Instrumented strength assessment in typically developing children and children with a neural or neuromuscular disorder: A reliability, validity and responsiveness study.

The aim of this study was to determine the clinimetric properties, i.e., reliability, validity and responsiveness of an instrumented strength assessment in typically developing (TD) children and children with cerebral palsy (CP) and Duchenne muscular dystrophy (DMD). Force (N), torque (Nm) and normalized torque (Nm/kg) were defined for maximal voluntary isometric contractions (MVICs) of the lower limb muscles using a pre-established protocol. Intraclass correlation coefficient (ICC), standard error of measurement (SEM) and minimal detectable change (MDC) of TD children (n = 14), children with CP (n = 11) and DMD (n = 11) were used to evaluate intra-rater reliability for the three cohorts and the inter-rater intersession as well as inter-rater intrasession reliability for TD children. Construct validity was assessed by comparing MVICs in TD children (n = 28) to children with CP (n = 26) and to children with DMD (n = 30), using the Kruskal Wallis and post-hoc Mann-Whitney U tests. Responsiveness was investigated by assessing changes in MVICs following a strength intervention in CP (n = 26) and a 1 and 2 year follow-up study in DMD (n = 13 and n = 6, respectively), using the Wilcoxon Signed-Rank test. The overall intra-rater reliability, was classified as good to excellent for 65.1%, moderate for 27.0% and poor for 7.9% of the measures (47.6%, 76.2%, and 66.7% good-excellent; 28.6%, 23.8%, and 33.7% moderate; 23.8%, 0%, and 0% poor in TD, CP, and DMD, respectively), while ICC values for TD children were slightly lower for inter-rater intrasession reliability (38.1% good-excellent, 33.3% moderate and 26.6% poor) and for inter-rater intersession reliability (47.6% good-excellent, 23.8% moderate and 28.6% poor). Children with CP and DMD were significantly weaker than TD children (p < 0.001) and the majority of these strength differences exceeded the MDC. Children with CP significantly improved strength after training, with changes that exceeded the SEMs, whereas only limited strength decreases over time were observed in the DMD cohort. In conclusion, the investigated instrumented strength assessment was sufficiently reliable to confirm known-group validity for both cohorts and could detect the responsiveness of children with CP after a strength intervention. However, more research is necessary to determine the responsiveness of this assessment in children with DMD regarding their natural decline.

Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls.

Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean ΔNSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0 -0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ΔNSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD.

North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up.

INTRODUCTION: The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. MATERIALS AND METHODS: We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52. RESULTS: The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001). DISCUSSION: Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up. CONCLUSION: Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.

Improving Care and Empowering Adults Living with SMA: A Call to Action in the New Treatment Era.

While Spinal Muscular Atrophy (SMA) has historically been managed with supportive measures, the emergence of innovative medicines has given those living with SMA hope for improved quality of life and has revolutionized care. Despite these advances, the use of therapies and changes in disease management strategies have focused on pediatric populations, leaving adults living with SMA, and those transitioning into adulthood, relatively neglected. Through a multi-faceted approach that gathered unbiased perspectives from clinical experts, validated insights from individuals with lived experiences, and substantiated findings with evidence from the literature, we have exposed unmet needs that are hindering the field and, ultimately, impacting care and quality of life for adults living with SMA. Here, we set new aspirations and calls to action to inspire continued research in this field, stimulate dialogue across the SMA community and inform policies that deliver effective management and care throughout an adult's journey living with SMA.

A new strength assessment to evaluate the association between muscle weakness and gait pathology in children with cerebral palsy.

AIM: The main goal of this validation study was to evaluate whether lower limb muscle weakness and plantar flexor rate of force development (RFD) related to altered gait parameters in children with cerebral palsy (CP), when weakness was assessed with maximal voluntary isometric contractions (MVICs) in a gait related test position. As a subgoal, we analyzed intra- and intertester reliability of this new strength measurement method. METHODS: Part 1 -Intra- and intertester reliability were determined with the intra-class correlation coefficient (ICC2,1) in 10 typical developing (TD) children (age: 5-15). We collected MVICs in four lower limb muscle groups to define maximum joint torques, as well as plantar flexor RFD. Part 2 -Validity of the strength assessment was explored by analyzing the relations of lower limb joint torques and RFD to a series of kinematic- and kinetic gait features, the GDI (gait deviation index), and the GDI-kinetic in 23 children with CP (GMFCS I-II; age: 5-15) and 23 TD children (age: 5-15) with Spearman's rank correlation coefficients. RESULTS: Part 1 -The best reliability was found for the torque data (Nm), with the highest ICC2,1 (0.951) for knee extension strength (inter) and the lowest (0.693) for dorsiflexion strength (intra). For plantar flexor RFD, the most reliable window size was 300 milliseconds (ICC2,1: 0.828 (inter) and 0.692 (intra)). Part 2 -The children with CP were significantly weaker than the TD children (p <0.001). Weakness of the dorsiflexors and plantar flexors associated with delayed and decreased knee flexion angle during swing, respectively. No other significant correlations were found. CONCLUSION: While our new strength assessment was reliable, intra-joint correlations between weakness, RFD, and gait deviations were low. However, we found inter-joint associations, reflected by a strong association between plantar- and dorsiflexor weakness, and decreased and delayed knee flexion angle during swing.

Gait assessment in children with duchenne muscular dystrophy during long-distance walking.

The aim of this study was to investigate the alteration of the gait pattern in 25 children with Duchenne muscular dystrophy, using body-worn inertial sensors during a long walking distance. Normalized spatiotemporal gait parameters and their variability were extracted from the angular velocity of the shanks; the smoothness of the trunk movement was assessed based on the spectral entropy of the acceleration norm. As compared to healthy children, patients with Duchenne muscular dystrophy showed significantly lower stride velocity and a less smooth trunk movement. When the group of patients was divided into mild and moderate based on the Motor Function Measure, the authors noticed significantly higher values both for cadence and stride velocity, as well as improved trunk smoothness in the mild versus moderate group. The potential of such parameters to distinguish between different disease states opens new perspectives for the objective assessment of efficacy of the new therapies associated with Duchenne muscular dystrophy.