Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

Pain in Parkinson's Disease: Current Concepts and a New Diagnostic Algorithm.

BACKGROUND: Pain is a significant burden for patients with Parkinson's disease (PD) with a high impact on quality of life. The present article aims at summarizing epidemiological, pathophysiological, clinical, and neurophysiological data regarding pain in PD. METHODS: In this domain, a procedure of systematic assessment is still lacking for the syndromic diagnosis and should take into account pain characteristics, effects of dopaminergic treatment, motor fluctuations, and non-PD-associated pain. FINDINGS: We propose an original questionnaire addressing an algorithm suitable for daily clinical practice. The questionnaire is based on a three-step approach addressing first the relationship between pain and PD (including temporal relationship with the course of the disease, association with motor fluctuations, and impact of antiparkinsonian treatment), before classifying pain into one of three main syndromes (i.e., musculoskeletal pain, psychomotor restlessness pain, and neuropathic pain). CONCLUSIONS: The proposed questionnaire allows the characteristics of each pain type to be determined according to its relationship with the disease and its treatment. The validation of the clinical use of this questionnaire will be the goal of a forthcoming work.

The natural history of multiple system atrophy: a prospective European cohort study.

BACKGROUND: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. METHODS: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. FINDINGS: 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1-11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09-3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02-4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5-0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1-10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. INTERPRETATION: Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.

Affective and cognitive Theory of Mind in patients with parkinson's disease.

Theory of Mind (ToM), which is the ability to infer other people's mental states such as beliefs or desires, is an important prerequisite for social interaction. Affective and cognitive subcomponents of ToM can be impaired selectively in neurological and psychiatric disorders. This study examines ToM in 21 Parkinson's disease (PD) patients and 21 healthy control (HC) subjects, using the computerized "Yoni task" that assesses affective and cognitive ToM abilities and an extensive battery of neuropsychological tests. Furthermore, questionnaires to assess health-related quality of life and depressive symptoms were applied and correlations to ToM were investigated. Compared to the control subjects, PD patients scored lower on both the affective (PD: 76% versus HC: 89%; p = 0.006) and cognitive (PD: 80% versus HC: 92%; p = 0.002) ToM subscales but not on control items (PD: 90% versus HC: 95%; p = 0.077). The ToM abilities were not associated with other cognitive functions, depressive symptoms or clinical data. However, affective ToM was correlated with health-related quality of life (p = 0.01). Parkinson patients are impaired in affective as well as cognitive ToM. These deficits are largely independent from other cognitive impairments, depressive symptoms and motor impairment. The relationship of affective ToM to the health-related quality of life of PD patients points to a clinical relevance of this issue and suggests that ToM dysfunctions must be regarded as an important non-motor feature of Parkinson's disease.

Predictors of freezing in Parkinson's disease: a survey of 6,620 patients.

Data from a survey of 6,620 Parkinson's disease patients were examined for correlation of freezing with age, sex, duration, subjective severity of Parkinson's disease, and antiparkinsonian medication. Forty-seven percent of the patients reported experiencing freezing regularly. Logistic regression analysis showed that freezing was significantly associated with a longer disease duration and a more advanced stage of the disease. Freezing episodes were more likely in men than in women and in patients taking, in addition to levodopa, Entacapone, Amantadine, or dopamine agonists. Finally, patients considering tremor as their main symptom reported freezing less frequently. Common antiparkinsonian drugs given in combination with levodopa were not negatively correlated with freezing. The results underline the necessity to develop appropriate countermeasures against this phenomenon, which is widely known to cause significant impairment of patients' quality of life and - as our data also showed - may cause traffic accidents in licensed patients.