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Background: Clinical trial scenarios can be modeled using data from observational studies, providing critical information for design of real-world trials. The Huntington's Disease Integrated Staging System (HD-ISS) characterizes disease progression over an individual's lifespan and allows for flexibility in the design of trials with the goal of delaying progression. Enrichment methods can be applied to the HD-ISS to identify subgroups requiring smaller estimated sample sizes., Objective: Investigate time to the event of functional decline (HD-ISS Stage 3) as an endpoint for trials in HD and present sample size estimates after enrichment., Methods: We classified individuals from observational studies according to the HD-ISS. We assessed the ability of the prognostic index normed (PIN) and its components to predict time to HD-ISS Stage 3. For enrichment, we formed groups from deciles of the baseline PIN distribution for HD-ISS Stage 2 participants. We selected enrichment subgroups closer to Stage 3 transition and estimated sample sizes, using delay in the transition time as the effect size., Results: In predicting time to HD-ISS Stage 3, PIN outperforms its components. Survival curves for each PIN decile show that groups with PIN from 1.48 to 2.74 have median time to Stage 3 of approximately 2 years and these are combined to create enrichment subgroups. Sample size estimates are presented by enrichment subgroup., Conclusions: PIN is predictive of functional decline. A delay of 9 months or more in the transition to Stage 3 for an enriched sample yields feasible sample size estimates, demonstrating that this approach can aid in planning future trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Minimal clinically important difference (MCID) represents the smallest within-person change on an outcome measure considered meaningful to the patient. Anchor-based MCID methods evaluate the relationship between changes in an outcome measure and the patient-reported clinical importance of that change., Objective: This study aims to estimate longitudinal MCID for clinically relevant outcome measures for individuals who have Stages 2 or 3 disease as measured by the Huntington's Disease Integrated Staging System (HD-ISS)., Methods: Data were drawn from Enroll-HD, a large global longitudinal, observational study and clinical research platform for HD family members. We analyzed HD participants (N = 11,070) by staging group using time frames ranging from 12 to 36 months. The anchor was the physical component summary score of the 12-item short-form health survey. HD-relevant motor, cognitive, and functional outcome measures were independent, external criterion outcomes. Complex analysis was conducted using multiple, independent, linear mixed effect regression models with decomposition to calculate MCID for each external criterion by group., Results: MCID estimates varied by progression stage. MCID estimates increased as stage progression increased and as the time frame increased. MCID values for key HD measures are provided. For example, starting in HD-ISS stage 2, meaningful group change over 24 months equals an average increase of 3.6 or more points on the Unified Huntington's Disease Rating Scale Total Motor Score., Conclusions: This is the first study to examine MCID estimation thresholds for HD. The results can be used to improve clinical interpretation of study outcomes and enable treatment recommendations to support clinical decision-making and clinical trial methodology. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Background: Atrophy in the striatum is a hallmark of Huntington's disease (HD), including the period before clinical motor diagnosis (before-CMD), but it extends to other subcortical structures. The study of the covariation of these structures could improve the detection of disease-related longitudinal progression before-CMD, provide mechanistic insights of the disease, and potentially be used to obtain accurate prospective estimates of atrophy before-CMD and early after-CMD., Methods: We analyzed data from 337 before-CMD individuals, 236 healthy control subjects, and 95 early after-CMD individuals from three studies, and we used nine subcortical regions volumes in two analyses. First, we discriminated before-CMD from healthy control trajectories by integrating volume changes from these regions. Second, we estimated prospective atrophy before-CMD and early after-CMD by considering the influence of a region's present volume over the future volume of another one., Results: Before-CMD progression was robustly detected across studies. Indeed, detection of before-CMD progression improved when multiple structures were integrated, as opposed to analyzing the striatum alone, likely because of the reduced partial correlation between caudate and thalamic volume change before-CMD. Our multivariate atrophy prediction model found a thalamus-caudate association that is consistent with this pattern, which yields an improved caudate atrophy prediction in early after-CMD., Conclusions: This study is the first attempt to validate before-CMD multivariate subcortical change detection across studies and to do multivariate prospective atrophy prediction in HD. These models achieve improved performance by detecting a dissociation between caudate and thalamic atrophy trajectories, and they provide a possible mechanistic understanding of the dynamics of HD. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background: Applying machine-learning algorithms to large datasets such as those available in Huntington's disease offers the opportunity to discover hidden patterns, often not discernible to clinical observation., Objectives: To develop and validate a model of Huntington's disease progression using probabilistic machine learning methods., Methods: Longitudinal data encompassing 2079 assessment measures from four observational studies (PREDICT-HD, REGISTRY, TRACK-HD, and Enroll-HD) were integrated and machine-learning methods (Bayesian latent-variable analysis and continuous-time hidden Markov models) were applied to develop a probabilistic model of disease progression. The model was validated using a separate Enroll-HD dataset and compared with existing clinical reference assessments (Unified Huntington's Disease Rating Scale [UHDRS] diagnostic confidence level, total functional capacity, and total motor scores) and CAG-age product., Results: Nine disease states were discovered based on 44 motor, cognitive, and functional measures, which correlated with reference assessments. The validation set included 3158 participants (mean age, 48.4 years) of whom 61.5% had manifest disease. Analysis of transition times showed that "early-disease" states 1 and 2, which occur before motor diagnosis, lasted ~16 years. Increasing numbers of participants had motor onset during "transition" states 3 to 5, which collectively lasted ~10 years, and the "late-disease" states 6 to 9 also lasted ~10 years. The annual probability of conversion from one of the nine identified disease states to the next ranged from 5% to 27%., Conclusions: The natural history of Huntington's disease can be described by nine disease states of increasing severity. The ability to derive characteristics of disease states and probabilities for progression through these states will improve trial design and participant selection. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments., Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers., Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention., Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments., Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: The identification of sensitive biomarkers is essential to validate therapeutics for Huntington disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset to identify a set of imaging markers robust to multicenter variation and to derive upper estimates on sample sizes for clinical trials in HD., Methods: We used 1 postprocessing pipeline to retrospectively analyze T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at 3 time points, from the PREDICT-HD, TRACK-HD, and IMAGE-HD studies. We used mixed effects models to adjust regional brain volumes for covariates, calculate effect sizes, and simulate possible treatment effects in disease-affected anatomical regions. We used our model to estimate the statistical power of possible treatment effects for anatomical regions and clinical markers., Results: We identified a set of common anatomical regions that have similarly large standardized effect sizes (>0.5) between healthy control and premanifest HD (PreHD) groups. These included subcortical, white matter, and cortical regions and nonventricular cerebrospinal fluid (CSF). We also observed a consistent spatial distribution of effect size by region across the whole brain. We found that multicenter studies were necessary to capture treatment effect variance; for a 20% treatment effect, power of >80% was achieved for the caudate (n = 661), pallidum (n = 687), and nonventricular CSF (n = 939), and, crucially, these imaging markers provided greater power than standard clinical markers., Interpretation: Our findings provide the first cross-study validation of structural imaging markers in HD, supporting the use of these measurements as endpoints for both observational studies and clinical trials. ANN NEUROL 2020;87:751-762., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background: Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease., Objectives: To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [ 18 F]MNI-659., Methods: The cross-sectional study (NCT02061722) included 45 Huntington's disease gene-expansion carriers stratified into four disease stages (early and late premanifest and Huntington's disease stages 1 and 2) and 45 age- and sex-matched healthy controls. The primary analysis compared striatal and pallidal phosphodiesterase 10A availability between Huntington's disease gene-expansion carriers and healthy controls as assessed by [ 18 F]MNI-659 binding. We assessed changes in phosphodiesterase 10A expression using several PET methodologies and compared with previously proposed measures of Huntington's disease progression (PET imaging of D 2/3 receptors and anatomical volume loss on MRI). The longitudinal follow-up study (NCT02956148) continued evaluation of phosphodiesterase 10A availability in 35 Huntington's disease gene-expansion carriers at a mean of 18 months from baseline of the cross-sectional study., Results: Primary analyses revealed that phosphodiesterase 10A availability in caudate, putamen, and globus pallidus was significantly lower in Huntington's disease gene-expansion carriers versus healthy controls across all stages. Striatal and pallidal phosphodiesterase 10A availability progressively declined in the premanifest stages and appeared to plateau between stages 1 and 2. The percentage decline of phosphodiesterase 10A availability measured cross-sectionally between Huntington's disease gene-expansion carriers and healthy controls was greater than that demonstrated by D 2/3 receptor availability or volumetric changes. Annualized rates of phosphodiesterase 10A change showed a statistically significant decline between the cross-sectional study and follow-up., Conclusions: [ 18 F]MNI-659 PET imaging is a biologically plausible biomarker of Huntington's disease progression that is more sensitive than the dopamine-receptor and volumetric methods currently used. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Impulse control disorders (ICDs) and related impulsive and compulsive behaviors (together called ICBs) have been increasingly recognized in the context of Parkinson's disease (PD) and treatment. The International Parkinson's and Movement Disorder Society commissioned a task force to assess available clinical screening instruments and rating scales, including their clinimetric properties, make recommendations regarding their utility, and suggest future directions in scale development and validation. The literature was systematically searched for scales measuring a range of reported ICBs in PD. A scale was designated "recommended" if the scale had been employed in PD studies, been used beyond the group that developed it, and had adequate clinimetric data published for PD. Numerous diagnostic screening tools and severity rating scales were identified for a range of ICBs, including compulsive medication use, punding/hobbyism, walkabout, pathological gambling, hypersexuality, compulsive or binge eating, compulsive buying, reckless driving, compulsive exercise, pyromania, trichotillomania, hoarding, kleptomania, intermittent explosive disorder, and internet addiction. For screening across the range of ICBs (except compulsive medication use), the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP) and QUIP-Rating Scale (QUIP-RS) are recommended, and for severity rating across the range of ICBs the QUIP-RS and the Ardouin Scale of Behavior in Parkinson's Disease are recommended. The Scale for Outcomes in Parkinson's Disease-Psychiatric Complications is recommended for rating of hypersexuality and the compulsive behaviors gambling/shopping. Further testing of established scales against gold standard diagnostic criteria is urgently required for all other individual ICBs in PD. © 2019 International Parkinson and Movement Disorder Society © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: To update evidence-based medicine recommendations for treating nonmotor symptoms in Parkinson's disease (PD)., Background: The International Parkinson and Movement Disorder Society Evidence-Based Medicine Committee's recommendations for treatments of PD were first published in 2002, updated in 2011, and now updated again through December 31, 2016., Methods: Level I studies testing pharmacological, surgical, or nonpharmacological interventions for the treatment of nonmotor symptoms in PD were reviewed. Criteria for inclusion and quality scoring were as previously reported. The disorders covered were a range of neuropsychiatric symptoms, autonomic dysfunction, disorders of sleep and wakefulness, pain, fatigue, impaired olfaction, and ophthalmologic dysfunction. Clinical efficacy, implications for clinical practice, and safety conclusions are reported., Results: A total of 37 new studies qualified for review. There were no randomized controlled trials that met inclusion criteria for the treatment of anxiety disorders, rapid eye movement sleep behavior disorder, excessive sweating, impaired olfaction, or ophthalmologic dysfunction. We identified clinically useful or possibly useful interventions for the treatment of depression, apathy, impulse control and related disorders, dementia, psychosis, insomnia, daytime sleepiness, drooling, orthostatic hypotension, gastrointestinal dysfunction, urinary dysfunction, erectile dysfunction, fatigue, and pain. There were no clinically useful interventions identified to treat non-dementia-level cognitive impairment., Conclusions: The evidence base for treating a range of nonmotor symptoms in PD has grown substantially in recent years. However, treatment options overall remain limited given the high prevalence and adverse impact of these disorders, so the development and testing of new treatments for nonmotor symptoms in PD remains a top priority. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: The objective of this review was to update evidence-based medicine recommendations for treating motor symptoms of Parkinson's disease (PD)., Background: The Movement Disorder Society Evidence-Based Medicine Committee recommendations for treatments of PD were first published in 2002 and updated in 2011, and we continued the review to December 31, 2016., Methods: Level I studies of interventions for motor symptoms were reviewed. Criteria for inclusion and quality scoring were as previously reported. Five clinical indications were considered, and conclusions regarding the implications for clinical practice are reported., Results: A total of 143 new studies qualified. There are no clinically useful interventions to prevent/delay disease progression. For monotherapy of early PD, nonergot dopamine agonists, oral levodopa preparations, selegiline, and rasagiline are clinically useful. For adjunct therapy in early/stable PD, nonergot dopamine agonists, rasagiline, and zonisamide are clinically useful. For adjunct therapy in optimized PD for general or specific motor symptoms including gait, rivastigmine is possibly useful and physiotherapy is clinically useful; exercise-based movement strategy training and formalized patterned exercises are possibly useful. There are no new studies and no changes in the conclusions for the prevention/delay of motor complications. For treating motor fluctuations, most nonergot dopamine agonists, pergolide, levodopa ER, levodopa intestinal infusion, entacapone, opicapone, rasagiline, zonisamide, safinamide, and bilateral STN and GPi DBS are clinically useful. For dyskinesia, amantadine, clozapine, and bilateral STN DBS and GPi DBS are clinically useful., Conclusions: The options for treating PD symptoms continues to expand. These recommendations allow the treating physician to determine which intervention to recommend to an individual patient. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than α2δ ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

The compromise of quality of life in Huntington's disease is a major issue, both for individuals with the disease as well as for their caregivers. The International Parkinson and Movement Disorder Society commissioned a review of the use and clinimetric validation status of measures used in Huntington's disease to assess aspects related with quality of life and to make recommendations on their use following standardized criteria. We included both patient-centered measures (patient health-related quality-of-life measures) and caregiver-centered measures (caregiver quality-of-life measures). After conducting a systematic literature search, we included 12 measures of patient health-related quality of life and 2 measures of caregiver quality of life. Regarding patient-centered measures, the Medical Outcomes Study 36-Item Short-Form Health Survey is "recommended" as a generic assessment of health-related quality of life in patients with Huntington's disease. The 12-Item Short Form Health Survey, the Sickness Impact Profile, the 12-item World Health Organization Disability Assessment Schedule, and the Huntington's Disease Health-Related Quality of Life questionnaire are "suggested." No caregiver-centered quality-of-life measure obtained a "recommended" status. The Alzheimer's Carer's Quality of Life Inventory and the Huntington's Disease Quality of Life Battery for Carers are "suggested." Recognizing that the assessment of patient health-related quality of life can be challenging in Huntington's disease, as patients may lack insight and there is insufficient clinimetric testing of these scales, the committee concluded that further validation of currently available health-related quality-of-life measures should be undertaken, namely, those Huntington's disease-specific health-related quality-of-life measures that have recently been reported and used. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Cognitive impairment is one of the main features of Huntington's disease and is present across the disease spectrum. As part of the International Parkinson's Disease and Movement Disorder Society-sponsored project to review all clinical rating scales used in Huntington's disease, a systematic review of the literature was performed to identify cognitive scales used in Huntington's disease and make recommendations for their use. A total of 17 cognitive scales were identified and evaluated. None of the scales met criteria for a "recommended" status. For assessing severity of cognitive dysfunction, the Montreal Cognitive Assessment was "recommended with caveats." The UHDRS Cognitive Assessment, the UHDRS-For Advanced Patients cognitive section, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Frontal Assessment Battery, the Mattis Dementia Rating Scale, the Mini-Mental State Examination, and the Repeatable Battery for the Assessment of Neuropsychological Status were "suggested" for evaluating severity of cognitive impairment. The MoCA was "suggested" as a screening tool for cognitive impairment. The major challenge in the assessment of cognition in Huntington's disease is the lack of a formal definition of dementia and/or mild cognitive impairment in this disease. The committee concluded that there is a need to further validate currently available cognitive scales in Huntington's disease, but that it is premature to recommend the development of new scales. Recently developed Huntington's disease-specific scales, such as the Huntington's Disease-Cognitive Assessment Battery, hold promise but require the completion of more comprehensive clinimetric development. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis and its pathogenesis is associated with the activity of mesenchymal cells (fibroblasts), being essentially characterized by a process of excessive accumulation resulting from the deposition of extracellular matrix components. The aim of this study was to characterize the morphological presentation of chronic and fibrotic lesions in the glomerular, tubular, interstitial, and vascular compartments in feline CKD, as well as the possible participation of myofibroblasts in renal fibrotic processes in this species. Cat kidneys were collected and processed according to the conventional techniques for light microscopy, circular polarization, immunohistochemistry, and electron microscopy. Fibrotic alterations were present in all compartments analyzed. The main findings in the glomerular compartment were different degrees of glomerular sclerosis, synechia formation, Bowman's capsule calcification, in addition to glomerular basement membrane thickening and pericapsular fibrosis. The tubulointerstitial compartment had intense tubular degeneration and the immunostaining in tubular cells for mesenchymal cell markers demonstrated the possibility of mesenchymal epithelial transition and consequent involvement of myofibroblasts in the development of interstitial tubule damage. Infiltration of inflammatory cells, added to vessel thickening and fibrosis, demonstrated the severity and role of inflammation in the development and perpetuation of damage. Thus, we may conclude that fibrotic lesions play a relevant role in feline CKD and the mechanism of perpetuation of these lesions need further elucidation regarding the origin and participation of myofibroblasts and consequent mesenchymal epithelial transition in this species., (© 2017 Wiley Periodicals, Inc.)

Objectives: The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study., Methods: We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs., Results: For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes., Discussion: Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Chronic kidney disease (CKD) is a relevant disease in feline clinic. The tubulointerstitial damage, with collagen deposition and fibrosis, is an important result of this process. The aim of this study was to quantify and correlate the deposition of collagen and severity of interstitial fibrosis (IF) in the kidney from cats in different stages of CKD. Kidney fragments from 10 adult cats with CKD were analyzed and stained by Masson's trichrome (MT) and Picrosirius red (PSR) for circular polarized microscopy. Random quantitative analysis was performed on MT sections to classify the degree of IF, per field area, with and without circular polarization. Statistics correlations were performed by Spearman's (ρ; p < .05). There was a significant correlation of IF quantification with the area of interstitial collagen deposition by polarized PSR (PSRp) (r = .7939, p = .0098) and nonpolarized PSR (PSRn) (r = .7781, p = .0080). There was a positive correlation of serum creatinine (sCr) at different stages of CKD with PSRp (r = .7939, p = .0098), PSRn (r = .8667, p = .0027) and MT (r = .7818, p = .0117). Correlations between the percentage of quantified area was also positive from PSRp to PSRn (r = .9030, p = .0009) and PSRp to MT (r = .7939, p = .0098). The PSRN was also correlated with MT (r = .9273, p = .0001). The correlation with IF and sCr follows the disease evolution and the quantification of collagen by PSR is an excellent tool for analyzing the disease severity at different stages., (© 2016 Wiley Periodicals, Inc.)

Background: Characterizing progression in Huntington's disease is important for study the natural course and selecting appropriate participants for clinical trials., Objectives: The aim was to develop a prognostic index for motor diagnosis in Huntington's disease and examine its predictive performance in external observational studies., Methods: The prediagnosis Neuro-biological Predictors of Huntington's Disease study (N = 945 gene-positive) was used to select a Cox regression model for computing a prognostic index. Cross-validation was used for selecting a model with good internal validity performance using the research sites as natural splits of the data set. Then, the external predictive performance was assessed using prediagnosis data from three additional observational studies, The Cooperative Huntington Observational Research Trial (N = 358), TRACK-HD (N = 118), and REGISTRY (N = 480)., Results: Model selection yielded a prognostic index computed as the weighted combination of the UHDRS total motor score, Symbol Digit Modalities Test, baseline age, and cytosine-adenine-guanine expansion. External predictive performance was very good for the first two of the three studies, with the third being a much more progressed cohort than the other studies. The databases were pooled and a final Cox regression model was estimated. The regression coefficients were scaled to produce the prognostic index for Huntington's disease, and a normed version, which is scaled relative to a 10-year 50% probability of motor diagnosis., Conclusion: The positive results of this comprehensive validity analysis provide evidence that the prognostic index is generally useful for predicting Huntington's disease progression in terms of risk of future motor diagnosis. The variables for the index are routinely collected in ongoing observational studies and the index can be used to identify cohorts for clinical trial recruitment. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Behavioral symptoms are an important feature of Huntington's disease and contribute to impairment in quality of life. The Movement Disorder Society commissioned the assessment of the clinimetric properties of rating scales in Huntington's disease to make recommendations regarding their use, following previously used standardized criteria. A systematic literature search was conducted to identify the scales used to assess behavioral symptoms in Huntington's disease. For the purpose of this review, 7 behavioral domains were deemed significant in Huntington's disease: irritability, anxiety, depression, apathy, obsessive-compulsive behaviors, psychosis, and suicidal ideation. We included a total of 27 behavioral rating scales, 19 of which were of a single behavioral domain and the remaining 8 scales included multiple behavioral domains. Three rating scales were classified as "recommended" exclusively for screening purposes: the Irritability Scale for irritability, the Beck Depression Inventory-II, and the Hospital Anxiety and Depression Scale for depression. There were no "recommended" scales for other purposes such as diagnosis, severity, or change in time or to treatment. The main challenges identified for assessment of behavioral symptoms in Huntington's disease are the co-occurrence of multiple behavioral symptoms, the particular features of a behavioral symptom in Huntington's disease, and the need to address stage- and disease-specific features, including cognitive impairment and lack of insight. The committee concluded that there is a need to further validate currently available behavioral rating scales in Huntington's disease to address gaps in scale validation for specific behavioral domains and purpose of use. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Since the identification of the Huntington's disease (HD) gene, knowledge has accumulated about mechanisms directly or indirectly affected by the mutated Huntingtin protein. Transgenic and knock-in animal models of HD facilitate the preclinical evaluation of these targets. Several treatment approaches with varying, but growing, preclinical evidence have been translated into clinical trials. We review major landmarks in clinical development and report on the main clinical trials that are ongoing or have been recently completed. We also review clinical trial settings and designs that influence drug-development decisions, particularly given that HD is an orphan disease. In addition, we provide a critical analysis of the evolution of the methodology of HD clinical trials to identify trends toward new processes and endpoints. Biomarker studies, such as TRACK-HD and PREDICT-HD, have generated evidence for the potential usefulness of novel outcome measures for HD clinical trials, such as volumetric imaging, quantitative motor (Q-Motor) measures, and novel cognitive endpoints. All of these endpoints are currently applied in ongoing clinical trials, which will provide insight into their reliability, sensitivity, and validity, and their use may expedite proof-of-concept studies. We also outline the specific opportunities that could provide a framework for a successful avenue toward identifying and efficiently testing and translating novel mechanisms of action in the HD field., (© 2014 International Parkinson and Movement Disorder Society.)

Cognitive dysfunction is central to Huntington's disease (HD) and undermines quality of life. Clinical trials are now targeting cognitive outcomes in HD; however, no cognitive battery has been optimized for HD clinical trials. We evaluated 16 cognitive tests in a 20-site, five-country, observational study designed to mimic aspects of a clinical trial (e.g., data collection managed by a contract research organization, repeated testing, prespecified statistical analyses). Fifty-five early HD, 103 premanifest HD (pre-HD), and 105 controls were tested at visit 1, visit 2 (1-3 days later), and visit 3 (5-7 weeks after visit 1). For inclusion in a recommended battery, tests were evaluated for sensitivity, practice effects, reliability, domain coverage, feasibility, and tolerability. Most tests differentiated controls from pre-HD and early HD and showed excellent psychometric properties. We selected six tests to constitute the Huntington's Disease Cognitive Assessment Battery (HD-CAB): Symbol Digit Modalities Test, Paced Tapping, One Touch Stockings of Cambridge (abbreviated), Emotion Recognition, Trail Making B, and the Hopkins Verbal Learning Test. These tests demonstrated sensitivity to disease status (Cohen's d effect sizes: early HD= -1.38 to -1.90 and pre-HD= -0.41 to -0.78), and acceptable reliability (r's 0.73-0.93). A composite score yielded large effect sizes (early HD = -2.44 and pre-HD = -0.87) and high reliability (r = 0.95). HD-CAB is the first cognitive battery designed specifically for use in late premanifest and early HD clinical trials. Adoption of the HD-CAB will facilitate evaluation of treatments to improve cognition in HD., (© 2014 International Parkinson and Movement Disorder Society.)

Health economic studies in Parkinson's disease (PD) have become increasingly common in recent years. Because several methodologies and instruments have been used to assess cost and outcomes in PD, the Movement Disorder Society (MDS) commissioned a Task Force to assess their properties and make recommendations regarding their use. A systematic literature review was conducted to explore the use of those instruments in PD and to determine which should be selected for this review. We assessed approaches to evaluate cost of illness (COI), cost effectiveness, and cost utilities, which include the use of direct (standard gamble, time trade-off. and visual analogue scales) and indirect instruments to measure health status and utilities. No validated instruments/models were identified for the evaluation of COI or cost-effectiveness in patients with PD; therefore, no instruments in this group are recommended. Among utility instruments, only a few of these outcome instruments have been used in the PD population, and only limited psychometric data are available for these instruments with respect to PD. Because psychometric data for further utility instruments in conditions other than PD already exist, the standard gamble and time trade-off methods and the EQ-5D (a European quality-of-life health states instrument) and Health Utility Index instruments met the criteria for scales that are "recommended (with limitations)," but only the EQ-5D has been assessed in detail in PD patients. The MDS Task Force recommends further study of these instruments in the PD population to establish core psychometric properties. For the assessment of COI, the Task Force considers the development of a COI instrument specifically for PD, like that available for Alzheimer's disease., (© 2013 Movement Disorder Society.)

The Movement Disorder Society established a task force to review rating scales for the assessment of tremor. Screening instruments used in identifying patients with tremor were also reviewed. Seven tremor severity scales, six activities of daily living (ADL)/disability scales, four quality-of-life scales, and five screening instruments were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and sensitivity to change were reviewed for each scale; and each scale was classified as recommended, suggested or listed based on whether 3, 2, or 1 of the following criteria were met: (1) used in the assessment of tremor (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no). Five tremor severity scales (the Fahn-Tolosa-Marin Tremor Rating Scale, the Bain and Findley Clinical Tremor Rating Scale, the Bain and Findley Spirography Scale, the Washington Heights-Inwood Genetic Study of Essential Tremor Rating Scale, and the Tremor Research Group Essential Tremor Rating Assessment Scale), one ADL/disability scale (the Bain and Findley Tremor ADL Scale), one quality-of-life scale (the Quality of Life in Essential Tremor Questionnaire), and one screening instrument (the Washington Heights-Inwood Genetic Study of Essential Tremor Rating Scale, version 1) are recommended using these criteria. However, all scales need a more comprehensive analysis of sensitivity to change in order to judge their utility in clinical trials and individual patient assessments. The task force recommends that further work with existing recommended scales be performed as opposed to the development of new tremor scales., (© 2013 International Parkinson and Movement Disorder Society.)

Background: The Unified Multiple System Atrophy Rating Scale (UMSARS) was developed to provide a surrogate measure of disease progression in multiple system atrophy. In the present study, the intrarater agreement of the motor examination part of the UMSARS was determined., Methods: All patients were first examined face to face, while being video-recorded, by two senior and two junior investigators. The patients' videotaped examinations were reevaluated after 3 months. Intrarater reliability for each item was analyzed by kappa statistics., Results: Overall weighted kappa (κ) values were at least substantial or excellent for all UMSARS motor examination items, except for ocular motor dysfunction, which showed only moderate intrarater agreement. Intrarater reliability was comparable between senior and junior raters, with all κ differences being ≤ 0.22., Conclusions: The motor examination part of the UMSARS was found to have satisfactory intrarater reliability in the present cohort., (Copyright © 2012 Movement Disorder Society.)

Health-related quality of life is an important patient-reported outcome used in intervention trials and for monitoring the consequences of health status on physical, mental, and social domains. Parkinson's disease is a complex disorder that strongly affects patients' quality of life. Several health-related quality of life tools have been used in Parkinson's disease. A Movement Disorder Society Task Force was commissioned to rate the psychometric quality of available health-related quality of life scales as applied to Parkinson's disease. Following the methodology adopted by previous work of the Movement Disorder Society Task Force, a review of generic and specific health-related quality of life scales applied in studies on Parkinson's disease was completed. Considering the scales from 3 perspectives-use in Parkinson's disease, use by multiple research groups, and clinimetric properties-a final classification as "recommended," "suggested," or "listed" was applied to each reviewed instrument. Four generic scales (EuroQoL, Nottingham Health Profile, 36-Item Short-Form Health Survey, and Sickness Impact Profile) and 5 specific scales (39-Item Parkinson's Disease Questionnaire, Parkinson's Disease Questionnaire Short Form, Parkinson's Disease Quality of Life Questionnaire, Parkinson's Impact Scale, and Scales for Outcomes in Parkinson's Disease-Psychosocial) reached the level of "recommended." The 39-item Parkinson's Disease Questionnaire is the most thoroughly tested and applied questionnaire. Three other generic measures (Quality of Life Questionnaire 15D, Schedule for the Evaluation of Individual Quality of Life-Direct Weighting, and World Health Organization Quality of Life Assessment Short Version) and the specific Parkinson's Disease Quality of Life Scale are "suggested." With a little additional effort in completing the stipulated requirements, they could reach the "recommended" level. At present there is a wide variety of health-related quality of life measures for application in the Parkinson's disease setting, and the task force does not recommend the development of a new scale. Selection of the most appropriate instrument for a particular objective requires consideration of the characteristics of each scale and the goals of the assessment., (Copyright © 2011 Movement Disorder Society.)

The Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM) Review of Treatments for Parkinson's Disease (PD) was first published in 2002 and was updated in 2005 to cover clinical trial data up to January 2004 with the focus on motor symptoms of PD. In this revised version the MDS task force decided it was necessary to extend the review to non-motor symptoms. The objective of this work was to update previous EBM reviews on treatments for PD with a focus on non-motor symptoms. Level-I (randomized controlled trial, RCT) reports of pharmacological and nonpharmacological interventions for the non-motor symptoms of PD, published as full articles in English between January 2002 and December 2010 were reviewed. Criteria for inclusion and ranking followed the original program outline and adhered to EBM methodology. For efficacy conclusions, treatments were designated: efficacious, likely efficacious, unlikely efficacious, non-efficacious, or insufficient evidence. Safety data were catalogued and reviewed. Based on the combined efficacy and safety assessment, Implications for clinical practice were determined using the following designations: clinically useful, possibly useful, investigational, unlikely useful, and not useful. Fifty-four new studies qualified for efficacy review while several other studies covered safety issues. Updated and new efficacy conclusions were made for all indications. The treatments that are efficacious for the management of the different non-motor symptoms are as follows: pramipexole for the treatment of depressive symptoms, clozapine for the treatment of psychosis, rivastigmine for the treatment of dementia, and botulinum toxin A (BTX-A) and BTX-B as well as glycopyrrolate for the treatment of sialorrhea. The practical implications for these treatments, except for glycopyrrolate, are that they are clinically useful. Since there is insufficient evidence of glycopyrrolate for the treatment of sialorrhea exceeding 1 week, the practice implication is that it is possibly useful. The treatments that are likely efficacious for the management of the different non-motor symptoms are as follows: the tricyclic antidepressants nortriptyline and desipramine for the treatment of depression or depressive symptoms and macrogol for the treatment of constipation. The practice implications for these treatments are possibly useful. For most of the other interventions there is insufficient evidence to make adequate conclusions on their efficacy. This includes the tricyclic antidepressant amitriptyline, all selective serotonin reuptake inhibitors (SSRIs) reviewed (paroxetine, citalopram, sertraline, and fluoxetine), the newer antidepressants atomoxetine and nefazodone, pergolide, Ω-3 fatty acids as well as repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression or depressive symptoms; methylphenidate and modafinil for the treatment of fatigue; amantadine for the treatment of pathological gambling; donepezil, galantamine, and memantine for the treatment of dementia; quetiapine for the treatment of psychosis; fludrocortisone and domperidone for the treatment of orthostatic hypotension; sildenafil for the treatment of erectile dysfunction, ipratropium bromide spray for the treatment of sialorrhea; levodopa/carbidopa controlled release (CR), pergolide, eszopiclone, melatonin 3 to 5 mg and melatonin 50 mg for the treatment of insomnia and modafinil for the treatment of excessive daytime sleepiness. Due to safety issues the practice implication is that pergolide and nefazodone are not useful for the above-mentioned indications. Due to safety issues, olanzapine remains not useful for the treatment of psychosis. As none of the studies exceeded a duration of 6 months, the recommendations given are for the short-term management of the different non-motor symptoms. There were no RCTs that met inclusion criteria for the treatment of anxiety disorders, apathy, medication-related impulse control disorders and related behaviors other than pathological gambling, rapid eye movement (REM) sleep behavior disorder (RBD), sweating, or urinary dysfunction. Therefore, there is insufficient evidence for the treatment of these indications. This EBM review of interventions for the non-motor symptoms of PD updates the field, but, because several RCTs are ongoing, a continual updating process is needed. Several interventions and indications still lack good quality evidence, and these gaps offer an opportunity for ongoing research. © 2011 Movement Disorder Society., (Copyright © 2011 Movement Disorder Society.)

The objective was to update previous evidence-based medicine reviews of treatments for motor symptoms of Parkinson's disease published between 2002 and 2005. Level I (randomized, controlled trial) reports of pharmacological, surgical, and nonpharmacological interventions for the motor symptoms of Parkinson's disease between January 2004 (2001 for nonpharmacological) and December 2010 were reviewed. Criteria for inclusion, clinical indications, ranking, efficacy conclusions, safety, and implications for clinical practice followed the original program outline and adhered to evidence-based medicine methodology. Sixty-eight new studies qualified for review. Piribedil, pramipexole, pramipexole extended release, ropinirole, rotigotine, cabergoline, and pergolide were all efficacious as symptomatic monotherapy; ropinirole prolonged release was likely efficacious. All were efficacious as a symptomatic adjunct except pramipexole extended release, for which there is insufficient evidence. For prevention/delay of motor fluctuations, pramipexole and cabergoline were efficacious, and for prevention/delay of dyskinesia, pramipexole, ropinirole, ropinirole prolonged release, and cabergoline were all efficacious, whereas pergolide was likely efficacious. Duodenal infusion of levodopa was likely efficacious in the treatment of motor complications, but the practice implication is investigational. Entacapone was nonefficacious as a symptomatic adjunct to levodopa in nonfluctuating patients and nonefficacious in the prevention/delay of motor complications. Rasagiline conclusions were revised to efficacious as a symptomatic adjunct, and as treatment for motor fluctuations. Clozapine was efficacious in dyskinesia, but because of safety issues, the practice implication is possibly useful. Bilateral subthalamic nucleus deep brain stimulation, bilateral globus pallidus stimulation, and unilateral pallidotomy were updated to efficacious for motor complications. Physical therapy was revised to likely efficacious as symptomatic adjunct therapy. This evidence-based medicine review updates the field and highlights gaps for research., (Copyright © 2011 Movement Disorder Society.)

Wearing-off occurs in the majority of patients with Parkinson's disease after a few years of dopaminergic therapy. Because a variety of scales have been used to estimate wearing-off, the Movement Disorder Society commissioned a task force to assess their clinimetric properties. A systematic review was conducted to identify wearing-off scales that have either been validated or used in Parkinson's patients. A scale was designated "Recommended" if it had been used in clinical studies beyond the group that developed it, if it had been specifically used in Parkinson's disease reports, and if clinimetric studies had established that it is valid, reliable, and sensitive. "Suggested" scales met 2 of the above criteria, and those meeting 1 were "Listed." We identified 3 diagnostic and 4 severity rating scales for wearing-off quantification. Two questionnaires met the criteria to be Recommended for diagnostic screening (questionnaires for 19 and 9 items), and 1 was Suggested (questionnaire for 32 items). Only the patient diaries were Recommended to assess wearing-off severity, with the caveat of relatively limited knowledge of validity. Among the other severity assessment tools, the Unified Parkinson Disease Rating Scale version 3 and the version revised from the Movement Disorders Society were classified as Suggested, whereas the Treatment Response Scale was Listed., (Copyright © 2011 Movement Disorder Society.)

Orthostatic hypotension is defined as a blood pressure fall of > 20 mm Hg systolic and/or 10 mm Hg diastolic within 3 minutes of an upright position. The Movement Disorders Society commissioned a task force to assess existing clinical rating scales addressing symptoms of orthostatic hypotension in Parkinson's disease. Seven neurologists and a clinimetrician assessed each scale's previous use and critiqued its clinimetric properties. A scale was "recommended" if it had been applied to populations of patients with Parkinson's disease, with data on its use in studies beyond the group that developed the scale, and was found to be clinimetrically valid. A scale was considered "suggested" if it had been applied to Parkinson's disease, but only 1 of the other criteria was applied. A scale was "listed" if it met only 1 criterion. Symptoms of orthostatic hypotension are generally assessed in scales on wider autonomic or nonmotor symptoms. Some scales designed to detect orthostatic hypotension-related symptoms provide information on their severity: the AUTonomic SCale for Outcomes in PArkinson's Disease and the COMPosite Autonomic Symptom Scale met criteria for recommended with some limitations; the Novel Non-Motor Symptoms Scale and the Orthostatic Grading Scale were classified as suggested. The Self-completed Non-Motor Symptoms Questionnaire for Parkinson's Disease was classified as suggested as a tool for screening orthostatic symptoms. However, these and the listed scales need further validation and application before they can be recommended for clinical use in patients with Parkinson's disease., (Copyright © 2011 Movement Disorder Society.)

This report presents the results of 2 randomized trials-Rembrandt and Vermeer-on the efficacy and safety of pardoprunox in patients with early Parkinson's disease. Patients with Parkinson's disease with a Unified Parkinson's Disease Rating Scale-Motor score ≥ 10 and modified Hoehn and Yahr stage ≤ 3 were randomized to pardoprunox (fixed doses of 6 mg/day [n = 115] or 12 mg/day [n = 118] or a flexible-dose range of 12-42 mg/day [n = 116]) or placebo (n = 119) in Rembrandt and pardoprunox 12-42 mg/day (n = 108), pramipexole 1.5-4.5 mg/day (n = 116), or placebo (n = 110) in Vermeer. Pardoprunox showed a significant benefit over placebo in the primary efficacy variable, least-square mean change from baseline in Unified Parkinson's Disease Rating Scale-Motor score: Rembrandt-fixed doses of 6 and 12 mg/day, -6.0 and -4.7 points, respectively; flexible-dose 12-42 mg/day, -5.5 points; placebo, -2.9 points; Vermeer-flexible-dose 12-42 mg/day, -4.9 points; placebo, -2.5 points; pramipexole, -5.7 points. No minimum effective dose was established. Secondary efficacy parameters supported the results of the primary efficacy variable. Pardoprunox tolerability was dose related: flexible-dose 12-42 mg/day showed the highest dropout rate due to treatment-emergent adverse events (Rembrandt, 56.0%; Vermeer, 46.3%) and overall incidence of treatment-emergent adverse events (Rembrandt, 97.4%; Vermeer, 92.6%), primarily due to nausea, somnolence, and dizziness. Because pardoprunox showed similar efficacy across all dose groups, these observations suggest that the 12-42 mg/day dose range was higher than therapeutically required. Furthermore, the early onset of treatment-emergent adverse events and dropouts observed for pardoprunox suggest that titration was too rapid. Pardoprunox significantly improved motor symptoms in patients with early Parkinson's disease, but further investigation into the dose and titration schedule is required to improve tolerability., (Copyright © 2010 Movement Disorder Society.)

There is a broad spectrum of sleep disturbances observed in Parkinson's disease (PD). A variety of scales have been applied to the evaluation of PD sleep and wakefulness, but only a small number have been assessed specifically for clinimetric properties in the PD population. The movement disorder society has commissioned this task force to examine these scales and to assess their use in PD. A systematic literature review was conducted to explore the use of sleep scales in PD and to determine which scales qualified for a detailed critique. The task force members, all of whom have extensive experience in assessing sleep in PD reviewed each of the scales using a structured proforma. Scales were categorized into recommended, suggested and listed according to predefined criteria. A total of 48 potential scales were identified from the search and reviewed. Twenty-nine were excluded because they did not meet review criteria or were variations of scales already included, leaving 19 scales that were critiqued and rated by the task force based on the rating criteria. Only six were found to meet criteria for recommendation or suggestion by the task force: the PD sleep scale (PDSS) and the Pittsburgh sleep quality index (PSQI) are recommended for rating overall sleep problems to screen and to measure severity, the SCOPA-sleep (SCOPA) is recommended for rating overall sleep problems both to screen and to measure severity, and for rating daytime sleepiness; the Epworth sleepiness scale (ESS) is recommended for rating daytime sleepiness to screen and to measure severity; the inappropriate sleep composite score (ISCS) is suggested for rating severe daytime sleepiness or sleep attacks to screen and to measure severity; and the Stanford sleepiness scale (SSS) is suggested for rating sleepiness and to measure severity at a specific moment. The task force does not recommend the development of new scales, but emphasizes the need for educational efforts to train physicians in sleep interview techniques and polysomnography., (© 2010 Movement Disorder Society.)

Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like α-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas., (© 2010 Movement Disorder Society.)

Drug-induced dyskinesia is a common phenomenon in Parkinson's disease (PD) and is often socially as well as physically disabling for patients. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. A task force composed six clinical researchers who systematically searched the literature for scales measuring dyskinesia in PD, evaluated the scales' previous use, performance parameters, and quality of validation data (if available). A scale was designated "Recommended" if the scale has been used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and if clinimetric studies have established that it is a valid, reliable, and sensitive. "Suggested" scales met two of the above criteria and those meeting one were "Listed." Based on the systematic review, eight rating scales for dyskinesia that have either been validated or used in PD were identified. These were the Abnormal Involuntary Movement Scale (AIMS), The Unified Parkinson's Disease Rating Scale (UPDRS) part IV, the Obeso Dyskinesia Rating Scale, the Rush Dyskinesia Rating Scale, the Clinical Dyskinesia Rating Scale (CDRS), the Lang-Fahn Activities of Daily Living Dyskinesia Scale, the Parkinson Disease Dyskinesia Scale (PDYS-26), and the Unified Dyskinesia Rating Scale (UDysRS). Based on this review, at present two of the reviewed dyskinesia scales (AIMS and the Rush Dyskinesia Rating Scale) fulfill criteria for Recommended for use in PD populations, albeit weakly so; all of the remaining met criteria to be Suggested. However, the two most recent scales (PDYS-26 and UDysRS) have excellent clinimetric properties and appear to provide a reliable and valid assessment tool of dyskinesia in PD. If they are used successfully beyond the groups that developed them, both have the potential to be re-ranked as Recommended. As further testing of these scales in PD is warranted, no new scales are needed until the available scales are fully tested clinimetrically.

In the 1990 s, previous knowledge and randomized controlled trials supported the establishment of today's therapeutic recommendations in Parkinson's disease (PD). Scientific evidence allows different options for the treatment of PD. Patterns of use of antiparkinsonian agents (APA) across European countries may thus reflect these options. We wanted to describe patterns of use of APA in Europe and characterize the changes in prescription habits between 2003 and 2007. We investigated APA outpatient sales in 26 European countries where all commercially available APA were studied. Data for molecules and brand names were collected through IMS Health. Treatment per 1000 inhabitants daily (DID) was obtained from the WHO defined daily dose. Prescription pattern changes were evaluated by market share. Prescription patterns varied widely. In most countries, levodopa/dopamine agonists accounted for half of the drug use; whereas in others, anticholinergics, MAO inhibitors and amantadine prevailed. The greatest increase occurred with monoamine oxidase inhibitors and levodopa. There was an increase in dopamine agonists and a decrease in anticholinergics. For a 6.8% dose consume increase, there was a 41.1% sales increase (in euro). We showed an increase in the consumption of APA over 5 years. There was significant heterogeneity in the use of APA in Europe, suggesting differences in drug treatment. Costs of medication increased more than did dose consume, implying an increase in the cost of individual patient treatment. Published evidence does not explain the observed differences in the prescribing of APA., ((c) 2010 Movement Disorder Society.)

Fatigue has been shown to be a consistent and common problem in Parkinson's disease (PD) in multiple countries and cultures. It is one of the most disabling of all symptoms, including motor dysfunction, and appears early, often predating the onset of motor symptoms. Several studies of the epidemiology of fatigue have been published, often using different scales, but few on treatment. The Movement Disorder Society (MDS) commissioned a task force to assess available clinical rating scales, critique their psychometric properties, summarize their clinical properties, and evaluate the evidence in support of their use in clinical studies in PD. Six clinical researchers reviewed all studies published in peer reviewed journals of fatigue in PD, evaluated the scales' previous use, performance parameters, and quality of validation data, if available. Scales were rated according to criteria provided by the MDS. A scale was "recommended" if it has been used in clinical studies beyond the group that developed it, has been used in PD and psychometric studies have established that it is a valid, reliable and sensitive to change in people with PD. Requiring a scale to have demonstrated sensitivity to change in PD specifically rather than in other areas in order to attain a rating of "recommended" differs from the use of this term in previous MDS task force scale reviews. "Suggested" scales failed to meet all the criteria of a "recommended" scale, usually the criterion of sensitivity to change in a study of PD. Scales were "listed" if they had been used in PD studies but had little or no psychometric data to assess. Some scales could be used both to screen for fatigue as well as to assess fatigue severity, but some were only used to assess severity. The Fatigue Severity Scale was "recommended" for both screening and severity rating. The Fatigue Assessment Inventory, an expanded version of the Fatigue severity Scale, is "suggested" for both screening and severity. The Functional Assessment of Chronic Illness Therapy-Fatigue was "recommended" for screening and "suggested" for severity. The Multidimensional Fatigue Inventory was "suggested" for screening and "recommended" for severity. The Parkinson Fatigue Scale was "recommended" for screening and "suggested" for severity rating. The Fatigue Severity Inventory was "listed" for both screening and severity. The Fatigue Impact Scale for Daily Use, an adaptation of the Fatigue Impact Scale was "listed" for screening and "suggested" for severity. Visual Analogue and Global Impression Scales are both "listed" for screening and severity. The committee concluded that current scales are adequate for fatigue studies in PD but that studies on sensitivity and specificity of the scales are still needed., ((c) 2010 Movement Disorder Society.)

This study examined the efficacy and safety of the partial dopamine agonist, pardoprunox (SLV308), in the treatment of patients with early Parkinson's disease (PD). Patients were randomized to receive pardoprunox (n = 69) or placebo (n = 70). Pardoprunox was titrated to each patient's optimal dose (9-45 mg/d) over 2 to 6 weeks and then maintained at this dose for a further 3 weeks. Concomitant anti-Parkinson treatment was not permitted. In the primary analysis, Unified PD Rating Scale (UPDRS)-Motor score was improved in pardoprunox-treated patients (overall mean dose 23.8 mg/d; -7.3 points), as compared with placebo (-3.0 points; P = 0.0001), from baseline to end point. At end point, there were more responders (> or = 30% reduction in UPDRS-Motor score) in the pardoprunox group (50.7%) than in the placebo group (15.7%; P < 0.0001). In other secondary analyses, UPDRS-activities of daily living (ADL) and -ADL+Motor scores were also significantly more improved in the pardoprunox group. Nausea was reported by 32 of 68 (47.1%) pardoprunox-treated patients (vs. 3/70, 4.3%, placebo-treated patients), with dizziness, somnolence, headache, and asthenia also reported by > or = 10 patients. In this exploratory proof-of-concept study, pardoprunox significantly improved motor function in patients with early PD. The efficacy and safety profile of pardoprunox justifies its further investigation in PD., (2010 Movement Disorder Society)

The report of an increased frequency of melanoma during the clinical development of rasagiline prompted a renewed interest in a possible association between skin cancer and Parkinson's disease (PD). The evaluation of this risk ended in a recommendation to perform a periodic dermatological examination as a follow-up measure of their treatment. The recognition of this safety concern lead to the need to clarify if the risk of skin cancer is indeed associated with PD and if levodopa or other anti-parkinsonian drugs might contribute to increase such risk. To answer these questions, we critically reviewed all clinical studies available concerning the association between skin cancer and PD. We found 26 studies on cancer occurrence in PD. The best data available suggest the risk of cancer is reduced in PD patients. However, specific cancers like thyroid and the female breast were reported at higher-than-expected rates. Additionally, it was suggested that PD patients have a higher frequency of melanoma and non-melanoma skin cancers than the general population. The data on non-melanoma skin cancer are less robust than the data on melanoma. Causal factors remain unknown. Due to the weak association between skin cancer and PD, no robust recommendation can be made regarding the need for periodic dermatological screening., ((c) 2010 Movement Disorder Society.)

Upper and lower gastrointestinal dysautonomia symptoms (GIDS)--sialorrhea, dysphagia, and constipation are common in Parkinson's disease (PD) and often socially as well as physically disabling for patients. Available invasive quantitative measures for assessing these symptoms and their response to therapy are time-consuming, require specialized equipment, can cause patient discomfort and present patients with risk. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. Six clinical researchers and a biostatistician systematically searched the literature for scales of sialorrhea, dysphagia, and constipation, evaluated the scales' previous use, performance parameters, and quality of validation data (if available). A scale was designated "Recommended" if the scale was used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and clinimetric studies have established that it is a valid, reliable, and sensitive. "Suggested" scales met at least part of the above criteria, but fell short of meeting all. Based on the systematic review, scales for individual symptoms of sialorrhea, dysphagia, and constipation were identified along with three global scales that include these symptoms in the context of assessing dysautonomia or nonmotor symptoms. Three sialorrhea scales met criteria for Suggested: Drooling Severity and Frequency Scale (DSFS), Drooling Rating Scale, and Sialorrhea Clinical Scale for PD (SCS-PD). Two dysphagia scales, the Swallowing Disturbance Questionnaire (SDQ) and Dysphagia-Specific Quality of Life (SWAL-QOL), met criteria for Suggested. Although Rome III constipation module is widely accepted in the gastroenterology community, and the earlier version from the Rome II criteria has been used in a single study of PD patients, neither met criteria for Suggested or Recommended. Among the global scales, the Scales for Outcomes in PD-Autonomic (SCOPA-AUT) and Nonmotor Symptoms Questionnaire for PD (NMSQuest) both met criteria for Recommended, and the Nonmotor Symptoms Scale (NMSS) met criteria for Suggested; however, none specifically focuses on the target gastrointestinal symptoms (sialorrhea, dysphagia, and constipation) of this report. A very small number of rating scales have been applied to studies of gastrointestinal-related dysautonomia in PD. Only two scales met "Recommended" criteria and neither focuses specifically on the symptoms of sialorrhea, dysphagia, and constipation. Further scale testing in PD among the scales that focus on these symptoms is warranted, and no new scales are needed until the available scales are fully tested clinimetrically.

Only in the last three decades, the restless legs syndrome (RLS) has been examined in randomized controlled trials. The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of the medical literature on treatment modalities used to manage patients with RLS. The task force performed a search of the published literature using electronic databases. The therapeutic efficacy of each drug was classified as being either efficacious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify. Implications for clinical practice were generated based on the levels of evidence and particular features of each modality, such as adverse events. All studies were classed according to three levels of evidence. All Level-I trials were included in the efficacy tables; if no Level-I trials were available then Level-II trials were included or, in the absence of Level-II trials, Level-III studies or case series were included. Only studies published in print or online before December 31, 2006 were included. All studies published after 1996, which attempted to assess RLS augmentation, were reviewed in a separate section. The following drugs are considered efficacious for the treatment of RLS: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Drugs considered likely efficacious are rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine. Drugs that are considered investigational are dihydroergocriptine, lisuride, methadone, tramadol, clonazepam, zolpidem, amantadine, and topiramate. Magnesium, folic acid, and exercise are also considered to be investigational. Sumanirole is nonefficacious. Intravenous iron dextran is likely efficacious for the treatment of RLS secondary to end-stage renal disease and investigational in RLS subjects with normal renal function. The efficacy of oral iron is considered investigational; however, its efficacy appears to depend on the iron status of subjects. Cabergoline and pergolide (and possibly lisuride) require special monitoring due to fibrotic complications including cardiac valvulopathy. Special monitoring is required for several other medications based on clinical concerns: opioids (including, but not limited to, oxycodone, methadone and tramadol), due to possible addiction and respiratory depression, and some anticonvulsants (particularly, carbamazepine and valproic acid), due to systemic toxicities., ((c) 2008 Movement Disorder Society.)