Binocular low-contrast letter acuity and the symbol digit modalities test improve the ability of the Multiple Sclerosis Functional Composite to predict disease in pediatric multiple sclerosis

Abstract

BackgroundOutcome measures to capture disability, such as the Multiple Sclerosis Functional Composite (MSFC), were developed to enhance outcome measurements for clinical trials in adults with multiple sclerosis (MS). The MSFC initially included three components: a timed 25-foot walk [T25FW], 9-hole peg test [9HPT], and the Paced Auditory Serial Addition Task [PASAT]. Modifications to the original MSFC, such as adding binocular low-contrast letter acuity (LCLA) or substituting the symbol digit modalities test (SDMT) for the PASAT, improved the capacity to capture neurologic impairment in adults. Similar outcome scales for pediatric MS have not yet been established. ObjectiveTo determine whether the three-component MSFC or a modified MSFC with LCLA and the SDMT better identifies neurological deficits in pediatric MS. MethodsWe evaluated 5 measures (T25FW, 9HPT, Children's PASAT [ChiPASAT], SDMT, and binocular LCLA [Sloan charts, 1.25% contrast]) in children with MS (disease onset <18 years) and healthy controls. To be able to compare measures whose scores have different scales, Z-scores were also created for each test based on the numbers of standard deviations from a control group mean, and these individual scale scores were combined to create composite scores. Logistic regression models, accounting for age, were used to determine whether the standard 3-component MSFC or modified versions (including 4 or 5 metrics) best distinguished children with MS from controls. ResultsTwenty pediatric-onset MS subjects, aged 6–21 years, and thirteen healthy controls, aged 6–19 years, were enrolled. MS subjects demonstrated worse scores on the 9HPT (p=0.004) and SDMT (p=0.001), but not the 25FTW (adjusted for height, p=0.63) or the ChiPASAT (p=0.10): all comparisons adjusted for age. Decreased (worse) binocular LCLA scores were associated with MS (vs. control status, p=0.03, logistic regression; p=0.08, accounting for age). The MSFC composite score for the traditional 3 components did not differ between the groups (p=0.28). Replacing the ChiPASAT with the SDMT (OR 0.72, p=0.05) better distinguished MS from controls. A modified MSFC-4 with the SDMT replacing the ChiPASAT and including binocular 1.25% LCLA had the greatest capacity to distinguish pediatric MS from controls (OR 0.89, p=0.04, logistic regression). Including all 5 metrics as a composite MSFC-5 did not improve the model (p=0.18). ConclusionsA modified MSFC (25FTW, 9HPT, SMDT, and binocular 1.25% LCLA) is more sensitive than the traditional MSFC or its components to capture the subtle impairments that characterize pediatric MS and should be validated in order to be considered for future pediatric MS trials.