Abstract
Kerestes R, Perry A, Vivash L, O'Brien TJ, Alvim MKM, Arienzo D, Aventurato ÍK, Ballerini A, Baltazar GF, Bargalló N, Bender B, Brioschi R, Bürkle E, Caligiuri ME, Cendes F, de Tisi J, Duncan JS, Engel JP Jr, Foley S, Fortunato F, Gambardella A, Giacomini T, Guerrini R, Hall G, Hamandi K, Ives-Deliperi V, João RB, Keller SS, Kleiser B, Labate A, Lenge M, Marotta C, Martin P, Mascalchi M, Meletti S, Owens-Walton C, Parodi CB, Pascual-Diaz S, Powell D, Rao J, Rebsamen M, Reiter J, Riva A, Rüber T, Rummel C, Scheffler F, Severino M, Silva LS, Staba RJ, Stein DJ, Striano P, Taylor PN, Thomopoulos SI, Thompson PM, Tortora D, Vaudano AE, Weber B, Wiest R, Winston GP, Yasuda CL, Zheng H, McDonald CR, Sisodiya SM, Harding IH; ENIGMA-Epilepsy Working Group. Epilepsia 2024;65(4):1072-1091. 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 (ηρ2max = .05) and longer epilepsy duration (ηρ2max = .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.
Commentary
The role of the cerebellum in epilepsy is poorly understood. The authors, the ENIGMA study group, is an international collaborative effort in combining imaging studies to understand the biology of epilepsy and other disorders. 1 This enables larger scale analysis of magnetic resonance imaging (MRI) datasets. In this study the authors used an artificial intelligence (AI) algorithm, ACAPULCO (Automatic Cerebellum Anatomical Parcellation Using U-Net with Locally Constrained Optimization) to analyse cerebellar volumes in people with epilepsy compared to normal controls. 2
Cerebellar changes, notably atrophy, have long been associated with chronic epilepsy. Despite being only 10% of brain volume, there are over 95 billion neurons in the cerebellum, more than the rest of the cortex put together—there must be a role of the cerebellum in epilepsy, but what is it?
This ENIGMA study looked at a mega-analysis (a pooling of raw data) of cerebellar MRI volumes from 1602 patients with epilepsy and 1022 healthy controls (age and sex matched).
MRI T1-weighted images were obtained using a set protocol, and ACAPULPO used to identify 28 subregions, and the corpus medullare (CM). The cerebellum consists of the anterior and posterior lobes (with various sublobules or crus), a flocculonodular lobe, and the CM (central white matter containing deep nuclei, such as the dentate nucleus). There are 3 tracts that connect the cerebellum to the rest of the brain; the inferior, middle and superior peduncles, contributing to a cerebello-cortical/subcortical network.
In this study, patients with left or right temporal lobe epilepsy (TLE), with hippocampal sclerosis (HS) or with no lesion, extratemporal focal epilepsy (ETLE) or genetic generalized epilepsy (GGE) were included and total and syndrome-specific groups analysed. Variables such as age at seizure onset, duration of seizures, and use of phenytoin (PHT) were available and incorporated into the analysis.
Linear fixed-effect regression models were used to compare patients and control groups, adjusting for age, intracranial volume and by site, looking at total cerebellar volume, and that of each of the 28 parcellated regions.
This statistical model produces a ‘d’ score (Cohen's d) with a confidence interval—which indicates the size of the difference between the test and control groups; 0.2 being mild, 0.4 moderate and > 0.6 a large effect size.
For all epilepsies versus controls, there was reduced volume of the whole cerebellum, with a moderate but significant effect size d = 0.42 (0.33-0.52).
The largest effect size (most atrophy) was in the CM and non-motor regions of the bilateral superior and inferior posterior lobes. Smaller volumes were seen with longer duration of epilepsy and were more prominent in TLE with HS or ETLE, and less prominent in GGE and nonlesional TLE. The authors noted a longer duration of epilepsy and more PHT use in the group with TLE with HS. No significant lateralizing features were found between right and left hemisphere focal epilepsies.
The role of the posterior lobes, and their network connections via the deep nuclei, across the superior cerebellar peduncle to the thalamus and beyond to cortex including prefrontal and posterior parietal cortex, frontoparietal, and salience resting state networks, is thought to be in control of cognitive, attention and emotional states, and therefore may play a role in epilepsy related co-morbidities. There was relative sparing of the anterior lobe, vermis and flocculonodular lobes, which are predominantly motor areas of the cerebellum. However, recent data also shows that motor areas of the cerebellum may influence motor components of seizures in some GGE. 3
The authors also used cortical thickness measurements in 782 patients and 804 controls at 8 sites, which showed an association between cortical and cerebellar volume loss for the group with TLE due to HS.
Many of us were taught to link cerebellar atrophy with PHT use. The authors had data on 161 patients with focal epilepsy on chronic PHT from 7 sites and showed a reduced cerebellar volume, with an effect size of d = 0.39 in 10 posterior lobe regions. Given most patients in the study were not on PHT, there are likely to be other factors associated with cerebellar atrophy but not yet fully understood. There are many potential causes of cerebellar atrophy such as alcohol use, genetic or degenerative factors, seizure burden, and use of medications apart from PHT, not controlled for in this study.
Overall, the evidence in this and other studies supports a direct link between chronic epilepsy and cerebellar volume loss.4–6
An inhibitory influence of the cerebellum on seizure control is postulated although poorly understood. Insight from neurophysiological or functional recordings of the cerebellum are limited due to low signal to noise ratio, internal cancelation of electroencephalography (EEG) and magnetoencephalography (MEG) due to internal anatomy, and lack of intracranial recordings. Studies of cerebellar neuromodulation exist but with variable results and which were not all reproducible.7,8
In this study, imaging AI shows again its advantages over the visual eye—I do not think I could tell if the posterior cerebellar lobes were abnormal. However, tools such as ACAPULCO are not yet available for general use as they are not FDA (Federal Drug Administration) approved or CE (Conformité Européene) marked for clinical use, so they remain a research tool for now. Perhaps it may become part of our AI toolkit for analysing the epilepsy MRI, and cerebellar atrophy patterns could become a biomarker for seizure severity, independent of laterality? Until then, knowing what subregions of the cerebellum are involved in an epilepsy has limited current clinical usefulness.
The cerebellum acts as a fine control center for locomotion, balance, emotion, and cognition—working out how cerebellar networks interact with the cerebral cortex could perhaps harness the power of those 95 billion controlling neurons and reveal new avenues to modulate and treat epilepsy and is worthy of further study.
