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

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

doi:10.1101/2023.10.21.562994

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

bioRxiv [Preprint]. 2023 Oct 23:2023.10.21.562994. doi: 10.1101/2023.10.21.562994.

Authors

Rebecca Kerestes¹, Andrew Perry², Lucy Vivash¹, Terence J O'Brien^{1

3}, Marina K M Alvim^{4

5}, Donatello Arienzo⁶, Ítalo K Aventurato^{4

5}, Alice Ballerini⁷, Gabriel F Baltazar^{4

5}, Núria Bargalló^{8

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10}, Benjamin Bender¹¹, Ricardo Brioschi^{4

5}, Eva Bürkle¹¹, Maria Eugenia Caligiuri¹², Fernando Cendes^{4

5}, Jane de Tisi¹³, John S Duncan¹³, Jerome P Engel Jr¹⁴, Sonya Foley¹⁵, Francesco Fortunato¹⁶, Antonio Gambardella^{12

16}, Thea Giacomini¹⁷, Renzo Guerrini¹⁸, Gerard Hall¹⁹, Khalid Hamandi^{15

20}, Victoria Ives-Deliperi²¹, Rafael B João^{4

5}, Simon S Keller^{22

23}, Benedict Kleiser²⁴, Angelo Labate^{25

26}, Matteo Lenge^{18

27}, Cassandra Marotta²⁸, Pascal Martin²⁴, Mario Mascalchi^{29

30}, Stefano Meletti^{7

31}, Conor Owens-Walton³², Costanza B Parodi³³, Saül Pascual-Diaz⁸, David Powell², Jun Rao⁶, Michael Rebsamen³⁴, Johannes Reiter³⁵, Antonella Riva³³, Theodor Rüber³⁵, Christian Rummel³⁴, Freda Scheffler²¹, Mariasavina Severino³³, Lucas S Silva^{4

5}, Richard J Staba¹⁴, Dan J Stein^{1

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40}, Pasquale Striano^{17

33}, Peter N Taylor^{13

19}, Sophia I Thomopoulos³², Paul M Thompson³², Domenico Tortora³³, Anna Elisabetta Vaudano^{7

31}, Bernd Weber³⁶, Roland Wiest³⁴, Gavin P Winston^{13

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38}, Clarissa L Yasuda^{4

5}, Hong Zheng³², Carrie R McDonald⁶, Sanjay M Sisodiya^{13

39}, Ian H Harding^{1

40}; ENIGMA-Epilepsy Working Group

Affiliations

¹ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
² Monash Bioinformatics Platform, Monash University, Melbourne, VIC, Australia.
³ Department of Medicine and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia.
⁴ Department of Neurology, University of Campinas - UNICAMP, Campinas, Brazil.
⁵ Brazilian Institute of Neuroscience and Neurotechnology, Campinas, Brazil.
⁶ Department of Psychiatry, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
⁷ Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
⁸ Magnetic Resonance Image Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
⁹ Department of Radiology of Center of Image Diagnosis (CDIC), Hospital Clinic de Barcelona, Barcelona, Spain.
¹⁰ CIBERSAM, Madrid, Spain.
¹¹ Department of Radiology, Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, Tübingen, Germany.
¹² Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy.
¹³ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
¹⁴ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹⁵ Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, UK.
¹⁶ Institute of Neurology, Department of Medical and Surgical Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy.
¹⁷ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.
¹⁸ Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
¹⁹ School of Computing, Newcastle University, Newcastle upon Tyne, United Kingdom.
²⁰ The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
²¹ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
²² Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
²³ The Walton Centre NHS Foundation Trust, Liverpool, UK.
²⁴ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁵ Neurophysiopatology and Movement Disorders Clinic, University of Messina, Messina, Italy.
²⁶ Regional Epilepsy Center, University of Messina, Messina, Italy.
²⁷ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
²⁸ Department of Neurology, Alfred Health, Melbourne, VIC, Australia.
²⁹ 'Mario Serio' Department of Clinical and Experimental Medical Sciences, University of Florence, Florence, Italy.
³⁰ Division of Epidemiology and Clinical Governance, Institute for Study, Prevention and network in Oncology of the Tuscany Region, Florence, Italy.
³¹ Neurology Unit, OCB Hospital, Azienda Ospedaliera-Universitaria Modena, Modena, Italy.
³² Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
³³ IRCCS Istituto 'Giannina Gaslini', Genova, Italy.
³⁴ Support Center for Advanced Neuroimaging, University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
³⁵ Department of Epileptology, University Hospital Bonn, Bonn, Germany.
³⁶ Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
³⁷ Epilepsy Society MRI Unit, Chalfont St Peter, UK.
³⁸ Department of Medicine (Division of Neurology), Queen's University Kingston, ON, Canada.
³⁹ Chalfont Centre for Epilepsy, Bucks, UK.
⁴⁰ Monash Biomedical Imaging, Monash University, Melbourne, VIC, Australia.

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 (ηρ²_max=0.05) and longer epilepsy duration (ηρ²_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.

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

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Abstract

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