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

PURPOSE: The 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. METHODS: Expert 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. RESULTS: The 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. CONCLUSIONS: Because 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.

Long-Term Outcomes of Hyperadrenergic Orthostatic Hypotension.

Purpose: Hyperadrenergic orthostatic hypotension is a subtype of orthostatic hypotension associated with elevated norepinephrine levels upon standing. Our previous study found that this subtype is characterized by less severe autonomic impairment compared to orthostatic hypotension with normal or low norepinephrine levels. However, long-term outcomes have not been determined. Thus, the purpose of this study was to evaluate the all-cause mortality and phenoconversion over 7 years. Methods: In this prospective observational study, 92 patients with orthostatic hypotension were recruited from the Vanderbilt Autonomic Dysfunction Center. 34 patients with upright norepinephrine levels above 600 pg/mL were included in the hyperadrenergic cohort and 58 composed the orthostatic hypotension cohort. Both cohorts were followed for 7 years while assessing all-cause mortality and phenoconversion to neurodegenerative autonomic disorders. Results: Hyperadrenergic patients showed an exaggerated orthostatic increase in norepinephrine to 938 ± 305 pg/mL upon head up tilt despite presenting with impaired autonomic reflexes. The 7-year mortality rate was 35% in the hyperadrenergic cohort compared to 22% in orthostatic hypotension (p = 0.01). The hyperadrenergic cohort had a greater phenoconversion rate to multiple system atrophy (p = 0.04), whereas the orthostatic hypotension cohort had greater phenoconversion to Parkinson's disease and dementia with Lewy bodies. Conclusions: Despite having less severe autonomic impairment, our data suggests that hyperadrenergic orthostatic hypotension has worse clinical outcomes than neurogenic orthostatic hypotension. Patients with hyperadrenergic orthostatic hypotension require careful monitoring, given that this condition may be associated with negative outcomes.

Diagnostic Value of Combined Acute Levodopa Challenge and Olfactory Testing to Predict Parkinson's Disease.

BACKGROUND: The diagnosis of Parkinson's disease (PD) can be challenging early in the disease course, when motor features are subtle. The objective of this study was to explore the diagnostic value of combining acute levodopa challenge and olfactory testing to predict PD. METHODS: Data from 210 patients with a recent onset of parkinsonism who had at least 2 years of follow-up and underwent acute levodopa challenge for the clinical prediction of long-term dopaminergic response and had olfactory testing with Sniffin' Sticks Test were evaluated. Single and combined diagnostic measures were analyzed. RESULTS: After 2 years of follow-up, a PD diagnosis was confirmed in 157 patients who fulfilled United Kingdom Parkinson's Disease Society Brain Bank criteria and was ruled out in 53. Sensitivity and specificity of acute levodopa challenge to predict PD diagnosis were 0.71 and 0.94, respectively. Sensitivity and specificity of olfactory tests were calculated according to the total olfactory score for hyposmia (0.61 and 0.77 respectively), the hyposmia identification subscore (0.63 and 0.74, respectively), and the anosmia score (0.40 and 0.85, respectively). The best combination identified was response to acute levodopa challenge together with hyposmia according to the total olfactory score (sensitivity, 0.90; specificity, 0.74; positive predictive value, 0.91; negative predictive value, 0.72; accuracy, 0.86). CONCLUSION: The combination of response to acute levodopa challenge with hyposmia according to the total olfactory score improved sensitivity for the early diagnosis of PD.