Multiple System Atrophy Rating Scale Research Articles

Altered Brain Volume, Microstructure Metrics and Functional Connectivity Features in Multiple System Atrophy.

In order to deeply understand the specific patterns of volume, microstructure, and functional changes in Multiple System Atrophy patients with cerebellar ataxia syndrome (MSA-c), we perform the current study by simultaneously applying structural (T1-weighted imaging), Diffusion tensor imaging (DTI), functional (BOLD fMRI) and extended Network-Based Statistics (extended-NBS) analysis. Twenty-nine MSA-c type patients and twenty-seven healthy controls (HCs) were involved in this study. First, we analyzed the whole brain changes of volume, microstructure, and functional connectivity (FC) in MSA-c patients. Then, we explored the correlations between significant multimodal MRI features and the total Unified Multiple System Atrophy Rating Scale (UMSARS) scores. Finally, we searched for sensitive imaging biomarkers for the diagnosis of MSA-c using support vector machine (SVM) classifier. Results showed significant grey matter atrophy in cerebellum and white matter microstructural abnormalities in cerebellum, left fusiform gyrus, right precentral gyrus and lingual gyrus. Extended-NBS analysis found two significant different connected components, featuring altered functional connectivity related to left and right cerebellar sub-regions, respectively. Moreover, the reduced fiber bundle counts at right Cerebellum_3 (Cbe3) and decreased fractional anisotropy (FA) values at bilateral Cbe9 were negatively associated with total UMSARS scores. Finally, the significant features at left Cbe9, Cbe1, and Cbe7b were found to be useful as sensitive biomarkers to differentiate MSA-c from HCs according to the SVM analysis. These findings advanced our understanding of the neural pathophysiological mechanisms of MSA from the perspective of multimodal neuroimaging.

Sensitivity to Change and Patient-Centricity of the Unified Multiple System Atrophy Rating Scale Items: A Data-Driven Analysis.

BackgroundThe Unified Multiple System Atrophy Rating Scale (UMSARS) is a commonly used semiquantitative rating scale to assess symptoms and measure disease progression in multiple system atrophy (MSA). However, it is currently incompletely understood which UMSARS items are the most sensitive to change and most relevant to the patient.ObjectiveThe objective of this study was to assess sensitivity to change and patient‐centricity of single UMSARS items.MethodsData were taken from the European Multiple System Atrophy Study Group Natural History Study and the Rasagiline for Multiple System Atrophy trial. Sensitivity of change of an item of the UMSARS was assessed by calculation of a sensitivity‐to‐change ratio using its mean slope of progression divided by the standard deviation of the slope when modeling its progression over time. Patient‐centricity was assessed through correlation of UMSARS items with quality‐of‐life measures.ResultsProgression rates above the mean in at least one of the two studies examined here were seen for seven items of UMSARS I and 11 items of UMSARS II. These items related to key motor functions such as swallowing, speech, handwriting, cutting food, hygiene, and dressing or walking, whereas items related to autonomic dysfunction were generally less sensitive to change in either data set. More UMSARS I items were identified as patient‐centric compared with UMSARS II items, and items most strongly impacting patients' quality of life were those affecting verbal communication skills, personal hygiene, and walking.ConclusionThe present results illustrate the potential to optimize the UMSARS to enhance sensitivity to change and patient centricity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

High-Frequency Repetitive Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex Shortly Alleviates Fatigue in Patients With Multiple System Atrophy: A Randomized Controlled Trial.

Background: Fatigue is a common symptom in patients with Multiple system atrophy (MSA), but effective treatments remain elusive. The present study aims to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) could relieve fatigue in patients with MSA.Methods: This is a single-center, randomized and double-blind trial. Twenty-two patients with MSA and fatigue were randomly allocated to receive 10 sessions of either active (N = 11) or sham (N = 11) 10 Hz rTMS over the left DLPFC. The participants were assessed at baseline (T0), after the last session of treatment (T1), and at 2-week (T2), and 4-week (T3) follow-up timepoints. The primary outcomes were Fatigue Severity Scale-9 (FSS-9) scores, with Unified Multiple System Atrophy Rating Scale (UMSARS), 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) as secondary outcomes.Results: Two-way repeated ANOVAs revealed significant group × time interactions for FSS-9 scores (p < 0.001), HAMD-17 scores (p = 0.01), HAMA scores (p = 0.01), and UMRSA part II (p = 0.05). Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FSS-9 and UMRSA part II scores at T1 and T2, but not at T3, and also in HAMD-17 and HAMA scores at T1, T2, and T3. No significant improvement was found in the sham group.Conclusion: High-frequency rTMS over the left DLPFC could provide short-term improvements for alleviating fatigue in patients with MSA, but the beneficial effects last no more than 4 weeks.

The Cold Hand Sign in Multiple System Atrophy: Frequency-Associated Factors and Its Impact on Survival.

Background: Few studies have focused on the cold hand sign (CHS), a red flag symptom, in multiple system atrophy (MSA).Objective: This study aimed to investigate the frequency and correlative factors of CHS in patients with MSA and the impact of its early occurrence on the survival of these patients.Methods: A total of 483 patients with MSA were enrolled in this study, and the motor and non-motor symptoms between patients with MSA with and without CHS were compared. Moreover, patients with disease duration ≤ 3 years at baseline were followed, and the association between CHS and survival of patients with MSA was examined.Results: The frequencies of CHS in patients with MSA were 20, 15.4, and 25.3% in MSA, MSA-parkinsonian subtype (MSA-P), and MSA-cerebellar subtype (MSA-C), respectively. Higher Unified Multiple System Atrophy Rating Scale (UMSARS) scores and higher Non-Motor Symptom Scale (NMSS) scores at baseline were associated with CHS in MSA. CHS was associated with shorter survival after adjusting for baseline diagnosis subtype, age at onset, sex, orthostatic hypotension, disease duration, autonomic onset, UMSARS total score, and NMSS score (p = 0.001; HR = 3.701; 95% CI = 1.765–7.760).Conclusion: CHS is not rare in patients with MSA. Greater disease severity and more severe non-motor symptoms were associated with CHS in patients with MSA. Patients with early occurrence of CHS had a poor prognosis.

Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies.

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson’s disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies.We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson’s disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data.α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson’s disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson’s disease clinical scores (e.g. Unified Parkinson’s Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson’s disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson’s disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity.In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson’s disease and may provide a way to distinguish variations within Parkinson’s disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson’s disease. The assay distinguished multiple system atrophy patients from Parkinson’s disease patients and in contrast to Parkinson’s disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.

Efficacy of Human Umbilical Cord Blood-Mononuclear Cell Transplantation for MSA Treatment and Its Effects on Changes in T-Cell Subsets in Peripheral Blood and Inflammatory Factors.

Objective This study is aimed at examining the efficacy of human umbilical cord blood-mononuclear cell (hUCB-MNCs) transplantation through lateral atlanto-occipital space puncture in multiple system atrophy (MSA) treatment and investigating changes in T-cell subsets in peripheral blood and inflammatory factors in patients before and after treatment. Methods A total of 20 patients with MSA who underwent hUCB-MNC transplantation through lateral atlanto-occipital space puncture in the Liaocheng People's Hospital were enrolled. Patients were followed up at 0, 1, 3, and 6 months after treatment, and the Unified Multiple System Atrophy Rating Scale (UMSARS) scores, TNF-α in the peripheral blood, IL-6, percentage of CD4, and CD4/CD8 ratio were evaluated and compared for each follow-up point; any adverse effects were recorded. Results UMSARS Part I scores were 20.55 ± 3.80, 19.20 ± 3.78, and 19.40 ± 4.11, 1, 3, and 6 months, respectively, after treatment and were significantly lower as compared to that before treatment (23.50 ± 4.72; P < 0.05). Similarly, UMSARS Part II scores 1, 3, and 6 months after treatment were 25.50 ± 5.01, 24.05 ± 5.01, and 24.25 ± 5.05, respectively, significantly lower as compared to that before treatment (30.15 ± 5.63; P < 0.05). The IL-6 values in the peripheral blood 1, 3, and 6 months after treatment were 5.25 ± 2.70 pg/m, 2.96 ± 1.75 pg/m, and 3.31 ± 1.62 pg/m, respectively, which were significantly lower (P < 0.05) than that before treatment (8.22 ± 4.69) pg/m. The TNF-α levels at 3 and 6 months after treatment were 13.08 ± 6.13 pg/m and 12.24 ± 4.76 pg/m, respectively, which were significantly lower than that before treatment (22.99 ± 13.30; P < 0.01). The CD4/CD8 ratios in the peripheral blood 1, 3, and 6 months after treatment were 1.09 ± 0.25, 1.30 ± 0.24, and 1.43 ± 0.22, respectively, which were significantly different than that before treatment (0.81 ± 0.24, P < 0.01). Similarly, the CD4 percentages 1, 3, and 6 months after treatment were 34.09 ± 1.79, 36.05 ± 1.50, and 36.47 ± 1.47, respectively, which were significantly different than that before treatment (0.81 ± 0.24; P < 0.01). Conclusion hUCB-MNC transplantation through lateral atlanto-occipital space puncture could significantly improve the symptoms and signs in patients with MSA and delay the disease progression. Thus, hUCB-MNCs may modulate immune activity and reduce the inflammatory response.

An Item Response Theory analysis of the Unified Multiple System Atrophy Rating Scale

IntroductionThe Unified Multiple System Atrophy Rating Scale (UMSARS) has four subscales that have been specifically designed for the clinical assessment of MSA patients. UMSARS I (activities of daily living) and II (motor examination) subscales are regularly used as primary endpoints in treatment trials. The main objective of this study was to identify UMSARS I and II subscale items that best describe progression over time. MethodsAll MSA patients seen at the French Reference Centre for MSA from 2007 to 2020 were included in a prospective cohort with an annual follow-up assessment including UMSARS. The repeated measures of the 26 UMSARS I and II items were analyzed using a longitudinal Item Response Theory model to identify the most informative items for each of the five UMSARS IV disease stages. Sample size estimates were further calculated for the most informative items as a group. ResultsA total of 557 MSA patients were included with a mean follow-up of 2.3 years. The majority of items progressed with disease duration or across the different UMSARS IV disability stages, with the exception of those related to dysautonomia. Roughly 70% of the scale information was carried by only 11/26 items, many reflecting the patient perspective. These yielded similar sample size estimates than UMSARS I + II items. ConclusionThis study provides important information about the progression of UMSARS I and II subscale items. Improvements seem particularly necessary regarding those assessing dysautonomia. A shortened scale may be useful as outcome for future clinical trials.

Serum Cystatin C as a Potential Predictor of the Severity of Multiple System Atrophy With Predominant Cerebellar Ataxia: A Case-Control Study in Chinese Population

Objective: Multiple system atrophy (MSA) is a serious neurodegenerative disease that is charactered by progressive neurological disability. The aim of this study was to investigate the correlation of serum oxidant factors with the severity of MSA.Methods: A total of 52 MSA patients and 52 age- and gender- matched healthy subjects were retrospectively enrolled in this study. Enzymatic colorimetric methods were used to assay the concentrations of uric acid (UA), serum creatinine (Scr), blood urea nitrogen (BUN), and cystatin C (Cys-C). Disease severity was evaluated by the Unified Multiple System Atrophy Rating Scale (UMSARS). The disease progression rate was defined by the change in UMSARS-IV (global disability score, GDS) over a 1-year period.Results: Comparisons between the two groups revealed that there were no significant differences in terms of serum Scr (70.81 ± 13.88 vs. 70.92 ± 14.19 μmol/L, p = 0.967). However, the serum levels of the other three biomarkers were significantly higher in the MSA patients (UA: 325.31 ± 84.92 vs. 291.19 ± 64.14 μmol/L, p = 0.023; BUN: 5.68 ± 1.67 vs. 4.60 ± 1.24 mmol/L, p < 0.001; Cys-C: 0.96 ± 0.15 vs. 0.89 ± 0.14 mg/L, p = 0.024). In addition, Pearson correlation analyses revealed that only serum Cys-C was significantly correlated to GDS (r = 0.281, p = 0.044). Subgroup analysis further demonstrated that serum Cys-C was the only factor that was positively associated with the disease severity in patients with MSA and predominant cerebellar ataxia (MSA-C) (r = 0.444, p = 0.018); there was no significant association in MSA patients with predominant Parkinsonism (MSA-P) (r = 0.118, p = 0.582). MSA-C patients with severe disability were shown to express higher serum levels of Cys-C than patients with mild disability (1.03 ± 0.13 vs. 0.88 ± 0.12 mg/L, p = 0.009). Finally, Kaplan-Meier plots revealed a significant difference in the 5-year probability of survival from severe disability between MSA-C patients with high- and low-concentrations of serum Cys-C (Log-rank test: X2 = 4.154, p = 0.042). ROC curve analysis confirmed that serum Cys-C exhibits good performance as a biomarker (AUC = 0.847).Conclusion: Our research indicated that oxidative stress plays a vital role in MSA. Serum Cys-C represents a potential prognostic biomarker to evaluate the severity of disease in patients with MSA-C.

Postganglionic Sudomotor Dysfunction and Brain Glucose Hypometabolism in Patients with Multiple System Atrophy.

Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. In this retrospective study, patients with probable MSA who underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18F-FDG-PET/CT results were collected. Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p = 0.037). In the regression analysis, both UMSARS Part I (β= 1.185, p = 0.013) and Part II (β= 1.266, p = 0.021) scores were significantly associated with the sudomotor sub-score. On 18F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without.

Camptocormia in patients with multiple system atrophy at different disease durations: frequency and related factors

BackgroundCamptocormia is common in patients with multiple system atrophy (MSA). The current study was aimed at assessing the frequency of camptocormia and its related factors in MSA patients with different disease durations. Also, the impact of camptocormia on disability was evaluated.MethodsA total of 716 patients were enrolled in the study. They were classified into three groups based on disease duration (≤ 3, 3–5, ≥ 5 years). Specific scales were used to evaluate the motor and non-motor symptoms. Disease severity was assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS). The binary logistic regression model was used to explore the factors related to camptocormia. To analyze the impact of camptocormia on disability in patients with disease duration less than 5 years, propensity score matching (PSM) and stratified Cox regression analysis were used.ResultsIn the current study, we found that the frequency of camptocormia was 8.9, 19.7 and 19.2% when the disease duration was ≤3, 3–5, ≥ 5 years, respectively. In the disease duration ≤3 years group, we found that MSA-parkinsonian subtype (MSA-P) (OR = 2.043, P = 0.043), higher total UMSARS score (OR = 1.063, P < 0.001), older age of onset (OR = 1.047, P = 0.042), and lower score on the frontal assessment battery (FAB) (OR = 0.899, P = 0.046) were associated with camptocormia. Only greater disease severity was associated with camptocormia in the group of patients with disease duration 3–5 years (OR = 1.494, P = 0.025) and in the group of patients with disease duration ≥5 years (OR = 1.076, P = 0.005). There was no significant impact of camptocormia on disability in patients with a disease duration of < 5 years (HR = 0.687, P = 0.463).ConclusionThe frequency of camptocormia increased with prolonged disease duration. Disease severity was related to camptocormia at different stages of the disease. The MSA-P subtype, older age of onset, and lower FAB score were associated with camptocormia in the early stage of the disease.

\u201cHot cross bun\u201d is a potential imaging marker for the severity of cerebellar ataxia in MSA-C

To evaluate the correlation between “hot cross bun” sign (HCBs) and disease severity in multiple system atrophy (MSA). We recruited patients with probable and possible MSA with parkinsonism (MSA-P) or the cerebellar ataxia (MSA-C) subtypes. Clinical and imaging characteristics were collected and comparison was performed between MSA-C and MSA-P cases. Spearman test was used to evaluate the correlation between HCBs and other variables. Curve estimate and general linear regression was performed to evaluate the relationship between HCBs and the Scale for Assessment and Rating of Ataxia (SARA). Unified Multiple System Atrophy Rating Scale (UMSARS) IV was used to assess the severity of disease. Multinomial ordered logistic regression was used to confirm the increased likelihood of disability for the disease. Eighty-one MSA with HCBs comprising of 50 MSA-C and 31 MSA-P were recruited. We demonstrated that the severity of HCBs showed a positive linear correlation with SARA scores in MSA-C. Multinomial ordered logistic regression test revealed that the increase in the HCBs grade may be associated with an increased likelihood of disability for the disease severity in MSA, especially in those with cerebellar ataxia subtype. We demonstrated that HCBs is a potential imaging marker for the severity of cerebellar ataxia. The increase in the HCBs grade may be associated with an increased likelihood of disability in MSA-C, but not MSA-P cases, suggesting that it may be a useful imaging indicator for disease progression in Chinese patients with MSA-C.

Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement.

PurposeThe unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA.MethodsExpert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations.ResultsThe UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others.ConclusionsBecause of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

Multiple system atrophy in Hokkaido, Japan: a prospective registry study of natural history and symptom assessment scales followed for 5 years

ObjectivesMultiple system atrophy (MSA) is a refractory neurodegenerative disease, but novel treatments are anticipated. An accurate natural history of MSA is important for clinical trials, but is insufficient. This regional...

Reliability and validity of Japanese version of Unified Multiple System Atrophy Rating Scale

AbstractBackground/AimThe Unified Multiple System Atrophy Rating Scale (UMSARS) has been broadly used to assess the progression of multiple system atrophy (MSA). In this study, we translated UMSARS into Japanese and tested the reliability and validity of the translated version for the assessment of Japanese patients with MSA.MethodUMSARS was translated into Japanese. For the evaluation of the reliability of the translated version, 60 and 70 participants with MSA were assessed by two neurologists using the Japanese versions of UMSARS‐I and UMSARS‐II, respectively. For the validation, 70 participants with MSA were evaluated by one neurologist using the Japanese versions of UMSARS‐I and UMSARS‐II, and other scales. Cronbach's alpha coefficient, Cohen's kappa coefficient [κ (w)], and Spearman rank correlation were calculated.ResultsCronbach's alpha coefficients of the Japanese versions of UMSARS‐I and UMSARS‐II were 0.87 and 0.90, respectively. The κ (w) values of UMSARS‐I and UMSARS‐II items were 0.61‐0.81 and 0.51‐0.86, respectively. The total UMSARS‐I score correlated well with the scores of Barthel Index, Schwab and England Activities of Daily Living Scale, Functional Independence Measure, and Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) part 2 (Spearman rank correlations, −0.75, −0.71, −0.82, and 0.81, respectively). The total UMSARS‐II score correlated well with the scores of International Cooperative Ataxia Rating Scale and MDS‐UPDRS part 3 (Spearman rank correlations, 0.85 and 0.86, respectively).ConclusionsThe Japanese version of UMSARS is reliable and valid for the assessment of the clinical severity of MSA in Japan.

Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations.

We assessed the clinimetric properties of ataxia rating scales and functional tests, and made recommendations regarding their use. A systematic literature search was conducted to identify the instruments used to rate ataxia symptoms. The identified rating scales and functional ability tests were reviewed and ranked by the panel as "recommended," "suggested," or "listed" for the assessment of patients with discrete cerebellar disorders, using previously established criteria. We reviewed 14 instruments (9 rating scales and 5 functional tests). "Recommended" rating scales for the assessment of symptoms severity were: for Friedreich's ataxia, the Friedreich's Ataxia Rating Scale, the International Cooperative Ataxia Rating Scale (ICARS), and the Scale for the Assessment and Rating of Ataxia (SARA); for spinocerebellar ataxias, ICARS and SARA; for ataxia telangiectasia: ICARS and SARA; for brain tumors, SARA; for congenital disorder of glycosylation-phosphomannomutase-2 deficiency, ICARS; for cerebellar symptoms in multiple sclerosis, ICARS; for cerebellar symptoms in multiple system atrophy: Unified Multiple System Atrophy Rating Scale and ICARS; and for fragile X-associated tremor ataxia syndrome, ICARS. "Recommended" functional tests were: for Friedreich's ataxia, Ataxia Functional Composite Score and Composite Cerebellar Functional Severity Score; and for spinocerebellar ataxias, Ataxia Functional Composite Score, Composite Cerebellar Functional Severity Score, and SCA Functional Index. We identified some "recommended" scales and functional tests for the assessment of patients with major hereditary ataxias and other cerebellar disorders. The main limitations of these instruments include the limited assessment of patients in the more severe end of the spectrum and children. Further research in these populations is warranted. © 2020 International Parkinson and Movement Disorder Society.

Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial

Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy. We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1-3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov (NCT02008721) and EudraCT (2012-000928-18), and is completed. Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned-47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference -0·94 [SE 1·41; 95% CI -3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Lüneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.

Evolution of prodromal parkinsonian features in a cohort of GBA mutation-positive individuals: a 6-year longitudinal study

ObjectivesGBA1 mutations are a frequent risk factor for Parkinson disease (PD). The aim of this study is to evaluate clinical features in a group of GBA1 mutation–positive individuals over a...

Evaluation of the frequency of non-motor symptoms of Parkinson\u2019s disease in adult patients with Gaucher disease type 1

BackgroundGaucher disease (GD) is caused by deficiency of beta-glucocerebrosidase (GCase) due to biallelic variations in the GBA1 gene. Parkinson’s disease (PD) is the second most common neurodegenerative condition. The classic motor symptoms of PD may be preceded by many non-motor symptoms (NMS), which include hyposmia, rapid eye movement (REM) sleep behavior disorder, constipation, cognitive impairment, and depression. Population studies have identified mutations in GBA1 as the main risk factor for idiopathic PD. The present study sought to evaluate the prevalence of NMS in a cohort of patients with GD type 1 from Southern Brazil.MethodologyThis is an observational, cross-sectional study, with a convenience sampling strategy. Cognition was evaluated by the Montreal Cognitive assessment (MoCa), daytime sleepiness by the Epworth Scale, depression by the Beck Inventory, constipation by the Unified Multiple System Atrophy Rating Scale, and REM sleep behavior disorder by the Single-Question Screen; hyposmia by the Sniffin’ Sticks. Motor symptoms were assessed with part III of the Unified Parkinson’s Disease Rating Scale. All patients were also genotyped for the GBA1 3′-UTR SNP (rs708606).ResultsTwenty-three patients (female = 13; on enzyme replacement therapy = 21, substrate reduction therapy = 2) with a mean age of 41.45 ± 15.3 years (range, 22–67) were included. Eight patients were found to be heterozygous for the 3′-UTR SNP (rs708606). Fourteen patients (8 over age 40 years) presented at least one NMS; daytime sleepiness was the most frequent (n = 10). Two patients (aged 63 and 64, respectively) also presented motor symptoms, probably drug-related.ConclusionsNMS were prevalent in this cohort. We highlight the importance of a multidisciplinary follow-up focusing on earlier diagnosis of PD, especially for patients with GD type 1 over the age of 40.

Pupillary dysfunction of multiple system atrophy: Dynamic pupillometric findings and clinical correlations

IntroductionAlthough autonomic dysfunction is the prominent clinical feature in multiple system atrophy (MSA), little is known about the pupillary autonomic aspect of MSA. We aimed to evaluate pupillary autonomic function in MSA patients using dynamic pupillometry, which can quantify the pupillary light reflex. MethodsDynamic pupillometry parameters were compared in 21 MSA patients and 21 healthy controls. Pupillometric parameters were correlated with total Unified Multiple System Atrophy Rating Scale (UMSARS) scores and autonomic symptom severity. ResultsAverage constriction (p = 0.034) and dilation (p = 0.003) velocities were significantly slowed in MSA patients compared with controls. Total UMSARS correlated with the average constriction (r = −0.527, p = 0.017) and maximum constriction (r = −0.658, p = 0.003) velocities. Autonomic symptom severity correlated with average constriction (r = −0.544, p = 0.013), maximum constriction (r = −0.607, p = 0.005) and average dilation (r = −0.499, p = 0.025) velocities. ConclusionDynamic pupillometry may provide useful information about pupillary autonomic dysfunction, which correlated with the clinical severity, in patients with MSA.

Prevalence of and factors associated with postural deformities in Chinese patients with multiple system atrophy

ObjectiveThe prevalence of postural deformities in patients with multiple system atrophy (MSA) has varied among previous studies. The objective of our study was to investigate the prevalence of and factors associated with postural deformities in Chinese MSA patients. MethodsA total of 732 MSA patients were consecutively enrolled in the current study. Clinical data including age, sex, age of onset, disease duration, onset symptom and treatment were collected. The Unified Multiple System Atrophy Rating Scale (UMSARS) was used to evaluate the severity of the disease. ResultsOne hundred and fourteen (15.6%) patients presented with camptocormia. Thirty-one (4.2%) patients manifested with Pisa syndrome. Twenty-four (3.3%) patients presented with antecollis. Patients who exhibited postural deformities were more common among the MSA patients with predominant parkinsonism (MSA-P) (P < 0.05). In addition, MSA patients with postural deformities had a longer disease duration compared to those patients without postural deformities (P < 0.001). After adjusting for disease duration, compared with patients without postural deformities, MSA patients with postural deformities presented with higher score of UMSARS-I (P < 0.001), UMSARS-II (P < 0.001), UMSARS-IV (P < 0.001), and total UMSARS (P < 0.001) scores. The binary logistic regression model indicated that the factors associated with postural deformity in MSA patients were the total UMSARS score (OR = 1.076, P < 0.001) and MSA-P subtype (OR = 3.870, P < 0.001). ConclusionPostural deformities were common in Chinese MSA patients. Camptocormia was the most common type of postural deformity, followed by Pisa syndrome and antecollis. The factors associated with postural deformity were the severity of the disease and MSA-P subtype.