Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study
Authors: Kerestes Rebecca , Perry Andrew , Vivash Lucy , O’Brien Terence J. , Alvim Marina K.M. , Arienzo Donatello , Aventurato Ítalo K. , Ballerini Alice , Baltazar Gabriel F. , Bargalló Núria , Bender Benjamin , Brioschi Ricardo , Bürkle Eva , Caligiuri Maria Eugenia , Cendes Fernando , de Tisi Jane , Duncan John S. , Engel Jerome P. , Foley Sonya , Fortunato Francesco , Gambardella Antonio , Giacomini Thea , Guerrini Renzo , Hall Gerard , Hamandi Khalid , Ives-Deliperi Victoria , João Rafael B. , Keller Simon S. , Kleiser Benedict , Labate Angelo , Lenge Matteo , Marotta Cassandra , Martin Pascal , Mascalchi Mario , Meletti Stefano , Owens-Walton Conor , Parodi Costanza B. , Pascual-Diaz Saül , Powell David , Rao Jun , Rebsamen Michael , Reiter Johannes , Riva Antonella , Rüber Theodor , Rummel Christian , Scheffler Freda , Severino Mariasavina , Silva Lucas S. , Staba Richard J. , Stein Dan J. , Striano Pasquale , Taylor Peter N. , Thomopoulos Sophia I. , Thompson Paul M. , Tortora Domenico , Vaudano Anna Elisabetta , Weber Bernd , Wiest Roland , Winston Gavin P. , Yasuda Clarissa L. , Zheng Hong , McDonald Carrie R. , Sisodiya Sanjay M. , Harding Ian H. ,   the ENIGMA-Epilepsy Working Group
Published: October 2023

ABSTRACTObjectiveThe intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two sites from the global ENIGMA-Epilepsy working group.MethodsA 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 i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness.ResultsAcross all epilepsies, reduced total cerebellar volume was observed (d=0.42). Maximum volume loss was observed in the corpus medullare (dmax=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (dmax= 0.47), Crus I/II (dmax= 0.39), VIIIA (dmax=0.45) and VIIIB (dmax=0.40). Earlier age at seizure onset (ηρ2max=0.05) and longer epilepsy duration (ηρ2max=0.06) 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.SignificanceWe provide robust evidence of deep cerebellar and posterior lobe subregional grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor 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 cerebellum subregions into neurobiological models of epilepsy.Key pointsCerebellar involvement in epilepsy is poorly understood within current cortico-centric models of this diseaseWe used a novel, deep learning segmentation tool to parcellate the cerebellum into 28 anatomical subunits using an international MRI dataset of 1,602 individuals with epilepsy (aged between 18 and 65 years old) including temporal lobe epilepsy with hippocampal sclerosis (TLE-HS,n=562), TLE non-lesional (TLE-NL,n=284), generalised genetic epilepsy (GGE,n=186) and extra temporal focal epilepsy (ETLE,n=251) and 1,022 controls.Across all epilepsies (vs. controls) robust changes in the corpus medullare and posterior lobe “non-motor” regions were observed, with maximal differences in bilateral VIIB and Crus II lobules. Lower volume of these regions correlated with longer disease duration. Anterior “motor lobe” regions were relatively spared.Findings were most pronounced in TLE-HS and ETLE groups, with distinct neuroanatomical profiles observed.Cortical thinning was associated with pronounced cerebellar volume loss in TLE-HS epilepsy, relative to controls.ETHICAL PUBLICATION STATEMENTWe 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.