Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials.

Jacqueline French, Nicola Specchio, Ingrid E Scheffer, Stéphane Auvin, J Helen Cross, Kette D Valente

Journal: Epilepsia 2025;66(4):1014-1023

PMID: 40013914

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Abstract

Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug-resistant seizures and developmental slowing or regression. DEEs encompass many epilepsy syndromes, although not all patients with a DEE can be classified into a specific syndrome. Our understanding of the etiologies of DEEs has been revolutionized with next-generation sequencing, with more than 900 genes implicated, in addition to structural causes. It is therefore now possible to consider precision medicine and novel therapeutic approaches for these devastating diseases with trials of repurposed and new drugs, including gene therapies. Trials are being designed to target either DEE diseases more broadly, specific DEE syndromes, or specific genetic DEEs. To serve this purpose, a clear operational definition of DEEs is needed to ensure that appropriate patients are selected for trials with precisely defined, targeted outcome measures. Herein we propose the operational definition of DEEs to set the stage for the development of DEE therapies.

Address: Epilepsy Research Centre, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.; Florey and Murdoch Children's Research Institutes, Melbourne, Victoria, Australia.; Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Parkville, Victoria, Australia.; Comprehensive Epilepsy Center, New York University Grossman School of Medicine, New York City, New York, USA.; Epilepsy Research Center, University of São Paulo Faculty of Medicine, São Paulo, Brazil.; Pediatric Neurology Department, CRMR Epilepsies Rares, Member of ERN EpiCARE, APHP, Robert Debré University Hospital, Paris, France.; Université Paris Cité, INSERM NeuroDiderot, Paris, France.; Institut Universitaire de France (IUF), Paris, France.; University College London (UCL) National Institute for Health and Care Research (NIHR) Biomedical Research Centres (BRC) Great Ormond Street Institute of Child Health, London, UK.; Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network, EpiCARE, Rome, Italy.; University Hospitals KU Leuven, Leuven, Belgium.

DOI: 10.1111/epi.18265

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MeSH Terms: Humans, Clinical Trials as Topic, Epilepsy, Epileptic Syndromes, Research Design, Anticonvulsants