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.
Highlights
Ethanol (EtOH) has long been known to exert a deleterious effect on the brain
We propose that the improvement of varied hyperkinetic movement disorders with modest doses of EtOH or Gamma-hyroxybutyric acid (GHB) does not derive from a simple pharmacologic effect on the GABA-A, GABA-B or GHB receptors
We posit that abnormal activation of the Purkinje cells and dentate nucleus, the major outflow of the cerebellum, are critical to this response
Summary
Ethanol (EtOH) has long been known to exert a deleterious effect on the brain. The acute effects of EtOH ingestion include mild dizziness, decreased reaction time, dulled perception, tremor, myoclonus and ataxia. Sodium oxybate (Xyrem), the sodium salt of GHB, has been studied as a potential treatment for refractory alcohol-responsive movement disorders. We propose that the improvement of varied hyperkinetic movement disorders with modest doses of EtOH or GHB does not derive from a simple pharmacologic effect on the GABA-A, GABA-B or GHB receptors. Evidence We present two lines of evidence to support this hypothesis: A: Evidence of the effect of modest doses of EtOH or GHB on cerebellar metabolism In a series of three papers, Volkow and colleagues investigated the effect of a modest dose of EtOH in normal individuals, employing doses that were not intoxicating or sedating In both women and men, a single low dose of EtOH produced the greatest metabolic reduction in the cerebellum, with no change in thalamic metabolism and a mild increased metabolism in striatum [58]. The final study with co-registered MRI localization confirmed this effect on
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