Disease severity and progression in progressive supranuclear palsy and multiple system atrophy: validation of the NNIPPS--Parkinson Plus Scale

Abstract

Background: The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study.

Methods and findings: Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar.

Conclusions: The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA.

Trial registration: ClinicalTrials.gov NCT00211224.

Figure 1. Dimensional scores of the PPS according to disease severity.

Dimensional sub scores are expressed as percentage of the maximum possible score in the dimension (as indicated in Table 1, far left column). Comparisons (Student's t tests) were made between the two sub-groups defined by the extreme values of the Clinician Global Impression of disease severity (CGI-ds) in the overall study population. CGI Borderline/Mild illness (score 1–2) n = 93, dotted line; CGI Severe/extremely severe illness (score 5–6) n = 142, solid line. ns: not significant at p<0.003 with Bonferroni correction.

Figure 2. Dimensional profiles of PSP and MSA at entry.

Overall profiles of Parkinson Plus Scale dimensional sub scores at entry for Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA). Dimensional sub scores are expressed as percentage of the total score to evaluate relative contribution of each dimension to overall severity score. Comparisons (Student's t tests) were made between the two strata. PSP n = 362, dotted line; MSA n = 398, solid line. Left: sub scores unrelated to strata inclusion/exclusion criteria- three comparisons reached significance level at p<0.003: Limb bradykinesia, Rigidity and Myoclonia cumulating to 3.4% overall difference in contribution to total score. Right: sub scores related to strata inclusion/exclusion criteria- all differences are significant at p<0.003 with 28.2% overall difference in contribution to total score. Contributions of dimensions related to inclusion criteria amount for 27.6% and 17.3% for PSP and MSA respectively; Contributions of dimensions related to exclusion criteria amount for 4.9% and 11.8% in PSP and MSA respectively.

Figure 3. Predictive validity: 3-year survival according to NNIPPS-PPS total score at entry.

Kaplan-Meier plot of the NNIPPS population broken down by quartiles of the NNIPPS-PPS total score at entry (grouping from lowest to highest severity: Group 1 score [0–65], Group 2 score [66–86], group 3 score [87–109], Group 4 score [110–182]. Log-rank analysis showed a highly significant difference (p<0.0001) between the four score groups with an inversely and linearly ordered survival according to score demonstrating an excellent predictive value of the NNIPPS-PPS.

Figure 4. Profiles of PSP and MSA rates of change in dimensional sub scores.

Left figure: Slopes of change in dimensional sub scores (excluding Cerebellar and Orthostatic sub scores) were expressed as percentage of the maximum possible score in the dimension. Progressive Supranuclear Palsy (PSP), n = 362, dotted line; Multiple System Atrophy (MSA), n = 398, solid line. PSP patients showed higher rates of progression in all but two sub scores (Myoclonia and Tremor) compared to MSA patients. Right figure: For each strata, slopes of change in dimensional sub scores were expressed as percentage of the total score slope of change (excluding Cerebellar and Orthostatic sub scores) to evaluate relative contribution of each dimension to overall severity progression rate. PSP n = 362, dotted line; MSA n = 398, solid line. PSP and MSA showed similar profiles for severity progression with a 15.3% cumulative difference in contribution of dimensions to overall slope, including dimensions related to inclusion/exclusion criteria (Oculomotor, Mental, Urinary, and Tremor). In both diseases, the Akineto-Rigid and Bulbar syndromes were those contributing most to overall severity progression (71.6% and 72.2% for PSP and MSA respectively).