Remi Stevelink, University Medical Center Utrecht
Dania Al-Toma, University Medical Center Utrecht
Floor E. Jansen, University Medical Center Utrecht
Herm J. Lamberink, University Medical Center Utrecht
Ali A. Asadi-Pooya, Thomas Jefferson UniversityFollow
Mohsen Farazdaghi, Shiraz University of Medical Sciences
Gonçalo Cação, Unidade Local de Saude do Alto Minho
Sita Jayalakshmi, Krishna Institute of Medical Sciences
Anuja Patil, Krishna Institute of Medical Sciences
Çiğdem Özkara, Istanbul University
Şenay Aydın, University of Health Sciences, Istanbul
Joanna Gesche, Odense University Hospital
Christoph P. Beier, Odense University Hospital
Linda J. Stephen, University of Glasgow
Martin J. Brodie, University of Glasgow
Gopeekrishnan Unnithan, Sree Chitra Tirunal Institute for Medical Sciences and Technology
Ashalatha Radhakrishnan, Sree Chitra Tirunal Institute for Medical Sciences and Technology
Julia Höfler, Paracelsus Medical University and Centre for Cognitive Neuroscience
Eugen Trinka, Paracelsus Medical University and Centre for Cognitive Neuroscience
Roland Krause, University of Luxembourg
Emanuele Cerulli Irelli, Sapienza University of Rome
Carlo Di Bonaventura, Sapienza University of Rome
Jerzy P. Szaflarski, University Of Alabama At Birmingham
Laura E. Hernández-Vanegas, National Institute of Neurology and Neurosurgery- Mexico
Monica L. Moya-Alfaro, National Institute of Neurology and Neurosurgery- Mexico
Yingying Zhang, West China Hospital of Sichuan University
Dong Zhou, West China Hospital of Sichuan University
Nicola Pietrafusa, Bambino Gesù Children's Hospital
Nicola Specchio, Bambino Gesù Children's Hospital
Giorgi Japaridze, Institute of Neurology and Neuropsychology- Georgia
Sándor Beniczky, Danish Epilepsy Centre
Mubeen Janmohamed, Monash University
Patrick Kwan, University of Melbourne
Marte Syvertsen, Vestre Viken Hospital Trust
Kaja K. Selmer, Oslo University Hospital
Bernd J. Vorderwülbecke, niversitätsmedizin Berlin
Martin Holtkamp, niversitätsmedizin Berlin
Lakshminarayanapuram G. Viswanathan, National Institute of Mental Health and Neurosciences- India
Sanjib Sinha, National Institute of Mental Health and Neurosciences
Betül Baykan, Istanbul University
Ebru Altindag, Istanbul Florence Nightingale Hospital
Felix von Podewils, University Medicine Greifswald
Juliane Schulz, University Medicine Greifswald
Udaya Seneviratne, The University of Melbourne
Alejandro Viloria-Alebesque, Hospital General de la Defensa
Ioannis Karakis, Emory University
Wendyl J. D'Souza, The University of Melbourne
Josemir W. Sander, Stichting Epilepsie Instellingen Nederland
Bobby P. C. Koeleman, University Medical Center Utrecht
Willem M. Otte, University Medical Center Utrecht
Kees P. J. Braun, University Medical Center Utrecht

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This is the author's final published version in eClinicalMedicine, Volume 53, November 2022, Article Number 101732.

The published version is available at Copyright © 2022 The Author(s). Published by Elsevier Ltd.


BACKGROUND: A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME.

METHODS: We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed - last updated on March 11, 2021 - including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF;

FINDINGS: Our search yielded 1641 articles; 53 were eligible, of which the authors of 24 studies agreed to collaborate by sharing IPD. Using data from 2518 people with JME, we found nine independent predictors of drug resistance: three seizure types, psychiatric comorbidities, catamenial epilepsy, epileptiform focality, ethnicity, history of CAE, family history of epilepsy, status epilepticus, and febrile seizures. Internal-external cross-validation of our multivariable model showed an area under the receiver operating characteristic curve of 0·70 (95%CI 0·68-0·72). Recurrence of seizures after ASM withdrawal (n = 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68-0·73).

INTERPRETATION: We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools.


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Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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