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Objective: To characterise postural tremors in patients with Parkinson's disease. Rest tremor is a well recognised cardinal symptom of Parkinson's disease, but postural tremors associated with the disease may cause more disability than the more typical rest tremor. Postural tremor of Parkinson's disease has been attributed to enhanced physiological tremor, clonus, or coexistent essential tremor. It is postulated that one type of postural tremor in Parkinson's disease represents a rest tremor that re-emerges after a variable delay while maintaining posture, hence "re-emergent tremor".Methods: Accelerometry, peak frequency, peak frequency amplitude, root mean square (RMS) amplitude, and latency were determined in 18 patients (mean age: 63.2 (SD 9.8) years) with Parkinson's disease who had clinically evident postural tremor, 20 (mean age: 66.9 (SD 5. 8) years) with typical essential tremor, and seven (mean age: 68.7 (SD 15.3) years) with the combination of pre-existing essential tremor and subsequent Parkinson's disease (essential tremor/Parkinson's disease). Latency, the time interval starting with the assumption of an outstretched posture and ending with the onset of postural tremor, was measured by marking the start time by a pulse produced from interrupting a beam to a photocell when the arm reached a horizontal position.Results: The latency for the re-emergent tremor (9.37 (SD 10.66) s), present in 12 of 18 patients with Parkinson's disease, was significantly (p<0.0005) longer than the latency for postural tremor of essential tremor (1.29 s in one patient, absent in 19 others); five of seven essential tremor/Parkinson's disease patients had an observed latency (6.57 (SD 8.23 s) which was also significantly (p<0.005) longer than that for essential tremor. There was no difference in the mean tremor frequency ( approximately 5.5 Hz) between the re-emergent tremor and the more typical Parkinson's disease rest tremor. The amplitudes were generally higher for the postural tremor associated with Parkinson's disease compared with those of essential tremor.Conclusion: These studies suggest that the re-emergent tremor of Parkinson's disease can be differentiated from the postural tremor of essential tremor and that it may share pathophysiological mechanisms with the more typical rest tremor. [ABSTRACT FROM AUTHOR]

Background: Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms., Objectives: To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences., Methods: Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias., Results: The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A)., Conclusions: These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics., (© 2024 International Parkinson and Movement Disorder Society.)

Introduction: In the United States (US), prophylactic treatment with the antiemetic trimethobenzamide has been used before initiating apomorphine therapy. However, US trimethobenzamide stores have been depleted, leaving uncertainty regarding whether antiemetic pretreatment is needed., Methods: This modified Delphi panel aimed to inform circumstances when apomorphine is initiated without antiemetic pretreatment. During Round 1, a panel of 9 US movement disorder specialists rated the appropriateness of prescribing apomorphine therapy with and without antiemetic pretreatment across 192 patient scenarios and were able to review their scores in relation to other scores. During the Round 2, consensus was defined for each scenario as either strong (>75 % agreement) or moderate (66 % agreement)., Results: There was strong consensus on 118 of 192 scenario's (97 as appropriate and 21 as inappropriate), moderate consensus on 29 scenarios, some agreement on 32 scenarios, and lack of agreement on 13 scenarios. In the absence of an antiemetic, there was strong consensus that titration schedules should be flexible and based on dose response. However, the group only reached moderate consensus on the speed of titration, highlighting the need for more systematic information on this area. In the presence of an antiemetic, panelists considered usual initial dosing and flexible titration to be appropriate in most scenarios except for when the patient is already experiencing dopaminergic adverse events., Conclusions: Experts generally reached consensus that apomorphine can usually be prescribed without antiemetic pretreatment. Recommendations described here reflect the areas of greatest agreement among a panel of experts based on current available evidence., Competing Interests: 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. Stuart H. Isaacson reports honoraria for CME, consultant, research grants, and/or promotional speaker on behalf of AbbVie, Acadia, Acorda, Adamas, Addex, Affiris, Alexva, Allergan, Amarantus, Amneal, Aptinyx, Axial, Axovant, Benevolent, Biogen, Britannia, Cadent, Cala, Cerecor, Cerevel, Cipla, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Impel, Intec Pharma, Ipsen, Jazz, Kyowa, Lundbeck, Merz, Michael J. Fox Foundation, Mitsubishi Tanabe, Neuralys, Neurocrine, NeuroDerm, Parkinson Study Group, Pharma2B, Prilenia, Promentis, Revance, Roche, Sanofi, Sunovion, Sun Pharma, Supernus, Teva, Theravance, UCB, Zambon. Richard B. Dewey, Jr., reports consulting fees from Amneal Pharmaceuticals and grant support from NINDS and the Jean Walter Center for Movement Disorders. Robert A. Hauser has received consulting fees from AbbVie, AgeX Therapeutics, Amneal Pharmaceuticals, Avanex, BlueRock Therapeutics, Canfield Scientific, Global Kinetics, Inhibikase, Jazz Pharmaceuticals, Kyowa Kirin, MDCE Suzhou, MedRhythms, Merck, Merz, Neurocrine, NeuroDerm, Orion, Ovid Therapeutics, PD Neurotechnology, Pharma Two B, Regenxbio, Revance, Sage Therapeutics, Scion NeuroStim, Sunovion, Supernus Pharmaceuticals, Tolmar, Tremor Research Group, Tris Pharma, UCB, and Vivifi Biotech. He has received speaking fees from Acorda, Amneal Pharmaceuticals, Cerevel, Inhibikase, Kyowa Kirin, Neurocrine Biosciences, Sunovion and Supernus. Dr Hauser holds stock in Revance Therapeutics and stock options in Enterin, Inhibikase and Axial Therapeutics, he has received intellectual property interests from a PD Diary through his University; he is supported in part by a Center of Excellence grant from the Parkinson Foundation. Dr Hauser’s University has received research support from Annovis Bio, Inc., Artizan Biosciences, Parkinson's & Movement Disorder Alliance, Inhibikase Therapeutics, AbbVie, Inc., Aeon Biopharma, Biogen MA, Bukwang Pharmaceutical Co., Ltd., Cavion, Inc., Cerevance, Inc., Cerevel Therapeutics, Cynapsus Therapeutics, Enterin, Inc., Genentech, Global Kinetics Corporation, Hoffman-La Roche Inc., Impax Laboratories, Integrative Research Laboratories Sweden, Lundbeck, Inc., Michael J. Fox Foundation for Parkinson's Research, National Parkinson's Foundation, Neuraly Inc., Neurocrine Biosciences, NeuroDerm, Pharma Two B Ltd, Revance Therapeutics, Sage Therapeutics, Sanofi Pharmaceuticals, Scion NeuroStim, SunPharma and UCB BioPharma. Rajeev Kumar has received consulting fees from AbbVie, Teva, Annexon, Enterin, Roche/ Genentech, Acorda Pharmaceuticals, Biovie, Cerevel and Supernus; He has received speaking fees/ honoraria from Supernus, Teva, Kyowa. He has received research grants from Annovis, Triplet Therapeutics, Neurocrine, Teva, Neuraly, AbbVie, Transposon Therapeutics, Lundbeck, Biohaven, Revance, CND Life Sciences, Neuron 23, PTC Therapeutics, Uniqure, Spark Neuro, Praxis, Scion Neurostim, Cognition Therapeutics, Alexza, Eli Lilly, Enterin, CHDI Foundation, Roche/ Genentech, Acorda Pharmaceuticals, Biogen, Cerevel, Prilenia Therapeutics, Supernus, BioVie, Sage Therapeutics, Neuroderm, Sanofi, Addex Pharmaceuticals, Integrative Research Labs, Takeda, Impax Laboratories and Pharma Two B. He has stock in Rocky Mountain Movement Disorders Center, CenExel RMCR and Research Catalyst, LLC. Mark Lew reports consultancy for Acorda, US WorldMeds, Adamas, Acadia, Neurocrine and Kyowa, and has acted as a speaker for, Adamas, Neurocrine, Acorda and Kyowa. He has research grants from the Parkinson’s Study Group, Michael J. Fox Foundation, UCB, Jazz Pharma, and the NIH. William G Ondo has research grants from Biogen, Sun, Restless Legs Syndrome Foundation, Parkinson’s Study Group, Dystonia Coalition (NIH), Cerevel, SCION, and Harmony, reports honorarium for speaking bureau from: TEVA, ACADIA, Acorda, Neurocrine, Supernus, Allergan, and Kyowa Kirin; reports consulting fees from Merz, Sage, Jazz, XWPharma, Neurocrine, Emalex, Supernus, Amneal, and Revance, and Royalties from the books Movement Disorders in Psychiatry, and UpToDate. Fernando Pagan is a Speaker/Consultant for Acorda, Amneal, Abbvie, Adamas, Kyowa Kirin, Merz, Neurocrine, Sunovion, Supernus, Teva, US World Meds. He reports an educational grant from Medtronic as well as research grants from Kyowa Kirin, US WorldMeds, Novartis, Sun Pharma, NIH/NIA, ADDF. He is a co-founder and equity holder of Keiferx LLC. Kelly E. Lyons has nothing to report. Rajesh Pahwa reports personal fees for consultancy from Abbott, AbbVie, ACADIA, Acorda, Allevion, Amneal, Artemida, BioVie, CalaHealth, Convatec, Global Kinetics, Inbeeo, Insightec, Jazz, Kyowa, Lundbeck, Merz, Neurocrine, NeuroDerm, Ono, PhotoPharmics, Sage, Sunovion, Supernus, UCB and Wren, and his institution has received fees from Abbott, AbbVie, Alexza, Annovis, Biogen, Bluerock, Bukwang, Cerevel, Global Kinetics, Jazz, Michael J Fox Foundation, NeuroDerm, Neuraly, Parkinson’s Foundation, Praxis, Roche, Sage, Scion, Sun Pharma, UCB, and Voyager., (© 2024 Published by Elsevier Ltd.)

Background: Cervical dystonia (CD) is the most common form of focal dystonia encountered in the clinic. Approximately one-third of CD patients have co-existing tremor in the head and hands. Assessment of tremor as regular or irregular in context of its oscillation trajectory, frequency, and amplitude is a major clinical challenge and can confound the diagnosis of CD. The misdiagnosis may lead to therapeutic failures, poor quality of life, and poor utilization of medical and financial resources., Methods: We analyzed the largest cohort of CD patients ( n = 3117) available to date, collected from 37 movement disorder centers in North America, Europe, and Asia. We used machine learning to determine what clinical features from clinician reports predicted the presence of tremor as well as its regular or irregular appearance., Results: Out of 3,117 CD patients, 1,367 had neck tremor. The neck tremor was interpreted as irregular in 1,022, regular in 345, and mixed (both irregular and regular) in 442. A feature importance analysis determined that greater severity of CD, longer disease duration, and older age, in descending order, predicted the presence of neck tremor. The probability of neck tremor was reduced if the dystonia affected other body parts in addition to the neck. We also found a significantly heightened risk for developing neck tremor in women. An additional feature importance analysis indicated that increased severity of dystonia affecting other body parts, severity of CD, and prolonged disease duration was associated with a lower likelihood of regular neck tremor while increased age predicted a higher likelihood., Conclusion: Machine learning recognized the most relevant clinical features that can predict concurrent neck tremor and its irregularity in a large multi-center dystonia cohort. These results may facilitate a more accurate description of neck tremor and improved care path in CD., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: There are several widely used clinical rating scales for documenting the severity and distribution of various types of dystonia., Objectives: The goal of this study was to evaluate the performance of the most commonly used scales in a large group of adults with the most common types of isolated dystonia., Methods: Global Dystonia Rating Scale (GDRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFM) scores were obtained for 3067 participants. Most had focal or segmental dystonia, with smaller numbers of multifocal or generalized dystonia. These scales were also compared for 209 adults with cervical dystonia that had Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores and 210 adults with blepharospasm that had Blepharospasm Severity Scale (BSRS) scores., Results: There were strong correlations between the GDRS and BFM total scores ( r  = 0.79) and moderate correlations for their sub scores ( r  > 0.5). Scores for both scales showed positive skew, with an overabundance of low scores. BFM sub-scores were not normally distributed, due to artifacts caused by the provoking factor. Relevant sub-scores of the GDRS and BFM also showed moderate correlations with the TWSTRS ( r  > 0.5) for cervical dystonia and the BSRS ( r  > 0.5) for blepharospasm., Conclusions: The BFM is more widely used than the GDRS, but these results suggest the GDRS may be preferable for focal and segmental dystonias. The overabundance of very low scores for both scales highlights challenges associated with discriminating very mild dystonia from other abnormal movements or variants of normal behavior., (© 2023 International Parkinson and Movement Disorder Society.)

Background: Dose optimization of sublingual apomorphine (SL-APO), a dopamine agonist for the treatment of OFF episodes in patients with Parkinson's disease (PD), has been performed under clinical supervision in clinical trials. SL-APO may be a candidate for home dosing optimization which would be less burdensome for patients., Objectives: To evaluate the feasibility and safety of home optimization of SL-APO in patients with PD and OFF episodes., Design: A multicenter, randomized, crossover study comparing SL-APO with subcutaneous apomorphine was conducted, comprising an open-label dose-optimization phase and a treatment phase. This non-comparative analysis focuses on the outcomes of the dose-optimization phase with SL-APO only., Methods: Patients with PD and OFF episodes received SL-APO at an initial dose of 10 mg in the clinic (open-label). Further optimization could continue at home in 5 mg increments during subsequent OFF episodes (maximum dose of 30 mg). Optimization and tolerability were assessed daily by patient-reported feedback via telephone. Patients reporting a FULL ON returned to the clinic for a dose-confirmation visit (DCV). In patients with inadequate response as determined during the DCV, the dose could be further optimized at home., Results: Home optimization was continued by 81.4% (83/102) of patients. Of these, 80.7% identified an effective, tolerable dose. Mean time between initial clinic visit and DCV 1 was 6.8 days, and the final optimized dose of SL-APO was 30 mg (mode). In total, 62.7% of patients reported ⩾1 adverse event; the most common included nausea (31.4%), dizziness (9.8%), somnolence (8.8%), dyskinesia (7.8%), and fatigue (5.9%). The safety profile in this study in which most patients performed home dose optimization was consistent with the study utilizing clinic-based optimization., Conclusion: After the first clinic dose, home dose optimization of SL-APO appears feasible in patients with PD and OFF episodes, with most patients identifying their optimal SL-APO dose at home., Trial Registration: This study is registered with EudraCT (2016-003456-7): Clinical Trials register - Search for eudract&#95;number:2016-003456-70., (© The Author(s), 2023.)

Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most appropriate for a rodent model of RLS. We also identified parameters by which to assess and quantify these bioequivalents. Investigating these factors, both individually and in combination, will help to identify their specific roles in the expression of rodent RLS-like phenotypes, which should provide significant translational implications for the diagnosis and treatment of RLS., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Introduction: Cervical dystonia (CD) is a neurologic movement disorder with potentially disabling effects and significant impact on quality of life of those affected. AbobotulinumtoxinA (aboBoNT-A) was initially approved for a dilution of 500 U/1 mL and subsequently for a dilution of 500 U/2 mL, providing flexibility for clinicians to treat CD. Here, we explore the safety and efficacy of the 500 U/2 mL dilution versus 500 U/1 mL dilution of aboBoNT-A in a retrospective analysis based on published clinical trial data., Methods: The safety and efficacy of aboBoNT-A in patients with CD was evaluated in three multicenter, double-blind, randomized, placebo-controlled trials and open-label extensions. Trials 1 (NCT00257660) and 2 (NCT00288509) evaluated the 500 U/1 mL dilution in 80 and 116 patients, respectively; Trial 3 (NCT01753310) evaluated the 500 U/2 mL dilution in 125 patients., Results: Comparison of the adjusted mean difference in TWSTRS total scores at Week 4 from baseline for aboBoNT-A in Trial 1 (-6.0; 95% CI, -10.8, -1.3), Trial 2 (-8.8; 95% CI, -12.9, -4.7), and Trial 3 (-8.7; 95% CI, -13.2, -4.2) showed similar, significant improvements. Dysphagia and muscle weakness patterns were comparable across the three trials, indicating that an increased dilution of aboBoNT-A does not result in an increased risk of diffusion-related adverse events., Conclusion: The results of these trials show that aboBoNT-A is similarly efficacious using either dilution, with similar safety and tolerability across trials. Having the 500 U/1 mL and 500 U/2 mL dilution volumes available provides further flexibility in administration, benefiting patient care., Competing Interests: SHI received honoraria, consultancy, and promotional speaker fees from Ipsen. ATP received consultant and speaker fees from Ipsen. AB received consultancy fees from Ipsen. KD received advisor/consultant/speaker fees from Ipsen. LB received honoraria from Ipsen. SHI, DT, and ATP received research grants/support from Ipsen. PM is employed by Ipsen, and SW is a former employee of Ipsen., (© 2021 The Author(s).)

Cervical dystonia (CD) is primarily treated with botulinum toxin, at intervals of ≥ 12 weeks. We present efficacy, patient-reported outcomes (PROs), and safety in adults with CD at the last available visit after a single set of abobotulinumtoxinA (aboBoNT-A) injections versus placebo using 500 U in a 2-mL injection volume. In this 12-week, randomized, double-blind trial, patients were ≥ 18 years of age with primary idiopathic CD, had a Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, and TWSTRS-Severity subscale score > 10 at baseline. Patients (N = 134) were randomized (2:1) to aboBoNT-A (n = 89) or placebo (n = 45), with aboBoNT-A patients treated with 500 units (U) if toxin-naïve, and 250 to 500 U based on previous onabotulinumtoxinA dose if non-naïve. Endpoints included total TWSTRS, Pain Numeric Rating Scale (NRS-Pain; 24-hour), Treatment Satisfaction Questionnaire for Medication, and other PROs for pain, depression, and global health. Results are for the intent-to-treat population, with "Week 12" (Wk12) comprising the last available post-baseline assessment (end-of-study or early withdrawal). Mean TWSTRS total scores improved from 42.5 at baseline to 35.4 at Wk12 with aboBoNT-A and 42.4 to 40.4 with placebo (treatment difference: -4.8; 95% confidence interval [CI]: -8.5, -1.1; p = 0.011). At Wk12, mean (95% CI) change from baseline in NRS-Pain was -1.0 (-1.59, -0.45) for aboBoNT-A and -0.2 (-0.96, 0.65) for placebo. AboBoNT-A demonstrated numeric improvements in other PROs. More aboBoNT-A-treated patients than patients receiving placebo reported being at least "somewhat satisfied" with treatment (60.4% vs 42.2%, respectively), symptom relief (57.0% vs 40.0%), and time for treatment to work (55.8% vs 33.3%). No new adverse events were reported. Results indicate that in patients with CD, treatment with aboBoNT-A using a 2-mL injection provided sustained improvement in the TWSTRS total score and patient-perceived benefits up to 12 weeks. Trial registration: Clinicaltrials.gov Identified: NCT01753310., Competing Interests: I, A. T. Patel, have read the journal’s policy and the authors of this manuscript have the following competing interests: Speaker: Allergan, Ipsen, Merz, Revance; Research support: Allergan, Ipsen, Revance. I, M. F. Lew, have read the journal’s policy and the authors of this manuscript have the following competing interests: Advisor/consultant/speaker: AbbVie, ACADIA, Acorda, Adamas, Cynapsus, Kyowa Kirin, Lundbeck, Neurocrine, Revance, Teva, US WorldMeds; Researcher: Biotie, Enterin Inc., Michael J. Fox Foundation, Parkinson Study Group, Pharm2B; I, A. Brashear, have read the journal’s policy and the authors of this manuscript have the following competing interests: Consulting: Ipsen, Revance; Research support: paid to Wake Forest (institution) and conflicts were managed by Wake Forest. I, K. Dashtipour, have read the journal’s policy and the authors of this manuscript have the following competing interests: Advisor/consultant, and/or speaker: AbbVie, ACADIA, Acorda, Adamas, Allergan, Amneal, Impax, Ipsen, Lundbeck, Neurocrine, Revance, Sunovion, Teva, US WorldMeds. I, S. Isaacson, have read the journal’s policy and the authors of this manuscript have the following competing interests: Honoraria for CME/consultant/promotional speaker: AbbVie, ACADIA, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Biogen, Britannia, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, UCB, US WorldMeds, Zambon; Honoraria for research grants: AbbVie, ACADIA, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Biogen, Britannia, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, UCB, US WorldMeds. I, R. A. Hauser, have read the journal’s policy and the authors of this manuscript have the following competing interests: Consulting: AbbVie, Academy for Continued Healthcare Learning, ACADIA, Acorda, Adamas, AstraZeneca, Back Bay Life Science, Biotie, Bracket, Cerecor, ClearView Healthcare Partners, ClinicalMind Medical and Therapeutic Communications, Cowen and Company, Cynapsus Therapeutics, Decision Resources Group, Eli Lilly, eResearch Technology, Expert Connect, Extera Partners, GE Healthcare, Gerson Lehrman Group, Globe Life Sciences, Guidepoint Global, Health Advances, Health and Wellness Partners, HealthLogix, Huron Consulting Group, Impax, Intec Pharma, Jazz Pharmaceuticals, Kyowa Kirin Pharmaceutical Development, LCN Consulting, LifeMax, The Lockwood Group, Lundbeck, MEDACorp, Medscape, Medtronic, Michael J. Fox Foundation, Movement Disorder Society, National Institutes of Health (NIH), Neurocrine Biosciences, Neuroderm, Neuropore Therapies, Outcomes Insights, Parkinson Foundation, Peerview Press, Pennside Partners, Pfizer, Pharma2B, Phase Five Communications, Piper Jaffray & Co, Prexton Therapeutics, Projects in Knowledge, Putnam Associates, Quintiles, RMEI Medical Education for Better Outcomes, Sarepta Therapeutics, Schlesinger Associates, Scion Neurostim, Seagrove Partners, Slingshot Insights, Sun Pharma, Sunovion, Teva, US WorldMeds, Vista Research, WebMD, Windrose Consulting Group; Research support: AbbVie, Acorda Therapeutics, AstraZeneca, Axovant Sciences, Biogen, Cavion, Dart NeuroScience, Enterin, F. Hoffman-La Roche, Impax, Intec Pharma, Jazz Pharmaceuticals, Lundbeck, Michael J. Fox Foundation, NeuroDerm, Parkinson’s Foundation, Prexton Therapeutics, Revance, Sunovion. I, W. Ondo, have read the journal’s policy and the authors of this manuscript have the following competing interests: Advisor/consultant/speaker: ACADIA, Acorda, Adamas, Jazz Pharmaceuticals, Neurocrine, Teva, UCB, US WorldMeds; Research support: Biogen, Lilly, Lundbeck, Sun Pharmaceuticals, Sunovian. I, P. Maisonobe, have read the journal’s policy and the authors of this manuscript have the following competing interests: Employment: Ipsen. I, S. Wietek, have read the journal’s policy and the authors of this manuscript have the following competing interests: Employment: Ipsen. I, B. Rubin, have read the journal’s policy and the authors of this manuscript have the following competing interests: Employment (former): Ipsen.

Highlights: This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients., Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use., Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey., Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of 'severe' or 'moderate' patients improving to 'mild' or 'slight'. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported., Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients., Competing Interests: Drs. Isaacson, Hallett, and Pahwa serve as clinical advisors for Cala Health. Dr. Ondo serves as a safety reviewer for Cala Health. Dr. Rajagopal is an employee of Cala Health. Ms. Chidester is a former employee of Cala Health. Dr. Rosenbluth is an employee and board member of Cala Health. Dr. Delp is a scientific advisor and board member of Cala Health., (Copyright: © 2020 The Author(s).)

Background: The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) has been used in large trials for essential tremor (ET), but its anchors for ratings from 0 to 4 of upper limb tremor are probably too low for patients with severe tremor (tremor amplitude >4 cm; grade 4). The Essential Tremor Rating Assessment Scale (TETRAS) is a validated clinical scale designed specifically for the assessment of ET severity. TETRAS has anchors that span a larger range of tremor amplitudes (>20 cm = grade 4), making it more suitable for assessing patients with severe ET. However, there is no direct comparison of these scales in any clinical trial., Methods: Upper limb postural and kinetic tremor items from both scales were compared using blinded, video-recorded examinations of patients with moderate-to-severe ET who participated in a trial of focused ultrasound thalamotomy., Results: FTM ratings of postural and kinetic tremor correlated strongly with those of TETRAS. However, FTM exhibited a ceiling effect for severe tremor. Rest tremor, exclusive to FTM, correlated poorly with postural and kinetic tremor and had very poor test-retest reliability. In contrast, wing-beating postural tremor, exclusive to TETRAS, exhibited excellent test-retest reliability and a strong correlation with kinetic and limbs-extended-forward postural tremor. Test-retest reliabilities of the other TETRAS and FTM ratings were excellent, and both scales had good sensitivity to treatment effect., Conclusions: TETRAS has 2 main advantages over FTM in the assessment of tremor severity: (1) the absence of a ceiling effect in patients with severe ET, and (2) the inclusion of wing-beating tremor.

Objective: Pontine infarction is a common type of stroke in the cerebral deep structures, resulting from occlusion of small penetrating arteries, may manifest as hemi-paralysis, hemi-sensory deficit, ataxia, vertigo, and bulbar dysfunction, but patients presenting with restless legs syndrome (RLS) are extremely rare. Herein, we reported five cases with RLS as a major manifestation of pontine infarction., Methods: Five cases of pontine infarction related RLS were collected from July 2013 to February 2016. The diagnosis of RLS was made according to criteria established by the International RLS Study Group (IRLSSG) in 2003. Neurological functions were assessed according to the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Severity of RLS was based on the International RLS Rating Scale (IRLS-RS). Sleep quality was assessed by Epworth Rating Scale (ERS), and individual emotional and psychological states were assessed by Hamilton Depression Scale (HDS) and Hamilton Anxiety Scale (HAS)., Results: The laboratory data at the onset including hemoglobin, serum concentration of homocysteine, blood urea nitrogen (BUN), creatinine, electrolytes, and thyroid hormones were normal. The electroencephalogram (EEG), lower-extremity somatosensory evoked potential (SEP), and nerve conduction velocity (NCV) in four limbs were normal. The average period of follow-up was 34.60 ± 12.76 months. The MRI examination showed acute or subacute pontine infarction lesions, 3 cases in the rostral inner side, 1 case in the rostral lateral and inner side, and 1 case in rostral lateral side. The neurological deficits included weakness in 4 cases, contralateral sensory deficit in 1 case, and ataxia in 2 cases. All 5 patients presented with symptom of RLS at or soon after the onset of infarction and 4 patients experienced uncomfortable sensations in the paralyzed limbs contralateral to the ischemic lesion. Their neurological deficits improved significantly 2 weeks later, but the symptoms of RLS did not resolve. Among them, 3/5 patients were treated with dopaminergic drugs. At the end of the follow-up, RLS symptom eventually resolved in 3 patients but persisted in two. The IRLS-RS, NIHSS and mRS scores were significantly lower at the onset than those at the last follow-up ( P  = 0.035, 0.024 and 0.049, respectively). However, there was no significant difference in the ERS, HDS and HAS scores ( P  = 0.477, 0.226 and 0.778, respectively)., Conclusion: RLS can be an onset manifestation of pontine infarction, clinicians should be aware of this potential symptom. RLS usually occurs in the paralyzed limbs contralateral to the infarction lesion. The pathogenesis still needs further investigation.

Background: In patients with motor fluctuations complicating Parkinson's disease (PD), delays in time-to-ON with levodopa are common. This open-label study aimed to assess the effect of apomorphine on time-to-ON in PD patients with morning akinesia., Methods: The safety population included 127 enrolled patients, and the full analysis set (FAS) included 88 patients. Patients completed a 7-day levodopa baseline period recording their time-to-ON following each morning dose of levodopa. Patients were titrated to an optimal dose of apomorphine (2-6 mg) while taking trimethobenzamide antiemetic therapy. Apomorphine was injected each morning for a 7-day treatment period and time-to-ON was self-recorded in 5-minute blocks. The primary efficacy variable was time-to-ON in the apomorphine treatment period versus the baseline levodopa period. Secondary assessments included and global impression scales. Safety and tolerability were assessed through adverse events (AEs)., Results: Patients receiving apomorphine achieved mean ± standard deviation (SD) time-to-ON 23.72 ± 14.55 minutes, reduced from 60.86 ± 18.11 minutes with levodopa ( P < 0.0001). Dose failures (defined as time-to-ON >60 minutes) were more commonly reported with levodopa versus apomorphine (46% vs. 7% of diary entries, respectively). Secondary endpoints supported the primary efficacy findings, with significant improvements from levodopa baseline to apomorphine treatment period (all P < 0.0001). The most common AEs were nausea and dizziness. Most patients who discontinued because of AEs did so in the titration phase., Conclusions: Apomorphine injections significantly reduced time-to-ON in PD patients experiencing delayed onset of their morning levodopa dose, and was well tolerated in most patients. After apomorphine treatment, fluctuating patients with morning akinesia experienced rapid and reliable improvement of time-to-ON.

Background: The pathophysiology of essential tremor, especially at the cellular level, is poorly understood. Although no drug has been specifically designed to treat essential tremor, several medications improve tremor, and others worsen it. Studying the mechanism of actions of these medications can help our understanding of tremor pathophysiology and contribute to future rational drug design., Methods: We reviewed literature, concentrating on mechanisms of action, of various medications that mitigate tremor., Results: Many medications have multiple mechanisms of actions, making simple correlations difficult. Medications that increase the duration of opening of gamma-aminobutyric acid (GABA)-A receptors are most consistently associated with tremor improvement. Interestingly, drugs that increase GABA availability have not been associated with improved tremor. Other mechanisms possibly associated with tremor improvement include antagonism of alpha-2 delta subunits associated with calcium channels, inhibition of carbonic anhydrase, and inhibition of the synaptic vesicle protein 2A. Drugs that block voltage-gaited sodium channels do not affect tremor. The ideal beta-adrenergic blocker requires B2 affinity (non-cardiac selective), has no sympathomimetic properties, does not require membrane stabilization properties, and may benefit from good central nervous system penetration., Discussion: To date, serendipitous observations have provided most of our understanding of tremor cellular physiology. Based on similarities to currently effective drugs or rational approximations and inferences, several currently available agents should be considered for tremor trials.

Objective: This systematic review was performed to elucidate dosing practices, dosing conversions, and related outcomes from randomized controlled trials that directly compared onabotulinumtoxinA (ONA) and abobotulinumtoxinA (ABO) at various dose conversion ratios for therapeutic use in movement disorders., Methods: A systematic review of 3 medical literature databases (PubMed, the Cochrane Library, and EMBASE) was performed to identify relevant comparative clinical studies, systematic reviews, and meta-analyses published in the English language between January 1991 and January 2015. Studies that met predefined inclusion criteria were selected for formal data extraction and quality assessment., Results: A total of 182 manuscripts were identified, of which 4 were included for analysis. Targeted clinical applications included neurological disorders. The studies compared ONA to ABO dose conversion ratios of 1:2.5 (n=1), 1:3 (n=2), and 1:4 (n=2). One study compared both 1:3 and 1:4 ratios. An ONA:ABO conversion factor of 1:2.5 was associated with similar efficacy and side effects. An ONA:ABO ratio of 1:3 provided similar or higher efficacy but an increased rate of adverse effects, and an ONA:ABO ratio of 1:4 was associated with higher efficacy but with an excessive rate of intolerable side effects., Conclusion: A dose conversion ratio of ONA to ABO between 1:2.5 and 1:3.0 provides comparable safety and efficacy for therapeutic movement disorders chemodenervation procedures.

Leg pain and discomfort are common complaints in any primary physician's clinic. Two common causes of pain or discomfort in legs are nocturnal leg cramps (NLC) and restless leg syndrome (RLS). NLC present as painful and sudden contractions mostly in part of the calf. Diagnosis of NLC is mainly clinical and sometimes involves investigations to rule out other mimics. RLS is a condition characterized by the discomfort or urge to move the lower limbs, which occurs at rest or in the evening/night. The similarity of RLS and leg cramps poses the issue of errors in diagnosing and differentiating the two. In this paper we review the pathopysiology of each entity and their diagnosis as well as treatment. The two conditions are then compared to appreciate the differences and similarities. Finally, suggestions are recommended for complete assessment.