Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study

ABSTRACT Objective The 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. 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 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. Results Across all epilepsies, reduced total cerebellar volume was observed ( d =0.42). Maximum volume loss was observed in the corpus medullare ( d max =0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB ( d max = 0.47), Crus I/II ( d max = 0.39), VIIIA ( d max =0.45) and VIIIB ( d max =0.40). Earlier age at seizure onset ( ηρ 2 max =0.05) and longer epilepsy duration ( ηρ 2 max =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. Significance We 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 points Cerebellar involvement in epilepsy is poorly understood within current cortico-centric models of this disease We 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 STATEMENT 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.

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