Table 1
Hyperkinetic movement disorders with reported response to EtOH or GHB. Hyperkinetic movement disorders responsive to EtOH or GHB are listed in Table 1. Tremor disorders appear in green, myoclonic disorders in blue, and dystonic disorders in red.
| 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 |
| Torticollis |
| Abductor spasmodic dysphonia (ABSD) |
| Adductor spasmodic dysphonia (ADSD) |
| Adductor spasmodic dysphonia in DYT-4 |
| Dopa-responsive dystonia (DYT-5, DRD) |
| Generalized dystonia |
Table 2
Summary table of published studies of hyperkinetic movement disorders treated with EtOH or Xyrem. Thirty-one published studies of hyperkinetic movement disorders treated with EtOH or GHB are presented in Table 2. Papers are grouped by diagnosis, with tremor disorders in green, myoclonic disorders in blue, and dystonic disorders in red. Columns, starting from the left, include: Reference (reference #3); Underlying diagnosis (ET—essential tremor, PWT—primary writing tremor, VT—vocal tremor, OT-orthostatic tremor, X-SMA—X-linked spinal muscular atrophy, PHM—posthypoxic myoclonus, PME—progressive myoclonic epilepsy; MD—myoclonus dystonia, MG—Meige, SD—spasmodic dysphonia, WC—writer’s cramp, GD—generalized dystonia, RAS—Rasmussen’s, DRD—dopa-responsive dystonia); n—number of reported patients; Selection of patients by response?—whether or not patients were chosen based on their response to EtOH (selected) or not (unselected); EtOH—patients who received EtOH and those with concentration of EtOH measured (Yes) or not (No); How achieved?—Mechanism of administration of EtOH; GHB—those patients who received GHB, and dosing; Placebo—whether or not a placebo administration was employed (Yes) or not (No); Measure/rating—mechanism of rating of the response, including rating scale, accelerometer, WHIGET (Washington Heights Inwood Generalized Essential Tremor rating scale), observation, UMRS (Unified Myoclonus Rating Scale); Effect size—estimation of % of benefit, or verbal description; t ratings—time points at which improvement was measured; t onset—time at which first benefit was measured; t max—time at which maximum benefit was observed; Dose response—whether a dose response was observed (Yes), not observed (No), or not known (N/A); Blinded rating—whether ratings were blinded (Yes) or not (No); Rebound—whether rebound worsening was observed (Yes) or not (No) or unknown (N/A); and, Tachyphylaxis—whether this was observed (Yes), not observed (No) or unknown (N/A).
| 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 [21] | 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 [22] | 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 [25] | 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 [26] | 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 [27] | 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 [28] | ET | 9 | Selected | 1–3 gm | No | WHIGET | 50% | 60’ | 45’ | 60’ | Yes | Yes | N/A | No | ||
| Growdon 1975 [29] | ET | 5 | Unselected | Yes | Oral bolus | No | Accelerometer | >50% | q 10’ | 15’ | 15’ | N/A | Yes | Yes | N/A | |
| Bain 1995 [30] | PWT | 7 | Unselected | No | History | No | Observation | greatly improved or abolished | N/A | N/A | N/A | N/A | No | N/A | N/A | |
| Koller [31] | PWT | 1 | Unselected | No | History | No | Observation | “improved” | N/A | N/A | N/A | N/A | No | Yes | N/A | |
| Sulica [32] | VT | 9 | Unselected | No | History | No | Observation | “improved” | N/A | N/A | N/A | N/A | No | N/A | N/A | |
| Massey [23] | VT | 4 | Unselected | No | History | No | Observation | “improved” | N/A | N/A | N/A | N/A | No | N/A | N/A | |
| Dias 2011 [24] | 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 [28] | PHM | 4 | Selected | 1–3 gm | No | UMRS | action myoclonus 45 →26 | N/A | 30’ | 60’ | Yes | Yes | No | No | ||
| Frucht 2005 [39] | PHM | 1 | Selected | No | Oral | 1–4 gm | No | UMRS | action myoclonus 108 →53 | N/A | 30’ | 60’ | Yes | Yes | No | No |
| Frucht 2005 [40] | PHM | 1 | Selected | 1–4 gm | No | UMRS | action myoclonus 108 →54 | N/A | 30’ | 60’ | Yes | Yes | No | No | ||
| Arpsella [41] | 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 [42] | PHM | 1 | Selected | No | Oral | 1–2 gm | No | Video rating | marked improvement | 60’ | 30’ | 60’ | Yes | No | No | No |
| Jain 1991 [43] | PHM | 1 | Selected | No | Oral | No | Observation | dramatic improvement | 30’; 60’; 240’ | 30’ | 30’ | Yes | No | No | No | |
| Lu 1991 [44] | PME | 3 | Selected | Yes | Oral | No | Observation | mild to dramatic improvement | 20’ | 20’ | 20’ | No | No | N/A | No | |
| Frucht 2005 [28] | PME | 2 | Selected | No | Oral | 1–3 gm | No | UMRS | moderate improvement | 60’ | 30’ | 60’ | Yes | Yes | No | No |
| Jain 1996 [45] | PME | 2 | Selected | Yes | Oral | No | Observation | disappearance of myoclonus | 300–360’ | 20’ | N/A | No | No | No | N/A | |
| Genton 1992 [46] | PME | 1 | Selected | Yes | Oral | No | Observation | dramatic | within a few minutes | 15’ | N/A | No | No | N/A | Yes | |
| Genton 1990 [47] | PME | 4 | Unselected | No | Oral | No | Observation | mild to dramatic improvement | N/A | 10’ | N/A | N/A | No | No | N/A | |
| Weissbach 2017 [48] | 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 [40] | MD | 2 | Selected | 1–4 gm | No | UMRS | action myoclonus 25 → 3; 35 → 15 | 60’ | 30’ | 60’ | Yes | Yes | No | No | ||
| Frucht 2005 [28] | MD | 1 | Selected | 1–4 gm | No | UMRS | moderate improvement | 60’ | 30’ | 60’ | Yes | Yes | No | No | ||
| Priori 2000 [49] | 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 [33] | 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 [34] | 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 [35] | 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 [36] | WC | 1 | Selected | Yes | Oral | No | Observation/physiology | near complete resolution | N/A | 10’ | 10’ | N/A | No | No | No | |
| Micheli 2017 [37] | GD | 1 | Selected | Yes | Oral | No | Observation | dramatic improvement | N/A | rapid | N/A | N/A | No | No | No | |
| Grantham 2014 [38] | DRD | 1 | Selected | Yes | Oral | No | Observation | complete resolution | N/A | rapid | N/A | N/A | No | No | No | |
| Totals | 276 | 15–45’ | ≤60’ |
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).
Video
Alcohol-responsive movement disorders—a unifying hypothesis? We present video examples of robust responses to EtOH or Xyrem in thirteen selected patients treated by the senior author in IRB-approved clinical trials or clinical practice over the last fifteen years. We specifically selected video segments that illustrated a robust response. Patient #1, a 37-year-old woman, underwent a routine gynecological surgery complicated by an unrecognized esophageal intubation leading to refractory severe PHM [47]. Despite treatment with clonazepam, valproic acid, phenobarbital, topiramate, zonisamide and levetiracetam, paroxysms of myoclonus affecting the trunk, head and limbs, are triggered by any attempt to move. Twenty minutes after ingesting two eight-ounce glasses of wine in the office, her myoclonus improved for the first time in three and a half years, enough for her to gesture fluidly (telling her husband to “shut up”). Her husband was deeply moved, stating that “the gesture has returned”. She was even able to walk with only mild support from her home aide while the EtOH effect lasted. She participated in a single patient, IRB-approved, add-on clinical trial of Xyrem, and brief clips of her attempts to pour water are shown before and one hour after ingesting 4 gm of Xyrem (although she tolerated this dose without sedation, in subsequent trials lower doses of Xyrem were employed), After the trial concluded, she was treated with Xyrem in open label fashion for a decade at doses of 1.5 gm every three hours, until her demise from medical illness. Patient #2 sustained an asthmatic arrest leading to PHM fifteen years before this video was taken. Despite treatment with clonazepam and levetiracetam, action and intention myoclonus and negative myoclonus on standing were significant. The video segment illustrates myoclonus before and one hour after ingestion of 2.5 gm of Xyrem [48]. Patient #3 developed severe PHM after a spontaneous bilateral pneumothorax leading to cardiopulmonary arrest. Despite treatment with valproic acid, levetiracetam and zolpidem, severe action and intention myoclonus were disabling. He was admitted to hospital in order to titrate increasing doses of Xyrem in an observed setting (he did not receive an EtOh challenge as he was only 19 years old). One hour after administration of 1.5 gm of Xyrem, action and intention myoclonus were reduced, allowing him to perform tasks such as brushing his hair for the first time. He has remained on Xyrem for the last three years with clear awareness of kinetics of the drug, and no evidence of tachyphylaxis [51]; bilateral DBS of the GPi was performed two years after this video was taken, with additional functional benefit. Patient #4 developed severe PHM after a cardiac arrest triggered by a pulmonary embolus. Despite treatment with clonazepam, valproic acid, zonisamide and levetiracetam, severe myoclonic jerks of his arms and torso left him completely functionally dependent. In this home video before and one hour after ingestion of six ounces of 80 proof vodka, significant improvement in myoclonus at rest and with action is evident. He did not tolerate Xyrem due to worsening depression, and he subsequently underwent bilateral DBS of the GPI, with surgical results pending at the time of this writing.
Patients #5–8 demonstrate the response of VT and ET to treatment with Xyrem in IRB-approved clinical trials [1843]. Patient #5, a 61-year-old woman with VT, is shown speaking and phonating before and one hour after ingesting one gram of Xyrem. A moderate-amplitude vocal tremor is evident before treatment, with modest reduction in the amplitude of tremor (without change in frequency). Patients #6–8, all with ET, are shown in brief video clips before and after treatment with Xyrem [36]. Patient #6 attempts to draw an Archimedes spiral with disastrous results; one hour after ingesting two grams of Xyrem he is able to perform the task. Patient #7 is shown before and one hour after administration of 1.5 gm of Xyrem. Interestingly, the video shows that after treatment she was aware that she could pour water with her left hand before she attempts to perform the task. Patient #8 was videotaped in fifteen-minute intervals after ingesting 1.5 gm of Xyrem to assess the pharmacokinetics of the improvement. Before treatment, action tremor of the right hand interferes with her attempt to pour water. Forty-five minutes after ingesting 1.5 gm of Xyrem, a significant reduction of tremor is seen, and tremor disappears at sixty minutes, surprising the patient and her husband. Despite this robust response, she did not continue treatment due to the sedative side effects of the drug.
The following three patients with SCGE-MD (#s 9, 10 and 11) are shown in brief clips taken during their participation in a clinical trial [36]. Patient #9 is shown pouring water before and one hour after administration of 2.5 gm of Xyrem. Patient #10 is more severely affected, with myoclonus affecting walking and pouring. Myoclonus was moderately improved at relatively high doses of Xyrem (video shown one hour after administration of four grams). The final patient was afflicted with predominant axial jerks triggered by actions such as pouring. One hour after administration of two gm of Xyrem, myoclonus was improved.
The final two patients, #s 12 and 13, participated in a study of the effects of Xyrem on SD with functional MRI [72]. Patient #12 is afflicted with ADSD and is usually treated successfully with botulinum toxin injections bilaterally to the thyroarytenoid muscles. Her ADSD was exquisitely responsive to EtOH, and she is shown before and one hour after administration of 1.5 gm of Xyrem with near resolution of vocal breaks. The final patient, patient #13, is afflicted with ABSD, and is shown before and one hour after administration of one gram of Xyrem, with resolution of his abductor breaks.