Epilepsy affects all age groups and is one of the most common and most disabling neurological disorders. The accurate diagnosis of seizures is essential as some patients will be misdiagnosed with epilepsy, whereas others will receive an incorrect diagnosis. Indeed, errors in diagnosis are common, and many patients fail to receive the correct treatment, which often has severe consequences. Although many patients have seizure control using a single medication, others require multiple medications, resective surgery, neuromodulation devices or dietary therapies. In addition, one-third of patients will continue to have uncontrolled seizures. Epilepsy can substantially impair quality of life owing to seizures, comorbid mood and psychiatric disorders, cognitive deficits and adverse effects of medications. In addition, seizures can be fatal owing to direct effects on autonomic and arousal functions or owing to indirect effects such as drowning and other accidents. Deciphering the pathophysiology of epilepsy has advanced the understanding of the cellular and molecular events initiated by pathogenetic insults that transform normal circuits into epileptic circuits (epileptogenesis) and the mechanisms that generate seizures (ictogenesis). The discovery of >500 genes associated with epilepsy has led to new animal models, more precise diagnoses and, in some cases, targeted therapies.
Subscribe to Journal
Get full journal access for 1 year
only $59.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Fisher, R. S. et al. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia 55, 475–482 (2014).
Fisher, R. S. et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 522–530 (2017).
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).
Wiebe, S., Blume, W. T., Girvin, J. P. & Eliasziw, M. A. Randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–318 (2001).
Hauser, W. A. & Beghi, E. First seizure definitions and worldwide incidence and mortality. Epilepsia 49, 8–12 (2008).
GBD 2015 Disease and Injury Incidence and Prevalence Collaborators et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1545–1602 (2016).
Ngugi, A. K., Bottomley, C., Kleinschmidt, I., Sander, J. W. & Newton, C. R. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia 51, 883–890 (2010).
Fiest, K. M. et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 88, 296–303 (2017).
Singh, A. & Trevick, S. The epidemiology of global epilepsy. Neurol. Clin. 34, 837–847 (2016).
Bharucha, N. E., Bharucha, E. P., Bharucha, A. E., Bhise, A. V. & Schoenberg, B. S. Prevalence of epilepsy in the Parsi community of Bombay. Epilepsia 29, 111–115 (1988).
Devinsky, O., Spruill, T., Thurman, D. & Friedman, D. Recognizing and preventing epilepsy-related mortality. Neurology 86, 779–786 (2016).
Levira, F. et al. Premature mortality of epilepsy in low- and middle-income countries: a systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia 58, 6–16 (2016).
Thurman, D. J. et al. The burden of premature mortality of epilepsy in high-income countries: a systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia 58, 17–26 (2017).
Twele, F., Töllner, K., Brandt, C. & Löscher, W. Significant effects of sex, strain, and anesthesia in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. Epilepsy Behav. 55, 47–56 (2016).
Noebels, J. Pathway-driven discovery of epilepsy genes. Nat. Neurosci. 18, 344–350 (2015). This article reviews discoveries in epilepsy genetics from de novo exome variants in patients, targeted mutations in model systems and in vivo and ex vivo systems to better understand epilepsy and its treatment.
Kitz, S. et al. Feline temporal lobe epilepsy: review of the experimental literature. J. Vet. Intern. Med. 31, 633–640 (2017).
Patterson, E. E. Canine epilepsy: an underutilized model. ILAR J. 55, 182–186 (2014).
Terrone, G., Salamone, A. & Vezzani, A. Inflammation and epilepsy: preclinical findings and potential clinical translation. Curr. Pharm. Des. 23, 5569–5576 (2018).
Dudek, F. E. & Staley, K. J. The time course of acquired epilepsy: implications for therapeutic intervention to suppress epileptogenesis. Neurosci. Lett. 497, 240–246 (2011).
Pitkänen, A., Lukasiuk, K., Dudek, F. E. & Staley, K. J. Epileptogenesis. Cold Spring Harb. Perspect. Med. 5, a022822 (2015).
Ravizza, T. et al. WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities. Epilepsia 58, 331–342 (2017).
Varvel, N. H., Jiang, J. & Dingledine, R. Candidate drug targets for prevention or modification of epilepsy. Annu. Rev. Pharmacol. Toxicol. 55, 229–247 (2015).
Buckmaster, P. S. Mossy fiber sprouting in the dentate gyrus. Jasper's Basic Mechanisms of the Epilepsieshttps://www.ncbi.nlm.nih.gov/books/NBK98174/ (2012).
Sloviter, R. S., Zappone, C. A., Harvey, B. D. & Frotscher, M. Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyper-inhibition in chronically epileptic rats. J. Comp. Neurol. 494, 944–960 (2006).
Heck, N., Garwood, J., Loeffler, J.-P., Larmet, Y. & Faissner, A. Differential upregulation of extracellular matrix molecules associated with the appearance of granule cell dispersion and mossy fiber sprouting during epileptogenesis in a murine model of temporal lobe epilepsy. Neuroscience 129, 309–324 (2004).
Hester, M. S. & Danzer, S. C. Hippocampal granule cell pathology in epilepsy — a possible structural basis for comorbidities of epilepsy? Epilepsy Behav. 38, 105–116 (2014).
Parent, J. M. & Kron, M. M. Neurogenesis and epilepsy. Jasper's Basic Mechanisms of the Epilepsieshttps://www.ncbi.nlm.nih.gov/books/NBK98198/ (2012).
Ribak, C. E. et al. Seizure-induced formation of basal dendrites on granule cells of the rodent dentate gyrus. Jasper's Basic Mechanisms of the Epilepsieshttps://www.ncbi.nlm.nih.gov/books/NBK98199/ (2012).
Orcinha, C. et al. Seizure-induced motility of differentiated dentate granule cells is prevented by the central Reelin fragment. Front. Cell. Neurosci. 10, 183 (2016).
Cho, K.-O. et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat. Commun. 6, 6606 (2015).
Zeng, L.-H., Rensing, N. R. & Wong, M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J. Neurosci. 29, 6964–6972 (2009).
Buckmaster, P. S. & Lew, F. H. Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. J. Neurosci. 31, 2337–2347 (2011).
Devinsky, O., Vezzani, A., Najjar, S., De Lanerolle, N. C. & Rogawski, M. A. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 36, 174–184 (2013).
Ortinski, P. I. et al. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci. 13, 584–591 (2010).
Robel, S. et al. Reactive astrogliosis causes the development of spontaneous seizures. J. Neurosci. 35, 3330–3345 (2015).
Boison, D. Adenosinergic signaling in epilepsy. Neuropharmacology 104, 131–139 (2016). This study examines the role of the purinergic system in epilepsy, exemplifying how one of many relevant signalling pathways influences epileptogenesis, comorbidities and epigenetics.
Oberheim, N. A. et al. Loss of astrocytic domain organization in the epileptic brain. J. Neurosci. 28, 3264–3276 (2008).
Steinhäuser, C., Grunnet, M. & Carmignoto, G. Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience 323, 157–169 (2016).
Eyo, U. B., Murugan, M. & Wu, L.-J. Microglia-neuron communication in epilepsy. Glia 65, 5–18 (2017).
Dubé, C. M. et al. Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J. Neurosci. 30, 7484–7494 (2010).
Tegelberg, S., Kopra, O., Joensuu, T., Cooper, J. D. & Lehesjoki, A.-E. Early microglial activation precedes neuronal loss in the brain of the Cstb−/− mouse model of progressive myoclonus epilepsy, EPM1. J. Neuropathol. Exp. Neurol. 71, 40–53 (2012).
Okuneva, O. et al. Abnormal microglial activation in the Cstb(−/−) mouse, a model for progressive myoclonus epilepsy, EPM1. Glia 63, 400–411 (2015).
Vezzani, A., Maroso, M., Balosso, S., Sanchez, M.-A. & Bartfai, T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav. Immun. 25, 1281–1289 (2011).
Aronica, E. et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia 58 (Suppl. 3), 27–38 (2017). This paper describes a rapidly evolving area in clinical and basic epilepsy science — the role of neuroinflammation in pathogenesis and treatment.
Russmann, V. et al. Minocycline fails to exert antiepileptogenic effects in a rat status epilepticus model. Eur. J. Pharmacol. 771, 29–39 (2016).
Wang, N. et al. Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neuroscience 287, 144–156 (2015).
Benson, M. J., Manzanero, S. & Borges, K. Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models. Epilepsia 56, 895–905 (2015).
Librizzi, L., Noè, F., Vezzani, A., de Curtis, M. & Ravizza, T. Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann. Neurol. 72, 82–90 (2012).
Xu, Y. et al. Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation. Nat. Commun. 8, 943 (2017).
Fabene, P. F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat. Med. 14, 1377–1383 (2008).
Bar-Klein, G. et al. Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis. Brain 140, 1692–1705 (2017).
Weissberg, I. et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol. Dis. 78, 115–125 (2015).
Nehlig, A. What is animal experimentation telling us about new drug treatments of status epilepticus? Epilepsia 48 (Suppl. 8), 78–81 (2007).
Dingledine, R. et al. Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci. Data 4, 170061 (2017).
van Loo, K. M. J. et al. Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1. Nat. Commun. 6, 8688 (2015).
Dezsi, G. et al. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 54, 635–643 (2013).
Russo, E. et al. Effects of early long-term treatment with antiepileptic drugs on development of seizures and depressive-like behavior in a rat genetic absence epilepsy model. Epilepsia 52, 1341–1350 (2011).
Catterall, W. A. Sodium channel mutations and epilepsy. Jasper's Basic Mechanisms of the Epilepsieshttps://www.ncbi.nlm.nih.gov/books/NBK98185/ (2012).
Benarroch, E. E. HCN channels: function and clinical implications. Neurology 80, 304–310 (2013).
McClelland, S. et al. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. eLife 3, e01267 (2014).
Grabenstatter, H. L. et al. The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol. Dis. 62, 73–85 (2014).
Henshall, D. C. et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 15, 1368–1376 (2016).
Henshall, D. C. & Kobow, K. Epigenetics and epilepsy. Cold Spring Harb. Perspect. Med. 5, a022731 (2015).
Machnes, Z. M. et al. DNA methylation mediates persistent epileptiform activity in vitro and in vivo. PLoS ONE 8, e76299 (2013).
Williams-Karnesky, R. L. et al. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J. Clin. Invest. 123, 3552–3563 (2013).
Göttlicher, M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969–6978 (2001).
Iori, V. et al. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol. Dis. 99, 12–23 (2017).
Reschke, C. R. et al. Potent anti-seizure effects of locked nucleic acid antagomirs targeting miR-134 in multiple mouse and rat models of epilepsy. Mol. Ther. Nucleic Acids 6, 45–56 (2017).
McNamara, J. O. & Scharfman, H. E. Temporal lobe epilepsy and the BDNF receptor, TrkB. Jasper's Basic Mechanisms of the Epilepsieshttps://www.ncbi.nlm.nih.gov/books/NBK98186/ (2012).
Scharfman, H. E. & Brooks-Kayal, A. R. Is plasticity of GABAergic mechanisms relevant to epileptogenesis? Adv. Exp. Med. Biol. 813, 133–150 (2014).
Ostendorf, A. P. & Wong, M. mTOR inhibition in epilepsy: rationale and clinical perspectives. CNS Drugs 29, 91–99 (2015).
Guo, D., Zeng, L., Brody, D. L. & Wong, M. Rapamycin attenuates the development of posttraumatic epilepsy in a mouse model of traumatic brain injury. PLoS ONE 8, e64078 (2013).
Way, S. W. et al. The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. Hum. Mol. Genet. 21, 3226–3236 (2012).
Hartman, A. L., Santos, P., Dolce, A. & Hardwick, J. M. The mTOR inhibitor rapamycin has limited acute anticonvulsant effects in mice. PLoS ONE 7, e45156 (2012).
Raffo, E., Coppola, A., Ono, T., Briggs, S. W. & Galanopoulou, A. S. A pulse rapamycin therapy for infantile spasms and associated cognitive decline. Neurobiol. Dis. 43, 322–329 (2011).
French, J. A. et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388, 2153–2163 (2016).
Boison, D. Adenosine kinase: exploitation for therapeutic gain. Pharmacol. Rev. 65, 906–943 (2013).
Li, T., Quan Lan, J., Fredholm, B. B., Simon, R. P. & Boison, D. Adenosine dysfunction in astrogliosis: cause for seizure generation? Neuron Glia Biol. 3, 353–366 (2007).
Masino, S. A. et al. A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. J. Clin. Invest. 121, 2679–2683 (2011).
Cacheaux, L. P. et al. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J. Neurosci. 29, 8927–8935 (2009).
Kim, S. Y. et al. TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults. Sci. Rep. 7, 7711 (2017).
Xanthos, D. N. & Sandkühler, J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat. Rev. Neurosci. 15, 43–53 (2014).
Rowley, S. & Patel, M. Mitochondrial involvement and oxidative stress in temporal lobe epilepsy. Free Radic. Biol. Med. 62, 121–131 (2013).
Pauletti, A. et al. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain 140, 1885–1899 (2017).
Vezzani, A. & Viviani, B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96, 70–82 (2015).
Mazarati, A. M., Lewis, M. L. & Pittman, Q. J. Neurobehavioral comorbidities of epilepsy: Role of inflammation. Epilepsia 58 (Suppl. 3), 48–56 (2017).
Kenney-Jung, D. L. et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann. Neurol. 80, 939–945 (2016).
Ben-Menachem, E., Kyllerman, M. & Marklund, S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res. 40, 33–39 (2000).
Kovac, S. & Walker, M. C. Neuropeptides in epilepsy. Neuropeptides 47, 467–475 (2013).
Biagini, G. et al. Neurosteroids and epileptogenesis. J. Neuroendocrinol. 25, 980–990 (2013).
Gao, F. et al. Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model. Pharmacol. Biochem. Behav. 103, 187–196 (2012).
Hong, S. et al. The PPARγ agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative stress following pilocarpine-induced status epilepticus. Neurol. Sci. 33, 559–566 (2012).
Mantoan Ritter, L. et al. WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55, 1693–1702 (2014).
Pitkänen, A., Buckmaster, P. S., Galanopoulou, A. S. & Moshé, S. L. Models of Seizures and Epilepsy 2nd edn Academic Press, 2017).
Raimondo, J. V. et al. Methodological standards for in vitro models of epilepsy and epileptic seizures. A TASK1-WG4 report of the AES/ILAE Translational Task Force of the ILAE. Epilepsia 58, 40–52 (2017).
Avoli, M. A brief history on the oscillating roles of thalamus and cortex in absence seizures. Epilepsia 53, 779–789 (2012).
Crunelli, V. & Leresche, N. Childhood absence epilepsy: genes, channels, neurons and networks. Nat. Rev. Neurosci. 3, 371–382 (2002).
Tsakiridou, E., Bertollini, L., de Curtis, M., Avanzini, G. & Pape, H. C. Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J. Neurosci. 15, 3110–3117 (1995).
Cope, D. W. et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat. Med. 15, 1392–1398 (2009).
Maheshwari, A. & Noebels, J. L. Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits. Prog. Brain Res. 213, 223–252 (2014).
Onat, F. Y., van Luijtelaar, G., Nehlig, A. & Snead, O. C. The involvement of limbic structures in typical and atypical absence epilepsy. Epilepsy Res. 103, 111–123 (2013).
Sitnikova, E. & van Luijtelaar, G. Electroencephalographic characterization of spike-wave discharges in cortex and thalamus in WAG/Rij rats. Epilepsia 48, 2296–2311 (2007).
Depaulis, A., David, O. & Charpier, S. The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies. J. Neurosci. Methods 260, 159–174 (2016).
Bai, X. et al. Dynamic time course of typical childhood absence seizures: EEG, behavior, and functional magnetic resonance imaging. J. Neurosci. 30, 5884–5893 (2010).
Perucca, P., Dubeau, F. & Gotman, J. Intracranial electroencephalographic seizure-onset patterns: effect of underlying pathology. Brain 137, 183–196 (2014).
Ayala, G. F., Matsumoto, H. & Gumnit, R. J. Excitability changes and inhibitory mechanisms in neocortical neurons during seizures. J. Neurophysiol. 33, 73–85 (1970).
Johnston, D. & Brown, T. H. Giant synaptic potential hypothesis for epileptiform activity. Science 211, 294–297 (1981).
de Curtis, M. & Avanzini, G. Interictal spikes in focal epileptogenesis. Prog. Neurobiol. 63, 541–567 (2001).
Toprani, S. & Durand, D. M. Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation. J. Physiol. 591, 5765–5790 (2013).
Koubeissi, M. Z., Kahriman, E., Syed, T. U., Miller, J. & Durand, D. M. Low-frequency electrical stimulation of a fiber tract in temporal lobe epilepsy. Ann. Neurol. 74, 223–231 (2013).
Keller, C. J. et al. Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex. Brain 133, 1668–1681 (2010).
Avoli, M. & de Curtis, M. GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity. Prog. Neurobiol. 95, 104–132 (2011).
Chauvière, L. et al. Changes in interictal spike features precede the onset of temporal lobe epilepsy. Ann. Neurol. 71, 805–814 (2012).
Salami, P. et al. Dynamics of interictal spikes and high-frequency oscillations during epileptogenesis in temporal lobe epilepsy. Neurobiol. Dis. 67, 97–106 (2014).
Zijlmans, M. et al. High-frequency oscillations as a new biomarker in epilepsy. Ann. Neurol. 71, 169–178 (2012).
Engel, J. & da Silva, F. L. High-frequency oscillations — where we are and where we need to go. Prog. Neurobiol. 98, 316–318 (2012).
Bragin, A., Benassi, S. K., Kheiri, F. & Engel, J. Further evidence that pathologic high-frequency oscillations are bursts of population spikes derived from recordings of identified cells in dentate gyrus. Epilepsia 52, 45–52 (2011).
Ogren, J. A. et al. Three-dimensional surface maps link local atrophy and fast ripples in human epileptic hippocampus. Ann. Neurol. 66, 783–791 (2009).
Avoli, M., de Curtis, M. & Köhling, R. Does interictal synchronization influence ictogenesis? Neuropharmacology 69, 37–44 (2013).
Bragin, A., Azizyan, A., Almajano, J., Wilson, C. L. & Engel, J. Analysis of chronic seizure onsets after intrahippocampal kainic acid injection in freely moving rats. Epilepsia 46, 1592–1598 (2005).
de Curtis, M. & Avoli, M. GABAergic networks jump-start focal seizures. Epilepsia 57, 679–687 (2016).
Grasse, D. W., Karunakaran, S. & Moxon, K. A. Neuronal synchrony and the transition to spontaneous seizures. Exp. Neurol. 248, 72–84 (2013).
Truccolo, W. et al. Single-neuron dynamics in human focal epilepsy. Nat. Neurosci. 14, 635–641 (2011).
Schevon, C. A. et al. Evidence of an inhibitory restraint of seizure activity in humans. Nat. Commun. 3, 1060 (2012).
Avoli, M. et al. Specific imbalance of excitatory/inhibitory signaling establishes seizure onset pattern in temporal lobe epilepsy. J. Neurophysiol. 115, 3229–3237 (2016).
Librizzi, L. et al. Interneuronal network activity at the onset of seizure-like events in entorhinal cortex slices. J. Neurosci. 37, 10398–10407 (2017).
Traynelis, S. F. & Dingledine, R. Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J. Neurophysiol. 59, 259–276 (1988).
Sessolo, M. et al. Parvalbumin-positive inhibitory interneurons oppose propagation but favor generation of focal epileptiform activity. J. Neurosci. 35, 9544–9557 (2015).
Ziburkus, J., Cressman, J. R., Barreto, E. & Schiff, S. J. Interneuron and pyramidal cell interplay during in vitro seizure-like events. J. Neurophysiol. 95, 3948–3954 (2006).
Trombin, F., Gnatkovsky, V. & de Curtis, M. Changes in action potential features during focal seizure discharges in the entorhinal cortex of the in vitro isolated guinea pig brain. J. Neurophysiol. 106, 1411–1423 (2011).
Uva, L. et al. A novel focal seizure pattern generated in superficial layers of the olfactory cortex. J. Neurosci. 37, 3544–3554 (2017).
Lado, F. A. & Moshé, S. L. How do seizures stop? Epilepsia 49, 1651–1664 (2008).
Farrell, J. S. et al. Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction. Epilepsia 58, 1493–1501 (2017).
Boido, D., Gnatkovsky, V., Uva, L., Francione, S. & de Curtis, M. Simultaneous enhancement of excitation and postburst inhibition at the end of focal seizures. Ann. Neurol. 76, 826–836 (2014).
Jefferys, J. G. Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions. Physiol. Rev. 75, 689–723 (1995).
Carlen, P. L. Curious and contradictory roles of glial connexins and pannexins in epilepsy. Brain Res. 1487, 54–60 (2012).
Tian, G.-F. et al. An astrocytic basis of epilepsy. Nat. Med. 11, 973–981 (2005).
Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011).
Marchi, N., Granata, T., Ghosh, C. & Janigro, D. Blood-brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches. Epilepsia 53, 1877–1886 (2012).
Crunelli, V., Carmignoto, G. & Steinhäuser, C. Novel astrocyte targets: new avenues for the therapeutic treatment of epilepsy. Neuroscientist 21, 62–83 (2015).
Heinemann, U., Kaufer, D. & Friedman, A. Blood-brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy. Glia 60, 1251–1257 (2012).
David, O. et al. Imaging the seizure onset zone with stereo-electroencephalography. Brain 134, 2898–2911 (2011).
Gnatkovsky, V. et al. Biomarkers of epileptogenic zone defined by quantified stereo-EEG analysis. Epilepsia 55, 296–305 (2014).
Bartolomei, F. et al. Defining epileptogenic networks: contribution of SEEG and signal analysis. Epilepsia 58, 1131–1147 (2017).
Mormann, F., Andrzejak, R. G., Elger, C. E. & Lehnertz, K. Seizure prediction: the long and winding road. Brain 130, 314–333 (2007).
Freestone, D. R. et al. Seizure prediction: science fiction or soon to become reality? Curr. Neurol. Neurosci. Rep. 15, 73 (2015).
Sun, F. T. & Morrell, M. J. Closed-loop neurostimulation: the clinical experience. Neurotherapeutics 11, 553–563 (2014).
Baud, M. O. et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat. Commun. 9, 88 (2018).
Blumcke, I. et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N. Engl. J. Med. 377, 1648–1656 (2017).
Hauser, W. A., Rich, S. S., Lee, J. R.-J., Annegers, J. F. & Anderson, V. E. Risk of recurrent seizures after two unprovoked seizures. N. Engl. J. Med. 338, 429–434 (1998).
[No authors listed.] Epilepsy imitators. International League Against Epilepsyhttps://www.epilepsydiagnosis.org/epilepsy-imitators.html. (2018).
Hesdorffer, D. C., Benn, E. K. T., Cascino, G. D. & Hauser, W. A. Is a first acute symptomatic seizure epilepsy? Mortality and risk for recurrent seizure. Epilepsia 50, 1102–1108 (2009).
Pohlmann-Eden, B. The first seizure and its management in adults and children. BMJ 332, 339–342 (2006).
Hermann, B. & Jacoby, A. The psychosocial impact of epilepsy in adults. Epilepsy Behav. 15, S11–S16 (2009).
Katchanov, J. & Birbeck, G. L. Epilepsy care guidelines for low- and middle- income countries: from WHO mental health GAP to national programs. BMC Med. 10, 107 (2012).
Hamiwka, L. D., Singh, N., Niosi, J. & Wirrell, E. C. Diagnostic inaccuracy in children referred with ‘first seizure’: role for a first seizure clinic. Epilepsia 48, 1062–1066 (2007).
Firkin, A. L. et al. Mind the gap: Multiple events and lengthy delays before presentation with a ‘first seizure’. Epilepsia 56, 1534–1541 (2015).
Jallon, P., Loiseau, P. & Loiseau, J. Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Epilepsia 42, 464–475 (2001).
Blumenfeld, H. Impaired consciousness in epilepsy. Lancet Neurol. 11, 814–826 (2012). This is an insightful paper on one of the most disabling symptoms of seizures and how seizures can inform us about brain function.
Dash, D. et al. Can home video facilitate diagnosis of epilepsy type in a developing country? Epilepsy Res. 125, 19–23 (2016).
Brigo, F. et al. Tongue biting in epileptic seizures and psychogenic events. Epilepsy Behav. 25, 251–255 (2012).
Benbadis, S. R. Value of tongue biting in the diagnosis of seizures. Arch. Intern. Med. 155, 2346–2349 (1995).
Ahmed, S. N. & Spencer, S. S. An approach to the evaluation of a patient for seizures and epilepsy. WMJ 103, 49–55 (2004).
Klar, N., Cohen, B. & Lin, D. D. M. Neurocutaneous syndromes. Handb. Clin. Neurol. 135, 565–589 (2016).
Hirtz, D. et al. Practice parameter: evaluating a first nonfebrile seizure in children: report of the quality standards subcommittee of the American Academy of Neurology, The Child Neurology Society, and The American Epilepsy Society. Neurology 55, 616–623 (2000).
Krumholz, A. et al. Practice Parameter: Evaluating an apparent unprovoked first seizure in adults (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 69, 1996–2007 (2007).
Schreiner, A. & Pohlmann-Eden, B. Value of the early electroencephalogram after a first unprovoked seizure. Clin. Electroencephalogr. 34, 140–144 (2003).
King, M. A. et al. Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet 352, 1007–1011 (1998).
Ramgopal, S. et al. Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy. Epilepsy Behav. 37, 291–307 (2014).
Ghougassian, D. F., d'Souza, W., Cook, M. J. & O’Brien, T. J. Evaluating the utility of inpatient video-EEG monitoring. Epilepsia 45, 928–932 (2004).
Berg, A. T. et al. Frequency, prognosis and surgical treatment of structural abnormalities seen with magnetic resonance imaging in childhood epilepsy. Brain 132, 2785–2797 (2009).
Hakami, T. et al. MRI-identified pathology in adults with new-onset seizures. Neurology 81, 920–927 (2013).
McBride, M. C. et al. Failure of standard magnetic resonance imaging in patients with refractory temporal lobe epilepsy. Arch. Neurol. 55, 346–348 (1998).
Bernasconi, A., Bernasconi, N., Bernhardt, B. C. & Schrader, D. Advances in MRI for ‘cryptogenic’ epilepsies. Nat. Rev. Neurol. 7, 99–108 (2011).
Bien, C. G. & Holtkamp, M. ‘Autoimmune epilepsy’: encephalitis with autoantibodies for epileptologists. Epilepsy Curr. 17, 134–141 (2017). This article is a focused review of the emerging field of autoantibody-induced epilepsy.
Brenner, T. et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 54, 1028–1035 (2013).
Dubey, D. et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol. 74, 397 (2017).
Irani, S. R. et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, 892–900 (2011).
Thomas, R. H. & Berkovic, S. F. The hidden genetics of epilepsy — a clinically important new paradigm. Nat. Rev. Neurol. 10, 283–292 (2014).
Scheffer, I. Epilepsy genetics revolutionizes clinical practice. Neuropediatrics 45, 70–74 (2014).
Mefford, H. C. Clinical genetic testing in epilepsy. Epilepsy Curr. 15, 197–201 (2015).
Poduri, A. When should genetic testing be performed in epilepsy patients? Epilepsy Curr. 17, 16–22 (2017).
McTague, A., Howell, K. B., Cross, J. H., Kurian, M. A. & Scheffer, I. E. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 15, 304–316 (2016).
Mefford, H. C. et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann. Neurol. 70, 974–985 (2011).
Mercimek-Mahmutoglu, S. et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia 56, 707–716 (2015).
Perucca, P. et al. Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res. 131, 1–8 (2017).
Pitkänen, A. Therapeutic approaches to epileptogenesis — hope on the horizon. Epilepsia 51, 2–17 (2010).
Löscher, W. & Schmidt, D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52, 657–678 (2011).
Chen, Z., Brodie, M. J., Liew, D. & Kwan, P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs. JAMA Neurol. 75, 279 (2018).
Ryvlin, P., Cucherat, M. & Rheims, S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials. Lancet Neurol. 10, 961–968 (2011).
Faught, E., Duh, M. S., Weiner, J. R., Guerin, A. & Cunnington, M. C. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology 71, 1572–1578 (2008).
Rogawski, M. A. & Löscher, W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci. 5, 553–564 (2004).
Novy, J., Patsalos, P. N., Sander, J. W. & Sisodiya, S. M. Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction? Epilepsy Behav. 20, 20–23 (2011).
Kho, L. K., Lawn, N. D., Dunne, J. W. & Linto, J. First seizure presentation: do multiple seizures within 24 hours predict recurrence? Neurology 67, 1047–1049 (2006).
Wiebe, S., Téllez-Zenteno, J. F. & Shapiro, M. An evidence-based approach to the first seizure. Epilepsia 49, 50–57 (2008).
Camfield, P., Camfield, C., Smith, S., Dooley, J. & Smith, E. Long-term outcome is unchanged by antiepileptic drug treatment after a first seizure: a 15-year follow-up from a randomized trial in childhood. Epilepsia 43, 662–663 (2002).
Marson, A. et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. Lancet 365, 2007–2013 (2005).
Glauser, T. et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 54, 551–563 (2013). This article is an evidence-based review of anti-seizure medication efficacies.
Marson, A. G. et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 369, 1016–1026 (2007).
Glauser, T. A. et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N. Engl. J. Med. 362, 790–799 (2010).
Hakami, T. et al. Substitution monotherapy with levetiracetam versus older antiepileptic drugs. Arch. Neurol. 69, 1563 (2012).
Werhahn, K. J. et al. A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy. Epilepsia 56, 450–459 (2015).
Ettinger, A. B. Psychotropic effects of antiepileptic drugs. Neurology 67, 1916–1925 (2006).
Perucca, P. et al. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology 76, 273–279 (2011).
Christensen, J., Vestergaard, M., Mortensen, P. B., Sidenius, P. & Agerbo, E. Epilepsy and risk of suicide: a population-based case–control study. Lancet Neurol. 6, 693–698 (2007).
Busko, M. FDA advisory members agree antiepileptics pose suicidality risk, nix need for black-box warning. Medscapehttp://www.medscape.com/viewarticle/577432 (2008).
Hesdorffer, D. C. & Kanner, A. M. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 50, 978–986 (2009).
Andersohn, F., Schade, R., Willich, S. N. & Garbe, E. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 75, 335–340 (2010).
Chen, P. et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N. Engl. J. Med. 364, 1126–1133 (2011).
Shiek Ahmad, B. et al. Falls and fractures in patients chronically treated with antiepileptic drugs. Neurology 79, 145–151 (2012).
Chukwu, J., Delanty, N., Webb, D. & Cavalleri, G. L. Weight change, genetics and antiepileptic drugs. Expert Rev. Clin. Pharmacol. 7, 43–51 (2013).
Kwan, P. & Brodie, M. J. Early identification of refractory epilepsy. N. Engl. J. Med. 342, 314–319 (2000).
Kwan, P. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51, 1069–1077 (2009).
Kwan, P., Schachter, S. C. & Brodie, M. J. Drug-resistant epilepsy. N. Engl. J. Med. 365, 919–926 (2011).
Sillanpää, M. & Schmidt, D. Early seizure frequency and aetiology predict long-term medical outcome in childhood-onset epilepsy. Brain 132, 989–998 (2009).
Téllez-Zenteno, J. F., Dhar, R. & Wiebe, S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 128, 1188–1198 (2005).
Lowe, A. J. et al. Epilepsy surgery for pathologically proven hippocampal sclerosis provides long-term seizure control and improved quality of life. Epilepsia 45, 237–242 (2004).
Bell, G. S. et al. Premature mortality in refractory partial epilepsy: does surgical treatment make a difference? J. Neurol. Neurosurg. Psychiatry 81, 716–718 (2010).
Devinsky, O. et al. Changes in depression and anxiety after resective surgery for epilepsy. Neurology 65, 1744–1749 (2005).
Schiltz, N. K., Kaiboriboon, K., Koroukian, S. M., Singer, M. E. & Love, T. E. Long-term reduction of health care costs and utilization after epilepsy surgery. Epilepsia 57, 316–324 (2016).
O’Brien, T. J. et al. The cost-effective use of 18F-FDG PET in the presurgical evaluation of medically refractory focal epilepsy. J. Nucl. Med. 49, 931–937 (2008).
Liubinas, S. V., Cassidy, D., Roten, A., Kaye, A. H. & O’Brien, T. J. Tailored cortical resection following image guided subdural grid implantation for medically refractory epilepsy. J. Clin. Neurosci. 16, 1398–1408 (2009).
Milby, A. H., Halpern, C. H. & Baltuch, G. H. Vagus nerve stimulation in the treatment of refractory epilepsy. Neurotherapeutics 6, 228–237 (2009).
Ryvlin, P. et al. Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy. Epilepsia 59, 562–572 (2018).
Fisher, R. et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51, 899–908 (2010).
Morrell, M. J. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77, 1295–1304 (2011).
Cook, M. J. et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. Lancet Neurol. 12, 563–571 (2013).
Cervenka, M. C., Henry, B. J., Felton, E. A., Patton, K. & Kossoff, E. H. Establishing an adult epilepsy diet center: experience, efficacy and challenges. Epilepsy Behav. 58, 61–68 (2016).
Lefevre, F. & Aronson, N. Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics 105, e46–e46 (2000).
Cervenka, M. C. et al. Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus. Neurology 88, 938–943 (2017).
Neal, E. G. et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7, 500–506 (2008).
Kossoff, E. H. & Dorward, J. L. The modified Atkins diet. Epilepsia 49, 37–41 (2008).
Kang, H. C., Chung, D. E., Kim, D. W. & Kim, H. D. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia 45, 1116–1123 (2004).
McAuley, J. W. et al. Comparing patients’ and practitioners’ views on epilepsy concerns: a call to address memory concerns. Epilepsy Behav. 19, 580–583 (2010).
Devinsky, O. et al. Development of the quality of life in epilepsy inventory. Epilepsia 36, 1089–1104 (1995).
Cowan, J. & Baker, G. A. A review of subjective impact measures for use with children and adolescents with epilepsy. Qual. Life Res. 13, 1435–1443 (2004).
Choi, H. et al. Seizure frequency and patient-centered outcome assessment in epilepsy. Epilepsia 55, 1205–1212 (2014).
Boylan, L. S. et al. Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 62, 258–261 (2004).
Kanner, A. M., Barry, J. J., Gilliam, F., Hermann, B. & Meador, K. J. Anxiety disorders, subsyndromic depressive episodes, and major depressive episodes: do they differ on their impact on the quality of life of patients with epilepsy? Epilepsia 51, 1152–1158 (2010).
Fiest, K. M. et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology 80, 590–599 (2013).
DiMatteo, M. R., Lepper, H. S. & Croghan, T. W. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch. Intern. Med. 160, 2101–2107 (2000).
Hamid, H. et al. Mood, anxiety, and incomplete seizure control affect quality of life after epilepsy surgery. Neurology 82, 887–894 (2014).
Fazel, S., Wolf, A., Långström, N., Newton, C. R. & Lichtenstein, P. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet 382, 1646–1654 (2013).
McKee, H. R. & Privitera, M. D. Stress as a seizure precipitant: Identification, associated factors, and treatment options. Seizure 44, 21–26 (2017).
Galtrey, C. M., Mula, M. & Cock, H. R. Stress and epilepsy: fact or fiction, and what can we do about it? Pract. Neurol. 16, 270–278 (2016).
Allendorfer, J. B. & Szaflarski, J. P. Contributions of fMRI towards our understanding of the response to psychosocial stress in epilepsy and psychogenic nonepileptic seizures. Epilepsy Behav. 35, 19–25 (2014).
Thapar, A., Kerr, M. & Harold, G. Stress, anxiety, depression, and epilepsy: investigating the relationship between psychological factors and seizures. Epilepsy Behav. 14, 134–140 (2009).
Atif, M., Sarwar, M. R. & Scahill, S. The relationship between epilepsy and sexual dysfunction: a review of the literature. Springerplus 5, 2070 (2016).
Yang, Y. & Wang, X. Sexual dysfunction related to antiepileptic drugs in patients with epilepsy. Expert Opin. Drug Saf. 15, 31–42 (2016).
Thompson, N. J. et al. Expanding the efficacy of Project UPLIFT: distance delivery of mindfulness-based depression prevention to people with epilepsy. J. Consult. Clin. Psychol. 83, 304–313 (2015).
Arida, R. M., de Almeida, A.-C. G., Cavalheiro, E. A. & Scorza, F. A. Experimental and clinical findings from physical exercise as complementary therapy for epilepsy. Epilepsy Behav. 26, 273–278 (2013).
de Lima, C. et al. Physiological and electroencephalographic responses to acute exhaustive physical exercise in people with juvenile myoclonic epilepsy. Epilepsy Behav. 22, 718–722 (2011).
Nyberg, J. et al. Cardiovascular fitness and later risk of epilepsy: a Swedish population-based cohort study. Neurology 81, 1051–1057 (2013).
Depienne, C. et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J. Med. Genet. 47, 404–410 (2010).
Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).
Xu, X. et al. Amplicon resequencing identified parental mosaicism for approximately 10% of ‘de novo’ SCN1A mutations in children with Dravet syndrome. Hum. Mutat. 36, 861–872 (2015).
Scheffer, I. E. et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann. Neurol. 75, 782–787 (2014).
Friedman, A. et al. Should losartan be administered following brain injury? Expert Rev. Neurother. 14, 1365–1375 (2014).
Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 376, 2011–2020 (2017).
Milligan, C. J. et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann. Neurol. 75, 581–590 (2014).
Barcia, G. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44, 1255–1259 (2012).
Heron, S. E. et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 44, 1188–1190 (2012).
Mikati, M. A. et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann. Neurol. 78, 995–999 (2015).
Bearden, D. et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann. Neurol. 76, 457–461 (2014).
Mullen, S. A. et al. Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine. Neurology 90, e67–e72 (2018).
Pitkänen, A. et al. Advances in the development of biomarkers for epilepsy. Lancet Neurol. 15, 843–856 (2016). This paper provides an excellent overview of diagnostic biomarkers that can inform about the clinical status effects of therapies as well as prognostic biomarkers that can inform about outcome.
Sykes, L., Wood, E. & Kwan, J. Antiepileptic drugs for the primary and secondary prevention of seizures after stroke. Cochrane Database Syst. Rev. 1, CD005398 (2014).
Beghi, E. et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 51, 671–675 (2010).
Sveinsson, O., Andersson, T., Carlsson, S. & Tomson, T. The incidence of SUDEP. Neurology 89, 170–177 (2017).
Devinsky, O. et al. Underestimation of sudden deaths among patients with seizures and epilepsy. Neurology 89, 886–892 (2017).
Hesdorffer, D. C. et al. Combined analysis of risk factors for SUDEP. Epilepsia 52, 1150–1159 (2011).
Devinsky, O., Hesdorffer, D. C., Thurman, D. J., Lhatoo, S. & Richerson, G. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 15, 1075–1088 (2016). This article reviews the clinical features and suspected pathophysiologies of SUDEP.
de Kovel, C. G. F. et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133, 23–32 (2010).
Ricos, M. G. et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann. Neurol. 79, 120–131 (2016).
Ishiura, H. et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat. Genet. 50, 581–590 (2018).
Crompton, D. E. & Berkovic, S. F. The borderland of epilepsy: clinical and molecular features of phenomena that mimic epileptic seizures. Lancet Neurol. 8, 370–381 (2009).
Hesdorffer, D. C. Comorbidity between neurological illness and psychiatric disorders. CNS Spectr. 21, 230–238 (2016). This paper examines the growing evidence linking the reciprocal relationship between epilepsy and psychiatric disorders.
Winawer, M. R., Connors, R. & EPGP Investigators. Evidence for a shared genetic susceptibility to migraine and epilepsy. Epilepsia 54, 288–295 (2013).
Jentink, J. et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N. Engl. J. Med. 362, 2185–2193 (2010).
Tomson, T. et al. Pregnancy registries: Differences, similarities, and possible harmonization. Epilepsia 51, 909–915 (2010).
Tomson, T. et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 10, 609–617 (2011).
Vajda, F. J., O’Brien, T. J., Graham, J. E., Lander, C. M. & Eadie, M. J. Dose dependence of fetal malformations associated with valproate. Neurology 81, 999–1003 (2013).
Vajda, F. J. E. et al. The teratogenic risk of antiepileptic drug polytherapy. Epilepsia 51, 805–810 (2009).
Holmes, L. B., Mittendorf, R., Shen, A., Smith, C. R. & Hernandez-Diaz, S. Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations. Arch. Neurol. 68, 1275–1281 (2011).
Vajda, F. J. E., O’Brien, T. J., Lander, C. M., Graham, J. & Eadie, M. J. Antiepileptic drug combinations not involving valproate and the risk of fetal malformations. Epilepsia 57, 1048–1052 (2016).
Meador, K. J. et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 12, 244–252 (2013). This is a landmark study on how ASDs can affect development and cognitive outcome.
Wood, A. G. et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia 56, 1047–1055 (2015).
Meador, K. J. et al. Breastfeeding in children of women taking antiepileptic drugs. JAMA Pediatr. 168, 729 (2014).
Perucca, P. & Mula, M. Antiepileptic drug effects on mood and behavior: molecular targets. Epilepsy Behav. 26, 440–449 (2013).
O.D. has received research funding from the US NIH, GW Pharmaceuticals, Novartis and PTC Pharmaceuticals. He has equity in Egg Rock Holdings, Empatica, Engage Therapeutics, Pairnomix, Rettco and Tilray. He is the Principal Investigator for the North American SUDEP Registry and the SUDC Registry and Research Collaborative. He currently receives research funding from NIH and the US Centers for Disease Control and Prevention. He consults for the Center for Discovery. A.V. has received consultancy fees from UCB Pharma and research grants from Ovid, Pfizer and Takeda. T.J.O.B. has received research funding from Eisai, the National Health and Medical Research Council of Australia, the NIH, the Royal Melbourne Hospital Neuroscience Foundation and UCB Pharma. N.J. currently receives research funding from Alberta Health, the Canadian Institute of Health Research and the NIH, and is an associate editor of Epilepsia and serves on the editorial board of Neurology. I.E.S. has served on scientific advisory boards for BioMarin, Eisai, GlaxoSmithKline, Nutricia and UCB Pharma, sits on the editorial boards of Epileptic Disorders and Neurology and might accrue future revenue on a pending patent. I.E.S. has also received speaker honoraria from Athena Diagnostics, Eisai, GlaxoSmithKline, Transgenomics and UCB Pharma, has received funding for travel from Athena Diagnostics, Biocodex, BioMarin, Eisai, GlaxoSmithKline and UCB Pharma, and has received research support from the American Epilepsy Society, the Australian Research Council, CURE, the Health Research Council of New Zealand, the March of Dimes, the National Health and Medical Research Council of Australia, the NIH, the US Department of Defense Autism Spectrum Disorder Research Program, and Perpetual Charitable Trustees. P.P. has received honoraria from Eisai. All other authors declare no competing interests.
About this article
European Journal of Pharmacology (2021)
Enrichment of Circular RNA Expression Deregulation at the Transition to Recurrent Spontaneous Seizures in Experimental Temporal Lobe Epilepsy
Frontiers in Genetics (2021)
Brain Research Bulletin (2021)
European Journal of Nuclear Medicine and Molecular Imaging (2021)