Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis

Remi Stevelink; Dania Al-Toma; Floor E Jansen; Herm J Lamberink; Ali A Asadi-Pooya; Mohsen Farazdaghi; Gonçalo Cação; Sita Jayalakshmi; Anuja Patil; Çiğdem Özkara; Şenay Aydın; Joanna Gesche; Christoph P Beier; Linda J Stephen; Martin J Brodie; Gopeekrishnan Unnithan; Ashalatha Radhakrishnan; Julia Höfler; Eugen Trinka; Roland Krause; EpiPGX Consortium; Emanuele Cerulli Irelli; Carlo Di Bonaventura; Jerzy P Szaflarski; Laura E Hernández-Vanegas; Monica L Moya-Alfaro; Yingying Zhang; Dong Zhou; Nicola Pietrafusa; Nicola Specchio; Giorgi Japaridze; Sándor Beniczky; Mubeen Janmohamed; Patrick Kwan; Marte Syvertsen; Kaja K Selmer; Bernd J Vorderwülbecke; Martin Holtkamp; Lakshminarayanapuram G Viswanathan; Sanjib Sinha; Betül Baykan; Ebru Altindag; Felix von Podewils; Juliane Schulz; Udaya Seneviratne; Alejandro Viloria-Alebesque; Ioannis Karakis; Wendyl J D'Souza; Josemir W Sander; Bobby P C Koeleman; Willem M Otte; Kees P J Braun

doi:10.1016/j.eclinm.2022.101732

Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis

EClinicalMedicine. 2022 Nov 11:53:101732. doi: 10.1016/j.eclinm.2022.101732. eCollection 2022 Nov.

Authors

Remi Stevelink^{1

2}, Dania Al-Toma¹, Floor E Jansen¹, Herm J Lamberink¹, Ali A Asadi-Pooya^{3

4}, Mohsen Farazdaghi³, Gonçalo Cação⁵, Sita Jayalakshmi⁶, Anuja Patil⁶, Çiğdem Özkara⁷, Şenay Aydın⁸, Joanna Gesche^{9

10}, Christoph P Beier^{9

10}, Linda J Stephen¹¹, Martin J Brodie¹¹, Gopeekrishnan Unnithan¹², Ashalatha Radhakrishnan¹², Julia Höfler¹³, Eugen Trinka^{13

14

15}, Roland Krause¹⁶; EpiPGX Consortium; Emanuele Cerulli Irelli¹⁷, Carlo Di Bonaventura¹⁷, Jerzy P Szaflarski¹⁸, Laura E Hernández-Vanegas¹⁹, Monica L Moya-Alfaro¹⁹, Yingying Zhang²⁰, Dong Zhou²⁰, Nicola Pietrafusa²¹, Nicola Specchio²¹, Giorgi Japaridze²², Sándor Beniczky^{23

24}, Mubeen Janmohamed²⁵, Patrick Kwan^{25

26}, Marte Syvertsen²⁷, Kaja K Selmer²⁸, Bernd J Vorderwülbecke²⁹, Martin Holtkamp²⁹, Lakshminarayanapuram G Viswanathan³⁰, Sanjib Sinha³⁰, Betül Baykan³¹, Ebru Altindag³², Felix von Podewils³³, Juliane Schulz³³, Udaya Seneviratne^{34

35}, Alejandro Viloria-Alebesque^{36

37}, Ioannis Karakis³⁸, Wendyl J D'Souza³⁴, Josemir W Sander^{20

39

40}, Bobby P C Koeleman², Willem M Otte¹, Kees P J Braun¹

Affiliations

¹ Department of Child Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, European Reference Network EpiCARE, Heidelberglaan 100, Utrecht, 3584 CX, Netherlands.
² Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, European Reference Network EpiCARE, Heidelberglaan 100, Utrecht, 3584 CX, Netherlands.
³ Epilepsy Research Center, Shiraz University of Medical Sciences, Zand, Shiraz, Iran.
⁴ Department of Neurology, Thomas Jefferson University, 909 Walnut Street, Philadelphia, PA, 19107, USA.
⁵ Department of Neurology, Unidade Local de Saude do Alto Minho, Estrada de Santa Luzia, Viana do Castelo, 4904-858, Portugal.
⁶ Department of Neurology, Krishna Institute of Medical Sciences, Minister Road, Secunderabad, 500003, India.
⁷ Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpaşa, Kocamustafapaşa caddesi, Istanbul, 34098, Turkey.
⁸ Department of Neurology, Yedikule Chest Diseases and Chest Surgery Training and Research Hospital, University of Health Sciences, Belgrat Kapı yolu, Istanbul, 34020, Turkey.
⁹ Department of Neurology, Odense University Hospital, J.B. Winsløws Vej 4, Odense, 5000, Denmark.
¹⁰ Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 4, Odense, 5000, Denmark.
¹¹ Epilepsy Unit, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.
¹² Department of Neurology, R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Chalakkuzhi, Medical College Road, Trivandrum, 695011, India.
¹³ Department of Neurology and Neuroscience Institute, Christian Doppler Medical Centre, Paracelsus Medical University and Centre for Cognitive Neuroscience, European Reference Network EpiCARE, Ignaz-Harrer Straße 79, Salzburg, 5020, Austria.
¹⁴ Karl Landsteiner Institute for Neurorehabilitation and Space Neurology, Hellbrunner Straße 34, Salzburg, 3100, Austria.
¹⁵ Department of Public Health, University for Health Sciences, Medical Informatics and Technology, Eduard-Wallnöfer-Zentrum 1, Hall in Tirol, 6060, Austria.
¹⁶ Bioinformatics Core Facility, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Ave du Swing, Belvaux, 4367, Luxembourg.
¹⁷ Department of Human Neurosciences, Epilepsy Unit, Sapienza, University of Rome, Viale dell'Università 30, Rome, 00185, Italy.
¹⁸ Departments of Neurology, Neurosurgery, and Neurobiology, UAB Epilepsy Center, University of Alabama at Birmingham Heersink School of Medicine, 1670 University Blvd, Birmingham, AL, 35294, USA.
¹⁹ Department of Clinical Research, Epilepsy Clinic, National Institute of Neurology and Neurosurgery, Insurgentes Sur 3877, Mexico, 14269, Mexico.
²⁰ Department of Neurology, West China Hospital of Sichuan University, 37 Guoxue Road, Chengdu, 610000, China.
²¹ Department of Neuroscience, Division of Neurology, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio, 4, Rome, 00165, Italy.
²² Department of Clinical Neurophysiology, Institute of Neurology and Neuropsychology, 83/11 Vazha-Pshavela Ave., Tbilisi, 186, Georgia.
²³ Department of Clinical Neurophysiology, Danish Epilepsy Centre, Filadelfia, Visby Allé 5, Dianalund, 4293, Denmark.
²⁴ Department of Clinical Neurophysiology, Aarhus University Hospital and Aarhus University, Palle Juul-Jensens Blvd. 99, Aarhus, 8200, Denmark.
²⁵ Department of Neurosciences, Central Clinical School, Monash University, 99 Commercial Road, Melbourne, Victoria, 3004, Australia.
²⁶ Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Grattan Street, Parkville, Victoria, Australia.
²⁷ Department of Neurology, Vestre Viken Hospital Trust, Dronninggata 28, Drammen, 3004, Norway.
²⁸ National Centre for Epilepsy & Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, G. F. Henriksens vei 29, Sandvika, 1337, Norway.
²⁹ Department of Neurology, Epilepsy-Center Berlin-Brandenburg, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany.
³⁰ Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore, 560029, India.
³¹ Department of Neurology and Clinical Neurophysiology, Istanbul Faculty of Medicine, Istanbul University, Millet Cad, Istanbul, 34390, Turkey.
³² Department of Neurology, Istanbul Florence Nightingale Hospital, Abide-i Hürriyet Cad, Istanbul, 34381, Turkey.
³³ Department of Neurology, Epilepsy Center, University Medicine Greifswald, Sauerbruchstraße, Greifswald, 17489, Germany.
³⁴ Department of Medicine, St Vincent's Hospital Melbourne, The University of Melbourne, 55 Victoria Parade, Melbourne, Victoria, 3065, Australia.
³⁵ Department of Medicine, The School of Clinical Sciences at Monash Health, Monash University, Clayton Road, Melbourne, Victoria, 3168, Australia.
³⁶ Department of Neurology, Hospital General de la Defensa, Vía Ibérica 1, Zaragoza, 50009, Spain.
³⁷ Instituto de Investigación Sanitaria (IIS) Aragón, Avda. San Juan Bosco 13, Zaragoza, 50009, Spain.
³⁸ Department of Neurology, Emory University School of Medicine, 49 Jesse Hill Jr. Drive SE, Office 335, Atlanta, GA, 30303, USA.
³⁹ Stichting Epilepsie Instellingen Nederland (SEIN), Achterweg 7, Heemstede, Netherlands.
⁴⁰ UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Abstract

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; https://osf.io/b9zjc/).

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.

Funding: MING fonds.

Keywords: Drug resistance; Individual participant data; JME; Juvenile myoclonic epilepsy; Medication withdrawal; Meta-analysis; Multivariable prediction; Prediction model; Refractory epilepsy; Remission; Seizure recurrence.