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Background: All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. Methods. To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. Results: We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). Conclusions: The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies. © 2013 Ashizawa et al.; licensee BioMed Central Ltd.

We evaluated the initial diagnosis and treatment patterns of 229 patients with Parkinson's disease, who presented to a university movement disorders center, regardless of where the diagnosis was first made and who initiated therapy. Patients with Parkinson's disease, under age 70, who were diagnosed prior to 1998, were almost twice as likely to receive levodopa/carbidopa as their initial medication when compared to those diagnosed after 1998. The initial diagnosis of Parkinson's disease took over 2 years to make in 25% of patients, and 70% of patients did not receive a Parkinson's disease diagnosis until 2 or more physicians were consulted. [ABSTRACT FROM AUTHOR]

Objective. Parkinson's disease (PD) causes significant economic burden for patients and caregivers. Social Security Disability Insurance (SSDI) provides insurance to workers in the United States who have been gainfully employed, but who are no longer able to work due to a medical condition. We performed a descriptive pilot study that examined PD patients' experience with SSDI. Methods. PD patients who were diagnosed with PD prior to age 60 and were followed at an academic movement disorders center were consecutively invited to participate in a survey concerning their employment history and experience with SSDI. Results. All 68 invited patients participated in the study (mean age 58 years, mean disease duration 9.5 years). Eighty-two percent of patients felt that they were too disabled to work full time at a mean of 3.4 years after PD diagnosis. Patients applied for SSDI at a mean of 5 years after diagnosis, and two-thirds of PD patients who applied for SSDI obtained it on their first attempt. The primary debilitating symptom that subjectively contributed to work disability was fatigue (49% of patients). Patients who successfully acquired SSDI had extensive documentation of physician visits, and the aid of a disability lawyer. Conclusions. Patients felt they were too disabled to work full time at a mean of 3.4 years after diagnosis. Those who applied for SSDI did so at a mean of 5 years after diagnosis. Patients who obtained SSDI awards had extensive documentation of medical records or the help of a disability lawyer. [ABSTRACT FROM AUTHOR]

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale to assess cerebellar ataxia but faces some criticisms about the relevancy of all its items., Objectives: To prepare for future clinical trials, we analyzed the progression of SARA and its items in several polyQ spinocerebellar ataxias (SCA) from various cohorts., Methods: We included data from patients with SCA1, SCA2, SCA3, and SCA6 from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) for a total of 850 carriers and 3431 observations. Longitudinal progression of the SARA and its items was measured. Cohort, stage and genetic effects were tested. We looked at the respective contribution of each item to the total scale. Sensitivity to change of the scale and the impact of item removal was evaluated by calculating sample sizes needed in various scenarios., Results: Longitudinal progression was significantly different between cohorts in SCA1, SCA2 and SCA3, the EUROSCA cohort having the fastest progression. Advanced-stage patients were progressing slower in SCA2 and SCA6. Items were not contributing equally to the full scale through ataxia severity: gait, stance, hand movement, and heel-shin contributed the most in the early stage, and finger-chase, nose-finger, and sitting in later stages. Few items drove the sensitivity to the change of SARA, but changes in the scale structure could not improve its sensitivity in all populations., Conclusion: SARA and its item's progression pace showed high heterogeneity across cohorts and SCAs. However, no combinations of items improved the responsiveness in all SCAs or populations taken separately., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated., Objectives: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life., Methods: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life., Results: Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi-variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA., Conclusions: Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs., (© 2024 International Parkinson and Movement Disorder Society.)

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cerebellar ataxia results from damage to the cerebellum and presents as movement incoordination and variability, gait impairment, and slurred speech. Patients with cerebellar ataxia can also have cognitive and mood changes. Although the identification of causes for cerebellar ataxia can be complex, age of presentation, chronicity, family history, and associated movement disorders may provide diagnostic clues. There are many genetic causes for cerebellar ataxia, and the common autosomal dominant and recessive ataxia are due to genetic repeat expansions. Step-by-step approach will lead to the identification of the causes. Symptomatic and potential disease-modifying therapies may benefit patients with cerebellar ataxia., Competing Interests: Financial disclosures/Conflicts of interest Dr S-H. Kuo has received funding from the National Institutes of Health: NINDS #R01 NS118179 (principal investigator), NINDS #R01 NS104423 (principal investigator), NINDS #R03 NS114871 (principal investigator), the Louis V. Gerstner Jr. Scholar Award, Parkinson's Foundation, National Ataxia Foundation, and International Essential Tremor Foundation. Dr S-H. Kuo served as the Scientific Advisor for Praxis Precision Medicines and Sage Therapeutics. Dr T.A. Zesiewicz has received personal compensation for serving on the advisory boards of Boston Scientific, Reata Pharmaceuticals, and Steminent Biotherapeutics. Dr T.A. Zesiewicz has received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics. Dr T.A. Zesiewicz has received royalty payments as co-inventor of varenicline for treating imbalance and nonataxic imbalance. Dr T.A. Zesiwicz has received research grant support as principle investigator for studies from AbbVie, Biogen, Biohaven Pharmaceuticals, Boston Scientific, Bukwang Pharmaceuticals Co, Ltd, Cala Health, Inc, Cavion, Friedreich’s Ataxia Research Alliance; Houston Methodist Research Institute, National Institutes of Health, REtrotope Inc; and Takeda Development Center Americas, Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Spinocerebellar ataxias (SCA) are a group of rare neurodegenerative diseases that dramatically affect the lives of affected individuals and their families. Despite having a clear understanding of SCA's etiology, there are no current symptomatic or neuroprotective treatments approved by the FDA., Areas Covered: Research efforts have greatly expanded the possibilities for potential treatments, including both pharmacological and non-pharmacological interventions. Great attention is also being given to novel therapeutics based in gene therapy, neurostimulation, and molecular targeting. This review article will address the current advances in the treatment of SCA and what potential interventions are on the horizon., Expert Opinion: SCA is a highly complex and multifaceted disease family with the majority of research emphasizing symptomatic pharmacologic therapies. As pre-clinical trials for SCA and clinical trials for other neurodegenerative conditions illuminate the efficacy of disease modifying therapies such as AAV-mediated gene therapy and ASOs, the potential for addressing SCA at the pre-symptomatic stage is increasingly promising.

Introduction: Friedreich's ataxia (FRDA) is a progressive, neurodegenerative disease that results in gait and limb ataxia, diabetes, cardiac hypertrophy, and scoliosis. At the cellular level, FRDA results in the deficiency of frataxin, a mitochondrial protein that plays a vital role in iron homeostasis and amelioration of oxidative stress. No cure currently exists for FRDA, but exciting therapeutic developments which target different parts of the pathological cascade are on the horizon., Areas Covered: Areas covered include past and emerging therapies for FRDA, including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others., Expert Opinion: While drug discovery has been challenging, new and exciting prospective treatments for FRDA are currently on the horizon, including pharmaceutical agents and gene therapy. Agents that enhance mitochondrial function, such as Nrf2 activators, dPUFAs and catalytic antioxidants, as well as novel methods of frataxin augmentation and genetic modulation will hopefully provide treatment for this devastating disease.

The modified Friedreich Ataxia Rating Scale (mFARS) is a disease specific, exam-based neurological rating scale commonly used as a outcome measure in clinical trials. While extensive clinimetric testing indicates it's validity in measuring disease progression, formal test-retest reliability was lacking. To fill this gap, we acquired results from screening and baseline visits of several large clinical trials and calculated intraclass correlation coefficients, coefficients of variance, standard error, and the minimally detectable changes. This study demonstrated excellent test-retest reliability of the mFARS, and it's upright stability subscore., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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).)

Early Parkinson disease is the approximate time period between initial diagnosis and the onset of motor fluctuations. Treatment requires an integrative approach, including identification of motor and nonmotor symptoms, choice of pharmacologic treatment, and emphasis on exercise. Patients should be treated for motor symptoms, whereas medications may be delayed for milder symptoms. The choice of treatment in patients with early Parkinson disease must be weighed against financial considerations, ease of administration, and potential long-term adverse events. Nonmotor symptoms should also be identified and treated. Exercise is an important component for treatment of Parkinson disease at any stage., (Published by Elsevier Inc.)

Friedreich's Ataxia (FRDA) is a devastating and progressive ataxia, marked by mitochondrial dysfunction and oxidative stress. Nrf2 activators such as omaveloxolone (Omav) modulate antioxidative mechanisms, and thus may be viable therapeutic agents in FRDA., Competing Interests: Dr Zesiewicz has received personal compensation for serving on the advisory boards of Boston Scientific, Reata Pharmaceuticals, Inc, and Steminent Biotherapeutics. Dr Zesiewicz has received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics. Dr Zesiewicz has received royalty payments as co-inventor of varenicline for treating imbalance (patent number 9463190) and nonataxic imbalance (patent number 9782404). Dr Zesiewicz has received research/grant support as principal investigator/investigator for studies from AbbVie Inc, Biogen, Biohaven Pharmaceutics, Boston Scientific, Bukwang Pharmaceuticals Co, Ltd, Cala Health, Inc, Cavion, Friedreich’s Ataxia Research Alliance, Houston Methodist Research Institute, National Institutes of Health (READISCA U01), Retrotope Inc, and Takeda Development Center Americas, Inc. Dr. Meyer is an employee of Reata Pharmaceuticals, Inc. The authors report no other conflicts of interest in this work., (© 2019 Ghanekar et al.)

Purpose of Review: Parkinson disease is a common neurodegenerative disorder that affects millions of people worldwide. Important advances in the treatment, etiology, and the pathogenesis of Parkinson disease have been made in the past 50 years. This article provides a review of the current understanding of Parkinson disease, including the epidemiology, phenomenology, and treatment options of the disease., Recent Findings: Parkinson disease is now recognized to be a heterogeneous condition marked by both motor and nonmotor symptoms. It is composed of preclinical, prodromal, and clinical phases. New medications with improved ease of administration have been approved for its treatment. Innovative surgical therapies for Parkinson disease may be used when motor symptoms persist despite optimal medical management., Summary: Parkinson disease is a complex, heterogeneous neurodegenerative disorder. Considerable progress has been made in its treatment modalities, both pharmacologic and surgical. While its cure remains elusive, exciting new research advances are on the horizon.

Objective: To systematically review evidence regarding ataxia treatment., Methods: A comprehensive systematic review was performed according to American Academy of Neurology methodology., Conclusions: For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study)., (© 2018 American Academy of Neurology.)

Introduction: Friedreich's Ataxia (FA) is a devastating, progressive, neurodegenerative disease. Objective measures that detect changes in neurological function in FA patients are needed to facilitate therapeutic clinical trials. The purpose of this pilot study was to analyze longitudinal changes in gait and balance in subjects with FA using the GAITRite Walkway System ® and Biodex Balance System™, respectively, and to test the ability of these measures to detect change over time compared to the Friedreich's Ataxia Rating Scale (FARS)., Methods: This was a 24-month longitudinal study comparing ambulatory FA subjects with age- and gender-matched, healthy controls. Eight FA subjects and 8 controls were tested at regular intervals using the GAITRite and Biodex Balance systems and the FARS., Results: In the FA group, comfortable and fast gait velocity declined 8.0% and 13.9% after 12 months and 24.1% and 30.3% after 24 months, respectively. Postural stability indices increased in FA subjects an average of 41% from baseline to 24 months, representing a decline in balance. Subjects with FA also demonstrated a 17.7% increase in FARS neurological exam scores over 24 months. There were no changes in gait or balance variables in controls. In the FA group, multiple gait and balance measures correlated significantly with FARS neurological exam scores., Conclusions: The GAITRite and Biodex Balance systems provided objective and clinically relevant measures of functional decline in subjects with FA that correlated significantly with performance measures in the FARS. Gait velocity may be an important objective measure to identify disease progression in adults with FA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: This Phase IV, double-blind, randomized, parallel-group study characterized the dose-response and tolerability of fixed doses of ropinirole prolonged release (PR)., Patients & Methods: Subjects with early Parkinson's disease (PD) received placebo or ropinirole PR 2, 4, 8, 12 or 24 mg once daily, up-titrated to randomized or highest tolerated dose, maintained for 4 weeks., Results: The primary end point was not met (change from baseline in Unified PD Rating Scale motor score). However, because the data were not normally distributed, prespecified nonparametric analysis of covariance suggested ropinirole PR (8 and 12 mg/day) was effective in treating motor symptoms. The adverse event profile was consistent with the known safety profile of ropinirole PR. There was no impulse control disorder reported. Although a higher than previously reported rate of sudden onset of sleep events was reported, these were not dose dependent and were likely to have been influenced by the method of data collection., Conclusion: The adverse event profile was consistent with the known safety profile of ropinirole PR and ropinirole PR (8 or 12 mg/day) improved motor symptoms of early PD.

Aim: This Phase IV, double-blind, randomized, parallel-group study characterized the dose-response and tolerability of fixed doses of ropinirole prolonged release (PR) in subjects with advanced Parkinson's disease., Patients & Methods: Subjects receiving concomitant l-dopa received once-daily ropinirole PR 4, 8, 12, 16 or 24 mg, or placebo, up-titrated for 13 weeks, maintained for 4 weeks., Results: At maintenance period week 4, ropinirole PR significantly reduced total awake 'Off-time' (16 mg; p = 0.027); increased absolute awake time spent 'On' without troublesome dyskinesia from baseline versus placebo (8 mg; p = 0.036); improved Unified Parkinson's Disease Rating Scale motor scores versus placebo (all doses; p = 0.005-0.016). Incidence of adverse events was similar between treatment groups; no dose-related trends were observed., Conclusion: Ropinirole PR (16 mg) reduced 'Off-time' with 8 mg the likely lowest maximally effective dose, and the safety profile was consistent with previous studies.

Friedreich's ataxia (FRDA) is an inherited, progressive neurodegenerative disease that typically affects teenagers and young adults. Therapeutic strategies and disease insight have expanded rapidly over recent years, leading to hope for the FRDA population. There is currently no US FDA-approved treatment for FRDA, but advances in research of its pathogenesis have led to clinical trials of potential treatments. This article reviews emerging therapies and discusses future perspectives, including the need for more precise measures for detecting changes in neurologic symptoms as well as a disease-modifying agent.

Introduction: Essential tremor is one of the most common movement disorders in the world, with prevalence in the general population of 0.4% to 3.9%., Methods and Outcomes: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of drug treatments in people with essential tremor of the hand? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview)., Results: At this update, searching of electronic databases retrieved 56 studies. After deduplication and removal of conference abstracts, 31 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 18 studies and the further review of 13 full publications. Of the 13 full articles evaluated, two RCTs were added at this update. We performed a GRADE evaluation for 11 PICO combinations., Conclusions: In this systematic overview, we categorised the efficacy for 13 interventions based on information about the effectiveness and safety of alprazolam, beta-blockers other than propranolol, botulinum A toxin-haemagglutinin complex, clonazepam, diazepam, gabapentin, levetiracetam, lorazepam, phenobarbital, primidone, propranolol, sodium oxybate, and topiramate.

Rotigotine (RTG) is a dopamine agonist that is used as mono and adjunct therapy to treat Parkinson's disease, and as therapy for moderate-to-severe restless legs syndrome. RTG is the only dopamine agonist currently available as a 24-hour/day transdermal system, providing once-a-day dosing. As a transdermal patch, RTG bypasses the gastrointestinal tract, making it a treatment option for patients with dysphagia. The use of RTG also avoids the need to schedule administration of medication around meals. This review provides a critical appraisal of RTG as treatment of Parkinson's disease and RLS., Competing Interests: T Kesayan, JD Shaw, T Jones, and JS Staffetti have nothing to disclose and have no conflict of interest in this work. TA Zesiewicz receives grant funding from Edison Pharmaceuticals, Inc., Sagene Pharmaceuticals, Inc., the Friedreich’s Ataxia Research Alliance, Osmotica Pharmaceutical Corp, Adamas Pharmaceuticals, Inc., and Baxter Pharmaceuticals, Inc. She has no other conflicts of interest in this work., (© 2015 Kesayan et al.)

Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons in the CNS and leading to paralysis and death. There are currently no effective treatments for ALS due to the complexity and heterogeneity of factors involved in motor neuron degeneration. A complex of interrelated effectors have been identified in ALS, yet systemic factors indicating and/or reflecting pathological disease developments are uncertain. The purpose of the study was to identify humoral effectors as potential biomarkers during disease progression., Methods: Thirteen clinically definite ALS patients and seven non-neurological controls enrolled in the study. Peripheral blood samples were obtained from each ALS patient and control at two visits separated by 6 months. The Revised ALS Functional Rating Scale (ALSFRS-R) was used to evaluate overall ALS-patient functional status at each visit. Eleven humoral factors were analyzed in sera. Cytokine levels (GM-CSF, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-α) were determined using the Bio-Rad Bio-Plex® Luminex 200 multiplex assay system. Nitrite, a breakdown product of NO, was quantified using a Griess Reagent System. Glutathione (GSH) concentrations were measured using a Glutathione Fluorometric Assay Kit., Results: ALS patients had ALSFRS-R scores of 30.5 ± 1.9 on their first visit and 27.3 ± 2.7 on the second visit, indicating slight disease progression. Serum multiplex cytokine panels revealed statistically significant changes in IL-2, IL-5, IL-6, and IL-8 levels in ALS patients depending on disease status at each visit. Nitrite serum levels trended upwards in ALS patients while serum GSH concentrations were drastically decreased in sera from ALS patients versus controls at both visits., Conclusions: Our results demonstrated a systemic pro-inflammatory state and impaired antioxidant system in ALS patients during disease progression. Increased levels of pro-inflammatory IL-6, IL-8, and nitrite and significantly decreased endogenous antioxidant GSH levels could identify these humoral constituents as systemic biomarkers for ALS. However, systemic changes in IL-2, IL-5, and IL-6 levels determined between visits in ALS patients might indicate adaptive immune system responses dependent on current disease stage. These novel findings, showing dynamic changes in humoral effectors during disease progression, could be important for development of an effective treatment for ALS.

Objective: To evaluate the efficacy of solifenacin succinate in Parkinson's disease (PD) patients suffering from overactive bladder (OAB)., Background: Urinary dysfunction is a commonly encountered non-motor feature in PD that significantly impacts patient quality of life., Design/methods: This was a double-blind, randomized, placebo-controlled, 3-site study with an open label extension phase to determine the efficacy of solifenacin succinate in idiopathic PD patients with OAB. Patients were randomized to receive solifenacin succinate 5-10 mg daily or placebo for 12 weeks followed by an 8-week open label extension. The primary outcome measure was the change in the mean number of micturitions per 24 h period. Secondary outcome measures included the change in the mean number of urinary incontinence episodes and the mean number of nocturia episodes., Results: Twenty-three patients were randomized in the study. There was no significant improvement in the primary outcome measure in the double-blind phase, but there was an improvement in the number of micturitions per 24 h period in the solifenacin succinate group compared to placebo at a mean dose of 6 mg/day (p = 0.01). In the open label phase, the mean number of urinary incontinence episodes per 24 h period decreased (p = 0.03), as did the number of nocturia episodes per 24 h period (p = 0.01). Adverse events included constipation and xerostomia, which resolved after treatment was discontinued., Conclusions: In this pilot trial, solifenacin succinate treatment led to an improvement in urinary incontinence, despite persistence in other OAB symptoms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Associations have been reported between the risk of Parkinson's disease (PD) and employment in certain fields. Most studies have focused on toxic exposures as potential causal explanations. However, PD also has been associated with personality characteristics that may influence occupational choices and patterns., Objective: This study evaluates the role of personality as indicated by occupational choices and employment patterns in the risk for PD., Methods: In-person interviews were conducted to assess occupational histories and early-adult personality indicators among 89 PD patients and 99 controls., Results: PD cases had fewer lifetime jobs than controls (mean for cases = 4.38 ± 2.20; mean for controls = 5.00 ± 2.26; p = 0.03). Among women, PD was positively associated with more complex work with people (OR = 1.45, 95% CI 1.12-1.89), representing a 95% increased risk for PD comparing women with the greatest complexity of work with those requiring the least complexity of work with people. Women PD cases also performed less complex work with things compared with controls (OR = 0.69 (95% CI 0.53-0.90)), translating into a 13-fold increased risk for PD among women whose work involved the least complex work with things compared with the most. The numbers of jobs and job types were associated with taking more activity risks as a young-adult (r = 0.19, p = 0.02; r = 0.26, p = 0.001, respectively)., Conclusions: Cases with PD held fewer lifetime jobs compared with controls. Occupational complexity was associated with the risk for PD among women, but not men. Further consideration of the possible influence of personality on occupational choices is warranted.

We advance the overarching hypothesis that stem cell therapy is a potent treatment for Friedreich's ataxia (FRDA). Here, we discuss the feasibility of autologous transplantation in FRDA, highlighting the need for the successful isolation of the FRDA patient's bone marrow-derived mesenchymal stem cells, followed by characterization that these cells maintain the GAA repeat expansion and the reduced FXN mRNA expression, both hallmark features of FRDA. Next, we discuss the need for assessment of the proliferative capability and pluripotency of FRDA patient's bone marrow-derived mesenchymal stem cells. In particular, we view the need for characterizing the in vitro differentiation of bone marrow-derived mesenchymal stem cells into the two cell types primarily affected in FRDA, peripheral neurons and cardiomyocytes. Finally, we discuss the need to test the application of bone marrow-derived mesenchymal stem cells as potent autologous donor cells for FRDA. The demonstration of the functional correction of the mutated gene in these cells will be a critical endpoint of determining the potential of stem cell therapy in FRDA. We envision a gene-based cell transplant strategy as a likely therapeutic approach for FRDA, involving stable insertion of functional human bacterial artificial chromosomes or BACs containing the intact FXN gene into stem cells, thereafter leading to the expression of frataxin protein in differentiated neurons/cardiomyocytes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Symptoms of cerebellar degeneration include ataxia or wide-based gait, visual and speech dysfunction, dysmetria, and dyscoordination. The etiology of cerebellar degeneration is vast and often complex, and requires neuroimaging, lab assessments, and a thorough family history to delineate its cause. There is currently no accepted treatment of hereditary cerebellar degeneration, although several pharmaceutical agents have shown potential promise.

Parkinson's disease (PD) is a progressive neurodegenerative disease, involving the dopaminergic, noradrenergic, serotonergic and cholinergic systems. In addition to its cardinal motor symptoms, PD is associated with a diverse range of non-motor symptoms (NMS) that may be more important than motor symptoms. Although there is evidence for a dopaminergic contribution for several NMS in PD, NMS have been underrecognized and undertreated by clinicians. There is evidence that dopaminergic therapy, including dopamine agonists, may alleviate some NMS, such as anxiety and depression. This review focuses on published data on the effects of the non-ergoline dopaminergic agonist rotigotine transdermal system in the treatment of NMS in patients with PD. Data on the effects of orally administered non-ergoline agonists, including ropinirole and pramipexole, on NMS are also summarized.

Objective: To examine the efficacy of cognitive speed of processing training (SOPT) among individuals with Parkinson disease (PD). Moderators of SOPT were also examined., Methods: Eighty-seven adults, 40 years of age or older, with a diagnosis of idiopathic PD in Hoehn & Yahr stages 1-3 and on a stable medication regimen were randomized to either 20 hours of self-administered SOPT (using InSight software) or a no-contact control condition. Participants were assessed at baseline and after 3 months of training (or an equivalent delay). The primary outcome measure was useful field of view test (UFOV) performance, and secondary outcomes included cognitive self-perceptions and depressive symptoms., Results: Results indicated that participants randomized to SOPT experienced significantly greater improvements on UFOV performance relative to controls, Wilks λ = 0.938, F 1,72 = 4.79, p = 0.032, partial η(2) = 0.062. Findings indicated no significant effect of training on secondary outcomes, Wilks λ = 0.987, F2,70 < 1, p = 0.637, partial η(2) = 0.013., Conclusions: Patients with mild to moderate stage PD can self-administer SOPT and improve their cognitive speed of processing, as indexed by UFOV (a robust predictor of driving performance in aging and PD). Further research should establish if persons with PD experience longitudinal benefits of such training and if improvements translate to benefits in functional activities such as driving., Classification of Evidence: This study provides Class III evidence that SOPT improves UFOV performance among persons in the mild to moderate stages of PD.

Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Opinion Statement: Essential tremor is one of the most common movement disorders in the world. Although millions of people worldwide are affected by ET, only one medication, propranolol, is approved by the United States Food and Drug Administration to treat it. None of the medications currently used as ET therapy were developed specifically for this purpose, and select antihypertensive and antiepileptic medications remain at the forefront of ET therapy. Propranolol and primidone are considered "effective" agents that treat ET; topiramate, atenolol, and alprazolam are "probably effective", and nimodipine, nadolol, and clonazepam are "possibly effective". Medications that probably do not adequately treat ET include levetiracetam and pregabalin. Gabapentin appears to improve ET when used as monotherapy, but not when used as adjunct therapy. Sotalol has been found to be "probably effective" in treating ET in previous reviews, but it may be associated with arrhythmias and should not be routinely recommended. Botulinum toxin A may reduce limb tremor, but may cause dose dependent weakness. Deep brain stimulation (DBS) of the VIM is used as an alternative to pharmacological therapy of ET in patients who fail to adequately respond to medical therapy. The magnitude of effect from DBS is greater than from medical management, but more severe side effects are possible with surgery. Future treatment options for ET will depend on valid animal models, and a better understanding of its pathophysiology.

Objective: To make evidence-based recommendations regarding management of tardive syndromes (TDS), including tardive dyskinesias (TDD), by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TDS treatment? 2) Does switching from typical to atypical DRBAs reduce TDS symptoms? 3) What is the efficacy of pharmacologic agents in treating TDS? 4) Do patients with TDS benefit from chemodenervation with botulinum toxin? 5) Do patients with TDS benefit from surgical therapy?, Methods: PsycINFO, Ovid MEDLINE, EMBASE, Web of Science, and Cochrane were searched (1966-2011). Articles were classified according to a 4-tiered evidence-rating scheme; recommendations were tied to the evidence., Results and Recommendations: Clonazepam probably improves TDD and ginkgo biloba probably improves TDS (both Level B); both should be considered as treatment. Risperidone may improve TDS but cannot be recommended as treatment because neuroleptics may cause TDS despite masking symptoms. Amantadine and tetrabenazine might be considered as TDS treatment (Level C). Diltiazem should not be considered as TDD treatment (Level B); galantamine and eicosapentaenoic acid may not be considered as treatment (Level C). Data are insufficient to support or refute use of acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B6, selegiline, clozapine, olanzapine, melatonin, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, α-methyldopa, reserpine, and pallidal deep brain stimulation as TDS treatments (Level U). Data are insufficient to support or refute TDS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Background: Many essential tremor patients continue to require tremor suppressing medications following deep brain stimulation. The true incidence of medication usage in the years following surgery remains unclear, and the use of medications has not been included in the post-operative analyses of tremor severity and also quality of life., Methods: Among 28 essential tremor patients treated with deep brain stimulation at a single center between January 2002 and April 2010, we analyzed the prevalence and dosage of pre-operative tremor suppressing medications versus post-operative medications at 12 and 36 months following surgery. We also assessed the influence of medication continuation on clinical outcome measures, such as the Fahn-Tolosa-Marin Tremor Rating Scale, and the 36 item short-form health quality of life survey., Results: Both unilateral and bilateral deep brain stimulation resulted in a decrease in primidone use (p = 0.0082, 0.046, respectively), and bilateral deep brain stimulation patients used less tremor suppressing medications 36 months following surgery (p = 0.02). The decision to discontinue primidone after surgery resulted in a non-significant long-term improvement in tremor motor score (23 points versus 15 points, p = 0.19), and did not significantly influence the physical and mental composite quality of life scores (p = 0.81, 0.23, respectively)., Conclusions: Bilateral deep brain stimulation effectively eliminated the need for tremor suppressing medications, while unilateral stimulation was not as effective in reducing medication usage. Clinicians and patients should be aware that discontinuation of primidone after surgery may worsen tremor in unilateral deep brain stimulation cases, but discontinuation will not likely impact quality of life., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Friedreich ataxia is a neurodegenerative disease characterized by gait abnormalities, cardiomyopathy, and diabetes. Congestive heart failure was recently reported as the most frequent cause of Friedreich ataxia mortality. Cardiac dysfunction is suspected to result from a frataxin deficiency that leads to oxidative damage in cardiac tissues and possible metabolic syndrome characteristics. In this report, we describe 2 patient cases whose cardiac function worsened dramatically in the presence of underlying endocrinopathies. We report on one Friedreich ataxia teenager with previously undiagnosed diabetes that resulted in diabetic ketoacidosis and rapid progression to severe left ventricular dysfunction. We also describe a Friedreich ataxia teenager whose underlying Graves disease led to rapid worsening of known cardiomyopathy. Cardiac management and treatment for the endocrinopathies returned cardiac function to baseline. We conclude that screening for and awareness of underlying endocrinopathies in Friedreich ataxia may provide novel therapeutic targets for preventing Friedreich ataxia-associated cardiac dysfunction.

Objective: Movement disorders are chronic illnesses that can lead to functional impairment and psychological distress. This study examined the relations between functional impairment, depression, and anxiety in individuals with movement disorders, and whether these associations were mediated by feelings of self-perceived burden., Method: This cross-sectional study sampled individuals (57 males and 57 females; mean age of 62) with chronic movement disorders from a movement disorders clinic. Patients completed measures of depression, anxiety, functional impairment, and self-perceived burden., Results: Functional impairment was associated with depression, but not anxiety, and was mediated by self-perceived burden for individuals with chronic movement disorders., Conclusions: Self-perceived burden may have an important role relative to individuals' adaptation to chronic illness with implications for future interventions., (© 2012 Wiley Periodicals, Inc.)

Objective: To evaluate the efficacy and tolerability of lubiprostone (Amitiza) for constipation in Parkinson disease (PD) in a double-blind, randomized, controlled study., Methods: Patients with PD and clinically meaningful constipation (constipation rating scale score > 10 [range: 0-28]) were recruited from 2 academic movement disorder centers to participate in the study. After enrollment, patients were initially followed for 2 weeks and then were randomly assigned 1:1 to lubiprostone, and the dose was titrated up to 48 μg/day. They returned 4 weeks later for a final assessment. Data included stool diaries and global impressions (co-primary endpoints), demographics, Unified Parkinson's Disease Rating Scale scores, constipation scale scores, visual analog scale (VAS) scores, a stool diary, and adverse events., Results: Fifty-four subjects (39 male, mean age 67.0 ± 10.1 years, and mean duration of PD 8.3 ± 5.4 years) were randomly assigned to lubiprostone or placebo. One patient in the drug group discontinued the study because of logistics, and one patient in the placebo group discontinued the study because of lack of efficacy. A marked or very marked clinical global improvement was reported by 16 of 25 (64.0%) subjects receiving drug vs 5 of 27 (18.5%) subjects receiving placebo (p = 0.001). The constipation rating scale (p < 0.05), VAS (p = 0.001), and stools per day in the diary (p < 0.001) all improved with drug compared with placebo. Adverse events with drug were mild, most commonly intermittent loose stools., Conclusion: In this randomized controlled trial, lubiprostone seemed to be well tolerated and effective for the short-term treatment of constipation in PD.

Objective: The objective of this double-blind, placebo-controlled, randomized study was to evaluate the efficacy of varenicline (Chantix), a partial agonist at α4β2 neuronal nicotinic acetylcholine receptors used for smoking cessation, in patients with spinocerebellar ataxia (SCA) 3., Methods: Patients with genetically confirmed SCA3 were randomly assigned to receive either varenicline (4 weeks for titration and 4 weeks at a dose of 1 mg twice daily) or placebo. Outcome measures included changes in the Scale for the Rating and Assessment of Ataxia (SARA) scores at endpoint (8 weeks) compared with baseline, a timed 25-foot walk and 9-hole peg test, measurements of mood and anxiety, and adverse events., Results: Twenty patients with SCA3 (mean age = 51 ± 10.98 years; mean disease duration = 14 ± 9.82 years; mean SARA score = 16.13 ± 4.67) were enrolled in the study, and data on 18 patients were analyzed in period I. The most common side effect associated with varenicline was nausea. Improvements were noted in the SARA subsections for gait (p = 0.04), stance (p = 0.03), rapid alternating movements (p = 0.003), and timed 25-foot walk (p = 0.05) and Beck Depression Inventory scores (p = 0.03) in patients taking varenicline compared with those taking placebo at endpoint, with a trend toward improvement in the SARA total score (p = 0.06) in the varenicline group., Conclusions: In this controlled study, varenicline significantly improved axial symptoms and rapid alternating movements in patients with SCA3 as measured by SARA subscores and was fairly well tolerated., Classification of Evidence: This study provides Class II evidence that varenicline improved the axial functions of gait, stance, and timed 25-foot walk but did not improve appendicular function, except for rapid alternating movements, in adult patients with genetically confirmed SCA3.