Selective voluntary motor control influences knee joint torque, work and power in children with spastic cerebral palsy.

BACKGROUND: Children with spastic cerebral palsy (CP) have damage to the corticospinal tracts that are responsible for selective motor control (SMC). Force, velocity and timing of joint movement are related biomechanical features controlled by the corticospinal tracts (CSTs) that are important for skilled movement. RESEARCH QUESTION: Does SMC influence knee joint biomechanics in spastic CP? METHODS: In this prospective study, relationships between SMC and knee biomechanics (peak torque, total work, average power) across a range of velocities (0-300 deg/s) were assessed using an isokinetic dynamometer in 23 children with spastic CP. SMC was assessed using Selective Control Assessment of the Lower Extremity (SCALE). Logistic and linear regression models were used to evaluate relationships between SCALE and biomechanical measures. RESULTS: The ability to produce knee torque diminished with increasing velocity for both Low (0-4 points) and High (5-10 points) SCALE limb score groups (p < 0.01). More knees in the High group produced extension torque at 300 deg/s (p < 0.05) and flexion torque at 30, 90,180, 240 and 300 deg/s (p < 0.05). The ability to produce torque markedly decreased above 180 deg/s for Low group flexion. For knees that produced torque, significant positive correlations between SCALE limb scores and joint torque (0 and 120 deg/s), work (120 deg/s) and power (120 deg/s) were found (p < 0.05). Greater knee torque, work and power for the High group was found for the extensors at most velocities and the flexors for up to 120 deg/s (p < 0.05). Few Low group participants generated knee flexor torque above 120 deg/s limiting comparisons. SIGNIFICANCE: Biomechanical impairments found for children with low SMC are concerning as skilled movements during gait, play and sport activities occur at high velocities. Differences in SMC should be considered when designing individualized assessments and interventions.

Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy.

Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.

Functional outcome measures in young, steroid-naïve boys with Duchenne muscular dystrophy.

The purpose of this study was to quantitate motor performance in 196 genetically confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate the test-retest reliability of measures of motor performance in young DMD boys, and to assess correlations among the different functional outcomes including timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a comparative effectiveness study of different steroid regimens in DMD. Eligible boys had to be able to rise from the floor independently and to perform pulmonary function testing consistently. The boys were evaluated with standardized assessments at the screening and baseline visits at 32 sites in 5 countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from floor, timed 10 m walk/run, six-minute walk distance, North Star Ambulatory Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9 years (range 4.1-8.1 years). Test-retest reliability was high for functional assessments, regardless of time lag between assessments (up to 90 days) and for the majority of age groups. Correlations were strong among the functional measures and timed tests, less so with FVC. Physiotherapy measures are reliable in a young, steroid-naïve population and rise from floor velocity appears to be a sensitive measure of strength in this population.

A Longitudinal Study of Quantitative Muscle Strength and Functional Motor Ability in Ambulatory Boys with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder, that is characterized by progressive muscle degeneration and loss of ambulation between 7-13 years of age. Novel pharmacological agents targeting the genetic defects and disease mechanisms are becoming available; however, corticosteroid (CS) therapy remains the standard of care. OBJECTIVE: The purpose of this longitudinal study was to elucidate the effect of CS therapy on the rate of muscle strength and gross motor skill decline in boys with DMD and assess the sensitivity of selected outcome measures. METHODS: Eighty-four ambulatory boys with DMD (49-180 months), 70 on CS, 14 corticosteroid naïve (NCS), participated in this 8-year multi-site study. Outcomes included; isokinetic dynamometry, the Standing (STD) and Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure (GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures determined the rate of change with age and the influence of steroids. RESULTS: Despite CS therapy the rate of decline in strength with age was significant in all muscle groups assessed. CS therapy significantly slowed decline in knee extensor strength, as the NCS group declined at 3x the rate of the CS group. Concurrently, WRJ skills declined in the NCS group at twice the rate of the CS group. 4-stair climb and 10 meter walk/run performance was superior in the boys on CS therapy. CONCLUSION: CS therapy slowed the rate of muscle strength decline and afforded longer retention of select gross motor skills in boys on CS compared to boys who were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may prove informative in assessing the efficacy of new therapeutics in ambulatory boys with DMD.

Brain Metabolism During A Lower Extremity Voluntary Movement Task in Children With Spastic Cerebral Palsy.

Reduced selective voluntary motor control (SVMC) is a primary impairment due to corticospinal tract (CST) injury in spastic cerebral palsy (CP). There are few studies of brain metabolism in CP and none have examined brain metabolism during a motor task. Nine children with bilateral spastic CP [Age: 6-11 years, Gross Motor Function Classification System (GMFCS) Levels II-V] completed this study. SVMC was evaluated using Selective Control Assessment of the Lower Extremity (SCALE) ranging from 0 (absent) to 10 (normal). Brain metabolism was measured using positron emission tomography (PET) scanning in association with a selective ankle motor task. Whole brain activation maps as well as ROI averaged metabolic activity were correlated with SCALE scores. The contralateral sensorimotor and superior parietal cortex were positively correlated with SCALE scores (p < 0.0005). In contrast, a negative correlation of metabolic activity with SCALE was found in the cerebellum (p < 0.0005). Subsequent ROI analysis showed that both ipsilateral and contralateral cerebellar metabolism correlated with SCALE but the relationship for the ipsilateral cerebellum was stronger (R 2 = 0.80, p < 0.001 vs. R 2 = 0.46, p = 0.045). Decreased cortical and increased cerebellar activation in children with less SVMC may be related to task difficulty, activation of new motor learning paradigms in the cerebellum and potential engagement of alternative motor systems when CSTs are focally damaged. These results support SCALE as a clinical correlate of neurological impairment.

Longitudinal community walking activity in Duchenne muscular dystrophy.

INTRODUCTION: Natural history studies for Duchenne muscular dystrophy (DMD) have not included measures of community ambulation. METHODS: Step activity (SA) monitors quantified community ambulation in 42 boys (ages 4-16 years) with DMD with serial enrollment up to 5 years by using a repeated-measures mixed model. Additionally, data were compared with 10-meter walk/run (10mWR) speed to determine validity and sensitivity. RESULTS: There were significant declines in average strides/day and percent strides at moderate, high and pediatric high rates as a function of age (P < 0.05). Significant correlations for 10mWR versus high and low stride rates were found at baseline (P < 0.05). SA outcomes were sensitive to change over 1 year, but the direction and parameter differed by age group (younger vs. older). Changes in strides/day and percentages of high frequency and low frequency strides correlated significantly with changes in 10mWR speed (P < 0.05). DISCUSSION: Community ambulation data provide valid and sensitive real-world measures that may inform clinical trials. Muscle Nerve 57: 401-406, 2018.

Lower-extremity selective voluntary motor control in patients with spastic cerebral palsy: increased distal motor impairment.

AIM: Multiple impairments contribute to motor deficits in spastic cerebral palsy (CP). Selective voluntary motor control (SVMC), namely isolation of joint movement upon request, is important, but frequently overlooked. This study evaluated the proximal to distal distribution of SVMC impairment among lower extremity joints. METHOD: Using a recently developed tool, the Selective Control Assessment of the Lower Extremity (SCALE), we evaluated the SVMC of the hip, knee, ankle, subtalar joint, and toes in a cross-sectional, observational study of 47 participants with spastic, diplegic, hemiplegic, and quadriplegic CP (22 males, 25 females; mean age 11 y 9 mo, SD 4 y 8 mo; Gross Motor Function Classification System levels I-IV). RESULTS: Statistically significant decreases in SCALE scores from hip to toes were found using the Page statistical test for trend (p<0.001). Statistically significant differences (p<0.05) were found between all joint pairs, except toes versus subtalar, toes versus ankle, and right ankle versus subtalar joints. Cross-tabulation of score frequencies for all pairs revealed that proximal joint scores were higher or equal to distal ones 81 to 100% of the time. Excluding toes versus subtalar joints, proximal scores exceeded distal ones 94 to 100% of the time. INTERPRETATION: We confirmed increasing proximal to distal SVMC impairment, which may have implications for treatment and research.

Selective Control Assessment of the Lower Extremity (SCALE): development, validation, and interrater reliability of a clinical tool for patients with cerebral palsy.

Normal selective voluntary motor control (SVMC) can be defined as the ability to perform isolated joint movement without using mass flexor/extensor patterns or undesired movement at other joints, such as mirroring. SVMC is an important determinant of function, yet a valid, reliable assessment tool is lacking. The Selective Control Assessment of the Lower Extremity (SCALE) is a clinical tool developed to quantify SVMC in patients with cerebral palsy (CP). This paper describes the development, utility, validation, and interrater reliability of SCALE. Content validity was based on review by 14 experienced clinicians. Mean agreement was 91.9% (range 71.4-100%) for statements about content, administration, and grading. SCALE scores were compared with Gross Motor Function Classification System Expanded and Revised (GMFCS-ER) levels for 51 participants with spastic diplegic, hemiplegic, and quadriplegic CP (GMFCS levels I - IV, 21 males, 30 females; mean age 11y 11mo [SD 4y 9mo]; range 5-23y). Construct validity was supported by significant inverse correlation (Spearman's r=-0.83, p<0.001) between SCALE scores and GMFCS levels. Six clinicians rated 20 participants with spastic CP (seven males, 13 females, mean age 12y 3mo [SD 5y 5mo], range 7-23y) using SCALE. A high level of interrater reliability was demonstrated by intraclass correlation coefficients ranging from 0.88 to 0.91 (p<0.001).