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Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

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posted on 2022-01-04, 09:33 authored by Christopher D Whelan, Andre Altmann, Juan A. Botía, Neda Jahanshad, Derrek P. Hibar, Julie Absil, Saud Alhusaini, Marina KM Alvim, Pia Auvinen, Emanuele Bartolini, Felipe PG Bergo, Tauana Bernardes, Karen Blackmon, Barbara Braga, Maria Eugenia Caligiuri, Anna Calvo, Sarah J. Carr, Shuai Chen, Andrea Cherubini, Philippe David, Martin Domin, Sonya Foley, Wendy França, Gerrit Haaker, Dmitry Isaev, Simon S. Keller, Raviteja Kotikalapudi, Magdalena A. Kowalczyk, Ruben Kuzniecky, Soenke Langner, Matteo Lenge, Kelly M. Leyden, Min Liu, Richard Q. Loi, Pascal Martin, Mario Mascalchi, Marcia E. Morita, Jose C. Pariente, Raul Rodríguez-Cruces, Christian Rummel, Taavi Saavalainen, Mira K. Semmelroch, Mariasavina Severino, Rhys H. Thomas, Manuela Tondelli, Domenico Tortora, Anna Elisabetta Vaudano, Lucy Vivash, Felix von Podewils, Jan Wagner, Bernd Weber, Yi Yao, Clarissa L. Yasuda, Guohao Zhang, Nuria Bargalló, Benjamin Bender, Neda Bernasconi, Andrea Bernasconi, Boris C. Bernhardt, Ingmar Blümcke, Chad Carlson, Gianpiero CavalleriGianpiero Cavalleri, Fernando Cendes, Luis Concha, Norman DelantyNorman Delanty, Chantal Depondt, Orrin Devinsky, Colin P. Doherty, Niels K. Focke, Antonio Gambardella, Renzo Guerrini, Khalid Hamandi, Graeme D. Jackson, Reetta Kälviäinen, Peter Kochunov, Patrick Kwan, Angelo Labate, Carrie R. McDonald, Stefano Meletti, Terence J. O'Brien, Sebastien Ourselin, Mark P. Richardson, Pasquale Striano, Thomas Thesen, Roland Wiest, Junsong Zhang, Annamaria Vezzani, Mina Ryten, Paul M. Thompson, Sanjay M. Sisodiya

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.


This study was supported in part by a Center grant (U54 EB020403) from the National Institutes of Health as part of the 2014 Big Data to Knowledge (BD2K) Initiative. The work was partly undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. We are grateful to the Wolfson Trust and the Epilepsy Society for supporting the Epilepsy Society MRI scanner. The UNICAMP research centre was funded by FAPESP (Sa˜o Paulo Research Foundation); Contract grant number: 2013/07559-3. The BRI at the Florey Institute of Neuroscience and Mental Health acknowledges funding from the National Health and Medical Research Council of Australia (NHMRC Project Grant 628952, Practitioner Fellowship 1060312). The UCSD research centre acknowledges support from the U.S. National Institute of Neurological Disorders and Stroke (NIH/NINDS, grant no. R01NS065838). The UNAM centre was funded by grants UNAM-DGAPA IB201712 and Conacyt 181508 RRC Graduate Fellowship Conacyt 329866. UNIMORE acknowledges funding from the Carismo Foundation (grant number: A.010@FCRMO RINT@MELFONINFO) and the Italian Ministry of Health, Emilia-Romagna Region (N. PRUA1GR-2013-00000120). Work conducted at Kuopio University Hospital was funded by Government Grant 5772810. Work at the University of Eastern Finland was funded by Vaajasalo Foundation and Saastamoinen Foundation. Funding sources for the King’s College London research centre include: National Institute for Health Research Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust; Medical Research Council (grants G0701310 and MR/K013998/ 1); Epilepsy Research UK. Work conducted at the University of Liverpool was funded by the UK Medical Research Council (grant MR/K023152/1). The Cardiff University centre acknowledges funding from Cardiff University Brain Research Imaging Centre, Cardiff and Vale University Health Board, Epilepsy Research UK and Health a



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Whelan CD, Altmann A, Botia JA, Jahanshad N, Hibar DP, Absil J, et al. Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study. Brain. 2018 [Epub ahead of print]

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