A GABAergic Dysfunction in the Olivary–Cerebellar–Brainstem Network May Cause Eye Oscillations and Body Tremor. II. Model Simulations of Saccadic Eye Oscillations

Abstract

Eye and body oscillations are shared features of several neurological diseases, yet their pathophysiology remains unclear. Recently, we published a report on two tennis players with a novel presentation of eye and body oscillations following self-administration of performance-enhancing substances. Opsoclonus/flutter and limb tremor were diagnosed in both patients. Common causes of opsoclonus/flutter were excluded. High-resolution eye movement recordings from one patient showed novel spindle-shaped, asymmetric saccadic oscillations (at ~3.6 Hz) and ocular tremor (~40-60 Hz). Based on these findings, we proposed that the oscillations are the result of increased GABAA receptor sensitivity in a circuit involving the cerebellum (vermis and fastigial nuclei), the inferior olives, and the brainstem saccade premotor neurons (excitatory and inhibitory burst neurons, and omnipause neurons). We present a mathematical model of the saccadic system, showing that the proposed dysfunction in the network can reproduce the types of saccadic oscillations seen in these patients.

Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome

“…The current theoretical mechanisms to explain the ocular oscillations in these patients involve simultaneous neuron dysfunction in the brainstem and cerebellum (1,4,5). The brainstem circuitry theoretically involves omnipause neuron (OPN) inability to regulate postinhibitory rebound (PIR) from oscillating excitatory (Excitatory burst Neuron [EBN]) and inhibitory burst neuron (IBN) circuits in the pons (6–8).…”

“…As a potential example, using abnormal eye movements in OMAS, one could draw an analogous explanation for the head and truncal tremor in our patient with a similar etiology. Irregular oscillations of motoneurons innervating the trunk and neck may originate in the cerebellum, particularly the regions of the FN that control movement of axial musculature (5,14) (see Video 1, Supplemental Digital Content , http://links.lww.com/WNO/A551). In our case, elevation of NSE (a neuronal lesion marker) and the absence of white matter changes on MRI (15) suggest Purkinje cell, cerebellar deep nuclei, and pontine neurons rather than cerebellar outflow tracts as the cause of the abnormal eye movement and the symmetric limb and truncal ataxia.…”

“…The underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication (1–4). A recent hypothesis suggests increased GABA A receptor sensitivity in the olivary-oculomotor vermis–fastigial nucleus (FN)—premotor saccade burst neuron circuit in the brainstem (5). Therefore, the management will focus on immunosuppression, searching for a possible underlying malignancy or infectious etiology, and modulation of GABA A hypersensitivity with benzodiazepines.…”

Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome

“…Modulation of these projections may alter circuitry of the cerebellum (vermis and fastigial nuclei), the inferior olives, and the brainstem saccade premotor neurons (excitatory and inhibitory burst neurons, and omnipause neurons). 25 Indeed, GluD2-deficient mice, with fewer functional synapses between the parallel fibers and Purkinje cells, have involuntary spontaneous eye and limb movements. 26 …”

“…These nuclei have roles in saccadic eye movements, omnipause neuron function, and ataxia. 25 The origin of the myoclonus in OMAS is not well explained on the basis of a purely cerebellar dysfunction and this aspect requires further investigation.…”