GABAAergic dysfunction in the olivary-cerebellar-brainstem network may cause eye oscillations and body tremor.

http://dx.doi.org/10.1016/j.clinph.2016.12.014 1388-2457/Published by Elsevier Ireland Ltd on behalf of International Fe Opsoclonus and flutter are ocular oscillations consisting of continuous, involuntary, conjugate saccades without intersaccadic intervals. If these saccadic oscillations are purely horizontal, they are called ocular flutter; if they have horizontal, vertical and torsional components, they are called opsoclonus. Behavioral disturbances, cerebellar ataxia, and limb tremor may co-occur. Several infectious, paraneoplastic, metabolic, and toxic etiologies cause these disturbances, but how neural circuits generate the oscillations is not clear. Two main hypotheses for the pathomechanism of opsoclonus/flutter have been proposed on the basis of different clinical and experimental observations. In the first, reduction of glycinergic inhibition generates oscillations in the positive feedback loop between saccadic brainstem burst neurons (Shaikh et al., 2007). In the second, disinhibition of cerebellar fastigial nuclei induces unwanted saccades through excitatory projections to the burst neurons (Wong et al., 2001). However, both theories remain controversial because they were not confirmed by lesion studies in animals, clinical findings, or model simulations (Lemos and Eggenberger, 2013). Analysis of high-resolution eye movement recordings from patients with opsoclonus/flutter might clarify the underlying mechanisms, but these are extremely rare. Here, novel observations from two patients with opsoclonus and body tremor subsequent to performance-enhancing substance abuse suggest that eye and body oscillations may be generated by a GABAergic dysfunction of the olivary-cerebellar-brainstem network. The study was approved by the local ethics committee and informed consent was obtained from the patients. Two tennis-players developed opsoclonus/flutter after a few months of self-administration of performance-enhancing substances. Patient 1, a 32-year-old male, presented with rapid onset of behavioral disturbances, vertigo, ataxia, head tremor, and opsoclonus causing visual blur and oscillopsia (Supplementary Video 1). Patient 2, a 34-year-old male, showed rapid progression of limb and axial tremor, vertigo, mood changes, ataxia, and ocular flutter (Supplementary Video 2). Common infectious, toxic, paraneoplastic, and metabolic causes of opsoclonus/flutter were excluded by negative brain MRI, blood, and CSF exams. Both patients reported an analogous typology, supply, and use of the enhancing chemicals, but only patient 1 provided a sample of the compound for testing, which led to the identification of anabolic androgenic steroids (AAS): nandrolone, stanozolol, and testosterone propionate. Treatment with intravenous IgG and benzodiazepine led to recovery in three-to-four weeks in both patients. In patient 2, limb tremor characterized by tonic motor activity at 8 Hz was recorded by electromyography (EMG) from the