TY - JOUR
T1 - Patterns of subregional cerebellar atrophy across epilepsy syndromes
T2 - An ENIGMA-Epilepsy study
AU - Kerestes, Rebecca
AU - Perry, Andrew
AU - Vivash, Lucy
AU - O'Brien, Terence J.
AU - Alvim, Marina K.M.
AU - Arienzo, Donatello
AU - Aventurato, Ítalo K.
AU - Ballerini, Alice
AU - Baltazar, Gabriel F.
AU - Bargalló, Núria
AU - Bender, Benjamin
AU - Brioschi, Ricardo
AU - Bürkle, Eva
AU - Caligiuri, Maria Eugenia
AU - Cendes, Fernando
AU - de Tisi, Jane
AU - Duncan, John S.
AU - Engel, Jerome P.
AU - Foley, Sonya
AU - Fortunato, Francesco
AU - Gambardella, Antonio
AU - Giacomini, Thea
AU - Guerrini, Renzo
AU - Hall, Gerard
AU - Hamandi, Khalid
AU - Ives-Deliperi, Victoria
AU - João, Rafael B.
AU - Keller, Simon S.
AU - Kleiser, Benedict
AU - Labate, Angelo
AU - Lenge, Matteo
AU - Marotta, Cassandra
AU - Martin, Pascal
AU - Mascalchi, Mario
AU - Meletti, Stefano
AU - Owens-Walton, Conor
AU - Parodi, Costanza B.
AU - Pascual-Diaz, Saül
AU - Powell, David
AU - Rao, Jun
AU - Rebsamen, Michael
AU - Reiter, Johannes
AU - Riva, Antonella
AU - Rüber, Theodor
AU - Rummel, Christian
AU - Scheffler, Freda
AU - Severino, Mariasavina
AU - Silva, Lucas S.
AU - Staba, Richard J.
AU - Stein, Dan J.
AU - Striano, Pasquale
AU - Taylor, Peter N.
AU - Thomopoulos, Sophia I.
AU - Thompson, Paul M.
AU - Tortora, Domenico
AU - Vaudano, Anna Elisabetta
AU - Weber, Bernd
AU - Wiest, Roland
AU - Winston, Gavin P.
AU - Yasuda, Clarissa L.
AU - Zheng, Hong
AU - McDonald, Carrie R.
AU - Sisodiya, Sanjay M.
AU - Harding, Ian H.
N1 - Funding Information:
The Bern research center was funded by the Swiss National Science Foundation (grant number 180365). The UNICAMP research center (Brazilian Institute of Neuroscience and Neurotechnology) was funded by Centros de Pesquisa, Inovação e Difusão, Fundação Amazônia Paraense de Amparo à Pesquisa (São Paulo Research Foundation; grant numbers 04032‐8, 06372‐3, 09230‐5, 11457‐8, 2013/03557‐9, and 233160). T.O. is supported by a National Health and Medical Research Council (NHMRC) Investigator grant (grant number APP1176426). F.C. is supported by Conselho Nacional de Pesquisa, Brazil (CNPq; grant number 315953/2021‐7). J.d.T and J.S.D. are supported by the the NIHR UCL/UCLH Biomedical Research Centre. R.G. is supported by the Tuscany Region for Health (grant DECODEE). K.H. is supported by Health and Care Research Wales. S.S.K. is supported by the Medical Research Council (MR/S00355X/1). P.M. is supported by the PATE program (F1315030) of the University of Tübingen. S.M. is supported by Italian Ministry of Health fund (grant number NET‐2013‐02355313). C.R. is supported by the Swiss League Against Epilepsy. R.J.S. is supported by the NIH (grant numbers R01 NS106957, RF1 NS033310, R01 NS1127524), and the Christina Louise George Trust. P.S. is supported by the PNRR‐MUR‐M4C2 PE0000006 Research Program “MNESYS”; IRCCS ‘G. Gaslini’ is a member of ERN‐Epicare. P.N.T. is supported by a UKRI Future Leaders Fellowship (MR/T04294X/1). S.I.T. and P.M.T. are supported by NIH grants R01MH116147, P41EB015922, and R01AG058854. G.P.W. was supported by the Medical Research Council (G0802012, MR/M00841X/1). C.L.Y. is supported by FASEP (grant numbers 2013/03557‐9: 06372‐3 11457‐8, 233160: 04032‐8, and 09230‐5; 2022/11786‐4), and CNPQ (grant number 315953/2021‐7). S.M.S. was supported by the Epilepsy Society. I.H.H was supported by the NHMRC (grant number 1184403).
Funding Information:
L.V. reports research funding from Biogen Australia, Life Molecular Imaging, and Eisai. T.J.O. has received consulting fees from Eisai, UCB, Supernus, Biogen, ES Therapeutics, Epidarex, LivaNova, and Kinoxis Therapeutics. He participates on the Data Safety Monitoring Board for ES Therapeutics and Kinoxis Therapeutics. He has served as President (past) for the Epilepsy Society of Australia, and is the current chair for the Australian Epilepsy Clinical Trials Network (AECTN) and the American Epilepsy Society (Translational Research Committee). B.B. is the cofounder of AIRAmed, a company that offers brain segmentation. P.M. has received honoraria as an advisory board member from Biogen unrelated to the submitted work. P.S. has received speaker fees and has served on advisory boards for BioMarin, Zogenyx, GW Pharmaceuticals; and has received research funding from Enecta, GW Pharmaceuticals, Kolfarma srl, and Eisai. A.E.V. received personal compensation as scientific advisory board member for Angelini Pharma unrelated to the submitted work. P.M.T. has received a research grant from Biogen, and was a paid consultant for Kairos Venture Capital, USA, for projects unrelated to this work. C.L.Y. has received personal payments from Torrent, Zodiac, and UCB. S.M.S. has received research grants from UCB Pharma and Jazz Pharmaceuticals; speaker fees from UCB, Eisai, and Zogenix; and honoraria or other fees from Eisai, Jazz Pharmaceuticals, Stoke Therapeutics, UCB, and Zogenix (payments to institution). The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Publisher Copyright:
© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
PY - 2024/4
Y1 - 2024/4
N2 - Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. Results: Across all epilepsies, reduced total cerebellar volume was observed (d =.42). Maximum volume loss was observed in the corpus medullare (dmax =.49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax =.47), crus I/II (dmax =.39), VIIIA (dmax =.45), and VIIIB (dmax =.40). Earlier age at seizure onset ((Formula presented.) =.05) and longer epilepsy duration ((Formula presented.) =.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.
AB - Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. Results: Across all epilepsies, reduced total cerebellar volume was observed (d =.42). Maximum volume loss was observed in the corpus medullare (dmax =.49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax =.47), crus I/II (dmax =.39), VIIIA (dmax =.45), and VIIIB (dmax =.40). Earlier age at seizure onset ((Formula presented.) =.05) and longer epilepsy duration ((Formula presented.) =.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.
KW - anterior lobe
KW - cerebellum
KW - epilepsy
KW - MRI
KW - posterior lobe
UR - http://www.scopus.com/inward/record.url?scp=85186573445&partnerID=8YFLogxK
U2 - 10.1111/epi.17881
DO - 10.1111/epi.17881
M3 - Article
C2 - 38411286
AN - SCOPUS:85186573445
SN - 0013-9580
VL - 65
SP - 1072
EP - 1091
JO - Epilepsia
JF - Epilepsia
IS - 4
ER -