, S. C. The postictal state: a neglected entity in the management of epilepsy. Epilepsy Behav. 1, 52–59 (2000).
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).
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).
Raimondo, J. V., Burman, R. J., Katz, A. A. & Akerman, C. J. Ion dynamics during seizures. Front. Cell Neurosci. 9, 419 (2015).
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).
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).
Weinand, M. E. et al. Cerebral blood flow and temporal lobe epileptogenicity. J. Neurosurg. 86, 226–232 (1997).
Phillips, T. J., Gom, R. C., Wolff, M. D. & Teskey, G. C. Caffeine exacerbates postictal hypoxia. Neuroscience 422, 32–43 (2019).
Arngrim, N. et al. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain 139, 723–737 (2016).
Myers, K. A., Johnstone, D. L. & Dyment, D. A. Epilepsy genetics: current knowledge, applications, and future directions. Clin. Genet. 95, 95–111 (2019).
Noebels, J. L. Single-gene models of epilepsy. Adv. Neurol. 79, 227–238 (1999).
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).
Prontera, P. et al. Epilepsy in hemiplegic migraine: genetic mutations and clinical implications. Cephalalgia 38, 361–373 (2018).
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).
Pelzer, N. et al. Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation. Neurology 90, e575–e582 (2018).
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).
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).
Dichgans, M. et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366, 371–377 (2005).
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).
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).
Chirchiglia, D. et al. Hemiplegic migraine and late-onset photosensitive epileptic seizures. Neurol. Sci. 37, 2009–2011 (2016).
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).
Chen, S. P., Tolner, E. A. & Eikermann-Haerter, K. Animal models of monogenic migraine. Cephalalgia 36, 704–721 (2016).
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).
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).
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).
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).
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).
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).
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).
Kahlig, K. M. et al. Divergent sodium channel defects in familial hemiplegic migraine. Proc. Natl Acad. Sci. USA 105, 9799–9804 (2008).
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).
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).
Wei, Y., Ullah, G. & Schiff, S. J. Unification of neuronal spikes, seizures, and spreading depression. J. Neurosci. 34, 11733–11743 (2014).
Riant, F. et al. De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology 75, 967–972 (2010).
Meneret, A. et al. PRRT2 mutations and paroxysmal disorders. Eur. J. Neurol. 20, 872–878 (2013).
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).
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).
Lonnqvist, T., Paetau, A., Valanne, L. & Pihko, H. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 132, 1553–1562 (2009).
Kuwajima, M. et al. MELAS syndrome with m.4450 G > A mutation in mitochondrial tRNAMet gene. Brain Dev. 41, 465–469 (2019).
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).
Winawer, M. R. & Connors, R., EPGP Investigators. Evidence for a shared genetic susceptibility to migraine and epilepsy. Epilepsia 54, 288–295 (2013).
The Brainstorm Consortium. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018).
Zaccara, G. & Perucca, E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord. 16, 409–431 (2014).
Patsalos, P. N. & Perucca, E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2, 473–481 (2003).
Marmura, M. J. & Kumpinsky, A. S. Refining the benefit/risk profile of anti-epileptic drugs in headache disorders. CNS Drugs 32, 735–746 (2018).
European Medicines Agency. Valproate and related substances. https://www.ema.europa.eu/en/medicines/human/referrals/valproate-related-substances-0 (2018).
European Medicines Agency. Topamax. European Medicines Agency https://www.ema.europa.eu/en/medicines/human/referrals/topamax (2009).
Tomson, T. et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia 56, 1006–1019 (2015).
Hernandez-Diaz, S. et al. Topiramate use early in pregnancy and the risk of oral clefts. Neurology 90, e342–e351 (2018).
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).
Buch, D. & Chabriat, H. Lamotrigine in the prevention of migraine with aura: a narrative review. Headache 59, 1187–1197 (2019).
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).
Romoli, M. et al. Antiepileptic drugs in migraine and epilepsy: who is at increased risk of adverse events? Cephalalgia 38, 274–282 (2018).
Jobst, B. C. & Cascino, G. D. Resective epilepsy surgery for drug-resistant focal epilepsy. JAMA 313, 285–293 (2015).
Kaur, A., Selwa, L., Fromes, G. & Ross, D. A. Persistent headache after supratentorial craniotomy. Neurosurgery 47, 633–636 (2000).
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).
Haanes, K. A. & Edvinsson, L. Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs 33, 525–537 (2019).
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).
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).
Charles, A. & Pozo-Rosich, P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet 394, 1765–1774 (2019).
Deng, P.-Y. & Li, Y.-J. Calcitonin gene-related peptide and hypertension. Peptides 26, 1676–1685 (2005).
Deen, M. et al. Blocking CGRP in migraine patients – a review of pros and cons. J. Headache Pain. 18, 1–9 (2017).
Tringali, G., Currò, D. & Navarra, P. Perampanel inhibits calcitonin gene-related peptide release from rat brainstem in vitro. J. Headache Pain 19, 107 (2018).
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).
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).
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).
Maa, E. & Figi, P. The case for medical marijuana in epilepsy. Epilepsia 55, 783–786 (2014).
Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 376, 2011–2020 (2017).
Devinsky, O. et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 90, e1204–e1211 (2018).
Devinsky, O. et al. Long‐term cannabidiol treatment in patients with Dravet syndrome: an open‐label extension trial. Epilepsia 60, 294–302 (2019).
Thiele, E. et al. Cannabidiol in patients with Lennox–Gastaut syndrome: interim analysis of an open-label extension study. Epilepsia 60, 419–428 (2019).
Devinsky, O. et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N. Engl. J. Med. 378, 1888–1897 (2018).
O’Connell, B. K., Gloss, D. & Devinsky, O. Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav. 70, 341–348 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03676049 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03196934 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02397863 (2015).
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).
European Medicines Agency. Epidyolex. European Medicines Agency https://www.ema.europa.eu/en/medicines/human/EPAR/epidyolex (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04360044 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03972124 (2021).
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).
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).
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).
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).
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).
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).
Andreou, A. P. et al. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain 139, 2002–2014 (2016).
Chou, D. E. et al. Acute migraine therapy with external trigeminal neurostimulation (ACME): a randomized controlled trial. Cephalalgia 39, 3–14 (2019).
Schoenen, J. et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology 80, 697–704 (2013).
Tassorelli, C. et al. Noninvasive vagus nerve stimulation as acute therapy for migraine. Neurology 91, e364–e373 (2018).
Silberstein, S. D. et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation. Neurology 87, 529–538 (2016).
Aihua, L. et al. A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy. Epilepsy Behav. 39, 105–110 (2014).
Rong, P. et al. Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial. Clin. Sci. https://doi.org/10.1042/CS20130518 (2014).
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).
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).
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).
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).
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).
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).
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).
Haut, S. R. et al. Behavioral interventions as a treatment for epilepsy. Neurology 90, e963–e970 (2018).
Hesdorffer, D. C. Comorbidity between neurological illness and psychiatric disorders. CNS Spectr. 21, 230–238 (2016).
Boison, D. & Aronica, E. Comorbidities in neurology: is adenosine the common link? Neuropharmacology 97, 18–34 (2015).
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).
Jackson, H. Hospital for the epileptic and paralysed: case illustrating the relation betwixt certain cases of migraine and epilepsy. Lancet 106, 244–245 (1875).
Gowers, W. R. Clinical lectures on the borderland of epilepsy. III–Migraine. Br. Med. J. 2, 1617–1622 (1906).
Lennox W. G., Lennox M. A. Epilepsy and Related Disorders (Little, Brown and Company, 1960).
Laplante, P., Saint-Hilaire, J. M. & Bouvier, G. Headache as an epileptic manifestation. Neurology 33, 1493–1493 (1983).
Andermann, F. Migraine-epilepsy relationships. Epilepsy Res. l, 213–226 (1987).
Schon, F. & Blau, J. N. Post-epileptic headache and migraine. J. Neurol. Neurosurg. Psychiatry. 50, 1148–1152 (1987).
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).
Ottman, R. & Lipton, R. B. Comorbidity of migraine and epilepsy. Neurology 44, 2105–2110 (1994).
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).
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).
Gorji, A. et al. Spreading depression in human neocortical slices. Brain Res. 6, 74–83 (2001).
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).
Rogawski, M. A. & Löscher, W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat. Med. 10, 685–692 (2004).
Welch, K. M. Brain hyperexcitability: the basis for antiepileptic drugs in migraine prevention. Headache 45, S25–S32 (2005).
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).
Cai, S., Hamiwka, L. D. & Wirrell, E. C. Peri-ictal headache in children: prevalence and character. Pediatr. Neurol. 39, 91–96 (2008).
Somjen, G. G. Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol. Rev. 81, 1065–1096 (2001).
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).
Enger, R. et al. Dynamics of ionic shifts in cortical spreading depression. Cereb. Cortex 25, 4469–4476 (2015).
Kramer, D. R., Fujii, T., Ohiorhenuan, I. & Liu, C. Y. Interplay between cortical spreading depolarization and seizures. Stereotact. Funct. Neurosurg. 95, 1–5 (2017).
So, N. K. & Blume, W. T. The postictal EEG. Epilepsy Behav. 19, 121–126 (2010).
Lhatoo, S. D. et al. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann. Neurol. 68, 787–796 (2010).
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).
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).
Bolay, H. et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8, 136–142 (2002).
Dreier, J. P. & Reiffurth, C. The stroke-migraine depolarization continuum. Neuron 86, 902–922 (2015).
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.
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.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
About this article
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
This article is cited by
Global, regional, and national time trends in incidence for migraine, from 1990 to 2019: an age-period-cohort analysis for the GBD 2019
The Journal of Headache and Pain (2023)
The Journal of Headache and Pain (2023)
The Journal of Headache and Pain (2023)
Neurovascular Compression-Induced Intracranial Allodynia May Be the True Nature of Migraine Headache: an Interpretative Review
Current Pain and Headache Reports (2023)
Cortical pain induced by optogenetic cortical spreading depression: from whole brain activity mapping
Molecular Brain (2022)