The cerebellum in epilepsy

Abstract

The cerebellum, a subcortical structure, is traditionally linked to sensorimotor integration and coordination, although its role in cognition and affective behavior, as well as epilepsy, is increasingly recognized. Cerebellar dysfunction in patients with epilepsy can result from genetic disorders, antiseizure medications, seizures, and seizure-related trauma. Impaired cerebellar function, regardless of cause, can cause ataxia (imbalance, impaired coordination, unsteady gait), tremor, gaze-evoked nystagmus, impaired slow gaze pursuit and saccade accuracy, as well as speech deficits (slurred, scanning, or staccato). We explore how cerebellar dysfunction can contribute to epilepsy, reviewing data on genetic, infectious, and neuroinflammatory disorders. Evidence of cerebellar dysfunction in epilepsy comes from animal studies as well as human neuropathology and structural magnetic resonance imaging (MRI), functional and diffusion tensor MRI, positron emission and single photon emission computerized tomography, and depth electrode electro-encephalography studies. Cerebellar lesions can infrequently cause epilepsy, with focal motor, autonomic, and focal to bilateral tonic-clonic seizures. Antiseizure medication-resistant epilepsy typically presents in infancy or before age 1 year with hemifacial clonic or tonic seizures ipsilateral to the cerebellar mass. Lesions are typically asymmetric benign or low-grade tumors in the floor of the fourth ventricle involving the cerebellar peduncles and extending to the cerebellar hemisphere. Electrical stimulation of the cerebellum has yielded conflicting results on efficacy, although methodological issues confound interpretation. Epilepsy-related comorbidities including cognitive and affective disorders, falls, and sudden unexpected death in epilepsy may also be impacted by cerebellar dysfunction. We discuss how cerebellar dysfunction may drive seizures and how genetic epilepsies, seizures and seizure therapies may drive cerebellar dysfunction, and how our understanding of epilepsy-related comorbidities through basic neuroscience, animals models and patient studies can advance our understanding and improve patient outcomes.

Keywords: cerebellum; epilepsy; neuropathology; stimulation.

FIGURE 1

Gross cerebellar anatomy.

FIGURE 2

Cerebellar cellular anatomy and organization.

FIGURE 3

Cerebellar atrophy with phenytoin use.

FIGURE 4

Cerebellar volume changes in epilepsy syndromes.

FIGURE 5

Cerebellar volume changes in left (L) and right (R) temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS).

FIGURE 6

Neuropathological changes in the cerebellum in epilepsy patients.

FIGURE 7

Lesional cerebellar epilepsy. A 26‐year‐old male patient with daily focal aware seizures characterized by nausea, shortness of breath, lacrimation, and strange feelings since early childhood. He also reported events with tunnel vision and left hemifacial‐ and upper hemibody paresthesia and occipital headaches. Examination during seizure revealed left‐sided mydriasis, delayed left pupillary response, nystagmus, and left peri‐ocular and chin myoclonus. Seizures continued despite carbamazepine and levetiracetam. Preoperative MRI: T1‐cortex‐isointense (A) and T2‐cortex isointense (B) lesion adjacent to the right inferior cerebellar peduncle. SPECT imaging: ictal hyperperfusion (C) and interictal hypoperfusion (D) of the cerebellum. Interictal surface EEG: left temporoparietal sharp waves. Stereo‐EEG (f) 10/s seizure pattern arising at intralesional contacts B2–B3 (f0) propagating to electrode A. Subtotal lesion resection (panel g) led to seizure freedom. (From Foit et al., 2017, with permission). EEG, electroencephalography; MRI, magnetic resonance imaging; SPECT, single‐photon emission computed tomography.

FIGURE 8

Optogenetic stimulation of the cerebellar nuclei inhibits generalized spike–wave discharges in mouse models of absence epilepsy. (Adapted from Kros et al., 2015, with permission.) (A) (Top left): Sagittal brain section identifying channelrhodopsin‐2 (ChR2) expression in cerebellar nuclei (CN) with projections to the thalamus. CN: Cerebellar nuclei; M1 primary motor cortex; S1: Primary sensory cortex. (B) (Top right) ECoG theta‐band power before and after open‐loop (bilateral 470 nm, unilateral 470 nm) stimulation, bilateral incorrect wavelength (590 nm) stimulation, and bilateral outside cerebellar nuclei stimulation and bilateral and unilateral closed‐loop stimulation. *** = p <.001. (C) (Bottom left): Electrocorticogram of bilateral M1 and left S1 demonstrating bilateral optogenetic stimulation (470 nm light pulsation for 100 ms; represented by the blue bar) terminates generalized spike–wave discharges. (D) (Bottom right): Electrocorticogram of contralateral M1 and S1 demonstrating unilateral optogenetic stimulation (470 nm light pulsation for 100 ms; represented by the blue bar) terminates generalized spike–wave discharges.