Limited sex‐specific structural alterations across common epilepsies: A worldwide ENIGMA study

Abstract Objective Epilepsy is characterized by widespread cortical and subcortical structural alterations beyond the epileptic zone. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy are seldomly reported in neuroimaging studies, partly due to limited sample sizes and single‐center designs. We therefore tested whether epilepsy‐related structural alterations differ between males and females, and whether the associations between structural measures and clinical characteristics vary by sex. Methods We analyzed clinician‐assigned biological sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multicenter cohort of 1253 epilepsy patients and 1077 healthy controls. We studied cortical thickness and subcortical volume in temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Results Both male and female patients with TLE showed widespread cortical and subcortical alterations in sex‐stratified analyses, whereas GGE showed more extensive alterations in female patients and only subtle alterations in male patients. However, no significant sex‐by‐diagnosis interactions were identified in either the TLE ( t = −2.153 to 1.705, all p FDR >.05) or GGE ( t = −1.797 to 2.774, all p FDR >.05) cohort. Likewise, no significant interactions were found between sex and age at onset ( t TLE = −1.835 to 1.092, t GGE = −2.394 to 1.392, all p FDR >.05) or disease duration ( t TLE = −2.643 to 2.048, t GGE = −1.234 to 2.017, all p FDR >.05) in either patient group. Significance Overall, although sex differences in behavioral and clinical outcomes of epilepsy have been consistently reported in previous studies, our results indicate that sex‐related clinical differences in epilepsy are not strongly captured by macroscale structural magnetic resonance imaging measures, and may instead arise from hormonal, neurochemical, or functional–network mechanisms.

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Journal
Epilepsia
Published
2026-10-14
DOI
https://doi.org/10.1002/epi.70515
Primary Topic
Epilepsy research and treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Limited sex‐specific structural alterations across common epilepsies: A worldwide ENIGMA study

Orrin Devinsky, Mohamad Zakaria Koubeissi, Boris C. Bernhardt, Victoria Lyn Ives-Deliperi et al.
Epilepsia
Epilepsy research and treatment
article

Limited sex‐specific structural alterations across common epilepsies: A worldwide ENIGMA study

Orrin Devinsky, Mohamad Zakaria Koubeissi, Boris C. Bernhardt, Victoria Lyn Ives-Deliperi, Sofia Maria Panzeri, Ella Sahlas, Matteo Lenge, Renzo Guerrini, K Schubert, Terence John O'Brien, Jonathan K. Kleen, Maria Eugenia Caligiuri, Francesco Fortunato, Sophia I. Thomopoulos, Sara K. Inati, Robert‐Paul Juster, Sofie Louise Valk, Stefano Meletti, Raúl Rodríguez‐Cruces, Judy Chen, Rafael Batista João, Jessica Royer, Anna Elisabetta Vaudano, Fernando Cendes, Niels K. Focke, Antonio Gambardella, Antonella Riva, Taha Gholipour, Tobias Bauer, Benjamin Sinclair, Mariasavina Severino, Patrick B. Moloney, Hamid Soltanian‐Zadeh, Sara Larivière, Leigh N. Sepeta, Lucy E. Vivash, Luis Concha, Carrie R. McDonald, Neda Bernasconi, Raluca Pana, Marian Galovic, Sean N. Hatton, Meike D. Hettwer, Donatello Arienzo, Travis R. Stoub, Heath Pardoe, Sanjay M. Sisodiya, Andrea Bernasconi, Huantao Wen, Marina K. M. Alvim, Alexander Ngo, Angelo Labate, Bianca Serio, Clarissa Lin Yasuda, Ke Xie, Paolo Bonanni, Pasquale Striano, Erik Hans Ulrich Rauf, Theodor Rüber, Raphaël Christin, Paul M. Thompson, Edward D. Boyd, Marlo Naish, Arielle Dascal, Bin Wan, Nina V. Valientes, Mirana Iliza, Lucas Scárdua‐Silva, Meng Law
article en

Abstract

Abstract Objective Epilepsy is characterized by widespread cortical and subcortical structural alterations beyond the epileptic zone. Importantly, the clinical manifestation of epilepsy, including seizure types, psychiatric comorbidities, and treatment responses, has been shown to differ between sexes. However, sex differences in structural alterations in epilepsy are seldomly reported in neuroimaging studies, partly due to limited sample sizes and single‐center designs. We therefore tested whether epilepsy‐related structural alterations differ between males and females, and whether the associations between structural measures and clinical characteristics vary by sex. Methods We analyzed clinician‐assigned biological sex differences in common epilepsies and their related clinical variables using structural neuroimaging biomarkers in an international multicenter cohort of 1253 epilepsy patients and 1077 healthy controls. We studied cortical thickness and subcortical volume in temporal lobe epilepsy (TLE) and genetic generalized epilepsy (GGE). Results Both male and female patients with TLE showed widespread cortical and subcortical alterations in sex‐stratified analyses, whereas GGE showed more extensive alterations in female patients and only subtle alterations in male patients. However, no significant sex‐by‐diagnosis interactions were identified in either the TLE ( t = −2.153 to 1.705, all p FDR >.05) or GGE ( t = −1.797 to 2.774, all p FDR >.05) cohort. Likewise, no significant interactions were found between sex and age at onset ( t TLE = −1.835 to 1.092, t GGE = −2.394 to 1.392, all p FDR >.05) or disease duration ( t TLE = −2.643 to 2.048, t GGE = −1.234 to 2.017, all p FDR >.05) in either patient group. Significance Overall, although sex differences in behavioral and clinical outcomes of epilepsy have been consistently reported in previous studies, our results indicate that sex‐related clinical differences in epilepsy are not strongly captured by macroscale structural magnetic resonance imaging measures, and may instead arise from hormonal, neurochemical, or functional–network mechanisms.

Epilepsia
Bishop's University (CA), University of Geneva (CH), University of Southern California (US), University of Modena and Reggio Emilia (IT), University of Parma (IT), Rush University Medical Center (US), Montreal Neurological Institute and Hospital (CA), The Royal Melbourne Hospital (AU), Children's National (US), Université de Sherbrooke (CA), University of Bonn (DE), Leipzig University of Applied Sciences (DE), Henry Ford Health System (US), University of Cape Town (ZA), University of California, San Francisco (US), Universidade Estadual de Campinas (UNICAMP) (BR), George Washington University (US), University of Zurich (CH), University of Tehran (IR), Florey Institute of Neuroscience and Mental Health (AU), University Hospital Bonn (DE), Istituto Giannina Gaslini (IT), German Center for Neurodegenerative Diseases (DE), The Alfred Hospital (AU), Henry Ford Hospital (US), University of California San Diego (US), Magna Graecia University (IT), NYU Langone Health (US), Monash Alfred Psychiatry Research centre (AU), University Hospital of Zurich (CH), Azienda Ospedaliero-Universitaria di Modena (IT), National Institute of Neurological Disorders and Stroke (US), Meyer Children's Hospital (IT), Chemistry and Chemical Engineering Research Center of Iran (IR), Universitätsmedizin Göttingen (DE), Max Planck Institute for Human Cognitive and Brain Sciences (DE), Jülich Aachen Research Alliance (DE), Stadtwerke Jülich (Germany) (DE), Azienda Ospedaliera Universitaria Senese (IT), Brazilian Institute of Neuroscience and Neurotechnology (BR), IRCCS Eugenio Medea (IT), Alfred Health (AU), UCL Queen Square Institute of Neurology (GB), Heinrich Heine University Düsseldorf (DE), University of Florence (IT), University College London (GB), Epilepsy Society (GB), McGill University (CA), Monash University (AU), New York University (US), Université de Montréal (CA), University of Göttingen (DE), University of Pennsylvania (US), University of Genoa (IT), Universidad Nacional Autónoma de México (MX), University of Palermo (IT), Leipzig University (DE)
Finding A Cure for Epilepsy and Seizures, Fondation Brain Canada, Université de Sherbrooke, Australian Government, Sick Kids Foundation, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Canada Research Chairs, Fundação de Amparo à Pesquisa do Estado de São Paulo, Bundesministerium für Bildung und Forschung, Consejo Nacional de Ciencia y Tecnología, Ministero della Salute, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Jacobs Foundation, Max-Planck-Gesellschaft, Hector Fellow Academy, Helmholtz Association, Epilepsy Society, National Institutes of Health, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Québec - Santé, European Research Council, National Health and Medical Research Council, Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México, Medical Research Future Fund
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