Use of MFM-20 to monitor SMA types 1 and 2 patients treated with nusinersen.

OBJECTIVE: To evaluate sensitivity to change and discriminant validity of the 20-item Motor Function Measure (MFM-20) in 2-7-year-old patients with spinal muscular atrophy types 1 (SMA1) or 2 (SMA2) treated with nusinersen. METHODS: Children aged 2 to 7 years old with SMA1 or SMA2 treated with nusinersen were assessed at least three times using the MFM-20 over an average follow-up time of 17 months. Evolution of 4-month-standardized MFM-20 scores was calculated for each MFM-20 domain (D1 standing and transfers, D2 axial and proximal, D3 distal) and for the total score (TS). RESULTS: Included in the study were 22 SMA1 subjects and 19 SMA2 subjects. Baseline MFM scores were significantly lower in patients with SMA1 than SMA2 (TS 29.5% vs. 48.3%, D1 4.5% vs. 10.6%, D2 43.6% vs. 72.6%, D3 51.2% vs. 75.0%). When considering the mean change during nusinersen treatment, standardized over a 4-month period, TS was improved for both SMA1 (+ 4.1%, SRM 1.5) and SMA2 (+ 2.8%, SRM 0.89) patients. For SMA1 patients, considerable changes were observed in D2 (+ 6.2%, SRM 0.89) and D3 (+ 6.0%, SRM 0.72), whereas the change in D1 was small (+ 0.5%, SRM 0.44). In SMA2 2 subjects, D3 was improved to a larger extent (+ 4.2%, SRM 0.53) than D1 (+ 1.8% SRM 0.63) or D2 (+ 3.2%, SRM 0.69). CONCLUSION: Our results validate use of MFM-20 to monitor function of young SMA1 and SMA2 subjects treated with nusinersen. Significant motor function improvements following treatment were observed in both SMA1 and SMA2 patients.

Motor function measure: validation of a short form for young children with neuromuscular diseases.

OBJECTIVE: To validate a useful version of the Motor Function Measure (MFM) in children with neuromuscular diseases aged <7 years old. DESIGN: Two prospective cohort studies that documented the MFM completion of children aged between 2 and 7 years old. SETTING: French-speaking rehabilitation departments from France, Belgium, and Switzerland. PARTICIPANTS: Healthy children (n=194) and children with a neuromuscular disease (n=88). INTERVENTIONS: Patients were rated by the MFM either once or twice by trained medical professionals, with a delay between the 2 MFMs ranging between 8 and 30 days. MAIN OUTCOME MEASURE: Intra- and interrater reliability of the MFM. RESULTS: The subtests making up the MFM-32, a scale monitoring severity and progression of motor function in patients with a neuromuscular disease in 3 functional domains, were carried out in healthy children aged 2 to 7 years. Twenty items of the MFM-32 were successfully completed by these children and were used to constitute the MFM-20. Principal component analysis of the MFM-20 confirmed the 3 functional domains. Inter- and intrarater reliability of the 3 subscores and total score were high (intraclass correlation coefficient >.90), and discriminant validity was good. CONCLUSIONS: The MFM-20 can be used as an outcome measure for assessment of motor function in young children with neuromuscular disease.

Evidence-Based, Implementable Motor Rehabilitation Guidelines for Individuals With Cerebral Palsy.

BACKGROUND: Cerebral palsy is a life-long condition that causes heterogeneous motor disorders. Motor rehabilitation interventions must be adapted to the topography of the symptoms, ambulatory capacity, and age of the individual. Current guidelines do not differentiate between the different profiles of individuals with cerebral palsy, which limits their implementation. OBJECTIVES: To develop evidence-based, implementable guidelines for motor rehabilitation interventions for individuals with cerebral palsy according to the age, topography of the cerebral palsy, and ambulatory capacity of the individual and to determine a level of priority for each intervention. METHODS: We used a mixed methods design that combined a systematic review of the literature on available motor rehabilitation interventions with expert opinions. Based on the French National Authority for Health methodology, recommendations were graded as strong, conditional, or weak. Interventions were then prioritized by the experts according to both the evidence and their own opinions on relevance and implementability to provide a guide for clinicians. All recommendations were approved by experts who were independent from the working group. RESULTS: Strong recommendations as first-line treatments were made for gait training, physical activities, and hand-arm bimanual intensive therapy for all children and adolescents with cerebral palsy. Moderate recommendations were made against passive joint mobilizations, muscle stretching, prolonged stretching with the limb fixed, and neurodevelopmental therapies for all children and adolescents with cerebral palsy. Strong recommendations as first-line treatments were made for gait training for all adults with cerebral palsy and moderate recommendations as moderate importance interventions for strengthening exercises and ankle-foot orthoses for motor impairment of the feet and the ankles. DISCUSSION: These guidelines, which combine research evidence and expert opinions, could help individuals with cerebral palsy and their families to codetermine rehabilitation goals with health professionals, according to their preferences.

Monitoring changes and predicting loss of ambulation in Duchenne muscular dystrophy with the Motor Function Measure.

AIM: To assess changes in motor function in patients with Duchenne muscular dystrophy using the Motor Function Measure (MFM). METHOD: Three studies were performed. Two studies included only physiotherapy-treated patients, with 13 patients (males mean age 11y 7mo, SD 1y 10mo, range 8-14y) in the 3-month study and 41 patients (males mean age 14y 1mo, SD 5y 5mo, range 6-32y) in the 1-year study. A third study compared 12 patients treated with steroids with 12 age- and motor-function-matched untreated patients (males mean age of treated patients 10y 2mo, SD 2y 2mo range 6-14) over a 12-month period. RESULTS: Over 3 months, the MFM D1 subscore (standing and transfers) decreased significantly (-4.7%; p<0.01). Over 1 year, all MFM subscores decreased significantly: -4.9% for D1 (p<0.01); -7.7% for D2 (axial and proximal motor capacity; p<0.01); -4.3% for D3 (distal motor capacity; p=0.03); and -5.8% for the total score (p<0.01). A threshold value for loss of ambulation and a predictive value 1 year before loss were estimated (total score 70% and D1 subscore 40%). Compared with the controls, patients treated with steroids had more stable total scores (-0.59 vs -5.87; p=0.02) and D2 subscores (0.98 vs -8.50; p<0.01). INTERPRETATION: These results support the use of the MFM in everyday patient management to prepare for loss of ambulation and in clinical trials to follow up patients receiving various treatments.

X-linked myotubular myopathy: A prospective international natural history study.

OBJECTIVES: Because X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures. METHODS: We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored. RESULTS: Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti-adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10. CONCLUSIONS: Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population. CLINICALTRIALSGOV IDENTIFIER: NCT02057705.

Motor and respiratory heterogeneity in Duchenne patients: implication for clinical trials.

AIMS: Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD). METHODS: The French dystrophinopathy database provided clinical, histochemical and molecular data of 278 DMD patients (mean longitudinal follow-up: 14.2 years). Diagnosis was based on mutation identification in the DMD gene. Three groups were defined according to the age at ambulation loss: before 8 years (group A); between 8 and 11 years (group B); between 11 and 16 years (group C). RESULTS: Motor and respiratory declines were statistically different between the three groups, as opposed to heart involvement. When acquired, running ability was lost at the mean age of 5.41 (group A), 7.11 (group B), 9.19 (group C) years; climbing stairs ability at 6.24 (group A), 7.99 (group B), 10,42 (group C) years, and ambulation at 7.10 (group A), 9.25 (group B), 12.01 (group C) years. Pulmonary growth stopped at 10.26 (group A), 12.45 (group B), 14.58 (group C) years. Then, forced vital capacity decreased at the rate of 8.83 (group A), 7.52 (group B), 6.03 (group C) percent per year. Phenotypic variability did not rely on specific mutational spectrum. CONCLUSION: Beside the most common form of DMD (group B), we provide detailed description on two extreme clinical subgroups: a severe one (group A) characterized by early severe motor and respiratory decline and a milder subgroup (group C). Compared to group B or C, four to six times fewer patients from group A are needed to detect the same decrease in disease progression in a clinical trial.

Multidimensional outcome assessment in cerebral palsy: is it feasible and relevant?

BACKGROUND: To examine feasibility and relevance of a multidimensional outcome assessment approach using instrumented 3-dimensional gait analysis, via the Gillette Gait Index (GGI), and a set of validated functional and health-related quality of life tools in diplegic cerebral palsy children, before introduction as a nationwide evaluation set. METHODS: A 3-year prospective government-funded multicenter study was conducted, recruiting patients during a 9-month period classified using the Gross Motor Function Classification System and the Rodda et al sagittal walking patterns. The Gross Motor Classification System Dimensions D and E, the 10-level Gillette Functional Assessment Questionnaire, the Energy Expenditure Index (EEI), the GGI out of 3D gait analysis, and health-related quality of life, assessed by self or proxy with the questionnaire "Vècu et Santè Perçu de l'Adolescent," were selected for the study. RESULTS: Cross-sectional data subset at inclusion of 160 spastic diplegic cerebral palsy patients, the largest series in our country, 6 to 18 years old (mean age, 11.0 years), are reported. The GGI correlated significantly (P < 0.001) with the Gross Motor Classification System, the Functional Assessment Questionnaire, and the EEI for all the patients, and all but one (EEI) correlated if grouped according to Gross Motor Function Classification System or Rodda. No systematic correlation was found between the quality of life scores and the other outcome tools. CONCLUSIONS: The outcome evaluation instrument set tested in our study helps to adopt common tools, to be integrated in an evidence-based practice and to compare health status and treatment outcome between countries, specifically in different linguistic environments like in European countries.