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. Chronic alcohol intoxication can also result in development of tolerance, dependence and psychiatric symptoms. Nevertheless, EtOH possesses a remarkable ability to improve the severity of specific hyperkinetic movement disorders. This effect may be obvious and profound, and presents a challenge to the treating physician who must balance the potential benefit from EtOH with the serious concerns of chronic EtOH administration.
EtOH acts on diverse receptors within the brain with low affinity and specificity, affecting a variety of different functional pathways . EtOH is distributed in the body similar to water, and its free diffusion through the blood-brain barrier explains its effect within 15–20 minutes of ingestion . Low doses of EOH suppress brain activity, with reductions in glucose metabolism in the cerebellum and occipital cortex . This effect may be mediated either by increased inhibition or reduced excitation. Although EtOH can suppress both NMDA and non-NMDA glutamatergic receptors, its main effect likely occurs by potentiation of inhibition of cerebral pathways . EtOH is a GABAergic molecule, mainly targeting the GABAA receptor–pentameric, ionotropic, ligand-gated chloride channels formed from different combinations of 19 possible subunits. In particular, α4β3δ and α6β3δ GABA receptors were showed to have a higher affinity for low doses of EtOH (i.e. few millimoles, as found in half a glass of wine), with important functional and topographical implications . Indeed, the presence of β3-subunits are associated with higher sensitivity to EtOH, while the presence of δ-subunits, which in vivo are found almost only in combination with the α4 and α6 subunits, determines the extrasynaptic localization of these receptors [4, 5, 6, 7]. Compared to other GABA receptors, those containing α6 and δ-subunits generate a tonic inhibition, instead of phasic inhibition . Of note, α4β3δ and α6β3δ GABA receptors are preferentially expressed in the cerebellum, and to a lesser extent in the hippocampus, thalamus and frontoparietal cortex, and the α6-contaning GABA receptors are found almost only in the cerebellar granule cells . Identification of the specific binding sites in these subunits may be relevant for designing drugs with selective EtOH effects and to explain variable responses to GABA receptor ligands related to specific polymorphisms in genes encoding for these subunits, as previously shown . For example, the compound AA29504 has been reported to have specific affinity for the αβδ receptors . On the other side, Purkinje cells are instead enriched with α1β2/3γ2 GABA receptors . Interestingly, GABAA receptors are the targets of other drugs, for example benzodiazepine (BZDs). Different from EtOH, these drugs bind specific BZD sites on GABA, particularly GABAA receptors rich in γ subunits which are mostly synaptic [13, 14]. GABAA receptors are also the target of phenobarbital and primidone, however while EtOH and BDZ increase the frequency of receptor opening, phenobarbital acts by increasing duration of opening, with a possible different effect on downstream pathways . In addition to acting as a GABAA receptor agonist, EtOH increases GABA release in the granule cells of the cerebellum through inhibition of nitric oxide synthase . Other receptors modulated by EtOH are glycine and adenosine where EtOH potentiates their inhibitory effect, as well as serotoninergic receptors and dopaminergic pathways .
PET studies have shown that patients with essential tremor (ET) treated with EtOH experience a reduction in cerebral blood flow in the cerebellum, and an increase in blood flow in the inferior olivary nucleus (ION) . This observation suggests a possible mechanism by which EtOH might reduce cerebellar-driven tremor, by suppressing cerebellar cortex hyperactivation (which has an inhibitory effect on the deep cerebellar nuclei). EtOH increases inhibitory output from the cerebellum to the ION (and thus increased blood flow in this area); consequently, ION stimulation is reduced and tremor is suppressed . Consistent with this idea, EtOH has also been reported to be a decoupling agent, able to inactivate gap junctions that are normally found in synaptic clefts and are particularly represented in the ION . EtOH also exerts an interesting effect on the striatum, where it potentiates GABAergic activity in the dorsomedial striatum which controls goal-directed actions (“associative” striatum), and inhibits GABAergic activity in the dorsolateral striatum (“sensory-motor” striatum), which controls unconscious, automatic actions .
The effect of EtOH analogues on alcohol-responsive movement disorders has also been studied. Gamma-hyroxybutyric acid (GHB) is a derivative of GABA with similar effects to EtOH. GHB is found as an endogenous molecule within the brain, although at very low concentrations. Sodium oxybate (Xyrem), the sodium salt of GHB, has been studied as a potential treatment for refractory alcohol-responsive movement disorders. Like EtOH, GHB reaches a peak dose within 35 minutes of administration, and plasma levels show a direct, non-linear dose response. At higher doses the sedative effect peaks later (40 vs 60 minutes at a dose of 25 vs 35 mg/kg, respectively) and decays slower, reaching baseline in no more than 3 hours . GHB binds with low affinity to the metabotropic GABAB receptor, the target of the drug baclofen, as well as distinct high-affinity binding sites . GHB’s interaction with GABAB receptors likely occurs only with administration of exogenous GHB  given this low affinity. GABAB receptors are expressed in the cortex, hippocampus, thalamus (especially in the ventroposterior lateral and medial thalamus responsible for the generation of oscillatory activities to the cortex), and cerebellum, particularly in the Purkinje cells [23, 24]. Different studies report an increased expression of the high-affinity binding sites for GHB in the frontal cortex and hippocampus, and a lower expression in the cerebellum . However, specific GHB receptors with low affinity have been identified in the cerebellum, especially in the Purkinje cells  (possibly missed by autoradiographic studies assessing the distribution of the high affinity binding sites). Different doses of GHB can target distinct receptors and pathways . Interestingly, low doses of GHB (1 μM) are active on the α4β3δ GABAA receptors, that, as reported above, are also the targets of low dose EtOH .
The complexity of the pharmacology of EtOH and GHB poses a significant obstacle to understanding the effectiveness of these agents in patients with alcohol-responsive hyperkinetic disorders. The pharmacokinetics and pharmacodynamics of EtOH are poorly explained by the binding characteristics of a single drug to one neurotransmitter receptor. A plausible model must explain the response of etiologically diverse disorders (posthypoxic myoclonus (PHM), ET and myoclonus-dystonia (MD)) to EtOH or GHB, and also explain the unique pharmacokinetics of this response: its rapid onset of action; the duration of benefit; its dose-dependence; and the lack of tachyphylaxis. Finally, a working hypothesis should be testable in animal models of these disorders, and in affected patients using functional imaging and neurophysiologic investigations.
We performed a Pubmed search using the following key words: alcohol, sodium oxybate, GHB, dystonia, tremor, chorea, tics, and myoclonus. All papers with reported response to EtOH or GHB (or its sodium salt, sodium oxybate, commercially available in the United States as the FDA-approved drug Xyrem) were reviewed. We refer to GHB and Xyrem interchangeably in the remainder of this paper, recognizing that patients treated in the United States received the drug Xyrem. We included all reported prospective studies or clinical observations, and also included historical descriptions of a response to EtOH when prospective observations were unavailable. The literature search identified the following hits: 468 papers for the terms “dystonia and alcohol” (5 were included in the manuscript); 309 papers for the terms “myoclonus and alcohol” (11 were included in the manuscript); 94 papers for the terms “tic and alcohol” (0 were included in the manuscript); 403 papers for the terms “chorea and alcohol” (0 were included in the manuscript); 2076 papers for the terms “tremor and alcohol” (11 were included in the manuscript); 11 papers for the terms “dystonia and GHB” or “dystonia and sodium oxybate” (1 was included in the manuscript); 12 papers for the terms “myoclonus and GHB” or “myoclonus and sodium oxybate” (9 were included in the manuscript); 9 papers for the terms “tremor and GHB” or “tremor and sodium oxybate” (1 was included in the manuscript); 0 papers for the terms “chorea and GHB” or “chorea and sodium oxybate” or “tics and GHB” or “tics and sodium oxybate”.
Table 1 lists fifteen alcohol-responsive hyperkinetic disorders, in which at least one patient in the literature responded to treatment with EtOH or GHB. Five tremor disorders responded to EtOH: essential tremor (ET), isolated vocal tremor (VT), primary writing tremor (PWT), orthostatic tremor (OT), and tremor in Kennedy’s disease [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40]. Six alcohol-responsive dystonic disorders were reported: torticollis, abductor spasmodic dysphonia (ABSD), adductor spasmodic dysphonia (ADSD), ADSD in DYT-4 dystonia, dopa-responsive dystonia (DYT-5, DRD), and generalized dystonia [41, 42, 43, 44, 45, 46]. Four alcohol-responsive myoclonic disorders have been reported: myoclonus-dystonia linked to epsilon sarcoglycan mutations (SCGE-MD), posthypoxic myoclonus (PHM), Unverricht-Lundborg disease (EPM-1), and sialidosis-type-1 [47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57]. Details of the published studies are summarized in Table 2.
|Essential tremor (ET)|
|Isolated vocal tremor (VT)|
|Primary writing tremor (PWT)|
|Orthostatic tremor (OT)|
|Tremor in Kennedy’s disease (X-linked Spinal Bulbar Muscular Atrophy)|
|Myoclonus-dystonia linked to epsilon sarcoglycan mutation (SCGE-MD)|
|Posthypoxic myoclonus (Lance Adams syndrome, PHM)|
|Progressive Myoclonic Epilepsy type 1, (EPM1)|
|Adult sialidosis type I|
|Abductor spasmodic dysphonia (ABSD)|
|Adductor spasmodic dysphonia (ADSD)|
|Adductor spasmodic dysphonia in DYT-4|
|Dopa-responsive dystonia (DYT-5, DRD)|
|Reference [#]||Diagnosis||n||Selection of patients by response?||EtOH [ ]||How achieved?||GHB||Placebo||Measure/Rating||Effect size||t ratings||t onset||t max||Dose response?||Blinded rating?||Rebound?||Tachyphylaxis?|
|Hopfner ||ET||71||Unselected||Yes||Oral:Widmark||Yes||Blinded Archimedes rating||Arch spiral: 50%||0, 20’, 40’, 60’, next AM||20’||60’||N/A||Yes||Yes||N/A|
|Knudsen ||ET||25||Unselected||Yes||Oral:Widmark||No||Blinded spirals; Tremor scale||>50%||0, 10’20’, 30’, 40’, 50’, 60’, 90’, next AM||10’||40’||N/A||Yes||Yes||N/A|
|Voller 2014 ||ET||15||Unselected||Yes||Oral breathalyzer||No||Acceleromter/TETRAS||40%||0, 20’, 40’, 60’, 80’, 100’, 120’||20’||60’||N/A||No||N/A||N/A|
|Zeuner 2003 ||ET||10||Selected||Tes||Oral bolus||No||Accelerometer/performance||>50%||0, 30’, 60’, 90’, 120’||30’||60’||N/A||No||N/A||N/A|
|de Haas 2012 ||ET||9||Selected||Yes||IV infusion||Yes||Accelerometer/performance||>50%||0, 60’, 150’, 240’, 330’, 420’||60’||60’||N/A||No||N/A||N/A|
|Frucht 2005 ||ET||9||Selected||1–3 gm||No||WHIGET||50%||60’||45’||60’||Yes||Yes||N/A||No|
|Growdon 1975 ||ET||5||Unselected||Yes||Oral bolus||No||Accelerometer||>50%||q 10’||15’||15’||N/A||Yes||Yes||N/A|
|Bain 1995 ||PWT||7||Unselected||No||History||No||Observation||greatly improved or abolished||N/A||N/A||N/A||N/A||No||N/A||N/A|
|Dias 2011 ||X-SMA||7||Unselected||N/A||N/A||No||Observation||significant resposne||N/A||N/A||N/A||N/A||No||N/A||N/A|
|Frucht 2005 ||PHM||4||Selected||1–3 gm||No||UMRS||action myoclonus 45 →26||N/A||30’||60’||Yes||Yes||No||No|
|Frucht 2005 ||PHM||1||Selected||No||Oral||1–4 gm||No||UMRS||action myoclonus 108 →53||N/A||30’||60’||Yes||Yes||No||No|
|Frucht 2005 ||PHM||1||Selected||1–4 gm||No||UMRS||action myoclonus 108 →54||N/A||30’||60’||Yes||Yes||No||No|
|Arpsella ||PHM||1||Selected||Yes||IV infusion||2 gm||No||UMRS||action myoclonus 112 →44||N/A||N/A||60’||Yes||No||N/A||N/A|
|Riboldi 2019 ||PHM||1||Selected||No||Oral||1–2 gm||No||Video rating||marked improvement||60’||30’||60’||Yes||No||No||No|
|Jain 1991 ||PHM||1||Selected||No||Oral||No||Observation||dramatic improvement||30’; 60’; 240’||30’||30’||Yes||No||No||No|
|Lu 1991 ||PME||3||Selected||Yes||Oral||No||Observation||mild to dramatic improvement||20’||20’||20’||No||No||N/A||No|
|Frucht 2005 ||PME||2||Selected||No||Oral||1–3 gm||No||UMRS||moderate improvement||60’||30’||60’||Yes||Yes||No||No|
|Jain 1996 ||PME||2||Selected||Yes||Oral||No||Observation||disappearance of myoclonus||300–360’||20’||N/A||No||No||No||N/A|
|Genton 1992 ||PME||1||Selected||Yes||Oral||No||Observation||dramatic||within a few minutes||15’||N/A||No||No||N/A||Yes|
|Genton 1990 ||PME||4||Unselected||No||Oral||No||Observation||mild to dramatic improvement||N/A||10’||N/A||N/A||No||No||N/A|
|Weissbach 2017 ||MD||17||Selected||Yes||Oral breathalyzer||No||UMRS||Mean score: 37 →20||300–360’||20’||N/A||No||No||N/A||N/A|
|Frucht 2005 ||MD||2||Selected||1–4 gm||No||UMRS||action myoclonus 25 → 3; 35 → 15||60’||30’||60’||Yes||Yes||No||No|
|Frucht 2005 ||MD||1||Selected||1–4 gm||No||UMRS||moderate improvement||60’||30’||60’||Yes||Yes||No||No|
|Priori 2000 ||MD||1||Selected||No||N/A||1–5 gm||No||Observation||80% improvement||N/A||N/.A||60’||N/A||No||No||No|
|Rumbach 2017 ||SD, SD/VT||45||Selected||Oral||1–1.5 gm||No||Speech rating of recordings||33% improvement||45’||30’||45’||No||Yes||N/A||N/A|
|Wilcox 2011 ||SD||7||Unselected||No||Oral||No||Observation||mild to sigificant||N/A||N/A||N/A||N/A||No||N/A||N/A|
|Biary 1985 ||CD||7||Unselected||Yes||IV infusion||Yes||Rating Scale||Dystonia score: 63 → 36||N/A||15’||15’||N/A||Yes||N/A||N/A|
|Lim 2012 ||WC||1||Selected||Yes||Oral||No||Observation/physiology||near complete resolution||N/A||10’||10’||N/A||No||No||No|
|Micheli 2017 ||GD||1||Selected||Yes||Oral||No||Observation||dramatic improvement||N/A||rapid||N/A||N/A||No||No||No|
|Grantham 2014 ||DRD||1||Selected||Yes||Oral||No||Observation||complete resolution||N/A||rapid||N/A||N/A||No||No||No|
Several common themes emerge from review of these case series. Observed improvements with modest doses of EtOH or Xyrem are rapid, sometimes visible 15 minutes after the drug is administered, and always evident by 45–60 minutes. Response to treatment is typically dose-dependent, lasts three to four hours, and worsens the next morning with rebound in the case of EtOH. Tachyphylaxis to treatment with Xyrem was not seen, and evidence for the phenomena with EtOH is unavailable. Over the last fifteen years, we have conducted five IRB-approved clinical trials of Xyrem in patients with alcohol-responsive movement disorders, including patients with PHM, ET, VT, SCGE-MD, ADSD and ABSB. We have administered the drug to more than one hundred patients in clinical trials or as part of clinical care where other therapeutic options have failed. The response to EtOH appears to predict response to Xyrem, and the pharmacokinetics and tolerability of the two agents appear to be very similar. In the accompanying video segment and video legend, we present select patient responses to EtOH or sodium oxybate; these video segments illustrate robust improvements, understanding that mild or moderate improvements are more typical. Improvements in Archimedes spirals (ET) and handwriting (PWT) with administration of Xyrem appear in Figure 1.
We propose a new model to explain the phenomenon of alcohol-response in select hyperkinetic movement disorders. A diagram illustrating this model and its supporting evidence appears in Figure 2.
We propose that the improvement of varied hyperkinetic movement disorders with modest doses of EtOH or GHB doesnotderive from a simple pharmacologic effect on the GABA-A, GABA-B or GHB receptors. Instead, we propose thatmodest doses of GHB or EtOH possess a specific and novel ability to normalize pathologic hypermetabolism of the cerebellar Purkinje cells and deep cerebellar nuclei.We further propose thatPurkinje cell dysfunction(either aberrant activation or abnormal synchronous firing)is the unifying feature linking these varied hyperkinetic disorders.
We present two lines of evidence to support this hypothesis:
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 . A second study using increasing modest doses of alcohol  again showed the largest metabolic reductions in the cerebellum as well as thalamus and mesencephalon. The final study with co-registered MRI localization confirmed this effect on the cerebellum and occipital cortex . These three papers illustrate that modest doses of EtOH selectively and preferentially reduce cerebellar metabolism. To our knowledge, the effect of a modest dose of GHB on cerebral metabolism in man or in animals has not been studied. Interestingly, in rat brain the GHB receptor is heavily expressed in the cerebellum but not in striatum or thalamus, and within the cerebellum GHB-receptor expression is highest within Purkinje cells . Taken together, these three pivotal studies support the idea that administration of EtOH at doses that do not produce intoxication or sedation selectively reduces cerebellar metabolism.
Two post-mortem studies of coeliac disease patients with cortical myoclonus have demonstrated selective loss of Purkinje cells, illustrating that isolated cerebellar pathology can generate cortical myoclonus [62, 63]. In EPM-1 (Unverricht-Lundborg disease), another disorder with prominent cortical myoclonus and EtOH-response, a post-mortem study showed a similar loss of Purkinje cells with involvement of the dentate nucleus [64, 65]. Many patients with EPM1 do not appear to have cerebellar atrophy on routine MRI imaging, but an MRI/MRS study of a cohort of patients demonstrated mild atrophy of cerebellar hemispheres, medulla and basis pontis . Cystatin B, the protein affected by EPM1, is selectively expressed in Purkinje cells and some molecular layer neurons in the developing and adult rat . In man cystatin B expression is limited to Purkinje cells and Bergmann fibers . The cerebellum has also been demonstrated to be critically important in PHM. In the best available animal model of PHM, Walsh demonstrated that circulatory arrest for eight minutes selectively injures bands of Purkinje cells, and is likely the signature lesion of PHM . PET study of patients with PHM demonstrated a metabolic topographic pattern of activation of the VL thalamus and pontine tegmentum . Re-analysis of this data and comparison to PET studies in SCGE-MD patients revealed hypermetabolism of the cerebellar cortex and dentate . Finally, a single patient with PHM demonstrated transient increased DWI signal in the cerebellum and thalami, and these signal abnormalities remitted as the patient’s myoclonus subsided . Taken together, these studies in animal and man of coeliac, EPM1 and PHM demonstrate a central role of the cerebellum and Purkinje cells in the generation of myoclonus.
Investigations in patients with SD and SCGE-MD support a pivotal role of the cerebellum and Purkinje cells in these disorders. In an fMRI study of SD patients treated with a single dose of Xyrem, clinical improvement in dysphonia and reduction in vocal breaks correlated with normalization of cerebellar activation . In a PET study, symptomatic SCGE-MD patients demonstrated activation of cerebellar cortex and dentate compared to non-manifesting SCGE carriers and healthy controls . In a post-mortem study of SCGE-MD patients, the brain-specific isoform of SCGE (exon 11b) was found to be highly expressed in Purkinje cells and dentate nucleus . Finally, an elegant selective knockdown model of SCGE in the cerebellum of adult mice produced a robust MD phenotype . SCGE was expressed in Purkinje cells and deep cerebellar nuclei, and administration of EtOH normalized output from these structures in SCGE knockdown mice but not in DYT-1 knockdown mice, illustrating their specific role in MD . Taken together, these studies support the critical role of the cerebellum, Purkinje cells and dentate in MD, and the likely mechanism of action of EtOH to normalize Purkinje cell and cerebellar output in this disorder.
Many studies in the last fifteen years have demonstrated the important role of the cerebellum in ET, and it is beyond the scope of this paper to review this evidence in detail. Briefly, pathologic changes in post-mortem tissue support Louis’ designation of ET as a “Purkinjeopathy”, with a loss of Purkinje cells up to about 30% [75, 76]. While no animal model fully replicates all of the clinical features of ET, Broersma demonstrated that ET tremor is correlated with bilateral cerebellar activation in lobules V, VI and VIII . Pedrosa demonstrated that the effect of EtOH on ET tremor is due to normalization of cerebellar activation .
We have proposed a model to explain a robust and reproducible improvement with modest doses of EtOH or GHB in certain hyperkinetic movement disorders. We posit that abnormal activation of the Purkinje cells and dentate nucleus, the major outflow of the cerebellum, are critical to this response. Purkinje cells are involved pathologically in coeliac disease, ET, and PHM, and expression of cystatin B, SCGE 11b, and the GHB receptor are selectively increased in Purkinje cells. Network studies in ET, PHM, MD and SD support the role of abnormal cerebellar activation in these conditions. Granule cells in the cerebellum can be implicated as well. Indeed, GABA receptors sensitive to low doses of EtOH and GHB are specifically found on these cells. A primary disfunction in the Purkinje cells due to cell loss or protein abnormalities, such as cystatin B in EPM1, could cause abnormal firing of these cells. Modulation of the inputs from the Granule cells could possibly restore the cerebellar hyperactivity. Normalization of this network by EtOH (ET, MD), and Xyrem (SD) has been shown to be associated with clinical improvement. We demonstrate by video our experience over the last fifteen years treating patients with these conditions, and illustrate the rapid and significant effects of EtOH and Xyrem at modest doses.
Perhaps the biggest obstacle to our model is the question of how modest doses of EtOH or Xyrem exert their selective effect on the cerebellum. Selective knock-down and optogenetic studies might allow investigation of this question, and high-resolution MRI and co-registered PET studies in patients and animal models would also be useful. It is also possible that the nature of Purkinje cell dysfunction differs in the various disorders. Coeliac disease and anoxia selectively injure a subset of Purkinje cells, perhaps resulting in hyperexcitability in the remaining cells. In contrast, Purkinje cell dysfunction without overt cell loss may underlie the genesis of ET and MD. Given the robust nature of the EtOH and GHB response in this group of patients, further work to understand these phenomena and to design better therapeutic options is warranted.
The authors have no competing interests to declare.
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