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.

Keywords: GHB; alcohol; dystonia; myoclonus; sodium oxybate; tremor.

Figure 1

Written examples of the effect of Xyrem on ET and PWT. Written examples of the effect of Xyrem on ET and PWT appear in Figure 1. In Figure 1A, Archimedes spiral samples correspond to the video segment of patient #8 while she was filmed at fifteen minute intervals (t = 0, 15 min, 30 min, 45 min, 60 min) after receiving 1.5 gm of Xyrem. A classic ET spiral is seen at t = 0, with a characterstic axis of maximum amplitude of tremor of approximately 60 degrees. Forty five minutes later, the amplitude of the tremor is reduced, and tremor is nearly absent at sixty minutes. The frequency of the tremor is unchanged by treatment. Benefits in Archimedes spiral correlate with clinical benefits in pouring water demonstrated in patient #8’s video segment. Handwriting samlpes of a portion of the “rainbow passage” in a patient with PWT are diplayed before and one hour after treatment with 1.5 gm of Xyrem (Figure 1B). The improvement of writing tremor is only modest, but legibility is improved.

Figure 2

Evidence supporting the hypothesis of the cerebellum and dentate nucleus in the pathogenesis of alcohol-responsive movement disorders. Evidence from imaging studies, neuropathology, animal models, and molecular evidences (such as protein expression) are captioned in the figure. The topographic distribution of involved brain regions and structures are shown in the scehematic representation of the cerebral and cerebellar hemispheres. The source of the evidence in human subjects (human silhouette) or in animal models (mouse cartoon) is also depicted. Different types of evidences are color coded (yellow: molecular studies – protein expression; light blue: pathology studies; green: imaging studies; purple: animal models). Activated areas (cerebellar cortex and thalamus) in these disorders are highlighted in the figure. ION: inferior olivary nucleus; FL: flocculonodular lobe; D: dentate nucleus; G: globose nucleus; E: emboliform nucleus; F: fastigial nucleus; SCP: superior cerebellar peduncle; RN: red nucleus; Th: thalamus; CM: centromedian nucleus; VPL: ventral posterolateral nucleus; VL: ventral lateral nucleus; MC: motor cortex; MD: myoclonus-dystonia; EPM1: Progressive myoclonic epilepsy type 1; ET: essential tremor; PHM: post-hypoxic myoclonus; CD: celiac disease; SD: spasmodic dysphonia; OT: orthostatic tremor; HS: healthy subjects; FDG-PET: fluoro-deoxy-glucose positron emission tomography. In the box in the left side corner: a schematic of magnification of the cellular structure of cerebellar cortex (P: Purkinje cell; MF: mossy fiber; GC: granular cells).