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Genetic generalized epilepsies in adults — challenging assumptions and dogmas

Nature Reviews Neurology volume 18, pages 71–83 (2022)Cite this article

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Abstract

Genetic generalized epilepsy (GGE) syndromes start during childhood or adolescence, and four commonly persist into adulthood, making up 15–20% of all cases of epilepsy in adults. These four GGE syndromes are childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic–clonic seizures alone. However, in ~20% of patients with GGE, characteristics of more than one syndrome are present. Novel insights into the genetic aetiology, comorbidities and prognosis of the GGE syndromes have emerged and challenge traditional concepts about these conditions. Evidence has shown that the mode of inheritance in GGE is mostly polygenic. Neuropsychological and imaging studies indicate similar abnormalities in unaffected relatives of patients with GGE, supporting the concept that underlying alterations in bilateral frontothalamocortical networks are genetically determined. Contrary to popular belief, first-line anti-seizure medication often fails to provide seizure freedom in combination with good tolerability. Nevertheless, long-term follow-up studies have shown that with advancing age, many patients can discontinue their anti-seizure medication without seizure relapses. Several outcome predictors have been identified, but prognosis across the syndromes is more homogeneous than previously assumed. Overall, overlap in pathophysiology, seizure types, treatment responses and outcomes support the idea that GGEs are not separate nosological entities but represent a neurobiological continuum.

Key points

  • Four genetic generalized epilepsy (GGE) syndromes affect ~0.1% of the adult population: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic–clonic seizures alone.

  • Pedigree studies have strongly suggested a genetic aetiology of GGE, but modes of inheritance are complex and the genetic mechanisms that underlie GGE are poorly understood.

  • Seizures and cognitive impairment in GGE arise from functional imbalances in frontothalamocortical brain networks.

  • Neuropsychiatric deficits and less favourable responsiveness to anti-seizure medication than previously assumed indicate that GGE is not necessarily benign.

  • Ethosuximide is the drug of choice for absence seizures, and valproic acid is effective against all generalized seizure types, but adverse effects, including teratogenicity, limit the usability of valproic acid.

  • Long-term outcomes seem to be homogeneous across the four GGE syndromes; seizure propensity decreases with advancing age so that successful discontinuation of anti-seizure medication becomes possible.

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Fig. 1: Prevalence of active GGE syndromes across the lifespan.
Fig. 2: Ictal EEG findings in genetic generalized epilepsies.

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Authors and Affiliations

  1. Epilepsy-Center Berlin-Brandenburg, Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Bernd J. Vorderwülbecke & Martin Holtkamp

  2. EEG and Epilepsy Unit, University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Bernd J. Vorderwülbecke

  3. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK

    Britta Wandschneider

  4. Department of Neurology, The Royal London Hospital, Barts Health NHS Trust, London, UK

    Britta Wandschneider

  5. Department of Epileptology and Neurology, University of Aachen, Aachen, Germany

    Yvonne Weber

  6. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

    Yvonne Weber

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B.J.V. and M.H. coordinated the overall process of manuscript production. All authors were involved in the design of the Review, performed literature searches and wrote chapters of the manuscript. B.J.V. and M.H. designed the figures. All authors reviewed and edited the manuscript before submission and gave final approval for submission.

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Correspondence to Martin Holtkamp.

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Competing interests

B.J.V. received funding from the German Research Foundation (DFG 422589384). B.W. receives funding from the Medical Research Council (MR/T005335/1). Y.W. is supported by the German Research Foundation (DFG, FOR2715, WE4896/4-1) and the German Federal Ministry of Education and Research (BMBF, TreatIon, 01GM1907A). Within the past 3 years, she has received consultancy fees and support for travel expenses and for the organization of conferences from Desitin and UCB. M.H. holds the ‘Friedrich von Bodelschwingh Endowed Professorship for Clinical and Experimental Epileptology’ at the Department of Neurology, Charité – Universitätsmedizin Berlin funded by the v. Bodelschwingh Foundation. Within the past 3 years, he has received speaker’s honoraria and/or consultancy fees from Arvelle, Bial, Desitin, Eisai, GW Pharmaceuticals, UCB and Zogenix. Funding bodies were not involved in the writing of the report or the decision to submit the paper for publication.

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Review criteria

Appropriate references were identified through searches of PubMed, with a focus on articles published between 1 January 2000 and 15 April 2021. Search terms were combinations of the terms “generalized”, “genetic”, “idiopathic”, “epilepsy”, “absence”, “myoclonic”, “myoclonus”, “tonic–clonic”, “grand mal”, “seizure”, “receptor”, “variant”, “cognitive”, “psychiatric”, “outcome”, “antiepileptic” and “antiseizure”. In addition, we searched our own bibliographies and those of relevant articles. Original research articles and, where appropriate, review articles and websites were included. The final reference list is based on originality and relevance to the scope of the review.

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Vorderwülbecke, B.J., Wandschneider, B., Weber, Y. et al. Genetic generalized epilepsies in adults — challenging assumptions and dogmas. Nat Rev Neurol 18, 71–83 (2022). https://doi.org/10.1038/s41582-021-00583-9

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