Skip to main content

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

Epilepsy

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Seizure classification.
Figure 2: Framework for the classification of the epilepsies.
Figure 3: Mechanisms of epileptogenesis.
Figure 4: | Ictogenesis of focal seizures.
Figure 5: Interictal abnormalities detected using EEG.
Figure 6: Epileptogenic lesions.

References

  1. 1

    Fisher, R. S. et al. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia 55, 475–482 (2014).

    PubMed  Google Scholar 

  2. 2

    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).

    PubMed  Google Scholar 

  3. 3

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

    PubMed  PubMed Central  Google Scholar 

  4. 4

    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).

    CAS  PubMed  Google Scholar 

  5. 5

    Hauser, W. A. & Beghi, E. First seizure definitions and worldwide incidence and mortality. Epilepsia 49, 8–12 (2008).

    PubMed  Google Scholar 

  6. 6

    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).

    Google Scholar 

  7. 7

    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).

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Fiest, K. M. et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 88, 296–303 (2017).

    PubMed  PubMed Central  Google Scholar 

  9. 9

    Singh, A. & Trevick, S. The epidemiology of global epilepsy. Neurol. Clin. 34, 837–847 (2016).

    PubMed  Google Scholar 

  10. 10

    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).

    CAS  PubMed  Google Scholar 

  11. 11

    Devinsky, O., Spruill, T., Thurman, D. & Friedman, D. Recognizing and preventing epilepsy-related mortality. Neurology 86, 779–786 (2016).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    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).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    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).

    PubMed  Google Scholar 

  14. 14

    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).

    PubMed  Google Scholar 

  15. 15

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Kitz, S. et al. Feline temporal lobe epilepsy: review of the experimental literature. J. Vet. Intern. Med. 31, 633–640 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Patterson, E. E. Canine epilepsy: an underutilized model. ILAR J. 55, 182–186 (2014).

    CAS  PubMed  Google Scholar 

  18. 18

    Terrone, G., Salamone, A. & Vezzani, A. Inflammation and epilepsy: preclinical findings and potential clinical translation. Curr. Pharm. Des. 23, 5569–5576 (2018).

    Google Scholar 

  19. 19

    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).

    CAS  PubMed  Google Scholar 

  20. 20

    Pitkänen, A., Lukasiuk, K., Dudek, F. E. & Staley, K. J. Epileptogenesis. Cold Spring Harb. Perspect. Med. 5, a022822 (2015).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Ravizza, T. et al. WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities. Epilepsia 58, 331–342 (2017).

    PubMed  Google Scholar 

  22. 22

    Varvel, N. H., Jiang, J. & Dingledine, R. Candidate drug targets for prevention or modification of epilepsy. Annu. Rev. Pharmacol. Toxicol. 55, 229–247 (2015).

    CAS  PubMed  Google Scholar 

  23. 23

    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).

  24. 24

    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).

    PubMed  PubMed Central  Google Scholar 

  25. 25

    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).

    CAS  PubMed  Google Scholar 

  26. 26

    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).

    PubMed  Google Scholar 

  27. 27

    Parent, J. M. & Kron, M. M. Neurogenesis and epilepsy. Jasper's Basic Mechanisms of the Epilepsieshttps://www.ncbi.nlm.nih.gov/books/NBK98198/ (2012).

  28. 28

    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).

  29. 29

    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).

    PubMed  PubMed Central  Google Scholar 

  30. 30

    Cho, K.-O. et al. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat. Commun. 6, 6606 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    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).

    CAS  PubMed  Google Scholar 

  34. 34

    Ortinski, P. I. et al. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci. 13, 584–591 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Robel, S. et al. Reactive astrogliosis causes the development of spontaneous seizures. J. Neurosci. 35, 3330–3345 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    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.

    CAS  PubMed  Google Scholar 

  37. 37

    Oberheim, N. A. et al. Loss of astrocytic domain organization in the epileptic brain. J. Neurosci. 28, 3264–3276 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Steinhäuser, C., Grunnet, M. & Carmignoto, G. Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience 323, 157–169 (2016).

    PubMed  Google Scholar 

  39. 39

    Eyo, U. B., Murugan, M. & Wu, L.-J. Microglia-neuron communication in epilepsy. Glia 65, 5–18 (2017).

    PubMed  Google Scholar 

  40. 40

    Dubé, C. M. et al. Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J. Neurosci. 30, 7484–7494 (2010).

    PubMed  PubMed Central  Google Scholar 

  41. 41

    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).

    CAS  PubMed  Google Scholar 

  42. 42

    Okuneva, O. et al. Abnormal microglial activation in the Cstb(−/−) mouse, a model for progressive myoclonus epilepsy, EPM1. Glia 63, 400–411 (2015).

    PubMed  Google Scholar 

  43. 43

    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).

    CAS  PubMed  Google Scholar 

  44. 44

    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.

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Russmann, V. et al. Minocycline fails to exert antiepileptogenic effects in a rat status epilepticus model. Eur. J. Pharmacol. 771, 29–39 (2016).

    CAS  PubMed  Google Scholar 

  46. 46

    Wang, N. et al. Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neuroscience 287, 144–156 (2015).

    CAS  PubMed  Google Scholar 

  47. 47

    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).

    CAS  PubMed  Google Scholar 

  48. 48

    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).

    PubMed  Google Scholar 

  49. 49

    Xu, Y. et al. Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation. Nat. Commun. 8, 943 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. 50

    Fabene, P. F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat. Med. 14, 1377–1383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Bar-Klein, G. et al. Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis. Brain 140, 1692–1705 (2017).

    PubMed  Google Scholar 

  52. 52

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Nehlig, A. What is animal experimentation telling us about new drug treatments of status epilepticus? Epilepsia 48 (Suppl. 8), 78–81 (2007).

    CAS  PubMed  Google Scholar 

  54. 54

    Dingledine, R. et al. Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci. Data 4, 170061 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Dezsi, G. et al. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia 54, 635–643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    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).

    CAS  PubMed  Google Scholar 

  58. 58

    Catterall, W. A. Sodium channel mutations and epilepsy. Jasper's Basic Mechanisms of the Epilepsieshttps://www.ncbi.nlm.nih.gov/books/NBK98185/ (2012).

  59. 59

    Benarroch, E. E. HCN channels: function and clinical implications. Neurology 80, 304–310 (2013).

    PubMed  Google Scholar 

  60. 60

    McClelland, S. et al. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. eLife 3, e01267 (2014).

    PubMed  PubMed Central  Google Scholar 

  61. 61

    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).

    CAS  PubMed  Google Scholar 

  62. 62

    Henshall, D. C. et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 15, 1368–1376 (2016).

    CAS  PubMed  Google Scholar 

  63. 63

    Henshall, D. C. & Kobow, K. Epigenetics and epilepsy. Cold Spring Harb. Perspect. Med. 5, a022731 (2015).

    PubMed  PubMed Central  Google Scholar 

  64. 64

    Machnes, Z. M. et al. DNA methylation mediates persistent epileptiform activity in vitro and in vivo. PLoS ONE 8, e76299 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Williams-Karnesky, R. L. et al. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J. Clin. Invest. 123, 3552–3563 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Göttlicher, M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969–6978 (2001).

    PubMed  PubMed Central  Google Scholar 

  67. 67

    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).

    CAS  PubMed  Google Scholar 

  68. 68

    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).

    CAS  PubMed  Google Scholar 

  69. 69

    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).

  70. 70

    Scharfman, H. E. & Brooks-Kayal, A. R. Is plasticity of GABAergic mechanisms relevant to epileptogenesis? Adv. Exp. Med. Biol. 813, 133–150 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Ostendorf, A. P. & Wong, M. mTOR inhibition in epilepsy: rationale and clinical perspectives. CNS Drugs 29, 91–99 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    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).

    CAS  PubMed  Google Scholar 

  77. 77

    Boison, D. Adenosine kinase: exploitation for therapeutic gain. Pharmacol. Rev. 65, 906–943 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    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).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Masino, S. A. et al. A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. J. Clin. Invest. 121, 2679–2683 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Cacheaux, L. P. et al. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J. Neurosci. 29, 8927–8935 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    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).

    PubMed  PubMed Central  Google Scholar 

  82. 82

    Xanthos, D. N. & Sandkühler, J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat. Rev. Neurosci. 15, 43–53 (2014).

    CAS  Google Scholar 

  83. 83

    Rowley, S. & Patel, M. Mitochondrial involvement and oxidative stress in temporal lobe epilepsy. Free Radic. Biol. Med. 62, 121–131 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Pauletti, A. et al. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain 140, 1885–1899 (2017).

    PubMed  PubMed Central  Google Scholar 

  85. 85

    Vezzani, A. & Viviani, B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96, 70–82 (2015).

    CAS  PubMed  Google Scholar 

  86. 86

    Mazarati, A. M., Lewis, M. L. & Pittman, Q. J. Neurobehavioral comorbidities of epilepsy: Role of inflammation. Epilepsia 58 (Suppl. 3), 48–56 (2017).

    PubMed  Google Scholar 

  87. 87

    Kenney-Jung, D. L. et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann. Neurol. 80, 939–945 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Ben-Menachem, E., Kyllerman, M. & Marklund, S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res. 40, 33–39 (2000).

    CAS  PubMed  Google Scholar 

  89. 89

    Kovac, S. & Walker, M. C. Neuropeptides in epilepsy. Neuropeptides 47, 467–475 (2013).

    CAS  PubMed  Google Scholar 

  90. 90

    Biagini, G. et al. Neurosteroids and epileptogenesis. J. Neuroendocrinol. 25, 980–990 (2013).

    CAS  PubMed  Google Scholar 

  91. 91

    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).

    CAS  PubMed  Google Scholar 

  92. 92

    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).

    PubMed  Google Scholar 

  93. 93

    Mantoan Ritter, L. et al. WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55, 1693–1702 (2014).

    PubMed  Google Scholar 

  94. 94

    Pitkänen, A., Buckmaster, P. S., Galanopoulou, A. S. & Moshé, S. L. Models of Seizures and Epilepsy 2nd edn Academic Press, 2017).

    Google Scholar 

  95. 95

    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).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Avoli, M. A brief history on the oscillating roles of thalamus and cortex in absence seizures. Epilepsia 53, 779–789 (2012).

    PubMed  PubMed Central  Google Scholar 

  97. 97

    Crunelli, V. & Leresche, N. Childhood absence epilepsy: genes, channels, neurons and networks. Nat. Rev. Neurosci. 3, 371–382 (2002).

    CAS  PubMed  Google Scholar 

  98. 98

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Cope, D. W. et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat. Med. 15, 1392–1398 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    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).

    PubMed  Google Scholar 

  101. 101

    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).

    PubMed  Google Scholar 

  102. 102

    Sitnikova, E. & van Luijtelaar, G. Electroencephalographic characterization of spike-wave discharges in cortex and thalamus in WAG/Rij rats. Epilepsia 48, 2296–2311 (2007).

    PubMed  Google Scholar 

  103. 103

    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).

    PubMed  Google Scholar 

  104. 104

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Perucca, P., Dubeau, F. & Gotman, J. Intracranial electroencephalographic seizure-onset patterns: effect of underlying pathology. Brain 137, 183–196 (2014).

    PubMed  Google Scholar 

  106. 106

    Ayala, G. F., Matsumoto, H. & Gumnit, R. J. Excitability changes and inhibitory mechanisms in neocortical neurons during seizures. J. Neurophysiol. 33, 73–85 (1970).

    CAS  PubMed  Google Scholar 

  107. 107

    Johnston, D. & Brown, T. H. Giant synaptic potential hypothesis for epileptiform activity. Science 211, 294–297 (1981).

    CAS  PubMed  Google Scholar 

  108. 108

    de Curtis, M. & Avanzini, G. Interictal spikes in focal epileptogenesis. Prog. Neurobiol. 63, 541–567 (2001).

    CAS  PubMed  Google Scholar 

  109. 109

    Toprani, S. & Durand, D. M. Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation. J. Physiol. 591, 5765–5790 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    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).

    PubMed  Google Scholar 

  111. 111

    Keller, C. J. et al. Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex. Brain 133, 1668–1681 (2010).

    PubMed  PubMed Central  Google Scholar 

  112. 112

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Chauvière, L. et al. Changes in interictal spike features precede the onset of temporal lobe epilepsy. Ann. Neurol. 71, 805–814 (2012).

    PubMed  Google Scholar 

  114. 114

    Salami, P. et al. Dynamics of interictal spikes and high-frequency oscillations during epileptogenesis in temporal lobe epilepsy. Neurobiol. Dis. 67, 97–106 (2014).

    PubMed  PubMed Central  Google Scholar 

  115. 115

    Zijlmans, M. et al. High-frequency oscillations as a new biomarker in epilepsy. Ann. Neurol. 71, 169–178 (2012).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Engel, J. & da Silva, F. L. High-frequency oscillations — where we are and where we need to go. Prog. Neurobiol. 98, 316–318 (2012).

    PubMed  PubMed Central  Google Scholar 

  117. 117

    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).

    PubMed  PubMed Central  Google Scholar 

  118. 118

    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).

    PubMed  PubMed Central  Google Scholar 

  119. 119

    Avoli, M., de Curtis, M. & Köhling, R. Does interictal synchronization influence ictogenesis? Neuropharmacology 69, 37–44 (2013).

    CAS  PubMed  Google Scholar 

  120. 120

    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).

    PubMed  Google Scholar 

  121. 121

    de Curtis, M. & Avoli, M. GABAergic networks jump-start focal seizures. Epilepsia 57, 679–687 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Grasse, D. W., Karunakaran, S. & Moxon, K. A. Neuronal synchrony and the transition to spontaneous seizures. Exp. Neurol. 248, 72–84 (2013).

    PubMed  Google Scholar 

  123. 123

    Truccolo, W. et al. Single-neuron dynamics in human focal epilepsy. Nat. Neurosci. 14, 635–641 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Schevon, C. A. et al. Evidence of an inhibitory restraint of seizure activity in humans. Nat. Commun. 3, 1060 (2012).

    PubMed  PubMed Central  Google Scholar 

  125. 125

    Avoli, M. et al. Specific imbalance of excitatory/inhibitory signaling establishes seizure onset pattern in temporal lobe epilepsy. J. Neurophysiol. 115, 3229–3237 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Librizzi, L. et al. Interneuronal network activity at the onset of seizure-like events in entorhinal cortex slices. J. Neurosci. 37, 10398–10407 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Traynelis, S. F. & Dingledine, R. Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J. Neurophysiol. 59, 259–276 (1988).

    CAS  PubMed  Google Scholar 

  128. 128

    Sessolo, M. et al. Parvalbumin-positive inhibitory interneurons oppose propagation but favor generation of focal epileptiform activity. J. Neurosci. 35, 9544–9557 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    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).

    PubMed  PubMed Central  Google Scholar 

  130. 130

    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).

    CAS  PubMed  Google Scholar 

  131. 131

    Uva, L. et al. A novel focal seizure pattern generated in superficial layers of the olfactory cortex. J. Neurosci. 37, 3544–3554 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Lado, F. A. & Moshé, S. L. How do seizures stop? Epilepsia 49, 1651–1664 (2008).

    PubMed  PubMed Central  Google Scholar 

  133. 133

    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).

    CAS  PubMed  Google Scholar 

  134. 134

    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).

    CAS  PubMed  Google Scholar 

  135. 135

    Jefferys, J. G. Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions. Physiol. Rev. 75, 689–723 (1995).

    CAS  PubMed  Google Scholar 

  136. 136

    Carlen, P. L. Curious and contradictory roles of glial connexins and pannexins in epilepsy. Brain Res. 1487, 54–60 (2012).

    CAS  PubMed  Google Scholar 

  137. 137

    Tian, G.-F. et al. An astrocytic basis of epilepsy. Nat. Med. 11, 973–981 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011).

    CAS  PubMed  Google Scholar 

  139. 139

    Marchi, N., Granata, T., Ghosh, C. & Janigro, D. Blood-brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches. Epilepsia 53, 1877–1886 (2012).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Crunelli, V., Carmignoto, G. & Steinhäuser, C. Novel astrocyte targets: new avenues for the therapeutic treatment of epilepsy. Neuroscientist 21, 62–83 (2015).

    PubMed  PubMed Central  Google Scholar 

  141. 141

    Heinemann, U., Kaufer, D. & Friedman, A. Blood-brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy. Glia 60, 1251–1257 (2012).

    PubMed  PubMed Central  Google Scholar 

  142. 142

    David, O. et al. Imaging the seizure onset zone with stereo-electroencephalography. Brain 134, 2898–2911 (2011).

    PubMed  Google Scholar 

  143. 143

    Gnatkovsky, V. et al. Biomarkers of epileptogenic zone defined by quantified stereo-EEG analysis. Epilepsia 55, 296–305 (2014).

    PubMed  Google Scholar 

  144. 144

    Bartolomei, F. et al. Defining epileptogenic networks: contribution of SEEG and signal analysis. Epilepsia 58, 1131–1147 (2017).

    PubMed  Google Scholar 

  145. 145

    Mormann, F., Andrzejak, R. G., Elger, C. E. & Lehnertz, K. Seizure prediction: the long and winding road. Brain 130, 314–333 (2007).

    PubMed  Google Scholar 

  146. 146

    Freestone, D. R. et al. Seizure prediction: science fiction or soon to become reality? Curr. Neurol. Neurosci. Rep. 15, 73 (2015).

    PubMed  Google Scholar 

  147. 147

    Sun, F. T. & Morrell, M. J. Closed-loop neurostimulation: the clinical experience. Neurotherapeutics 11, 553–563 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Baud, M. O. et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat. Commun. 9, 88 (2018).

    PubMed  PubMed Central  Google Scholar 

  149. 149

    Blumcke, I. et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N. Engl. J. Med. 377, 1648–1656 (2017).

    PubMed  Google Scholar 

  150. 150

    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).

    CAS  PubMed  Google Scholar 

  151. 151

    [No authors listed.] Epilepsy imitators. International League Against Epilepsyhttps://www.epilepsydiagnosis.org/epilepsy-imitators.html. (2018).

  152. 152

    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).

    PubMed  Google Scholar 

  153. 153

    Pohlmann-Eden, B. The first seizure and its management in adults and children. BMJ 332, 339–342 (2006).

    PubMed  PubMed Central  Google Scholar 

  154. 154

    Hermann, B. & Jacoby, A. The psychosocial impact of epilepsy in adults. Epilepsy Behav. 15, S11–S16 (2009).

    PubMed  PubMed Central  Google Scholar 

  155. 155

    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).

    PubMed  PubMed Central  Google Scholar 

  156. 156

    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).

    CAS  PubMed  Google Scholar 

  157. 157

    Firkin, A. L. et al. Mind the gap: Multiple events and lengthy delays before presentation with a ‘first seizure’. Epilepsia 56, 1534–1541 (2015).

    PubMed  Google Scholar 

  158. 158

    Jallon, P., Loiseau, P. & Loiseau, J. Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Epilepsia 42, 464–475 (2001).

    CAS  PubMed  Google Scholar 

  159. 159

    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.

    PubMed  PubMed Central  Google Scholar 

  160. 160

    Dash, D. et al. Can home video facilitate diagnosis of epilepsy type in a developing country? Epilepsy Res. 125, 19–23 (2016).

    PubMed  Google Scholar 

  161. 161

    Brigo, F. et al. Tongue biting in epileptic seizures and psychogenic events. Epilepsy Behav. 25, 251–255 (2012).

    PubMed  Google Scholar 

  162. 162

    Benbadis, S. R. Value of tongue biting in the diagnosis of seizures. Arch. Intern. Med. 155, 2346–2349 (1995).

    CAS  PubMed  Google Scholar 

  163. 163

    Ahmed, S. N. & Spencer, S. S. An approach to the evaluation of a patient for seizures and epilepsy. WMJ 103, 49–55 (2004).

    PubMed  Google Scholar 

  164. 164

    Klar, N., Cohen, B. & Lin, D. D. M. Neurocutaneous syndromes. Handb. Clin. Neurol. 135, 565–589 (2016).

    PubMed  Google Scholar 

  165. 165

    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).

    CAS  PubMed  Google Scholar 

  166. 166

    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).

    CAS  PubMed  Google Scholar 

  167. 167

    Schreiner, A. & Pohlmann-Eden, B. Value of the early electroencephalogram after a first unprovoked seizure. Clin. Electroencephalogr. 34, 140–144 (2003).

    CAS  PubMed  Google Scholar 

  168. 168

    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).

    CAS  PubMed  Google Scholar 

  169. 169

    Ramgopal, S. et al. Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy. Epilepsy Behav. 37, 291–307 (2014).

    PubMed  Google Scholar 

  170. 170

    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).

    PubMed  Google Scholar 

  171. 171

    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).

    PubMed  PubMed Central  Google Scholar 

  172. 172

    Hakami, T. et al. MRI-identified pathology in adults with new-onset seizures. Neurology 81, 920–927 (2013).

    PubMed  Google Scholar 

  173. 173

    McBride, M. C. et al. Failure of standard magnetic resonance imaging in patients with refractory temporal lobe epilepsy. Arch. Neurol. 55, 346–348 (1998).

    CAS  PubMed  Google Scholar 

  174. 174

    Bernasconi, A., Bernasconi, N., Bernhardt, B. C. & Schrader, D. Advances in MRI for ‘cryptogenic’ epilepsies. Nat. Rev. Neurol. 7, 99–108 (2011).

    PubMed  Google Scholar 

  175. 175

    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.

    PubMed  PubMed Central  Google Scholar 

  176. 176

    Brenner, T. et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 54, 1028–1035 (2013).

    PubMed  Google Scholar 

  177. 177

    Dubey, D. et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol. 74, 397 (2017).

    PubMed  Google Scholar 

  178. 178

    Irani, S. R. et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, 892–900 (2011).

    PubMed  Google Scholar 

  179. 179

    Thomas, R. H. & Berkovic, S. F. The hidden genetics of epilepsy — a clinically important new paradigm. Nat. Rev. Neurol. 10, 283–292 (2014).

    PubMed  Google Scholar 

  180. 180

    Scheffer, I. Epilepsy genetics revolutionizes clinical practice. Neuropediatrics 45, 70–74 (2014).

    PubMed  Google Scholar 

  181. 181

    Mefford, H. C. Clinical genetic testing in epilepsy. Epilepsy Curr. 15, 197–201 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. 182

    Poduri, A. When should genetic testing be performed in epilepsy patients? Epilepsy Curr. 17, 16–22 (2017).

    PubMed  PubMed Central  Google Scholar 

  183. 183

    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).

    PubMed  Google Scholar 

  184. 184

    Mefford, H. C. et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann. Neurol. 70, 974–985 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    Mercimek-Mahmutoglu, S. et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia 56, 707–716 (2015).

    CAS  PubMed  Google Scholar 

  186. 186

    Perucca, P. et al. Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res. 131, 1–8 (2017).

    CAS  PubMed  Google Scholar 

  187. 187

    Pitkänen, A. Therapeutic approaches to epileptogenesis — hope on the horizon. Epilepsia 51, 2–17 (2010).

    PubMed  PubMed Central  Google Scholar 

  188. 188

    Löscher, W. & Schmidt, D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52, 657–678 (2011).

    PubMed  Google Scholar 

  189. 189

    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).

    PubMed  Google Scholar 

  190. 190

    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).

    PubMed  Google Scholar 

  191. 191

    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).

    CAS  PubMed  Google Scholar 

  192. 192

    Rogawski, M. A. & Löscher, W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci. 5, 553–564 (2004).

    CAS  PubMed  Google Scholar 

  193. 193

    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).

    PubMed  Google Scholar 

  194. 194

    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).

    PubMed  Google Scholar 

  195. 195

    Wiebe, S., Téllez-Zenteno, J. F. & Shapiro, M. An evidence-based approach to the first seizure. Epilepsia 49, 50–57 (2008).

    PubMed  Google Scholar 

  196. 196

    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).

    PubMed  Google Scholar 

  197. 197

    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).

    CAS  PubMed  Google Scholar 

  198. 198

    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.

    CAS  PubMed  Google Scholar 

  199. 199

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Glauser, T. A. et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N. Engl. J. Med. 362, 790–799 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Hakami, T. et al. Substitution monotherapy with levetiracetam versus older antiepileptic drugs. Arch. Neurol. 69, 1563 (2012).

    PubMed  Google Scholar 

  202. 202

    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).

    CAS  PubMed  Google Scholar 

  203. 203

    Ettinger, A. B. Psychotropic effects of antiepileptic drugs. Neurology 67, 1916–1925 (2006).

    CAS  PubMed  Google Scholar 

  204. 204

    Perucca, P. et al. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology 76, 273–279 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    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).

    PubMed  Google Scholar 

  206. 206

    Busko, M. FDA advisory members agree antiepileptics pose suicidality risk, nix need for black-box warning. Medscapehttp://www.medscape.com/viewarticle/577432 (2008).

  207. 207

    Hesdorffer, D. C. & Kanner, A. M. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 50, 978–986 (2009).

    PubMed  Google Scholar 

  208. 208

    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).

    CAS  PubMed  Google Scholar 

  209. 209

    Chen, P. et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N. Engl. J. Med. 364, 1126–1133 (2011).

    CAS  PubMed  Google Scholar 

  210. 210

    Shiek Ahmad, B. et al. Falls and fractures in patients chronically treated with antiepileptic drugs. Neurology 79, 145–151 (2012).

    PubMed  Google Scholar 

  211. 211

    Chukwu, J., Delanty, N., Webb, D. & Cavalleri, G. L. Weight change, genetics and antiepileptic drugs. Expert Rev. Clin. Pharmacol. 7, 43–51 (2013).

    PubMed  Google Scholar 

  212. 212

    Kwan, P. & Brodie, M. J. Early identification of refractory epilepsy. N. Engl. J. Med. 342, 314–319 (2000).

    CAS  PubMed  Google Scholar 

  213. 213

    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).

    PubMed  Google Scholar 

  214. 214

    Kwan, P., Schachter, S. C. & Brodie, M. J. Drug-resistant epilepsy. N. Engl. J. Med. 365, 919–926 (2011).

    CAS  PubMed  Google Scholar 

  215. 215

    Sillanpää, M. & Schmidt, D. Early seizure frequency and aetiology predict long-term medical outcome in childhood-onset epilepsy. Brain 132, 989–998 (2009).

    PubMed  Google Scholar 

  216. 216

    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).

    PubMed  Google Scholar 

  217. 217

    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).

    PubMed  Google Scholar 

  218. 218

    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).

    CAS  PubMed  Google Scholar 

  219. 219

    Devinsky, O. et al. Changes in depression and anxiety after resective surgery for epilepsy. Neurology 65, 1744–1749 (2005).

    CAS  PubMed  Google Scholar 

  220. 220

    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).

    PubMed  Google Scholar 

  221. 221

    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).

    PubMed  Google Scholar 

  222. 222

    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).

    PubMed  Google Scholar 

  223. 223

    Milby, A. H., Halpern, C. H. & Baltuch, G. H. Vagus nerve stimulation in the treatment of refractory epilepsy. Neurotherapeutics 6, 228–237 (2009).

    PubMed  PubMed Central  Google Scholar 

  224. 224

    Ryvlin, P. et al. Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy. Epilepsia 59, 562–572 (2018).

    CAS  PubMed  Google Scholar 

  225. 225

    Fisher, R. et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51, 899–908 (2010).

    PubMed  Google Scholar 

  226. 226

    Morrell, M. J. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77, 1295–1304 (2011).

    PubMed  Google Scholar 

  227. 227

    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).

    PubMed  Google Scholar 

  228. 228

    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).

    PubMed  Google Scholar 

  229. 229

    Lefevre, F. & Aronson, N. Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics 105, e46–e46 (2000).

    CAS  PubMed  Google Scholar 

  230. 230

    Cervenka, M. C. et al. Phase I/II multicenter ketogenic diet study for adult superrefractory status epilepticus. Neurology 88, 938–943 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231

    Neal, E. G. et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7, 500–506 (2008).

    PubMed  Google Scholar 

  232. 232

    Kossoff, E. H. & Dorward, J. L. The modified Atkins diet. Epilepsia 49, 37–41 (2008).

    CAS  PubMed  Google Scholar 

  233. 233

    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).

    PubMed  Google Scholar 

  234. 234

    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).

    PubMed  Google Scholar 

  235. 235

    Devinsky, O. et al. Development of the quality of life in epilepsy inventory. Epilepsia 36, 1089–1104 (1995).

    CAS  PubMed  Google Scholar 

  236. 236

    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).

    PubMed  Google Scholar 

  237. 237

    Choi, H. et al. Seizure frequency and patient-centered outcome assessment in epilepsy. Epilepsia 55, 1205–1212 (2014).

    PubMed  Google Scholar 

  238. 238

    Boylan, L. S. et al. Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 62, 258–261 (2004).

    CAS  PubMed  Google Scholar 

  239. 239

    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).

    PubMed  Google Scholar 

  240. 240

    Fiest, K. M. et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology 80, 590–599 (2013).

    PubMed  PubMed Central  Google Scholar 

  241. 241

    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).

    CAS  PubMed  Google Scholar 

  242. 242

    Hamid, H. et al. Mood, anxiety, and incomplete seizure control affect quality of life after epilepsy surgery. Neurology 82, 887–894 (2014).

    PubMed  PubMed Central  Google Scholar 

  243. 243

    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).

    PubMed  PubMed Central  Google Scholar 

  244. 244

    McKee, H. R. & Privitera, M. D. Stress as a seizure precipitant: Identification, associated factors, and treatment options. Seizure 44, 21–26 (2017).

    PubMed  Google Scholar 

  245. 245

    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).

    PubMed  Google Scholar 

  246. 246

    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).

    PubMed  Google Scholar 

  247. 247

    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).

    PubMed  Google Scholar 

  248. 248

    Atif, M., Sarwar, M. R. & Scahill, S. The relationship between epilepsy and sexual dysfunction: a review of the literature. Springerplus 5, 2070 (2016).

    PubMed  PubMed Central  Google Scholar 

  249. 249

    Yang, Y. & Wang, X. Sexual dysfunction related to antiepileptic drugs in patients with epilepsy. Expert Opin. Drug Saf. 15, 31–42 (2016).

    CAS  PubMed  Google Scholar 

  250. 250

    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).

    PubMed  Google Scholar 

  251. 251

    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).

    PubMed  Google Scholar 

  252. 252

    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).

    PubMed  Google Scholar 

  253. 253

    Nyberg, J. et al. Cardiovascular fitness and later risk of epilepsy: a Swedish population-based cohort study. Neurology 81, 1051–1057 (2013).

    PubMed  Google Scholar 

  254. 254

    Depienne, C. et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J. Med. Genet. 47, 404–410 (2010).

    CAS  PubMed  Google Scholar 

  255. 255

    Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256

    Xu, X. et al. Amplicon resequencing identified parental mosaicism for approximately 10% of ‘de novoSCN1A mutations in children with Dravet syndrome. Hum. Mutat. 36, 861–872 (2015).

    PubMed  PubMed Central  Google Scholar 

  257. 257

    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).

    CAS  PubMed  Google Scholar 

  258. 258

    Friedman, A. et al. Should losartan be administered following brain injury? Expert Rev. Neurother. 14, 1365–1375 (2014).

    CAS  PubMed  Google Scholar 

  259. 259

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

    CAS  PubMed  Google Scholar 

  260. 260

    Milligan, C. J. et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann. Neurol. 75, 581–590 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 261

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. 262

    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).

    CAS  PubMed  Google Scholar 

  263. 263

    Mikati, M. A. et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann. Neurol. 78, 995–999 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 264

    Bearden, D. et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann. Neurol. 76, 457–461 (2014).

    CAS  PubMed  Google Scholar 

  265. 265

    Mullen, S. A. et al. Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine. Neurology 90, e67–e72 (2018).

    CAS  PubMed  Google Scholar 

  266. 266

    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.

    PubMed  Google Scholar 

  267. 267

    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).

    Google Scholar 

  268. 268

    Beghi, E. et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 51, 671–675 (2010).

    PubMed  Google Scholar 

  269. 269

    Sveinsson, O., Andersson, T., Carlsson, S. & Tomson, T. The incidence of SUDEP. Neurology 89, 170–177 (2017).

    PubMed  Google Scholar 

  270. 270

    Devinsky, O. et al. Underestimation of sudden deaths among patients with seizures and epilepsy. Neurology 89, 886–892 (2017).

    PubMed  PubMed Central  Google Scholar 

  271. 271

    Hesdorffer, D. C. et al. Combined analysis of risk factors for SUDEP. Epilepsia 52, 1150–1159 (2011).

    PubMed  Google Scholar 

  272. 272

    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.

    PubMed  Google Scholar 

  273. 273

    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).

    PubMed  Google Scholar 

  274. 274

    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).

    CAS  PubMed  Google Scholar 

  275. 275

    Ishiura, H. et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat. Genet. 50, 581–590 (2018).

    CAS  PubMed  Google Scholar 

  276. 276

    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).

    CAS  PubMed  Google Scholar 

  277. 277

    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.

    PubMed  Google Scholar 

  278. 278

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

    CAS  PubMed  PubMed Central  Google Scholar 

  279. 279

    Jentink, J. et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N. Engl. J. Med. 362, 2185–2193 (2010).

    CAS  PubMed  Google Scholar 

  280. 280

    Tomson, T. et al. Pregnancy registries: Differences, similarities, and possible harmonization. Epilepsia 51, 909–915 (2010).

    PubMed  Google Scholar 

  281. 281

    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).

    CAS  PubMed  Google Scholar 

  282. 282

    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).

    CAS  PubMed  Google Scholar 

  283. 283

    Vajda, F. J. E. et al. The teratogenic risk of antiepileptic drug polytherapy. Epilepsia 51, 805–810 (2009).

    PubMed  Google Scholar 

  284. 284

    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).

    PubMed  Google Scholar 

  285. 285

    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).

    CAS  PubMed  Google Scholar 

  286. 286

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  287. 287

    Wood, A. G. et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia 56, 1047–1055 (2015).

    CAS  PubMed  Google Scholar 

  288. 288

    Meador, K. J. et al. Breastfeeding in children of women taking antiepileptic drugs. JAMA Pediatr. 168, 729 (2014).

    PubMed  PubMed Central  Google Scholar 

  289. 289

    Perucca, P. & Mula, M. Antiepileptic drug effects on mood and behavior: molecular targets. Epilepsy Behav. 26, 440–449 (2013).

    PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

Introduction (O.D. and I.E.S.); Epidemiology (N.J.); Mechanisms/pathophysiology (A.V., M.d.C. and I.E.S.); Diagnosis, screening and prevention (P.P. and I.E.S.); Management (T.J.O.B.); Quality of life (O.D.); Outlook (I.E.S. and O.D.); and Overview of Primer (O.D.).

Corresponding author

Correspondence to Orrin Devinsky.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary box 1

Epilepsy syndromes by age of seizure onset. (PDF 88 kb)

Supplementary Table 1

Precision therapies. (PDF 124 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Devinsky, O., Vezzani, A., O'Brien, T. et al. Epilepsy. Nat Rev Dis Primers 4, 18024 (2018). https://doi.org/10.1038/nrdp.2018.24

Download citation

Further reading

Search

Quick links

Nature Briefing

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

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