Variation in prognosis and treatment outcome in juvenile myoclonic epilepsy: a Biology of Juvenile Myoclonic Epilepsy Consortium proposal for a practical definition and stratified medicine classifications
Authors: Rubboli Guido , Beier Christoph P , Selmer Kaja K , Syvertsen Marte , Shakeshaft Amy , Collingwood Amber , Hall Anna , Andrade Danielle M , Fong Choong Yi , Gesche Joanna , Greenberg David A , Hamandi Khalid , Lim Kheng Seang , Ng Ching Ching , Orsini Alessandro ,   BIOJUME Consortium, Strug Lisa , Panjwani Naim , Lin Fan , Andrade Danielle , Zarubova Jana , Šobíšková Zuzana , Cechovaz  , Pracoviste  , Kajsova Michaela , Rubboli Guido , Møller Rikke S , Gardella Elena , Beier Christoph P , Gesche Joanna , Miranda Maria , Talvik Inga , Striano Pasquale , Orsini Alessandro , Fong Choong Yi , Ng Ching Ching , Lim Kheng Seang , Selmer Kaja K , Syvertsen Marte , Bala Pronab , Kitching Amy , Irwin Kate , Walding Lorna , Adams Lynsey , Jegathasan Uma , Swingler Rachel , Wane Rachel , Aram Julia , Sudarsan Nikil , Mullan Dee , Ramsay Rebecca , Richmond Vivien , Sargent Mark , Frattaroli Paul , Taylor Matthew , Home Marie , Uka Sal , Kilroy Susan , Nortcliffe Tonicha , Salim Halima , Holroyd Kelly , Hamandi Khalid , McQueen Alison , Mcaleer Dympna , Jayachandran Dina , Egginton Dawn , MacDonald Bridget , Chang Michael , Deekollu David , Gaurav Alok , Hamilton Caroline , Takon Jaya Natarajan Inyan , Cotta Janet , Moran Nick , Bland Jeremy , Belderbos Rosemary , Collier Heather , Henry Joanne , Milner Matthew , White Sam , Koutroumanidis Michalis , Stern William , Richardson Mark P , Quirk Jennifer , Ceballos Javier Peña , Anastasia  , Papathanasiou  , Stavropoulos Ioannis , Lozsadi Dora , Swain Andrew , Quamina Charlotte , Crooks Jennifer , Majeed Tahir , Raj Sonia , Patel Shakeelah , Young Michael , Maguire Melissa , Ray Munni , Peacey Caroline , Makawa Linetty , Chhibda Asyah , Sacre Eve , Begum Shanaz , O’Malley Martin , Yeung Lap , Holliday Claire , Woodhead Louise , Rhodes Karen , Thomas Rhys , Ellawela Shan , Glenton Joanne , Calder Verity , Davis John , McAlinden Paul , Francis Sarah , Robson Lisa , Lanyon Karen , Mackay Graham , Stephen Elma , Thow Coleen , Connon Margaret , Kirkpatrick Martin , MacFarlane Susan , Macleod Anne , Rice Debbie , Kumar Siva , Campbell Carolyn , Collins Vicky , Whitehouse William , Giavasi Christina , Petrova Boyanka , Brown Thomas , Picton Catie , O’Donoghue Michael , West Charlotte , Navarra Helen , Slaght Seán J , Edwards Catherine , Gribbin Andrew , Nelson Liz , Warriner Stephen , Angus-Leppan Heather , Ehiorobo Loveth , Camara Bintou , Samakomva Tinashe , Mohanraj Rajiv , Parker Vicky , Pandey Rajesh , Charles Lisa , Cotter Catherine , Desurkar Archana , Hyde Alison , Harrison Rachel , Reuber Markus , Clegg Rosie , Sidebottom Jo , Recto Mayeth , Easton Patrick , Waite Charlotte , Howell Alice , Smith Jacqueline , Clegg Rosie , Mariguddi Shyam , Haslam Zena , Galizia Elizabeth , Cock Hannah , Mencias Mark , Truscott Samantha , Daly Deirdre , Mhandu Hilda , Said Nooria , Rees Mark , Chung Seo-Kyung , Pickrell Owen , Fonferko-Shadrach Beata , Baker Mark , Whiting Amy , Swain Louise , O’Brien Kirsty , Scott Fraser , Ghaus Naveed , Castle Gail , Bartholomew Jacqui , Needle Ann , Ball Julie , Clough Andrea , Sastry Shashikiran , Agrawal Charlotte Busby Amit , Dickerson Debbie , Duran Almu , Khan Muhammad , Thrasyvoulou Laura , Irvine Eve , Tittensor Sarah , Daglish Jacqueline , Kumar Sumant , Backhouse Claire , Mewies Claire , Aram Julia , Sudarsan Nikil , Mullan Dee , Ramsay Rebecca , Richmond Vivien , Skinner Denise , Sargent Mark , Bharat Rahul , Sharman Sarah-Jane , Saraswatula Arun , Cockerill Helen , Greenberg David A , Striano Pasquale , Thomas Rhys H , Zarubova Jana , Richardson Mark P , Strug Lisa J , Pal Deb K 
Published: June 2023

Abstract
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.