Objective response to ethanol in essential tremor: results from a standardized ethanol challenge study.

BACKGROUND AND OBJECTIVES: Ethanol has been reported to improve tremor severity in approximately two thirds of patients with essential tremor (ET), but the accuracy of that proportion is not certain and the mechanism of action is unknown. The goal of this study was to investigate alcohol response on tremor by applying an a priori objective response definition and subsequently to describe the responder rate to a standardized ethanol dose in a cohort of 85 ET patients. A secondary analysis evaluated other tremor and nontremor features, including demographics, tremor intensity, breath alcohol concentration, nontremor effects of alcohol, self-reported responder status to ethanol, and prior ethanol exposure. METHODS: This was a prospective, open-label, single-dose challenge of oral ethanol during which motor and nonmotor measurements were obtained starting immediately prior to ethanol administration and subsequently every 20 min for 120 min. We defined tremor reduction as a 35% decline in power in the patient's tremor frequency recorded during spiral drawing 60 min after ethanol administration. RESULTS: In total, 80% of patients were considered alcohol responsive using our objective definition. Responder status and change in the objective tremor metrics were significantly correlated with the change in breath alcohol concentration levels after ethanol administration, but no other relationships to nontremor metrics were found. DISCUSSION: A high percentage of patients actually respond to acute ethanol. However, their self-reported response does not correlate well with their objective response. Objective response correlates with breath alcohol level but not with sedation, indicating a specific effect of ethanol on tremor.

Task-dependent variability of Essential Tremor.

INTRODUCTION: In Essential Tremor (ET), tremor characteristics and the impairment caused by tremor may vary from task to task. A variability of tremor frequency between postural and kinetic tasks has been proposed in ET, suggesting either multiple central oscillating networks, or peripheral or proprioceptive feedback-mechanisms. This electrophysiological study aimed to assess tremor frequencies and amplitudes in tasks involving postural and kinetic tremor, and compare findings within and across tasks, to delineate physiological differences underlying individually affected manual tasks in ET. METHODS: 40 ET patients were included in the study. Tremor was characterized clinically, as well as electrophysiologically using accelerometry and digitizing tablet tasks. Tremor amplitude measures and frequencies were extracted for tasks involving kinetic (digital spiral drawing, handwriting), as well as postural tremor. Tremor was compared between and within tasks. RESULTS: Digital spiral tremor frequencies were significantly higher compared to postural tremor frequencies, as measured by accelerometry, with a mean difference of >2 Hz (p < 0.001). Within-task variability of repeated digital spirals revealed a significant amplitude reduction over time in both hands (p < 0.001), with an up to 32% reduction compared to the first spiral. CONCLUSION: ET exhibited a frequency variability, which was dependent on activation condition, suggesting neurophysiologically distinct pathways between postural and kinetic tremor. The reduction of tremor amplitudes observed in repeated digital spiral drawing may be explained by a learning effect or adaptation, and should be considered as non-random factor of variability when using spirals in ET to assess effects of interventions.

Dose-escalation study of octanoic acid in patients with essential tremor.

BACKGROUND: Recently, 1-octanol has been shown to have efficacy in treating patients with essential tremor (ET). The primary metabolite of 1-octanol is octanoic acid (OA), which is now thought to be the active substance that mediates tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of oral OA in patients with ET and assess the pharmacokinetics (PK) and pharmacodynamics (PD) profile of OA. METHODS: The MTD was studied using an open-label, single-ascending 3 + 3 dose-escalation design. Predefined single doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as dose-limiting toxicity. Tremor was assessed using accelerometry, digital spiral analysis, and a standard clinical rating scale at baseline and up to 600 minutes after intake. Safety assessments and PK sampling were also performed. RESULTS: Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy measures suggested a dose-dependent reduction of tremor. Accordingly, a single unified PK/PD model with an effect compartment and sigmoid maximum effect (Emax) response could be built that accounted well for the time profiles of plasma concentrations as well as effects on tremor severity across the 5 dose levels. CONCLUSION: Although our trial did not reach an MTD, a dose-dependent effect was demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future studies are needed to explore the safety in higher dose ranges and to confirm dose-dependent efficacy in a placebo-controlled design. TRIAL REGISTRATION: Clinicaltrials.gov NCT01468948FUNDING. NINDS Intramural Research Program; TG Therapeutics Inc.

Treatment of essential tremor with long-chain alcohols: still experimental or ready for prime time?

AIM: To review current literature on long-chain alcohols and their derivatives as novel pharmacotherapy for the treatment of essential tremor (ET). BACKGROUND: Currently available and recommended pharmacotherapies for ET are often limited by suboptimal treatment effects, frequent adverse effects, and drug interactions. While ethanol is reported to profoundly decrease tremor severity in the majority of patients with ET, preclinical experience suggests that long-chain alcohols such as 1-octanol might lead to a comparable tremor reduction without ethanol's typical side effects of sedation and intoxication. Here, we review the literature on the first clinical trials on 1-octanol and its metabolite octanoic acid (OA) for the treatment of ET. METHODS: The literature on preclinical and clinical trials on long-chain alcohols as well as OA was reviewed and summarized, and an outlook given on next phases of development. DISCUSSION: 1-octanol was demonstrated to be safe and effective in a double-blind, placebo-controlled low-dose trial, and open-label data showed excellent tolerability and dose-dependent efficacy up to 128 mg/kg. Despite 1-octanol's efficacy, its future viability as an effective therapy is limited by its pharmacological properties that require large volumes to be orally administered. Pharmacokinetic data indicate that OA is the active metabolite of 1-octanol. Preclinical efficacy data for OA are positive, and human pilot data demonstrated excellent safety as well as efficacy in secondary outcome measures of tremor amplitudes. OA also has more favorable pharmacological properties for drug delivery; hence, OA may be worth developing as a pharmaceutical.

Alcohol challenge and sensitivity to change of the Essential Tremor Rating Assessment Scale.

BACKGROUND: The ability of the Essential Tremor (ET) Rating Assessment Scale (TETRAS) to detect changes in tremor severity is unknown. METHODS: Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dL breath alcohol content (brAC). Effects were investigated independently with accelerometry and TETRAS. RESULTS: Accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant. TETRAS and accelerometry showed a significant effect of time point using repeated-measures analysis of variance. The difference between baseline and each of the following six time points as well as the correlation of TETRAS with brAC were significant. The calculated minimum detectable change of TETRAS was 8.9% and the effect size was d = 4.75 (95% confidence interval: 3.60-5.90). CONCLUSION: We demonstrated sensitivity to change of the TETRAS performance scale after a therapeutic intervention, which further establishes its potential for use in both clinical and research settings.

Repetitive transcranial magnetic stimulation attenuates the perception of force output production in non-exercised hand muscles after unilateral exercise.

We examined whether unilateral exercise creates perception bias in the non-exercised limb and ascertained whether rTMS applied to the primary motor cortex (M1) interferes with this perception. All participants completed 4 interventions: 1) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand (EX), 2) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand whilst receiving rTMS over the contralateral M1 (rTMS+EX); 3) 15-min of rTMS over the 'trained' M1 (rTMS) and 4) 15-min rest (Rest). Pre and post-interventions, the error of force output production, the perception of effort (RPE), motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were measured in both hands. EX did not alter the error of force output production in the trained hand (Δ3%; P>0.05); however, the error of force output production was reduced in the untrained hand (Δ12%; P<0.05). rTMS+EX and rTMS alone did not show an attenuation in the error of force output production in either hand. EX increased RPE in the trained hand (9.1±0.5 vs. 11.3±0.7; P<0.01) but not the untrained hand (8.8±0.6 vs. 9.2±0.6; P>0.05). RPE was significantly higher after rTMS+EX in the trained hand (9.2±0.5 vs. 10.7±0.7; P<0.01) but ratings were unchanged in the untrained hand (8.5±0.6 vs. 9.2±0.5; P>0.05). The novel finding was that exercise alone reduced the error in force output production by over a third in the untrained hand. Further, when exercise was combined with rTMS the transfer of force perception was attenuated. These data suggest that the contralateral M1 of the trained hand might, in part, play an essential role for the transfer of force perception to the untrained hand.

Postural control in patients with liver cirrhosis: a posturographic study.

BACKGROUND: Ataxia has been suggested in the literature to be a symptom of hepatic encephalopathy (HE), but so far has not been objectively quantified. In this study, we wanted to objectively quantify ataxia in patients with liver cirrhosis. METHODS: One hundred and seven patients with liver cirrhosis were tested for postural control using posturography and compared with 25 controls. For quantification of HE, we used the number connection tests A and B, ammonia levels (NH3), and the partial pressure of ammonia in the arterial blood (pNH3). RESULTS: Patients showed an impaired postural control compared with controls. Patients with Child C cirrhosis had lower scores in the posturography than those with Child A or B cirrhosis. Patients with alcohol-induced (AIC) Child B cirrhosis achieved lower scores in the posturography than those with non-alcohol-induced (NAIC) Child B cirrhosis. Patients with AIC Child C had lower scores than the corresponding NAIC patients, although this did not reach statistical significance. In the NAIC group Child C patients, in the AIC group Child B and C patients had lower scores than the controls. Patients with abnormal results in the number connection tests, as well as those with high NH3 and pNH3 levels showed worse postural control than those with normal results. CONCLUSION: Patients with cirrhosis have an impaired postural control compared with controls and this impairment deteriorates with progression of liver disease. HE as well as past alcohol abuse contribute to the pathogenesis of ataxia in liver cirrhosis and past alcohol abuse leads to an earlier and more pronounced manifestation of ataxia in the affected patients.

Respective potencies of Botox and Dysport in a human skin model: a randomized, double-blind study.

Mouse units used to quantify the activity of botulinum A toxin preparations are not equivalent and issues concerning efficacy and safety remain with regard to their respective potencies and diffusion qualities in human tissue. We compared the effects of Botox (BOT) and Dysport (DYS) in different doses and dilutions in a human skin model. Eighteen (8 women, 10 men) healthy volunteers, aged 28.4 years +/- 5.7 years were injected intradermally with pure saline, BOT and DYS at 16 points in the abdomen in random order and in a double-blind condition, using two conversion ratios (1:3 and 1:4) and three different dilution schemes. For an objective outcome, the Ninhydrin sweat test was used to compare the anhidrotic areas. Both preparations showed a linear dose and dilution relationship with similar variances of responses for anhidrosis and hypohidrosis, indicating the same reliability of response. The dose equivalence conversion ratios (BOT: DYS) were 1:1.3 for anhidrosis and 1:1.6 for hypohidrosis (1:1.1-1.5 and 1:1.4-1.8 95% confidence intervals). The diffusion characteristics of both products were similar. A dose equivalence factor of more than 1:2 (BOT:DYS) is not supported by these objective and reproducible data.

Long-latency afferent inhibition during phasic finger movement in focal hand dystonia.

In the motor system, one specific movement is generated, and, simultaneously, other possible movements are suppressed; a process called surround inhibition. Focal hand dystonia (FHD) is a movement disorder characterized by a loss of surround inhibition. In order to explain the deficit in surround inhibition induced by volitional movement in FHD patients, we examined the inhibitory circuit activated by afferent stimulation at "long latency". We studied 14 patients (age 48.9+/-13.2 years, 3 females, 11 males) with idiopathic task-related FHD. To measure long-latency afferent inhibition (LAI), transcranial magnetic stimulation (TMS) was applied to the affected hemisphere for FHD patients and to the dominant hemisphere for 17 healthy volunteers. Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) and first dorsal interosseous (FDI) during rest and during voluntary phasic flexion of the second digit. Subjects were given electrical stimulation to either their fifth digit (homotopic to ADM, heterotopic to FDI) or their second digit (heterotopic to FDI, homotopic to ADM) at twice sensory perceptual threshold 180 ms prior to TMS application. Additionally, F-waves were recorded from ADM. At rest, we found a significant decrease in ADM MEP amplitudes with both homotopic and heterotopic stimulation compared to the corresponding non-stimulated trials. There was a trend toward less LAI in FHD patients. During movement, LAI was significantly decreased in both patients and controls. There was no significant group effect. The results for LAI in FDI were similar to those from ADM. F-wave area in ADM was greater during movement for both homo- and heterotopic stimulation. We found no difference in F-wave area between patients and healthy volunteers. Our results indicate that LAI is unlikely to be an underlying mechanism that contributes to the generation of normal surround inhibition in healthy volunteers or in the disruption of surround inhibition in FHD.

Effects of brain polarization on reaction times and pinch force in chronic stroke.

BACKGROUND: Previous studies showed that anodal transcranial DC stimulation (tDCS) applied to the primary motor cortex of the affected hemisphere (M1affected hemisphere) after subcortical stroke transiently improves performance of complex tasks that mimic activities of daily living (ADL). It is not known if relatively simpler motor tasks are similarly affected. Here we tested the effects of tDCS on pinch force (PF) and simple reaction time (RT) tasks in patients with chronic stroke in a double-blind cross-over Sham-controlled experimental design. RESULTS: Anodal tDCS shortened reaction times and improved pinch force in the paretic hand relative to Sham stimulation, an effect present in patients with higher impairment. CONCLUSION: tDCS of M1affected hemisphere can modulate performance of motor tasks simpler than those previously studied, a finding that could potentially benefit patients with relatively higher impairment levels.

Pain sensation during intradermal injections of three different botulinum toxin preparations in different doses and dilutions.

BACKGROUND: Pain sensation associated with injections of botulinum neurotoxin (BoNT) is commonly reported. To date differences in pain sensation between the commercially available products containing BoNT have not been quantified. OBJECTIVES: The pain sensations during injection of Dysport, Botox, Neurobloc, and pure saline (control) were compared. In addition, the nociceptive effect of different volumes used for the dilution of the same BoNT dose was investigated. METHODS: In a prospective, double-blind, controlled trial, 10 healthy subjects were injected intradermally with Dysport (12 U), Botox (3 and 4 U), Neurobloc (150 and 300 U) reconstituted in 0.9% saline, and pure saline. Pain sensation was quantified during injections. RESULTS: Neurobloc injections caused significantly more injection pain than Botox, Dysport, and saline. No significant differences between Dysport, Botox, and saline were found, although there was a trend toward less pain with pure saline injections. Higher pain levels with higher volumes could not be demonstrated significantly. CONCLUSION: Our data demonstrate that BoNT type B injections are associated with substantial pain. There is a considerable difference between the commercially available BoNT type B compared to the two BoNT type A preparations. Therefore, considering mitigation of injection pain seems necessary when using BoNT type B.

Contralateral hand anesthesia transiently improves poststroke sensory deficits.

OBJECTIVE: To test a possible strategy to alleviate somatosensory deficits after stroke. METHODS: Here, we applied ischemic nerve block to the intact hand of patients with chronic stroke, which in healthy subjects elicits improvements in sensibility of the other hand. RESULTS: We found that sensibility in the affected hand improved with intact hand anesthesia, but not with intact foot anesthesia or no anesthesia. INTERPRETATION: We conclude that reduction of sensory input from the intact hand leads to site-specific improvements in tactile discriminative skills in the affected hand after the period of anesthesia, a potentially relevant finding in designing neurorehabilitative interventions.

Short-latency afferent inhibition during selective finger movement.

During individual finger movement, two opposite phenomena occur at the level of the central nervous system that could affect other intrinsic hand muscle representations, unintentional co-activation, and surround inhibition (SI). At rest, excitability in the motor cortex (M1) is inhibited at about 20 ms after electric stimulation of a peripheral nerve [short-latency afferent inhibition (SAI)]. We sought to determine whether SAI changes during selective index finger movement. Effects were measured by the response to transcranial magnetic stimulation in two functionally distinct target muscles of the hand [abductor digiti minimi muscle (ADM), first dorsal interosseus muscle (FDI)]. An increase in SAI in the ADM during index finger movement compared to at rest could help explain the genesis of SI. Electrical stimulation was applied to either the little finger (homotopic for ADM, heterotopic for FDI) or the index finger (heterotopic for ADM, homotopic for FDI). During index finger movement, homotopic SAI was present only in the ADM, and the effect of peripheral stimulation was greater when there was less co-activation. Heterotopic SAI found at rest disappeared with movement. We conclude that during movement, homotopic SAI on the muscle in the surround of the intended movement may contribute to SI.

Long-latency afferent inhibition during selective finger movement.

Stimulation of a peripheral nerve of a hand at rest modulates excitability in the motor cortex and, in particular, leads to inhibition when applied at an interval of approximately 200 ms (long-latency afferent inhibition; LAI). Surround inhibition (SI) is the process that inhibits neighboring muscles not involved in a particular task. The neuronal mechanisms of SI are not known, and it is possible that LAI might contribute to it. Using transcranial magnetic stimulation (TMS) with and without movement of the index finger, the motor-evoked potentials (MEPs) were measured of two functionally distinct target muscles of the hand (abductor digiti minimi muscle = ADM, 1st dorsal interosseus muscle = FDI). Electrical stimulation was applied 180 ms before TMS to either the fifth finger or the index finger. Both homotopic and heterotopic finger stimulation resulted in LAI without movement. With index finger movement, motor output further decreased with homo- and heterotopic stimulation in the ADM. In the moving FDI, however, there was no change with either homo- or heterotopic stimulation. Additionally, in the unstimulated movement trials, LAI increased with the amount of unintentional co-activation that occurred despite attempts to maintain the ADM at rest. However, with finger stimulation added, there were almost no increased MEPs despite co-activation. These findings suggest that LAI increases during movement and can enhance SI.

Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil.

OBJECTIVE: Standard coils used in research and the clinic for noninvasive magnetic stimulation of the human brain are not capable of stimulating deep brain regions directly. As the fields induced by these coils decrease rapidly as a function of depth, only very high intensities would allow functional stimulation of deep brain regions and such intensities would lead to undesirable side effects. We have designed a coil based on numerical simulations and phantom brain measurements that allows stimulation of deeper brain regions, termed the Hesed coil (H-coil). In the present study we tested the efficacy and some safety aspects of the H-coil on healthy volunteers. METHODS: The H-coil was compared to a regular figure-8 coil in 6 healthy volunteers by measuring thresholds for activation of the abductor pollicis brevis (APB) representation in the motor cortex as a function of distance from each of the coils. RESULTS: The rate of decrease in the coil intensity as a function of distance is markedly slower for the H-coil. The motor cortex could be activated by the H-coil at a distance of 5.5 cm compared to 2 cm with the figure-8 coil. CONCLUSIONS: The present study indicate that the H-coil is likely to have the ability of deep brain stimulation and without the need of increasing the intensity to extreme levels that would cause a much greater stimulation in cortical regions. SIGNIFICANCE: The ability of non-invasive deep brain stimulation potentially opens a wide range of both research and therapeutic applications.

Ninhydrin sweat test: a simple method for detecting antibodies neutralizing botulinum toxin type A.

Approximately 5% of patients with cervical dystonia receiving repeated botulinum neurotoxin A (BoNT/A) injections develop secondary loss of treatment benefit. Currently available tests to directly detect neutralizing BoNT/A antibodies (BoNT/A-AB) are either expensive or time consuming. To establish a simple, clinically useful test for antibody detection, we adapted the ninhydrin sweat test (NST). Eighteen dystonic patients with secondary nonresponse and clinically suspected BoNT/A-AB formation were tested for BoNT/A-AB in the mouse diaphragm test (MDT). In addition, the size of the anhidrotic area was determined by the NST 21 days after an intradermal dose of 10 U Dysport into the hypothenar region of the left palm. In nine patients, positive BoNT-AB titers were found in the MDT. There was a significant correlation between the BoNT/A-AB titers and the anhidrotic area (Spearman's rho = -0.9, P < 0.0001). Both tests provided comparably good results with respect to qualitative antibody detection. In the clinical situation of secondary nonresponse to BoNT/A therapy, the economical NST may be a helpful tool to detect neutralizing BoNT/A-AB.