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Introduction: Primidone and propranolol are primary treatments for essential tremor, however the exact mechanisms underlying their efficacy are not fully elucidated. Understanding how these medications alleviate tremor may guide the development of additional pharmacologic treatments. Our prospective observational study employed transcranial magnetic stimulation (TMS) to explore mechanisms of primidone and propranolol effects in essential tremor. Eyeblink classical conditioning (EBCC) was tested as a potential predictor of treatment response., Methods: Patients with essential tremor underwent two evaluations: prior to commencing primidone or propranolol and following a minimum of three months of treatment. Tremor severity was assessed using accelerometry and clinically. TMS was employed to study changes in corticospinal excitability - resting and active motor thresholds, resting and active input/output curves and intracortical excitability - cortical silent period (CSP), short interval intracortical inhibition intensity curve (SICI), long interval intracortical inhibition (LICI), intracortical facilitation (ICF), and short afferent inhibition (SAI). EBCC, a marker of cerebellar function, was studied at baseline., Results: Of the 54 enrolled patients (28 primidone, 26 propranolol), 35 completed both visits. Primidone effect on decreasing hand tremor was associated with decreased corticospinal excitability, prolongation of CSP, increased LICI, increased SAI and decreased SICI. Propranolol effect on hand tremor was associated with decreased corticospinal excitability and increased SAI. Better EBCC at baseline predicted better response to primidone., Conclusions: Primidone exerts its therapeutic effects by blocking voltage-gated sodium channels and by modulating GABA-A and GABA-B intracortical circuits. Propranolol's central effects are likely mediated via noradrenergic modulation of GABA outflow., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Essential tremor (ET) is a chronic, progressive neurological disease that affects an estimated 7 million individuals in the United States (ie, 2.2% of the entire U.S. population). Despite its high prevalence, there are a few published studies on patterns of prescription medication use among patients., Objective: The aim was to examine prescription drug medication use among ET patients., Methods: This is a cross-sectional study of ET patients, age ≥40, with at least 1 prescription medication fill using the Optum's de-identified Clinformatics Data Mart Database from 2018 through 2019. We examined patterns of fills of key agents used to treat ET., Results: The final sample comprised 36,839 ET patients in the United States; 89% had at least 1 prescription drug claim over a 2-year period, indicating that 9 of 10 ET patients take a medication to treat their disease. For each of the 3 most frequently prescribed medications, only a modest fraction (1/5 to 1/4) of patients were taking that medication. Adherence to these agents was 52% to 61%. A high percentage of patients had fills for more than 1 of the main agents we studied., Conclusion: These data illustrate a need for medication in the ET population. There is only 1 FDA-approved medication to treat ET, propranolol, and less than 25% of ET patients used this drug during our study period. At the same time, no single agent was utilized by more than one quarter of ET patients, adherence was low, and use of multiple agents was common. For such a common disease, the pharmacotherapeutic landscape is impoverished., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Essential tremor (ET) is one of the most prevalent movement disorders; despite this, there remains an unmet need for novel therapies. The treatment of rats with harmaline modulates the rhythmicity of inferior olivary neurons, resulting in generalized tremor with a frequency of 9-12 Hz in rats, comparable to that of human ET (4-12 Hz)., Purpose: Interestingly, cannabinoids reduce tremor, therefore we have assessed the cannabinoid nabiximols (NBX; marketed as Sativex) a complex botanical drug mixture, in the harmaline-rat model of ET., Method: We tested the effects of acute (single dose) and subchronic (10 days) treatment of NBX (at 5.2, 10.4 and 20.8 mg kg -1 p.o.) administered prior to harmaline and acute NBX (20.8 mg kg -1 ) administered post-harmaline in male SD rats. Propranolol (20 mg kg -1  i.p.) was used as a positive control. Observed Scoring (OS) was carried out prior to placement in a tremor-monitoring apparatus for the calculation of Tremor Index (TI) and Motion Power Percentage (MPP)., Results: Acute and subchronic NBX significantly attenuated harmaline-induced tremor at 10.4 and 20.8 mg kg -1 , respectively, for each parameter (OS, TI, and MPP) when administered pre-harmaline as did propranolol (20 mg kg -1 ). NBX did not attenuate harmaline-induced tremor when administered post-harmaline., Conclusions: These data suggest efficacy of acute and subchronic NBX to reduce tremors, based on OS, TI and MPP readouts if administered prior to harmaline. These data are the first to indicate the preclinical effects of an oral botanical cannabinoid formulation, NBX, in an animal model of ET., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sally Loomis reports financial support was provided by Jazz Pharmaceuticals Inc. Andrew McCreary reports financial support was provided by Jazz Pharmaceuticals Inc. David Virley reports financial support was provided by Jazz Pharmaceuticals Inc. Elena Samoylenko reports financial support was provided by Jazz Pharmaceuticals Inc. Sally Loomis reports a relationship with Jazz Pharmaceuticals Inc. that includes: employment and equity or stocks. Andrew McCreary reports a relationship with Jazz Pharmaceuticals Inc. that includes: employment and equity or stocks. David Virley reports a relationship with Jazz Pharmaceuticals Inc. that includes: employment and equity or stocks. Elena Samoylenko reports a relationship with Jazz Pharmaceuticals Inc. that includes: employment and equity or stocks. Sally Loomis has patent issued to GW Pharmaceuticals. Andrew McCreary has patent issued to GW Pharmaceuticals. David Virley has patent issued to GW Pharmaceuticals. Elena Samoylenko has patent issued to GW Pharmaceuticals. NA If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological field. We carry out a review of the currently available treatments. The first intervention is the use of non-pharmacological and non-surgical strategies (general advice, occupational therapy, speech therapy, psychotherapy). With discrete advances, the pharmacological treatment is not very satisfactory. Only 30-60% of patients have a positive response, and in these the anti-tremor effectiveness is 40-60%. The first-line drugs are still propranolol and primidone. In cases with severe tremor we will consider a surgical option, the method of choice being thalamotomy using high-intensity focused ultrasound. In the future we must continue to study the pathophysiology of TE, develop drugs specifically designed for TE and improve the technology of available invasive techniques., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Essential tremor (ET) is a neurological disease that impairs motor and cognitive functioning. A variant of the Lingo-1 genetic locus is associated with a heightened ET risk, and increased expression of cerebellar Lingo-1. Lingo-1 has been associated with neurodegenerative processes; however, neuroprotection from ET-associated degeneration can be conferred by the protein Sirt1. Sirt1 activity can be promoted by Resveratrol (Res) and 1,25-dihydroxyvitamin D3 (VitD3), and thus these factors may exert neuroprotective properties through a Sirt1 mechanism. As Res and VitD3 are linked to Sirt1, enhancing Sirt1 could counteract the negative effects of increased Lingo-1. Therefore, we hypothesized that a combination of Res-VitD3 in a harmaline injection model of ET would modulate Sirt1 and Lingo-1 levels. As expected, harmaline exposure (10 mg/kg/every other day; i.p.) impaired motor coordination, enhanced tremors, rearing, and cognitive dysfunction. When Res (5 mg/kg/day; i.p.) and VitD3 (0.1 mg/kg/day; i.p.) were given to adult rats (n = 8 per group) an hour before harmaline, tremor severity, rearing, and memory impairment were reduced. Individual treatment with Res and VitD3 decreased Lingo-1 gene expression levels in qPCR assays. Co-treatment with Res and VitD3 increased and decreased Sirt1 and Lingo-1 gene expression levels, respectively, and in some cases, beneficial effects on behavior were noted, which were not seen when Res or VitD3 were individually applied. Taken together, our study found that Res and VitD3 improved locomotor and cognitive deficits, modulated Sirt1 and Lingo-1. Therefore, we would recommend co-treatment of VitD3 and Res to leverage complementary effects for the management of ET symptoms., (© 2024. The Author(s).)

Background: Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of α6β3δ extra-synaptic GABA A receptors, that in vitro respond to non-intoxicating alcohol levels. We previously found that low-dose alcohol reduces harmaline tremor in wild-type mice, but not in littermates lacking δ or α6 subunits. Here we addressed whether low-dose alcohol requires the β3 subunit for tremor suppression., Methods: We tested whether low-dose alcohol suppresses tremor in cre-negative mice with intact β3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the α6 subunit promotor. Tremor in the harmaline model was measured as a percentage of motion power in the tremor bandwidth divided by overall motion power., Results: Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicle-treated controls in floxed β3 cre- mice, but had no effect on tremor in floxed β3 cre+ littermates that have β3 knocked out. This was not due to potential interference of α6 expression by the insertion of the cre gene into the α6 gene since non-floxed β3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol., Discussion: As α6β3δ GABA A receptors are sensitive to low-dose alcohol, and cerebellar granule cells express β3 and are the predominant brain site for α6 and δ expression together, our overall findings suggest alcohol acts to suppress tremor by modulating α6β3δ GABA A receptors on these cells. Novel drugs that target this receptor may potentially be effective and well-tolerated for essential tremor., Highlights: We previously found with the harmaline essential tremor model that GABA A receptors containing α6 and δ subunits mediate tremor suppression by alcohol. We now show that β3 subunits in α6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating α6β3δ extra-synaptic GABA A receptors., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background: SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABA A receptors., Objective: KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET)., Methods: Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo., Results: Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder., Conclusion: These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Essential tremor, the world's most prevalent movement disorder, lacks a clear understanding of its pathophysiology. Propranolol, a non-specific beta-blocker capable of crossing the blood-brain barrier, is a primary choice for essential tremor treatment. While its tremor-reducing effects are generally attributed to peripheral actions, various uses hint at central adrenergic effects. Nevertheless, propranolol's precise impact on the central nervous system in essential tremor subjects remains unexplored., Methods: In this study, we employed transcranial magnetic stimulation to assess the influence of propranolol on the excitability of the primary motor cortex (M1) in patients with essential tremor, compared to an age- and sex-matched control group. Cortical excitability parameters were measured following placebo and propranolol administration, encompassing resting and active motor thresholds, motor evoked potential characteristics, cortical silent period, and the input/output curve., Results: Distinct effects were observed across the two cortical hemispheres. Essential tremor patients displayed inhibition of the left M1 cortex and heightened excitability in the right M1 cortex four hours after propranolol administration, but not following placebo., Conclusions: These findings suggest potential differential noradrenergic excitatory and inhibitory modulation. However, comprehensive understanding necessitates further investigations, including left-handed participants and more diverse essential tremor subpopulations. This study underscores the need for continued exploration to unravel propranolol's complex effects on motor cortex excitability in essential tremor., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

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., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Essential tremor (ET) is one of the most common neurological disorders, but information on treatment pattern is still scant. The aim of this study was to describe the demographic and clinical characteristics, treatment patterns, and determinants of drug use in patients with newly diagnosed ET in France and the United Kingdom., Methods: Incident cases of ET diagnosed between January 1, 2015 and December 31, 2018 with 2 years of follow-up were identified by using The Health Improvement Network (THIN®) general practice database. During the follow-up, we assessed the daily prevalence of use and potential switches from first-line to second-line treatment or other lines of treatment. Logistic regression models were conducted to assess the effect of demographic and clinical characteristics on the likelihood of receiving ET treatment., Results: A total of 2957 and 3249 patients were selected in the United Kingdom and France, respectively. Among ET patients, drug use increased from 12 months to 1 month prior the date of index diagnosis (ID). After ID, nearly 40% of patients received at least one ET treatment, but during follow-up drug use decreased and at the end of the follow-up approximately 20% of patients were still on treatment. Among treated patients, ≤10% maintained the same treatment throughout the entire follow-up, nearly 20% switched, and 40%-75% interrupted any treatment. Results from the multivariate analysis revealed that, both in France and the United Kingdom, patients receiving multiple concomitant therapies and affected by psychiatric conditions were more likely to receive an ET medication., Conclusion: This study shows that ET is an undertreated disease with a lower-than-expected number of patients receiving and maintaining pharmacological treatment. Misclassification of ET diagnosis should be acknowledged; thus, results require cautious interpretation., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials., Methods: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24., Results: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia., Conclusions: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Prior work using GABA A receptor subunit knockouts and the harmaline model has indicated that low-dose alcohol, gaboxadol, and ganaxolone suppress tremor via α6βδ GABA A receptors. This suggests that drugs specifically enhancing the action of α6βδ or α6βγ2 GABA A receptors, both predominantly expressed on cerebellar granule cells, would be effective against tremor. We thus examined three drugs described by in vitro studies as selective α6βδ (ketamine) or α6βγ2 (Compound 6, flumazenil) receptor modulators., Methods: In the first step of evaluation, the maximal dose was sought at which 6/6 mice pass straight wire testing, a sensitive test for psychomotor impairment. Only non-impairing doses were used to evaluate for anti-tremor efficacy in the harmaline model, which was assessed in wildtype and α6 subunit knockout littermates., Results: Ketamine, in maximally tolerated doses of 2.0 and 3.5 mg/kg had minimal effect on harmaline tremor in both genotypes. Compound 6, at well-tolerated doses of 1-10 mg/kg, effectively suppressed tremor in both genotypes. Flumazenil suppressed tremor in wildtype mice at doses (0.015-0.05 mg/kg) far lower than those causing straight wire impairment, and did not suppress tremor in α6 knockout mice., Discussion: Modulators of α6βδ and α6βγ2 GABA A receptors warrant attention for novel therapies as they are anticipated to be effective and well-tolerated. Ketamine likely failed to attain α6βδ-active levels. Compound 6 is an attractive candidate, but further study is needed to clarify its mechanism of action. The flumazenil results provide proof of principle that targeting α6βγ2 receptors represents a worthy strategy for developing essential tremor therapies., Highlights: We tested for harmaline tremor suppression drugs previously described as in vitro α6βδ or α6βγ2 GABA A receptor-selective modulators. Well-tolerated flumazenil doses suppressed tremor in α6-wildtype but not α6-knockout mice. Compound 6 and ketamine failed to display this profile, likely from off-target effects. Selective α6 modulators hold promise as tremor therapy., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Background: Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatment of ET affecting extremities., Objective: We conducted a proof-of-concept, open-label phase II study to examine the efficacy and central effects of sodium oxybate in patients with alcohol-responsive ETv., Methods: All subjects received 1.0 to 1.5 g of oral sodium oxybate and underwent brain functional magnetic resonance imaging. The primary endpoint was the number of patients (% from total) with reduced ETv symptoms by at least 10% at about 40 to 45 minutes after sodium oxybate intake based on the combined visual analog scale score of ETv symptom severity. The secondary endpoint included changes in brain activity after sodium oxybate intake compared to baseline., Results: Sodium oxybate reduced ETv symptoms on average by 40.8% in 92.9% of patients. Drug effects were observed about 40 to 45 minutes after intake, lasting about 3.5 hours, and gradually wearing off by the end of the fifth hour. The central effects of sodium oxybate were associated with normalized activity in the cerebellum, inferior/superior parietal lobules, inferior frontal gyrus, and insula and re-established functional relationships between these regions., Conclusions: Sodium oxybate showed high efficacy in ETv patients, with a likely central action on disorder pathophysiology. Sodium oxybate may be an effective novel oral drug for treatment of alcohol-responsive ETv patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Functional ultrasound (fUS), an emerging hemodynamic-based functional neuroimaging technique, is especially suited to probe brain activity and primarily used in animal models. Increasing use of pharmacological models for essential tremor extends new research to the utilization of fUS imaging in such models. Harmaline-induced tremor is an easily provoked model for the development of new therapies for essential tremor (ET). Furthermore, harmaline-induced tremor can be suppressed by the same classic medications used for essential tremor, which leads to the utilization of this model for preclinical testing. However, changes in local cerebral activities under the effect of tremorgenic doses of harmaline have not been completely investigated. In this study, we explored the feasibility of fUS imaging for visualization of cerebral activation and deactivation associated with harmaline-induced tremor and tremor-suppressing effects of propranolol. The spatial resolution of fUS using a high frame rate imaging enabled us to visualize time-locked and site-specific changes in cerebral blood flow associated with harmaline-evoked tremor. Intraperitoneal administration of harmaline generated significant neural activity changes in the primary motor cortex and ventrolateral thalamus (VL Thal) regions during tremor and then gradually returned to baseline level as tremor subsided with time. To the best of our knowledge, this is the first functional ultrasound study to show the neurovascular activation of harmaline-induced tremor and the therapeutic suppression in a rat model. Thus, fUS can be considered a noninvasive imaging method for studying neuronal activities involved in the ET model and its treatment.

Importance: The gold-standard treatment for laryngeal dystonia (LD) and essential tremor of the vocal tract (ETVT) is botulinum toxin (BoNT) chemodenervation. Although safe and effective, it is not curative, and periodic injections are required. Some medical insurance companies only cover injections at a 3-month interval, though some patients benefit from injections more frequently., Objective: To determine the proportion and characteristics of patients who receive BoNT chemodenervation treatment in intervals shorter than 90 days., Design, Setting, and Participants: This retrospective cohort study across 3 quaternary care neurolaryngology specialty practices in Washington and California recruited patients who underwent at least 4 consecutive laryngeal BoNT injections for LD and/or ETVT in the past 5 years. Data were collected from March through June 2022 and analyzed from June through December 2022., Exposure: Laryngeal BoNT treatment., Main Outcomes and Measures: Biodemographic and clinical variables, injection characteristics, evolution during the 3 interinjection intervals, and lifetime laryngeal BoNT treatment data were collected from patient medical records. Logistic regression was used to assess association to the short-interval outcome, defined as an average injection interval shorter than 90 days., Results: Of 255 patients included from the 3 institutions, 189 (74.1%) were female, and the mean (SD) age was 62.7 (14.3) years. The predominant diagnosis was adductor LD (n = 199 [78.0%]), followed by adductor dystonic voice tremor (n = 26 [10.2%]) and ETVT (n = 13 [5.1%]). Seventy patients (27.5%) received short-interval injections (<90 days). The short-interval group was younger than the long-interval group (≥90 days), with a mean (SD) age of 58.6 (15.5) years and 64.2 (13.5) years, respectively, and a mean difference of -5.7 years (95% CI, -9.6 to -1.8 years). There were no patient-related differences between the short- and long-interval groups in terms of sex, employment status, or diagnosis., Conclusions and Relevance: This cohort study demonstrated that while insurance companies often mandate a 3-month or greater interval for BoNT chemodenervation financial coverage, there is a considerable subset of patients with LD and ETVT who receive short-interval treatment to optimize their vocal function. Short-interval chemodenervation injections demonstrate a similar adverse effect profile and do not appear to predispose to resistance through antibody formation.

Background: A long-standing question is why essential tremor often responds to non-intoxicating amounts of alcohol. Blood flow imaging and high-density electroencephalography have indicated that alcohol acts on tremor within the cerebellum. As extra-synaptic δ-subunit-containing GABA A receptors are sensitive to low alcohol levels, we wondered whether these receptors mediate alcohol's anti-tremor effect and, moreover, whether the δ-associated GABA A receptor α6 subunit, found abundantly in the cerebellum, is required., Methods: We tested the hypotheses that low-dose alcohol will suppress harmaline-induced tremor in wild-type mice, but not in littermates lacking GABA A receptor δ subunits, nor in littermates lacking α6 subunits. As the neurosteroid ganaxolone also activates extra-synaptic GABA A receptors, we similarly assessed this compound. The harmaline mouse model of essential tremor was utilized to generate tremor, measured as a percentage of motion power in the tremor bandwidth (9-16 Hz) divided by background motion power at 0.25-32 Hz., Results: Ethanol, 0.500 and 0.575 g/kg, and ganaxolone, 7 and 10 mg/kg, doses that do not impair performance in a sensitive psychomotor task, reduced harmaline tremor compared to vehicle-treated controls in wild-type mice but failed to suppress tremor in littermates lacking the δ or the α6 GABA A receptor subunit., Discussion: As cerebellar granule cells are the predominant brain site intensely expressing GABA A receptors containing both α6 and δ subunits, these findings suggest that this is where alcohol acts to suppress tremor. It is anticipated that medications designed specifically to target α6βδ-containing GABA A receptors may be effective and well-tolerated for treating essential tremor., Highlights: How does alcohol temporarily ameliorate essential tremor? This study with a mouse model found that two specific kinds of GABA receptor subunits were needed for alcohol to work. As receptors with both these subunits are found mainly in cerebellum, this work suggests this is where alcohol acts to suppress tremor., Competing Interests: The author has no competing interests to declare., (Copyright: © 2023 The Author(s).)

Based on the evidence level, the first-line agents for managing essential tremors include sympathomimetic agents and primidone; however, from a tolerability standpoint, sympathomimetic agents are the first choice. Arotinolol is the first treatment of choice because it is the only drug developed in Japan approved for treating essential tremors. If sympathomimetic agents are unavailable or ineffective, a change to primidone, or a combination of both, should be considered. Benzodiazepines and other anti-epileptic drugs should also be administered.

Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T-type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T-type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T-type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond., (© 2023 Praxis Precision Medicines Inc. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: The aim of this study was to assess the safety and efficacy of perampanel in patients with refractory essential tremor (ET)., Methods: We recruited patients from our movement disorders clinic with the diagnosis of severe refractory ET, and perampanel 4 mg at night was initiated.Assessments were conducted at baseline and after 1 month of treatment with perampanel 4 mg/d. Details about tolerance and effectiveness were collected. Clinical evaluation was conducted with the Fahn-Tolosa-Marín scale, and statistical analysis was carried out with Wilcoxon matched pairs signed rank test., Results: This study included 18 patients with severe ET (11 females, 7 males; mean age: 75.1 ± 12.03 years; mean duration of ET: 17.4 ± 17.03 years). Perampanel significantly improved patients' average score with refractory ET ( P ≤ 0.0001). This improvement has been occasionally quite relevant. However, a proportion of patients did not tolerate perampanel because of several adverse effects including dizziness, ataxia, irritability, and instability., Conclusions: Perampanel had a markedly positive antitremor effect in patients with ET and could be an alternative treatment. However, this drug is not devoid of adverse effects., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Propranolol, a nonselective beta-adrenergic blocker, has long been used as one of the standard treatments for essential tremor (ET). Repetitive transcranial magnetic stimulation (rTMS) has also been used for a long time as a substitution therapy for ET patients., Objective: The main aim of this study was to evaluate the antitremor effect of 1-Hz (low-frequency) cerebellar rTMS and compare it to the use of propranolol in ET patients., Methods: In this single-blinded, randomized, controlled pilot study, a total of 38 patients with ET were randomized into two groups. One group (n = 20) received 1200 pulses of 1-Hz rTMS at an intensity of 90% of the resting motor threshold to the bilateral cerebellar region for 10 days. Another group (n = 18) received oral propranolol for 30 days. The initial dose was 30 mg/day, which was increased to 60 mg/day after 5 days, then to 90 mg/day on the 11th day, and continued thereafter for 20 days. The Fahn-Tolosa-Marin (FTM) clinical scale was assessed at baseline and at days 5, 10, and 30 to evaluate tremor severity, specific motor tasks, and functional disability., Results: Low-frequency rTMS of the cerebellum significantly improved tremor severity, specific motor tasks (writing, spiral drawing, and pouring), and FTM total scores on days 10 and 30. Nevertheless, we found no significant difference in functional disability at any point in time (p > .05). There were no statistically significant differences in FTM Part A, Part B, Part C scores and total scores of patients in propranolol group on days 5 and 10 compared with before treatment (p > .05). However, FTM total scores and FTM Part A, Part B, and Part C scores were significantly improved for patients when the dose of propranolol was 90 mg/day on day 30. Our study showed that there was no statistically significant difference in the total FTM scores and FTM Part A, Part B, and Part C scores between rTMS and propranolol on days 5, 10, and 30 (p > .05)., Conclusion: We conclude that both cerebellar low-frequency rTMS and propranolol could be effective treatment options for patients with ET, but it is not clear which method is more effective., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Ethanol has been shown to suppress essential tremor (ET) in patients at low-to-moderate doses, but its mechanism(s) of action remain unknown. One of the ET hypotheses attributes the ET tremorgenesis to the over-activated firing of inferior olivary neurons, causing synchronic rhythmic firings of cerebellar Purkinje cells. Purkinje cells, however, also receive excitatory inputs from granule cells where the α6 subunit-containing GABA A receptors (α6GABA A Rs) are abundantly expressed. Since ethanol is a positive allosteric modulator (PAM) of α6GABA A Rs, such action may mediate its anti-tremor effect. Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of ethanol and α6GABA A R-selective pyrazoloquinolinone PAMs. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Ethanol significantly and dose-dependently attenuated action tremor at non-sedative doses (0.4-2.4 g/kg, i.p.). Propranolol and α6GABA A R-selective pyrazoloquinolinones also significantly suppressed tremor activity. Neither ethanol nor propranolol, but only pyrazoloquinolinones, restored burrowing activity in harmaline-treated mice. Importantly, intra-cerebellar micro-injection of furosemide (an α6GABA A R antagonist) had a trend of blocking the effect of pyrazoloquinolinone Compound 6 or ethanol on harmaline-induced tremor. In addition, the anti-tremor effects of Compound 6 and ethanol were synergistic. These results suggest that low doses of ethanol and α6GABA A R-selective PAMs can attenuate action tremor, at least partially by modulating cerebellar α6GABA A Rs. Thus, α6GABA A Rs are potential therapeutic targets for ET, and α6GABA A R-selective PAMs may be a potential mono- or add-on therapy., (© 2023. The American Society for Experimental Neurotherapeutics, Inc.)

Introduction: Essential tremor (ET) affects approximately 7 million people in the USA, yet public recognition of the disease and its impact remain low., Methods: A retrospective observational study examined US claims data from 2015 to 2019 using the Compile database. ET diagnoses were captured using longitudinal data from 2015 to 2019 and for the year 2019, with diagnosis estimates extrapolated to the general US population. Confirmed ET was identified by an ET diagnosis code with at least two relevant prescriptions or by two diagnosis codes for ET and unspecified tremor at least 90 days apart. Comorbidity and treatment use data were extracted, and medication compliance and 2-year treatment persistence were assessed as measures of treatment adherence., Results: A total of 1,336,183 patients with ET diagnoses codes were identified from 2015 through 2019, corresponding to 2,226,971 projected US diagnoses. In 2019, 128,263 patients had a confirmed ET diagnosis, corresponding to 213,772 projected US confirmed diagnoses. Of these, 96% had at least one comorbidity, and 64% received at least one pharmacologic treatment. Propranolol (24%) and primidone (20%) comprised the most common ET prescriptions. Two-year medication discontinuation rates were approximately 40%., Conclusion: Our findings revealed that 1 million people were diagnosed and sought treatment for ET in the USA from 2015 to 2019. Projected population estimates of approximately 2 million people diagnosed suggest a further 1 million remain untreated. Our findings highlight the complexity of patient care in ET, complicated by delayed diagnoses, multiple comorbidities, and lack of effective and tolerable therapies that can mitigate treatment adherence limitations., (© 2022. The Author(s).)

Background: There are no prospective, longitudinal studies investigating patterns of medication use among essential tremor (ET) patients. Our goal was to fill this knowledge gap. We also had a unique opportunity to examine medication use patterns primarily among elders with longstanding ET. We hypothesized that by the time ET patients reach advanced ages, medication changes would be uncommon - that is, they may have reached some kind of equipoise., Methods: A prospective, longitudinal cohort of ET cases was evaluated across three time points. Cases were not ascertained from a treatment setting, thereby removing important selection biases. Each reported current medications and dosages of each., Results: There were 144 cases (mean baseline age = 76.1 ± 9.4 years). The mean observation period = 2.9 ± 0.2 years. Primidone and propranolol were the most commonly used medications, although almost one-half of cases (44.4%) reported using neither during this period. A third of primidone users (33.3%) and a quarter of propranolol users (24.6%) reported changes in use vs. nonuse during the observation period. The majority of our cases made some change in their daily medication dosage during the course of the study - 73.3% of primidone users and 57.9% of propranolol users., Conclusion: In this prospective, longitudinal study, use vs. nonuse and daily dosage of both primidone and propranolol fluctuated across time for a sizable proportion of ET cases. Even among elders with chronic, longstanding ET, there is considerable ongoing medication adjustment, underscoring the need to improve the medication situation for ET patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Voice tremor is a common, yet debilitating symptom for patients suffering from a number of tremor-associated disorders. The key to targeting effective treatments for voice tremor requires a fundamental understanding of the pathophysiology that underpins the tremor mechanism and accurate identification of the disease in affected patients. An updated review of the literature detailing the current understanding of voice tremor (with or without essential tremor), its accurate diagnosis and targeted treatment options was conducted, with a specific focus on the role of botulinum neurotoxin. Judicious patient selection, following detailed characterisation of voice tremor qualities, is essential to optimising treatment outcomes for botulinum neurotoxin therapy, as well as other targeted therapies. Further focused investigation is required to characterise the response to targeted treatment in voice tremor patients and to guide the development of innovative treatment options.

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug-resistant tremor in Parkinson's disease (PD)., Objective: The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early-stage tremor-dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy., Methods: We prospectively enrolled patients with early-stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD-FUS) and patients treated with oral dopaminergic therapy (PD-ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12 months after thalamotomy., Results: We included 10 patients in the PD-FUS group and 20 patients in the PD-ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD-ODT group 6 months after thalamotomy., Conclusions: In early-stage tremor-dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Botulinum toxin type A (BoNT-A) therapy for upper-limb tremor has emerged as a promising option. However, it is unclear in real-world practices whether a technology-guided approach can compare with expert clinical assessments (including surface anatomy and palpation) for improving outcomes. This retrospective study aims to review our clinical outcomes of treating essential tremor (ET) and Parkinson's disease (PD) tremor using either clinical- or kinematic-based injection pattern determination methods., Methods: 68 ET and 45 PD patients received at least one injection for their upper-limb tremor (unilateral or bilateral) in the last 7 years. Demographics of patients and BoNT-A injections were collected. A Mann-Whitney U statistical test was used to compare outcome measures between ET and PD cohorts., Results: Mean age (72 ± 9 years), number of injections (5), years receiving therapy (~2 years), clinic- (~57%) or kinematic-based patterns, and self-paying (52%) were similar between both cohorts. BoNT-A as a monotherapy in both upper limbs was received in more ET than PD patients. Double reconstitution of Xeomin ® in the wrist flexors/extensors, supinator, biceps, and triceps were most injected. Discontinuation due to no benefit/weakness was not dependent on the injection pattern determination approach., Conclusions: Kinematic-based BoNT-A injections produced similar treatment outcomes to injections based on the clinical expertise of the expert injector. This suggests that kinematics could be used by a non-expert to attain equivalent efficacy potentially improving access to this treatment.

Abstract: Essential tremor (ET) is one of the most common neurological diseases. Despite this high prevalence, treatment options remain limited. Recent advances in mechanistic research have led to renewed interest in developing newer pharmacotherapeutic agents. Although this is promising, there remains surprisingly little knowledge of the magnitude of the vast ET patient population who would benefit from and/or engage with such agents. This is because the vast bulk of ET patients in the population has milder tremor and does not seek medical care for their tremor. How many of these would be interested in taking a new agent? Hence, the level of unmet need, from the patient perspective and from a public health perspective, is totally unclear. In this article, the author systematically reviews peer-reviewed data on several pertinent questions that relate to this unmet need. The questions are as follows: (1) What proportion of the population of ET cases sees a health care provider for their tremor? (2) What proportion of the ET population has a tremor that is severe enough for them to want to take a medication for their tremor? (3) How do other factors such as age, sex, education, health literacy, and locale affect the receptivity to treatment in ET? (4) What is the patient use of the current ET medications? (5) Is the unmet need greater in some groups of ET cases than others? For each of these questions, available data are carefully reviewed and analyzed, and gaps in knowledge identified for further investigation., Competing Interests: Conflicts of Interest and Source of Funding: The author has no conflicts of interest to declare. Study funding: NIH R01 NS117745, R01 NS086736, and R01 NS088257., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction Essential tremor (ET) is a common movement disorder in the elderly. Bilateral postural tremor usually involves the hands and forearms; the primary diagnostic criteria can be with or without a kinetic tremor. Anticonvulsants are frequently prescribed as a primary medication, and botulinum toxin and deep brain stimulation as secondary options. In this case report, a patient with ET received medical painting therapy guided by the principles of anthroposophy and the work of Liane Collot d´Herbois. Case Presentation A 78-year-old woman presented ET, depression and bipolar symptoms. Additionally, she reported insomnia, constipation, lumbar pain, and sciatic pain. Current medications included lithium carbonate, folic acid, levothyroxine, and zinc, and she had refused to take propranolol for her ET. She agreed to begin medical painting therapy. Over 5 months, she had 16 sessions of medical painting therapy, carried out in 2 stages. The first stage consisted of 6 free painting sessions for patient evaluation, followed by the second stage of 10 therapeutic sessions. Conclusion The patient reported an increased quality of life (including emotional aspects) and a decrease in her ET, as evidenced by the patient's handwriting. Further research is needed to understand the strengths and limitations of this therapy for ET and related conditions.

Background: Essential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello-thalamo-cortical circuitry and may be dependent on T-type calcium channel activity. T-type calcium channels regulate sigma band electroencephalogram (EEG) power during non-rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX-944 is a novel T-type calcium channel blocker in development for essential tremor., Objectives: Using a rat tremor model and sigma-band EEG power, we assessed pharmacodynamically-active doses of PRAX-944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials., Methods: Harmaline-induced tremor and spontaneous locomotor activity were used to assess PRAX-944 efficacy and tolerability, respectively, in rats. Sigma-power was used as a translational biomarker of T-type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants., Results: In rats, PRAX-944 dose-dependently reduced tremor by 50% and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side effects. These doses also reduced sigma-power by ~30% to 50% in rats. In healthy participants, sigma-power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated., Conclusions: In rats, PRAX-944 reduced sigma-power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma-power indicate that robust T-type calcium channel blockade was achieved at well-tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

For essential tremors that are refractory to standard medical treatment, surgical treatment is considered when there is obstruction in activities of daily living. However, there are patients who do not wish to undergo or are contraindicated for surgical treatment. In this paper, we explored what is considered to be the standard medical treatment and when surgery cannot be performed. In Japan, medical treatment is based on the use of arotinolol and primidone, and combination therapy and second-line drugs are extensively discussed. Furthermore, an algorithm of the treatment for essential tremors in Japan has been provided.

Objective: Essential tremor (ET) as a neurological disorder is accompanied by cognitive and motor disturbances. Despite the high incidence of ET, the drug treatment of ET remains unsatisfactory. Recently, abscisic acid (ABA) has been reported to have positive neurophysiological effects in mammals. Here, the effects of ABA on harmaline-induced motor and cognitive impairments were investigated in rats., Methods: Male Wistar rats weighing 120-140 g were divided into control, harmaline (30 mg/kg, ip), ABA vehicle (DMSO+normal saline), and ABA (10 μg/rat, icv, 30 min before harmaline injection) groups. Exploratory, balance and motor performance, anxiety, and cognitive function were assessed using footprint, open field, wire grip, rotarod, and shuttle box tests., Results: The results indicated that ABA (10 μg/rat) can improve harmaline-induced tremor in rats. The administration of ABA significantly increased time spent on wire grip and rotarod. In addition, ABA had a promising effect against the cognitive impairments induced by harmaline., Conclusion: Taken together, ABA has positive effects on locomotor and cognitive impairments induced by tremor. However, further studies are required to determine the exact mechanisms of ABA on the ET., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Tremor is one of the most common movement disorders, though it can arise in the context of several unrelated neurological disorders whose pharmacology and anatomical origins differ greatly. Treatment of tremors can take advantage of several medications and neurosurgical treatments. Medications useful for treating tremor are discussed in this review, including those for action tremor as seen in essential tremor, the resting tremor of Parkinson's disease, orthostatic tremor, cerebellar tremor, Holmes tremor, dystonic tremor, and drug-induced tremors. A medication that is useful for most types of tremors is the beta-blocker propranolol, though even in essential tremor it can fail to be effective at tremor control. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Tremor is one of the common movement disorders worldwide. In the recent classification tremor has been classified into two axes (I and II). Based on axis I feature tremor can be classified as isolated and combined tremor syndrome. Common tremor syndromes include Parkinsonism-associated tremors, essential tremor including essential tremor plus, dystonic tremors, and others. Tremor may also occur secondary to demyelinating, infectious and inflammatory diseases, and stroke. Adequate management of tremor has been an unmet need in clinical practice. Most of the anti-tremor medications have limited efficacy and are. associated with undesirable adverse effects, especially in elderly patients. Several studies have reported good outcomes with the use of botulinum neurotoxin for the treatment of tremor and it has emerged as a useful therapeutic option in tremor syndromes refractory to pharmacological agents. This review describes the role of botulinum neurotoxin in different tremor conditions. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Although first line therapies for essential tremor have been identified from small clinical trials, responses are variable. We conducted a survey of tremor management in a large sample of ET cases., Methods: The Movement Disorders Clinical Case Registry within a US Veterans Health Administration medical center was used to identify 1468 patients with ET., Results: Of 1468 charts reviewed, 1074 (73.19%) met criteria for ET with characterization of temporal course and treatment; 291/1074 subjects (27.1%) did not receive any treatment. Almost half (500/1074; 46.6%) of the patients received monotherapy, 196/1074 (18.2%) two, 66/1074 (6.1%) three, and 21/1074 (2.0%) four or more medications. Of all prescriptions, primidone was the most used (546/1172; 46.6%), followed by propranolol (419; 35.8%), topiramate (122; 10.4%) and gabapentin (35; 3.0%). Medication response was available for a total of 1030 prescriptions, of which 138 (13.4%) were discontinued due to side effects; 180 (17.5%) prescriptions were ineffective. Furthermore, 52/1074 patients (4.8%) were treated with botulinum toxin injections and 41/1074 (3.8%) underwent deep brain stimulation surgery., Discussion: Our data suggest that more widespread recognition of limitations underlying conventional approaches, as well as increased referrals for nonpharmacological therapies, may be necessary to achieve improved outcomes in ET populations., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Tremor is a common movement disorder. Essential tremor (ET) is the most common etiology of tremor, while hands tremor is the most disabling type of tremor. This study aimed to explore the effects of Botulinum toxin (BoNT) on tremor within 6 weeks of treatment, and the muscular weakness adverse effect within 6 weeks specifically in randomized controlled trials. PubMed, Embase, and Cochrane Library databases were searched. Tremor severity and grip strength after BoNT treatment were investigated. BoNT significantly attenuated hand tremor severity in patients with either essential tremor (ET), Parkinson's disease or multiple sclerosis (Standardized mean difference [SMD] = -0.59, 95% confidence interval [CI], -0.95 to -0.24, p = 0.001, I 2 = 46%). Regarding people with ET, BoNT significantly reduced their tremor severity, including hands tremor and head tremor within 6 weeks of treatment (SMD = -0.58, 95% CI, -0.28 to -0.88, p = 0.002, I 2 = 0%). Electromyography (EMG) but not anatomical guidance BoNT injection provided significant benefit on the relief of tremor in both conditions. The principal adverse event was weakness, but it did not worse within 6 weeks of BoNT treatment (SMD = -0.35, 95% CI, -0.83 to 0.12, p = 0.07, I 2 = 57%), as assessed by the subjective grip strength. In conclusion, BoNT was an effective treatment for the hand tremor and ET, and EMG guidance injection was preferred. In addition, the muscular weakness adverse effect was not significant.

γ-Aminobutyric acid (GABA) is the most prevalent inhibitory CNS neurotransmitter. Activating GABA-A receptors hyperpolarizes cells via Cl - influx, which inhibits action potentials. Although the exact pathophysiologies of tremor are incompletely understood, proposed neuroanatomy extensively implicates GABA pathways. Pathological studies and imaging studies also show GABA abnormalities in patients with ET. Most importantly, medications that activate GABA-A receptors, such as primidone, often improve tremor. Ongoing clinical trials and physiology research should further refine potential future GABAergic targets and treatments, which are currently the most promising targets for pharmacological intervention., (Copyright © 2022 Elsevier Inc. All rights reserved.)

MR-guided focused ultrasound (MRg-FUS) is a new noninvasive method for the treatment of contralateral disabling and pharmacoresistant tremor. Clinical studies have confirmed the high efficacy and safety of using MRg-FUS in patients with essential tremor and Parkinson's disease, in short and long-term studies. Advantages of this method in comparison with currently used invasive and noninvasive technics, potential brain target areas, the possibility of bilateral intervention, indications and contraindications are discussed.

Background: There are few medications for the treatment of essential tremor (ET). One of these, primidone, which is one of only two front-line agents, is associated with considerable adverse drug reactions (ADRs). It is unclear why some primidone-treated ET patients develop ADRs whereas others do not, and why these ADRs seem to be more prevalent in ET patients than primidone-treated patients with epilepsy., Objective: To review several possible explanations underlying the above-referenced differences., Methods: A literature search was conducted in PubMed in October 2021. Studies reporting the ADRs of primidone in different neurological conditions were comprehensively reviewed., Discussion: Although there were no head-to-head data, a review of the previous studies on ET and epilepsy patients indicates that the former is relatively more intolerant to primidone. Moreover, not all ET patients develop ADR of similar nature or severity. We discuss several potential mechanisms for this variability in the intolerance to primidone. These include: (i) older age (ET vs. epilepsy patients), (ii) cross-tolerance to primidone in patients with epilepsy, (iii) neurobiological (GABA-related) abnormalities associated with ET., Conclusion: We speculate that there are several possible explanations for primidone intolerance in ET. These possibilities should be tested in future studies, and we propose the roadmap for designing these studies. It is of value to obtain detailed insight into these complex issues because primidone remains one of the few frontline anti-tremor medications in ET. Answers to issues we have raised in this article could facilitate more customized formulation of primidone in ET patients., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

Objectives/hypothesis: The purpose of this study was to characterize the clinical features, tremor variability, and factors related to octanoic acid (OA) treatment response in essential voice tremor (EVT)., Study Design: Prospective, double blind, placebo-controlled, crossover study with secondary analysis., Methods: Clinical tremor features in 16 individuals with EVT were comprehensively assessed, and correlations with acoustic tremor severity were determined. Intrasubject and intersubject variability measures were analyzed from 18 repeated measures for each acoustic tremor variable. Clinical correlates of treatment response were evaluated, and cumulative effects over a 2-week period of OA drug dosing were assessed., Results: Participants with EVT were 90% female with a mean age of 70.31 (±8.68) years at the time of testing. Neurologist-rated body tremor beyond the vocal tract region was present in 69% of participants, and multiple vocal tract regions contributed to the voice tremor. The mean frequency of amplitude tremor was 4.67 Hz (±0.88). Respiratory tremor was evident in 50% of participants. Participants experienced moderate voice-related disability as assessed on the Voice Handicap Index-10 (19.38, ±8.50), and increased speaking effort. Acoustic tremor severity was significantly associated with severity of tremor affecting vocal tract structures. Overall intrasubject consistency was strong (single measures intraclass correlation coefficient = 0.701, P < .01), with high intersubject variability. Acoustic tremor severity was significantly, positively associated with treatment response, and results suggested a cumulative OA benefit for magnitude of amplitude tremor., Conclusions: This study identified common clinical correlates of EVT and demonstrated positive associations between acoustic tremor severity, severity of affected vocal tract structures, and response to treatment., Level of Evidence: 2 Laryngoscope, 131:E2792-E2801, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Available essential tremor (ET) therapies have limitations., Objectives: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor., Methods: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry., Results: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%)., Conclusions: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Essential tremor (ET) is one of the most prevalent movement disorders and the most common cause of abnormal tremors. However, it cannot be treated efficiently with the currently available pharmacotherapy options. The pathophysiology of harmaline-induced tremor, most commonly used model of ET, involves various neurotransmitter systems including glutamate as well as ion channels. Agmatine, an endogenous neuromodulator, interacts with various glutamate receptor subtypes and ion channels, which have been associated with its' beneficial effects on several neurological disorders. The current study aims to assess the effect of agmatine on the harmaline model of ET. Two separate groups of male rats were injected either with saline or agmatine (40 mg/kg) 30 min prior to single intraperitoneal injection of harmaline (20 mg/kg). The percent duration, intensity and frequency of tremor and locomotor activity were evaluated by a custom-built tremor and locomotion analysis system. Pretreatment with agmatine reduced the percent tremor duration and intensity of tremor induced by harmaline, without affecting the tremor frequency. However, it did not affect the decreased spontaneous locomotor activity due to harmaline. This pattern of ameliorating effects of agmatine on harmaline-induced tremor provide the first evidence for being considered as a treatment option for ET., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Botulinum toxin type A (BoNT-A) injection patterns customized to each patient's unique tremor characteristics produce better efficacy and lower adverse effects compared to the fixed-muscle-fixed-dose approach for Essential Tremor (ET) and Parkinson's disease (PD) tremor therapy. This article outlined how a kinematic-based dosing method to standardize and customize BoNT-A injections for tremors was developed. Seven ET and eight PD participants with significant tremor reduction and minimal perceived weakness using optimized BoNT-A injections determined by clinical and kinematic guidance were retrospectively selected to develop the kinematic-based dosing method. BoNT-A dosages allocated per joint were paired to baseline tremor amplitudes per joint. The final kinematic-based dosing method was prospectively utilized to validate BoNT-A injection pattern selection without clinical/visual assessments in 31 ET and 47 PD participants with debilitating arm tremors (totaling 122 unique tremor patterns). Whole-arm kinematic tremor analysis was performed at baseline and 6-weeks post-injection. Correlation and linear regression analyses between baseline tremor amplitudes and the change in tremor amplitude 6-weeks post-injection, with BoNT-A dosages per joint, were performed. Injection patterns determined using clinical assessment and interpretation of kinematics produced significant associations between baseline tremor amplitudes and optimized BoNT-A dosages in all joints. The change in elbow tremor was only significantly associated with the elbow total dose as the change in the wrist and shoulder tremor amplitudes were not significantly associated with the wrist and shoulder dosages from the selected 15 ET and PD participants. Using the kinematic-based dosing method, significant associations between baseline tremor amplitudes and the change (6-weeks post-first treatment) in tremor at each joint with BoNT-A dosages for all joints was observed in all 78 ET and PD participants. The kinematic-based dosing method provided consistency in dose selection and subsequent tremor reduction and can be used to standardize tremor assessments for whole-arm tremor treatment planning.

Essential tremor (ET) is a common clinical syndrome characterized by action tremors affecting both upper limbs that can compromise manual tasks' execution and impair functional and social performance. The primary pharmacological treatment is symptomatic, but effective medicines are somewhat limited. There is a clear need to find new effective therapies for the treatment of ET. Cannabidiol (CBD) is a modulator of CB1 receptor and CB1 agonists can reduce tremors in experimental models. We hypothesized that a single acute CBD intake would reduce tremors in ET patients. We performed a randomized, controlled, double-blind, crossover study on 19 patients with ET. They were 10 males and 9 females, had mean 63 years of age, and mean 23 years of disease duration and had insufficient control of their tremors with the usual pharmacological treatment. They ingested a single oral dose of CBD (300 mg) or placebo in two experimental sessions performed 2-weeks apart. Patients were evaluated immediately before and after oral ingestion (60 min and 210 min), using the Fahn-Tolosa-Marin clinical scale. There was no carryover effect. There were no significant differences in upper limb tremors score, specific motor task tremor scores (writing and drawing/pouring) or clinical impression of change after treatment with placebo or CBD. In conclusion, a single 300 mg oral dose of CBD had no significant effect on the severity of upper limb tremors of ET patients. Our findings did not exclude the possibility that chronic treatment with CBD could have a symptomatic effect., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: This study aims to evaluate the effectiveness of botulinum toxin therapy, as a monotherapy, and its effect on quality of life in patients with essential tremor (ET) who are resistant to medical treatment or cannot tolerate optimum drug doses in the population., Method: This retrospective research was conducted between February 2019 and December 2019 with 15 adult patients (9 men and 6 women) in the 50-to-70 age group, who had a definite diagnosis of ET as evaluated by the same clinician. With the help of electroneuromyography, intramuscular onabotulinum toxin A (BoNT-A) injection was administered to the related muscles, not exceeding 100 U in total. Demographic characteristics and duration of disease of all patients were recorded. The tremor severity of patients before the injection, 1 month after the injection, and 3 months after the injection was assessed by the Fahn-Tolosa-Marín Tremor Rating Scale (FTM-TRS), applied by the same clinician during the face-to-face interviews, in addition to the Questionnaire for Essential Tremor (QUEST), which was filled out by participants., Results: The first month and third month mean QUEST and FTM-TRS scores were statistically lower than that before the procedure in patients with ET after BoNT-A injection (P = 0.001, P = 0.001, P = 0.001, and P = 0.001). In addition, the mean FTM-TRS and QUEST scores for the first month after the procedure were significantly lower than the mean FTM-TRS and QUEST scores for the third month (P = 0.005 and P = 0.007)., Conclusion: We believe that our study is valuable because there is no research on the effect of BoNT-A administration on ET treatment in the our country population and because the effect of BoNT-A treatment on quality of life in patients with ET was evaluated using the ET-specific QUEST scale., Competing Interests: Conflicts of Interest and Source of Funding: The author has no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hand tremor associated with Parkinson disease (PD) and essential tremor (ET) can often become challenging to treat in clinical practice. Local injections of botulinum toxin-A (BoNT-A) for hand tremor is an evolving field with newer injection techniques being utilized in clinical studies. The utility of BoNT-A therapy for ET and PD-tremor however, has been questioned based on the high incidence of finger and hand weakness after treatment., Method: The study includes detailed analysis of the techniques utilized in BoNT injection in ET and PD tremor., Results: There were 4 high-quality investigations which consisted of Class I or II double-blind placebo-controlled trials and one medium-quality study that was a prospective, open label, class III investigation., Discussion: This paper discusses two recently developed technology-based injection methods for BoNT-A therapy of ET and PD tremor, which includes comprehensive EMG screening of forearm and arm muscles with selective injections (Yale method) and the whole arm kinematic tremor assessment developed by Jog et al. In recent years, controlled, blinded studies of these two methods have shown significant post-injection reduction of finger, hand and whole limb tremor compared to the previously published controlled clinical trials not using these methodologies., Competing Interests: No funding received for this paper. Mittal has no conflict of interest. Jog is a scientific advisor and receives research financial support from the following companies: AbbVie, Allergan Inc., Boston Scientific, Ipsen, MDDT Inc., Medtronic, Merz Pharma, Novartis, and Teva Pharmaceuticals. Lee is a former researcher at the London Movement Disorders Centre and now is an MDDT Inc. employee. Jog and Lee are both shareholders of MDDT Inc. In addition, Jog and Lee are commercializing the medical devices TremorTek™ and Hinge Diagnostics™ and have patents PCT/CA2013/000804, PCT/CA2014/050893 assigned to MDDT Inc. Jabbari has received research financial support in the past from Allergan Inc, Merz Pharma and Ipsen., (Copyright: © 2020 The Author(s).)

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn-Tolosa-Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 ( p = 0.003) and Week 8 ( p = 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 ( p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 ( p = 0.004) and Week 8 ( p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.