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 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 (d_max = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (d_max = .47), crus I/II (d_max = .39), VIIIA (d_max = .45), and VIIIB (d_max = .40). Earlier age at seizure onset ( $\eta {\rho }_{\max }^2$ = .05) and longer epilepsy duration ( $\eta {\rho }_{\max }^2$ = .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.

Keywords: MRI; anterior lobe; cerebellum; epilepsy; posterior lobe.

Fig 1.

Atlas-based effect size (Cohen’s d) maps, MNI-based coronal slices (top: y= −72; bottom: y= −54) and forest plots (Cohen’s d +/− 95% confidence interval) of the significant between-group differences for all epilepsies vs. healthy controls (HC). Note: positive effect sizes reflect epilepsy patients < HC. Regions significant at P < 0.05 FDR corrected are depicted in color (see Table S5 for full tabulation).

Fig 2.

Scatter-plots showing the association between a) duration of illness and b) age at seizure onset, and total cerebellar volume in epilepsy patients, P < 0.001.

Fig 3.

Atlas-based effect size (Cohen’s d) maps, MNI-based coronal slices (top: y= −72; bottom: y= −54) and forest plots (Cohen’s d +/− 95% confidence interval) of the significant between-group differences for TLE-HS-L (top panel) and TLE-HS-R (lower panel) vs. healthy controls (HC). Positive effect sizes reflect TLE-HS-L and TLE-HS-R < HC respectively. Regions significant at P < 0.05 FDR corrected are depicted in color (red-yellow for epilepsy < HC; blue for epilepsy > HC); see Table S6 for full tabulation).

Fig 4.

Atlas-based effect size (Cohen’s d) maps, MNI-based coronal slices (top: y= −72; bottom: y= −54) and forest plots (Cohen’s d +/− 95% confidence interval) of the significant between-group differences for GGE vs. healthy controls (HC). Note: positive effect sizes reflect epilepsy < HC. Regions significant at P < 0.05 FDR corrected are depicted in color. See Table S8 for full tabulation.

Fig 5.

Atlas-based effect size (Cohen’s d) maps, MNI-based coronal slices (top: y= −72; bottom: y= −54) and forest plots (Cohen’s d +/− 95% confidence interval) of the significant between-group differences for ETLE vs. healthy controls (HC). Note: positive effect sizes reflect epilepsy patients < HC. Regions significant at P < 0.05 FDR corrected are depicted in color (red-yellow for ETLE < HC; blue for ETLE > HC); see Table S9 for full tabulation.