Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities and treatment response, as they relate to diagnostic and prognostic purposes, has not been explored. In this paper, we aim to provide an evidence-based definition of juvenile myoclonic epilepsy showing that with a predefined and limited set of mandatory features, variation in juvenile myoclonic epilepsy phenotype can be exploited for prognostic purposes. Our study is based on clinical data collected by the Biology of Juvenile Myoclonic Epilepsy Consortium augmented by literature data. We review prognosis research on mortality and seizure remission, predictors of antiseizure medication resistance and selected adverse drug events to valproate, levetiracetam and lamotrigine. Based on our analysis, a simplified set of diagnostic criteria for juvenile myoclonic epilepsy includes the following: (i) myoclonic jerks as mandatory seizure type; (ii) a circadian timing for myoclonia not mandatory for the diagnosis of juvenile myoclonic epilepsy; (iii) age of onset ranging from 6 to 40 years; (iv) generalized EEG abnormalities; and (v) intelligence conforming to population distribution. We find sufficient evidence to propose a predictive model of antiseizure medication resistance that emphasises (i) absence seizures as the strongest stratifying factor with regard to antiseizure medication resistance or seizure freedom for both sexes and (ii) sex as a major stratifying factor, revealing elevated odds of antiseizure medication resistance that correlates to self-report of catamenial and stress-related factors including sleep deprivation. In women, there are reduced odds of antiseizure medication resistance associated with EEG-measured or self-reported photosensitivity. In conclusion, by applying a simplified set of criteria to define phenotypic variations of juvenile myoclonic epilepsy, our paper proposes an evidence-based definition and prognostic stratification of juvenile myoclonic epilepsy. Further studies in existing data sets of individual patient data would be helpful to replicate our findings, and prospective studies in inception cohorts will contribute to validate them in real-world practice for juvenile myoclonic epilepsy management.

Abigail Wexner Research Institute Nationwide Children's Hospital Columbus 43215 USA

Adult Epilepsy Genetics Program Krembil Research Institute University of Toronto Toronto M5T 0S8 Canada

Danish Epilepsy Centre Filadelfia Dianalund 4293 Denmark

Department of Basic and Clinical Neurosciences Institute of Psychiatry Psychology and Neuroscience King's College London London SE5 8AF UK

Department of Clinical and Experimental Medicine Pisa University Hospital Pisa 56126 Italy

Department of Neurology 2nd Faculty of Medicine Charles University Prague 150 06 Czech Republic

Department of Neurology Cardiff and Vale University Health Board Cardiff CF14 4XW UK

Department of Neurology Drammen Hospital Vestre Viken Health Trust Oslo 3004 Norway

Department of Neurology Odense University Hospital Odense 5000 Denmark

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genova Genova 16132 Italy

Department of Research and Innovation Division of Clinical Neuroscience Oslo University Hospital Oslo 0372 Norway

Departments of Statistical Sciences and Computer Science and Division of Biostatistics The University of Toronto Toronto M5G 1Z5 Canada

Division of Neurology Department of Medicine Faculty of Medicine University of Malaya Kuala Lumpur 50603 Malaysia

Division of Paediatric Neurology Department of Pediatrics Faculty of Medicine University of Malaya Kuala Lumpur 50603 Malaysia

Institute of Biological Sciences Faculty of Science University of Malaya Kuala Lumpur 50603 Malaysia

Institute of Clinical Medicine University of Copenhagen Copenhagen 2200 Denmark

Motol University Hospital Prague 150 06 Czech Republic

MRC Centre for Neurodevelopmental Disorders King's College London London SW1H 9NA UK

National Centre for Epilepsy Oslo University Hospital Oslo 1337 Norway

Newcastle upon Tyne NHS Foundation Trust Newcastle upon Tyne NE7 7DN UK

Pediatric Neurology and Muscular Disease Unit IRCCS Istituto 'G Gaslini' Genova 16147 Italy

Program in Genetics and Genome Biology The Hospital for Sick Children Toronto M5G 1X8 Canada

School of Neuroscience Institute of Psychiatry Psychology and Neuroscience King's College London SE5 8AF UK

Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne NE1 7RU UK

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