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

Background Outcome 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. Objective To determine whether the three-component MSFC or a modified MSFC with LCLA and the SDMT better identifies neurological deficits in pediatric MS. Methods We 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. Results Twenty 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). Conclusions A 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.

The Multiple Sclerosis Functional Composite and Symbol Digit Modalities Test as outcome measures in pediatric multiple sclerosis

“…These contrasting findings may be secondary to our study population, which includes a larger age- and sex-matched control population. Consistent with a prior report, 16 our data support the utility of the 9HPT to reliably discriminate pediatric MS patients from healthy controls. With a median disease duration of 2 years in this cohort, our collective data would suggest that early impairments in several neurocognitive and physical domains are present and quantifiable via the metrics studied.…”

“…SDMT has been considered a valid tool to assess this particular impairment in patients with MS and has been an outcome measure of interest, particularly for pediatric MS clinical trials. 12–14,16 Like these previous publications, our data support the use of the SDMT in discriminating between healthy, non-MS peers and pediatric MS patients. Interestingly, performance variability among the MS cohort was relatively low, despite variable disease durations.…”

“…However, Waldman and colleagues did assess its value in 20 pediatric MS patients versus 13 healthy controls and found no discriminatory value between their cohorts. 16 Our data supports the individual abilities of the T25FW and PASAT to significantly discriminate pediatric MS patients from age- and sex-matched, non-MS peers. These contrasting findings may be secondary to our study population, which includes a larger age- and sex-matched control population.…”

“…12–15 There is a paucity of data assessing the utility of the timed-25-foot walk (T25FW), paced auditory serial addition test (PASAT), and 9-hole peg test (9HPT) within a pediatric MS cohort. 16 In this study, we aim to characterize the utility of current adult-validated MS assessments in differentiating pediatric MS patients from healthy, non-MS peers, which serves as a first step toward identifying outcome measures that may be more sensitive in detecting the impairments that are noted in pediatric MS.…”

A systematic literature review of the burden of pediatric multiple sclerosis in North America and Europe

“…These studies reported that patients with pediatric MS experience significantly worse fatigue than healthy controls. Overall, the results of the European studies were similar to those from the North American studies, highlighting fatigue as a common symptom experienced by patients with pediatric MS. (32,59,(73)(74)(75)(76)(77)(78)(79)(80). In these studies, the percentage of patients with cognitive impairment ranged from 32% to 35%.…”