Sex-specific disease modifiers in juvenile myoclonic epilepsy

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  • Amy Shakeshaft
  • Naim Panjwani
  • Amber Collingwood
  • Holly Crudgington
  • Anna Hall
  • Danielle M. Andrade
  • Christoph P. Beier
  • Choong Yi Fong
  • Elena Gardella
  • Joanna Gesche
  • David A. Greenberg
  • Khalid Hamandi
  • Jeanette Koht
  • Kheng Seang Lim
  • Rikke S. Møller
  • Ching Ching Ng
  • Alessandro Orsini
  • Mark I. Rees
  • Kaja K. Selmer
  • Pasquale Striano
  • Marte Syvertsen
  • Rhys H. Thomas
  • Jana Zarubova
  • Mark P. Richardson
  • Lisa J. Strug
  • Deb K. Pal

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.

OriginalsprogEngelsk
Artikelnummer2785
TidsskriftScientific Reports
Vol/bind12
Udgave nummer1
Antal sider12
ISSN2045-2322
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
AS, NP, AC, HC, AH, CPB, CYF, EG, JG, DAG, KH, JK, KSL, RSM, CCN, AO, MIR, GR, JZ, MPR, LJS and DKP report no conflicts of interest. DA reports a grant and honoraria from Biocodex, honoraria from Eisai, royalties from UpToDate and grants from Ontario Brain Institute, McLaughlin Foundation and Dravet Syndrome Foundation, outside the present work. KKS reports a travel grant from UCB Nordic outside the present work. PS reports grants from Proveca and personal fees from Kolfarma, outside the present work. MS reports honoraria from Eisai. RHT reports honoraria from Sanofi, Eisai, GW Pharma, UCB Pharma, Zogenix, Arvelle and Bial and meeting support from LivaNova and Novartis outside the present work.

Funding Information:
This work was supported by the Canadian Institutes of Health Research: Biology of Juvenile Myoclonic Epilepsy 201503MOP‐342469 (DKP, LJS) and 201809FDN-407295 (LJS); UK Medical Research Council, Centre for Neurodevelopmental Disorders MR/N026063/1 (DKP, MPR); UK Medical Research Council, Programme Grant MR/K013998/1, (MPR); PhD stipend from UK Medical Research Council and the Sackler Institute for Translational Neurodevelopment (AS); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service Foundation Trust (DKP, MPR); UK Engineering and Physical Sciences Research Council, Centre for Predictive Modelling in Healthcare (EP/N014391/1 (MPR)); DINOGMI Department of Excellence of MIUR 2018–2022 (legge 232 del 2016 (PS)); Wales BRAIN Unit and Research Delivery Staff funded by Welsh Government through Health and Care Research Wales (KH); Biomarin srl, ENECTA srl, GW Pharmaceuticals, Kolfarma srl. and Eisai (PS); South-Eastern Regional Health Authority, Norway (Project Number 2016129) (JK); The Research Council of Norway (Project Number 299266 (MS)); Epilepsy Research UK (RT, MR); Health & Care Research Wales (MR), Wales Gene Park (MR), Abertawe Bro Morgannwg University NHS R&D (MR); UCB (GR); Nationwide Children’s Hospital (DAG); Odense University Hospital (JG); University of Southern Denmark (17/18517 (CPB)).

Funding Information:
BIOJUME is funded by the Canadian Institutes of Health Research (MOP-142405, FRN-167282) and received ethical approval from the National Health Service (NHS) Health Research Authority (South Central-Oxford C Research Ethics Committee, reference 16/SC/0266) and the Research Ethics Board of the Hospital for Sick Children, Toronto (REB#1000033784). Local ethical approvals were also held for all international sites. All procedures complied with appropriate regulatory requirements and ethical principles in line with the Declaration of Helsinki. Informed consent was obtained and documented for all participants. Assent was obtained from minors (under 16), and informed consent was obtained on their behalf by a parent or legally appropriate guardian. All clinical data from participants were de-identified before entry into the central database. Acknowledgements

Publisher Copyright:
© 2022, The Author(s).

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