Alcohol-Responsive Hyperkinetic Movement Disorders—a Mechanistic Hypothesis

Abstract

Patients with essential tremor, vocal tremor, torticollis, myoclonus-dystonia and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from ingestion of a modest amount of alcohol (ethanol). Despite considerable investigation, the mechanism of ethanol's ability to produce this effect remains a mystery. In this paper, we review the pharmacology of ethanol and its analogue GHB (or sodium oxybate), summarize the published literature of alcohol-responsive hyperkinetic movement disorders, and demonstrate videos of patients we have treated over the last fifteen years with either an ethanol challenge or with chronic sodium oxybate therapy. We then propose a novel explanation for this phenomenon-namely, that ingestion of modest doses of ethanol (or sodium oxybate) normalizes the aberrant motor networks underling these disorders. We propose that alcohol and its analogues improve clinical symptoms and their physiologic correlate by restoring the normal firing pattern of the major outflow pathways of the cerebellum (the Purkinje cells and deep cerebellar nuclei), We present evidence to support this hypothesis in animal models and in affected patients, and suggest future investigations to test this model.

Cerebellar transcranial current stimulation – An intraindividual comparison of different techniques

“…This could also lead to an increase of corticospinal excitability due to the reduction of inhibitory influence of Purkinje cells on cerebello-thalamo-cortical pathways. The possibility of influencing Purkinje cells and/or inter-connected neuronal circuits non-invasively potentially has high clinical relevance, because especially the pathophysiology of alcohol-responsive movement disorders, e.g., essential tremor and myoclonus dystonia, seems to be related to activity of these cell types ( Frucht and Riboldi, 2020 ; Madelein van der Stouwe et al, 2020 ). All these models explain an effect of stimulation of the cerebellum via direct or indirect cerebello-neocortical projections.…”

Looking “Cherry Red Spot Myoclonus” in the Eyes: Clinical Phenotype, Treatment Response, and Eye Movements in Sialidosis Type 1

“…SBX, a sodium salt of γ-hydroxybutyrate, has been traditionally used and approved for cataplexy in narcolepsy. However, this medication has been proven to be beneficial in alcohol-responsive movement disorders, such as tremor, post-hypoxic myoclonus, myoclonus dystonia, and spasmodic dysphonia [ 7 8 9 10 11 ]. In all of our patients, this treatment significantly improved quality of life, though one had to discontinue use due to side effects.…”

Synaptic effects of ethanol on striatal circuitry: therapeutic implications for dystonia

“…A recent preclinical evidence demonstrated that adult mice with knockdown of Sgce in the cerebellum, but not in the basal ganglia, develop overt motor symptoms, including dystonia, which can be improved by administration of ethanol [ 101 ]. Moreover, very recently, Frucht and Riboldi proposed a model to explain the clinical improvement with low doses of EtOH in MD, supporting an abnormal activation of the Purkinje cells and dentate nucleus and a likely mechanism of action of EtOH to normalize abnormal cerebellar output in this disorder, paving the way for future speculation [ 102 ].…”

“…GHB is supposed to have a low affinity to the metabotropic GABA B receptor, either directly or via conversion to GABA [ 114 ] as well as an action via the GHB receptors that bind to extrasynaptic GABA A receptors [ 116 ]. However, other mechanisms of action may be involved, since other GABA B agonists, such as baclofen, have minimal effects on myoclonus [ 102 ]. A recent study on 531 patients with alcohol‐responsive laryngeal dystonia treated with SXB demonstrated an impressive improvement of dystonic symptoms, presumably as a result of the modulation of the abnormal plasticity within the cortical and subcortical circuitry [ 117 ].…”

“…A recent study on 531 patients with alcohol‐responsive laryngeal dystonia treated with SXB demonstrated an impressive improvement of dystonic symptoms, presumably as a result of the modulation of the abnormal plasticity within the cortical and subcortical circuitry [ 117 ]. It is worth noting that what emerges from clinical trials is that the response to small doses of alcohol in SGCE ‐MD, adductor spasmodic dysphonia (ADSD), and abductor spasmodic dysphonia (ABSD) predicts the response to SXB [ 102 ].…”