Delivering the diagnosis of multiple system atrophy: a multicenter survey on Japanese neurologists' perspectives.

BACKGROUND: Multiple system atrophy (MSA) is a progressive, incurable, life-threatening neurodegenerative disease uniquely characterized by the risk of sudden death, which makes diagnosis delivery challenging for neurologists. Empirical studies on breaking a diagnosis of MSA are scarce, with no guidelines currently established. This study aimed to investigate neurologists' current practices and experiences in delivering the diagnosis of MSA. METHODS: We conducted a multicenter online survey and employed a mixed-methods (quantitative and qualitative) study design in which responses to open-ended questions were analyzed qualitatively using critical incident technique. RESULTS: Among the 194 neurologists surveyed, 166 opened the survey (response rate = 85.6%), of whom 144 respondents across various Japanese regions completed the survey. Accordingly, 92.3% and 82.8% of the participating neurologists perceived delivering the diagnosis of MSA and explaining the risk of sudden death as difficult, respectively. Factors independently associated with difficulties in diagnosis delivery included explaining the importance of the family decision making process in life-prolonging treatment, perceived difficulties in delivering information regarding the risk of sudden death, and perceived difficulties in differential diagnosis of MSA. CONCLUSIONS: Our findings showed that the majority of neurologists perceived delivering the diagnosis of MSA and explaining the risk of sudden death as difficult, which could have been associated with the difficulty of breaking the diagnosis of MSA. Difficulty in conveying bad news in MSA are caused by various factors, such as empathic burden on neurologists caused by the progressive and incurable nature of MSA, the need to explain complex and important details, including the importance of the family decision-making process in life-prolonging treatment, difficulty of MSA diagnosis, and communication barriers posed by mental status and cognitive impairment in patients or their family members. Neurologists consider various factors in explaining the risk of sudden death (e.g., patient's personality, mental state, and degree of acceptance and understanding) and adjust their manner of communication, such as limiting their communication on such matters or avoiding the use of the term "sudden death" in the early stages of the disease. Although neurologists endeavor to meet the basic standards of good practice, there is room for the multiple aspects for improvement.

Prevalence of multiple system atrophy: A literature review.

INTRODUCTION: This paper aims to provide a literature overview on multiple system atrophy (MSA) prevalence in European and other pan-European populations. METHODS: A literature search (PubMed, EMBASE) was performed through 2022 to identify published studies on MSA prevalence in European countries. Of these search results, titles and abstracts were screened for relevance. A standardized assessment tool was used for systematically data extraction and comparison. For studies where only the incidence rate was reported, MSA prevalence was derived based on the incidence and duration of disease. RESULTS: A total of 24 studies conducted in 14 countries and published between 1995 and 2022 were identified. The prevalence of MSA was reported in 18 (75%) studies and was derived from six (25%) incidence studies. These studies were mainly prospective population-based studies or multi-center studies from specific regions or specialty clinical settings. Two earlier studies in Germany and the Netherlands were conducted using door-to-door design. The time period of evaluation of prevalence ranged from 1990 to 2018. The crude prevalence of MSA ranged from 0.5/100,000 in Spain to 17/100,000 in Japan. Age-specific prevalence rates were provided in five studies, and the reported age ranges varied. The gender-specific crude prevalence was estimated as 2.75/100,000 for men and 1.19/100.000 for women. The derived prevalence was higher (ranging from 0.7-18.9/100,000) than studies where the prevalence was reported. CONCLUSION: The variations observed in MSA prevalence may result from differences in age distributions of the study populations, study methodology, diagnostic criteria and case assessment strategies of MSA. Thus, the comparability of these studies is limited.

Reliability of the unified multiple system atrophy rating scale using the telephone.

OBJECTIVE: The unified multiple system atrophy rating scale (UMSARS) was used to evaluate various symptoms of multiple system atrophy (MSA). And UMSARS part 1 was originally developed for use in interviews, but the need for telemedicine is increasing in COVID-19 pandemic. The purpose of this study is to evaluate the reliability of the UMSARS part 1 telephone survey. METHODS: Thirty-two MSA patients took the UMSARS part 1 face-to-face, followed by two more telephone evaluations. Intraclass correlation coefficients (ICC) and Cronbach's alpha (α) coefficients were calculated, and the inter-rater reliability was determined. At the same time, we asked about the problems in COVID-19 pandemic. RESULTS: The study participants included 15 men and 17 women with mean age of 67.1 years (SD, 8.3). For the total UMSARS part 1 score, the inter-rater ICC and Cronbach's α coefficient were 0.89 to 0.92, and 0.84 to 0.87, respectively. More than half of the items had a relatively high ICC. Cronbach's α coefficients were more than 0.7 for all items. Changes that occurred in COVID-19 pandemic included reduced outings and lack of rehabilitation in about half of the cases. CONCLUSION: The UMSARS part 1 has high inter-rater reliability and internal consistency. Evaluation of subjective symptoms showed that some variability could occur. In addition, there was concern about the influence of lack of rehabilitation due to COVID-19 pandemic.

Frequency and outcomes of gastrostomy insertion in a longitudinal cohort study of atypical parkinsonism.

BACKGROUND: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) show a high prevalence and rapid progression of dysphagia, which is associated with reduced survival. Despite this, the evidence base for gastrostomy is poor, and the optimal frequency and outcomes of this intervention are not known. We aimed to characterise the prevalence and outcomes of gastrostomy in patients with these three atypical parkinsonian disorders. METHOD: We analysed data from the natural history and longitudinal cohorts of the PROSPECT-M-UK study with up to 60 months of follow-up from baseline. Survival post-gastrostomy was analysed using Kaplan-Meier survival curves. RESULTS: In a total of 339 patients (mean age at symptom onset 63.3 years, mean symptom duration at baseline 4.6 years), dysphagia was present in >50% across all disease groups at baseline and showed rapid progression during follow-up. Gastrostomy was recorded as recommended in 44 (13%) and performed in 21 (6.2%; MSA 7, PSP 11, CBS 3) of the total study population. Median survival post-gastrostomy was 24 months compared with 12 months where gastrostomy was recommended but not done (p = 0.008). However, this was not significant when correcting for age and duration of symptoms at the time of procedure or recommendation. CONCLUSIONS: Gastrostomy was performed relatively infrequently in this cohort despite the high prevalence of dysphagia. Survival post-gastrostomy was longer than previously reported, but further data on other outcomes and clinician and patient perspectives would help to guide use of this intervention in MSA, PSP and CBS.

The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis.

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management. OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study.

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6-22 and HR: 3.6, 95% CI: 1.1-12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2-6), trouble swallowing (HR 2.5, 95% CI: 1.4-4.5) and changes in speech (HR:2.4, 95% CI:1.1-4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1-5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2-38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6-46), preserved olfaction (HR: 8.7, 95% CI: 1.7-45), anhidrosis (HR: 1.8, 95% CI: 1-3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1-2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.

Frequency of Comorbid Pathologies and Their Clinical Impact in Multiple System Atrophy.

BACKGROUND: Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood. OBJECTIVE: We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates. METHODS: This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact. RESULTS: The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction. CONCLUSIONS: The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.

Estimating the prevalence and incidence of multiple system atrophy in the USA: Insights from a national claims database.

INTRODUCTION: Published literature on the prevalence and incidence of multiple system atrophy (MSA) in the US are scarce or based on relatively older studies. The objective of this study was to estimate the prevalence and cumulative incidence of MSA in the US. METHODS: This was a retrospective study of individuals aged 30 years or older in a large US claims database from 2016 to 2021. The primary endpoint was ≥1 MSA claim. Persons with ≥2 MSA claims were also examined. Incident cases aged ≥30 years with a minimum of one-year of continuous enrollment prior to and following cohort entry were identified. Prevalence and cumulative incidence of MSA were estimated for year 2021 and were also standardized to the 2021 US population. RESULTS: The crude prevalence of MSA was 7.2 per 100,000 persons in 2021 and increased with age. After standardization to the US population, the age-adjusted prevalence was 12.4 per 100,000 translating to 41,133 persons in the 2021 US population. In persons with ≥2 MSA claims, the crude and age-adjusted prevalence were 3.1 and 5.7 per 100,000 persons. The crude cumulative incidence of MSA for individuals aged 30 years and older was 9.8 per 100,000 persons in 2021. The estimated cumulative incidence of MSA in individuals 30 years or older, age-adjusted to the 2021 U S. population, was 14.2 per 100,000. CONCLUSION: This study provides real-world evidence on the prevalence and cumulative incidence of MSA in the US to better understand the medical care needs and treatment.

Longitudinal evolution of sleep disturbances in early multiple system atrophy: a 2-year prospective cohort study.

BACKGROUND: The progression of sleep disturbances remains unclear in patients with early multiple system atrophy (MSA). We aimed to explore the frequency, severity, and coexistence of 2-year longitudinal changes of sleep disturbances including REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and Parkinson's disease-related sleep problems (PD-SP) in early MSA. METHODS: MSA patients with a disease duration < 3 years were enrolled to complete a 2-year follow-up visit. Sleep disturbances including RBD, EDS, and PD-SP were assessed using the RBD Screening Questionnaire, Epworth sleepiness scale, and PD sleep scale-2, respectively. RESULTS: A total of 220 patients with MSA enrolled in the study and 90 patients completed the 2-year follow-up visit. The score of all three sleep disturbances significantly increased over the 2-year follow-up in MSA and MSA with the predominant parkinsonism group (all p < 0.05). The frequency of PD-SP (from 14.5 to 26.7%) and EDS (from 17.7 to 37.8%) was progressively increased (all p < 0.05) except for RBD (from 51.8 to 65.6%, p = 0.152) over the 2-year follow-up in MSA. The frequency of coexistence of two or three sleep disturbances also increased over time. The most common sleep disturbance was RBD, followed by EDS and PD-SP over the 2-year follow-up. CONCLUSIONS: The present study demonstrated that the frequency of different types of sleep disturbances progressively increased except for RBD and the coexistence of two or three sleep disturbances became more common over time in early MSA. Our study suggested that the assessment and management of sleep disturbances should begin early in MSA.

Association Between Orthostatic Hypotension and Dementia in Patients With Parkinson Disease and Multiple System Atrophy.

BACKGROUND AND OBJECTIVES: Orthostatic hypotension (OH) increases dementia risk in patients with Parkinson disease (PD), although the underlying mechanisms and whether a similar association between OH and cognitive impairment exists in other synucleinopathies remain unknown. The aim is to evaluate the association between OH and dementia risk in patients with PD, and cognitive impairment risk in patients with multiple system atrophy (MSA), and to explore relevant clinical and neuropathologic factors to understand underlying pathogenic mechanisms. METHODS: This is a retrospective cohort study. Medical records throughout the entire disease course of consecutive patients with neuropathology-confirmed PD and MSA from the Queen Square Brain Bank were systematically reviewed. Time of onset and severity of OH-related symptoms were documented, and their association with other clinical and neuropathologic variables was evaluated. Dementia risk for patients with PD and cognitive impairment risk for patients with MSA were estimated using multivariable hazard regression. RESULTS: One hundred thirty-two patients with PD and 137 with MSA were included. Patients with MSA developed OH more frequently, earlier in the disease course and with more severe symptoms. Cumulative dementia prevalence was higher in patients with PD. Multivariable adjusted regression models showed that early OH, but not its symptom severity, increased dementia risk in patients with PD by 14% per year (hazard ratio [HR] = 0.86; 95% CI, 0.80-0.93) and cognitive impairment risk in patients with MSA by 41% per year (HR = 0.59; 95% CI, 0.42-0.83). Early OH was not associated with increased α-synuclein, ß-amyloid, tau, Alzheimer, or cerebrovascular pathologies. No significant associations were found between severity of OH symptoms and other clinical or neuropathologic variables. DISCUSSION: Early OH, but not its symptom severity, increases the risk of cognitive impairment in patients with PD and MSA. OH is not associated with more extensive Lewy, ß-amyloid, tau, Alzheimer, or cerebrovascular pathologies. It is likely that OH contributes to cognitive impairment in patients with PD and MSA by hypoxia-induced nonspecific neurodegeneration. Further research should evaluate whether improving brain perfusion by treating OH may modify the risk of dementia in these conditions.

A Mouse Model of Multiple System Atrophy: Bench to Bedside.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson's disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. MSA has no efficient therapy to date. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.

Prevalence and Clinical Characteristics of Dementia and Cognitive Impairment in Multiple System Atrophy: A Systematic Review and Meta-Analysis.

BACKGROUND: Cognitive impairment is a clinical feature of multiple system atrophy (MSA). However, the prevalence and factors influencing the prevalence of cognitive impairment and dementia in MSA patients remain unclear. OBJECTIVE: We aim to provide an estimate of the prevalence of cognitive impairment and dementia in patients with MSA and to evaluate the possible effect of demographic, clinical and methodological factors on the prevalence. METHODS: We systematically searched the PubMed, Embase, and Web of science databases to identify studies that report the prevalence of cognitive impairment or dementia in MSA published up to February 2022. We computed the estimates of the pooled prevalence using random-effects models. Heterogeneity was investigated by subgroup analyses and meta-regression. Differences between MSA patients with and without cognitive impairment in demographic and clinical features were explored. RESULTS: A total of 23 studies comprising 2064 MSA patients were included in meta-analysis. The pooled prevalence of cognitive impairment in MSA patients was 37% (95% CI: 29% -45%), the prevalence of dementia was 11% (95% CI: 7% -15%). The subgroup analyses showed the prevalence of dementia in pathologically-confirmed MSA was 7% (95% CI: 0% -12%), in clinically diagnosed MSA was 14% (95% CI: 10% -18%). Cognitive impairment in MSA patients was associated with older age, lower education, longer disease duration and more severe motor symptoms. CONCLUSION: Cognitive impairment is a common non-motor symptom in MSA. Dementia can develop in a few patients with MSA as well, but usually in the late stage.

COVID-19 pandemic and the international classification of functioning in multiple system atrophy: a cross-sectional, nationwide survey in Japan.

The present study aimed to determine the magnitude of and risk factors for the effects of the COVID-19 pandemic on the international classification of functioning, disability and health (ICF) in patients with multiple system atrophy (PwMSA). The study was part of a cross-sectional, nationwide, multipurpose mail survey for Japanese PwMSA from October to December, 2020. The primary outcome was the impact of the early COVID-19 pandemic on ICF functioning, consisting of body function, activity, and participation. Age, sex, disease type, disease duration, and dwelling place were asked as participants' characteristics, and the multiple system impairment questionnaire (MSIQ), patient health questionnaire-2, modified rankin scale, barthel index, life-space assessment (LSA), and EuroQoL were examined. Multivariate logistic regression analyses were performed to identify independent risk factors for a worse function score due to the COVID-19 pandemic for each ICF functioning domain. A total of 155 patients (mean age 65.6 [SD 8.1] years; 43.9% women; mean disease duration 8.0 [SD 6.2] years; 65% MSA with cerebellar ataxia, 13% MSA with parkinsonism, 9% MSA with predominant autonomic features) were analyzed. Of the ICF functioning domains, the respondents reported that the early COVID-19 pandemic affected body function in 17.4%, activity in 17.6%, and participation in 46.0%. The adjusted multivariate model identified MSIQ and LSA as the two variables that independently contributed to all domains. The COVID-19 pandemic affected ICF functioning of PwMSA in Japan, and the severity of disease-related impairments and a large daily living space were common risk factors. These results help support the focus on patient characteristics for medical and social welfare support.

Prevalence and associated factors of frailty and sarcopenia in multiple system atrophy and progressive supranuclear palsy: a cross-sectional study.

OBJECTIVE: To investigate the prevalence of, and clinicodemographic factors associated with, frailty and sarcopenia in patients with multiple system atrophy or progressive supranuclear palsy. METHODS: A total of 264 participants were recruited in this study. Demographic and clinical data were collected through structured interviews. Frailty was assessed with the clinical frailty scale (CFS), and sarcopenia was assessed with the simple five-item scoring questionnaire (SARC-F). RESULTS: The prevalence of frailty and sarcopenia was 48.57% and 35.71% in multiple system atrophy, and 51.09% and 39.13% in progressive supranuclear palsy. Multiple system atrophy patients with frailty or sarcopenia were more likely to be female and have longer disease duration, greater motor impairment, greater non-motor burden, and lower life quality. In multiple system atrophy, frailty was associated with reduced motor function and sarcopenia was associated with female sex, reduced motor function, and orthostatic hypotension. Progressive supranuclear palsy patients with frailty or sarcopenia had more severe motor impairment and non-motor burden, longer disease duration, and lower life quality. In progressive supranuclear palsy, frailty was associated with mentation and gait/midline symptoms, while sarcopenia was associated with reduced daily activity and severe gait/midline symptoms. CONCLUSION: Frailty and sarcopenia may be more common among patients with multiple system atrophy or progressive supranuclear palsy than among the general population, and they are associated with more severe forms of the two diseases. Prospective studies are necessary to clarify causal relationships between frailty/sarcopenia and clinical manifestations of multiple system atrophy and progressive supranuclear palsy.

Seizure prevalence in neurodegenerative diseases-a study of autopsy proven cases.

BACKGROUND AND PURPOSE: Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND. METHODS: Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared amongst ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined. RESULTS: In all, 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n = 144; LBD, n = 103; PSP, n = 93; FTLD, n = 53; MSA, n = 36; CBD, n = 25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p = 0.005), LBD (p = 0.001), MSA (p = 0.005) and PSP (p < 0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p = 0.017). CONCLUSIONS: Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk.

Fatigue in Patients With Multiple System Atrophy: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Nonmotor symptoms are common in patients with multiple system atrophy (MSA), but there is limited knowledge regarding fatigue in MSA. This study aimed to investigate the frequency and evolution of fatigue and the factors related to fatigue and its progression in patients with MSA at an early stage. METHODS: Patients with probable MSA were comprehensively evaluated at both baseline and the 1-year follow-up, including their motor and nonmotor symptoms. Fatigue and anxiety were assessed using the Fatigue Severity Scale (FSS) and Hamilton Anxiety Rating Scale (HARS), respectively. Orthostatic hypotension (OH) was defined as a decrease in the systolic or diastolic blood pressure by at least 30 and 15 mm Hg, respectively. The binary logistic regression model and linear regression model were used to analyze the factors related to fatigue and its progression, respectively. RESULTS: This study enrolled 146 patients with MSA. The frequency of fatigue was 60.3%, 55.1%, and 64.9% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. The frequency of fatigue and the FSS score in patients with MSA increased from baseline to the 1-year follow-up (p < 0.05). Young age (odds ratio [OR] 0.939, 95% confidence interval [CI] 0.894-0.987), OH (OR 2.806, 95% CI 1.253-6.286), and high HARS score (OR 1.014, 95% CI 1.035-1.177) were associated with fatigue in MSA. OH was associated with fatigue in MSA-P (OR 3.391, 95% CI 1.066-10.788), while high HARS score was associated with fatigue in MSA-C (OR 1.159, 95% CI 1.043-1.287). In addition, only low FSS scores at baseline were associated with the annual progression rate of FSS scores in MSA, MSA-P, and MSA-C (p < 0.05). Neurofilament light chain, α-synuclein, glial fibrillary acidic protein, brain-derived neurotrophic factor, and triggering receptor expressed on myeloid cell-2 were not significantly associated with fatigue and its progression in MSA. DISCUSSION: Fatigue was prevalent in early-stage MSA, and it increased and remained persistent over time. This study demonstrated that OH and anxiety were associated with fatigue in patients with MSA.

Fatigue prevalence and associated factors in patients with multiple system atrophy.

OBJECTIVE: Fatigue was reported a determinant of poor quality of life in multiple system atrophy (MSA) patients. This study aimed to determine fatigue prevalence and associated demographic, motor, and non-motor symptoms in MSA patients. MATERIALS AND METHODS: A total of 174 MSA patients met "Probable" diagnostic criteria were included in this cross-sectional study. Fatigue Severity Scale (FSS) was used to measure fatigue prevalence. Unified MSA Rating Scale (UMSARS), Non-Motor Symptoms Scale (NMSS), Hamilton Depression Rating Scale-17 (HDRS-17), Hamilton Anxiety Scale (HAMA), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), and Mini-Mental State Exam (MMSE) were used for comprehensive clinical assessments. Nonparametric Mann-Whitney or Pearson's chi-square test was used to compare the patient score with or without fatigue (defined as a mean FSS score≥4). Binary logistic regression analysis was performed to determine features independently associated with the presence of fatigue. RESULTS: Fifty (28.7%) patients enrolled reported fatigue. Results of multivariate analysis revealed that anxiety (OR = 3.01, 95% CI = 1.43-6.31), excessive daytime sleepiness (OR = 2.70, 95% CI = 1.23-5.90), and use of sleep medicine (OR = 3.58, 95% CI = 1.39-9.24) were significantly associated with fatigue in MSA patients. CONCLUSIONS: Fatigue is common in our MSA patients. Anxiety, excessive daytime sleepiness, and current sleep medicine use may be associated with an increased risk of fatigue. However, the severity of motor symptoms may not be associated with fatigue. Our findings highlight the need to identify, investigate, and treat fatigue in MSA.

A Questionnaire-Based Study on Clinical REM Sleep Behavior Disorder and Subtypes in Multiple System Atrophy.

OBJECTIVES: Studies documenting the association between rapid eye movement sleep behavior disorder (RBD) and subtypes of multiple system atrophy (MSA) are rare. In this study, we investigated the presence of clinical RBD in MSA patients and compared the prevalence and severity of RBD in patients with MSA-P and MSA-C subtypes. METHODS: We evaluated 54 consecutive patients presenting with MSA and hospitalized in the neurology ward of Beijing Hospital from February 2012 to June 2020. The healthy control (HC) group consisted of 100 healthy individuals who came to our hospital for physical examination. The clinical diagnosis of RBD was based on the minimal diagnostic criteria of International Classification of Sleep Disorders, revised. The severity of clinical RBD was rated on a digital scale from 0 to 3. The patients were divided into 2 subgroups: MSA-P and MSA-C. The MSA and HC groups were compared in terms of frequency of clinical RBD. The MSA-P and MSA-C subgroups were compared with each other for age, sex, onset age, disease duration, and features of clinical RBD. The correlation between severity of clinical RBD and clinical characteristics of MSA was analyzed in the patient groups. RESULTS: The frequency of clinical RBD in MSA and HC groups was 70.4% (38/54) and 5% (5/100), respectively. The difference between 2 groups was significant (χ2 = 74.453, p = 0.000). Among the patients, 57.4% (31/54) had the MSA-P subtype. There were no significant differences between MSA-P and MSA-C subtypes in the prevalence (χ2 = 1.734, p = 0.188) and severity (χ2 = 1.776, p = 0.412) of clinical RBD. The onset of clinical RBD during the premotor period was not different between the subtypes of MSA, either in patients' number of preceding the onset of motor symptoms (χ2 = 0.581, p = 0.446) or the preceding time (Z = -0.550, p = 0.582). For the MSA-C patients, there was a negative correlation between the score of severity of the RBD scale and RBD preceding motor symptoms (r = -0.482, p = 0.020). CONCLUSION: In our study, the prevalence of clinical RBD is unrelated to the subtypes of MSA. The onset of clinical RBD during the premotor period was not different between subtypes of MSA. However, we found that the severity of RBD occurring before the motor symptoms was more than that occurring after the motor symptoms in MSA-C patients. Our results showed that MSA-P and MSA-C patients may have a probable indicator for the similar pathologic mechanism of the disease and its sleep problems.

High prevalence of serum anti-NH2-terminal of α-enolase antibodies in patients with multiple system atrophy and corticobasal syndrome.

BACKGROUND: Hashimoto's encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. METHODS: We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson's disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. RESULTS: Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. CONCLUSIONS: Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.