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. 
Published: February 2024

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 ( = .05) and longer epilepsy duration ( = .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.