Carole Vuillerot

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).

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.

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.

Influence of a two-year steroid treatment on body composition as measured by Dual X-Ray Absorptiometry in boys with Duchenne Muscular Dystrophy

Steroids are nowadays routinely used as a long-term treatment in Duchenne muscular dystrophy (DMD). Their effects on body composition were assessed using dual X-ray absorptiometry. The study followed over 2 years 29 genetically confirmed DMD patients: 21 in the steroid-treated group and 8 in the steroid-naïve group. After 2 years of steroid treatment, the lean tissue mass values increased significantly (p<0.0001), the percentage of body fat mass remained practically constant (p=0.94) in comparison with the initial visit. In the steroid-naïve patients, there were no significant increases in the lean tissue mass but deterioration in body composition confirmed by a significant increase in the percentage of body fat mass. Besides, significant negative correlations were found between the percentage of body fat mass and the MFM total score (R=-0.79, n=76, p<0.0001). A 2-year steroid treatment improves significantly body composition of boys with DMD through a significant increase in lean tissue mass. We suggest that a thorough check of body composition should be carried out before steroid treatment discontinuation in case of overweight gain.

English Cross-Cultural Translation and Validation of the Neuromuscular Score: A System for Motor Function Classification in Patients With Neuromuscular Diseases

OBJECTIVE To develop and validate an English version of the Neuromuscular (NM)-Score, a classification for patients with NM diseases in each of the 3 motor function domains: D1, standing and transfers; D2, axial and proximal motor function; and D3, distal motor function. DESIGN Validation survey. SETTING Patients seen at a medical research center between June and September 2013. PARTICIPANTS Consecutive patients (N=42) aged 5 to 19 years with a confirmed or suspected diagnosis of congenital muscular dystrophy. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES An English version of the NM-Score was developed by a 9-person expert panel that assessed its content validity and semantic equivalence. Its concurrent validity was tested against criterion standards (Brooke Scale, Motor Function Measure [MFM], activity limitations for patients with upper and/or lower limb impairments [ACTIVLIM], Jebsen Test, and myometry measurements). Informant agreement between patient/caregiver (P/C)-reported and medical doctor (MD)-reported NM scores was measured by weighted kappa. RESULTS Significant correlation coefficients were found between NM scores and criterion standards. The highest correlations were found between NM-score D1 and MFM score D1 (ρ=-.944, P<.0001), ACTIVLIM (ρ=-.895, P<.0001), and hip abduction strength by myometry (ρ=-.811, P<.0001). Informant agreement between P/C-reported and MD-reported NM scores was high for D1 (κ=.801; 95% confidence interval [CI], .701-.914) but moderate for D2 (κ=.592; 95% CI, .412-.773) and D3 (κ=.485; 95% CI, .290-.680). Correlation coefficients between the NM scores and the criterion standards did not significantly differ between P/C-reported and MD-reported NM scores. CONCLUSIONS Patients and physicians completed the English NM-Score easily and accurately. The English version is a reliable and valid instrument that can be used in clinical practice and research to describe the functional abilities of patients with NM diseases.

Orthopedic Management of Scoliosis by Garches Brace and Spinal Fusion in SMA Type 2 Children

Background: Scoliosis is the most debilitating issue in SMA type 2 patients. No evidence confirms the efficacy of Garches braces (GB) to delay definitive spinal fusion. Objective: Compare orthopedic and pulmonary outcomes in children with SMA type 2 function to management. Method: We carried out a monocentric retrospective study on 29 SMA type 2 children who had spinal fusion between 1999 and 2009. Patients were divided in 3 groups: group 1-French patients (12 children) with a preventive use of GB; group 2-French patients (10 children) with use of GB after the beginning of the scoliosis curve; and group 3-Italian patients (7 children) with use of GB after the beginning of the scoliosis curve referred to our centre to perform orthopedic preoperative management. Results: Mean preoperative and postoperative Cobb angle were significantly lower in the group 1 of proactively braced than in group 2 or 3 (Anova p = 0.03; Kruskal Wallis test p = 0.05). Better surgical results were observed in patients with a minor preoperative Cobb angle (r = 0.92 p <  0.0001). Fewer patients in the group 1 proactively braced required trunk casts and/or halo traction and an additional anterior fusion in comparison with patients in the group 2 and 3. Moreover, major complications tend to be less in the group 1 proactively braced. No significant differences were found between groups in pulmonary outcome measures. Conclusions: A proactive orthotic management may improve orthopedic outcome in SMA type 2. Further prospective studies comparing SMA management are needed to confirm these results. Level of Evidence: Therapeutic Level III. See Instructions to Authors on jbjs.org for a complete description of levels of evidence (Retrospective comparative study).

Nusinersen in spinal muscular atrophy type 1 patients older than 7 months: A cohort study

Objective To evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1). Methods Patients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Childrens Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32). Results We treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (SMN2) gene. Conclusions Our results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease. ClinicalTrials.gov identifier: NCT02865109. Classification of evidence This study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.

Validation of a Digital Interface for Assessment of Motor Function Based on MFM

Patients with neuromuscular diseases undergo frequent motor assessments. The MFM scale (Motor Function Measure) is a validated scale for all neuromuscular diseases. Tasks 18, 19, and 22 have the potential to have a digitized version on a Tablet. This article proposes to digitalize a first version of items 18, 19 and 22 based on MFM. The results show that the scores were similar for the Tablet version and the paper version.

Is going beyond Rasch analysis necessary to assess the construct validity of a motor function scale

OBJECTIVE To examine whether a Rasch analysis is sufficient to establish the construct validity of the Motor Function Measure (MFM) and discuss whether weighting the MFM item scores would improve the MFM construct validity. DESIGN Observational cross-sectional multicenter study. SETTING Twenty-three physical medicine departments, neurology departments, or reference centers for neuromuscular diseases. PARTICIPANTS Patients (N=911) aged 6 to 60 years with Charcot-Marie-Tooth disease (CMT), facioscapulohumeral dystrophy (FSHD), or myotonic dystrophy type 1 (DM1). INTERVENTIONS None. MAIN OUTCOME MEASURE(S) Comparison of the goodness-of-fit of the confirmatory factor analysis (CFA) model vs that of a modified multidimensional Rasch model on MFM item scores in each considered disease. RESULTS The CFA model showed good fit to the data and significantly better goodness of fit than the modified multidimensional Rasch model regardless of the disease (P<.001). Statistically significant differences in item standardized factor loadings were found between DM1, CMT, and FSHD in only 6 of 32 items (items 6, 27, 2, 7, 9 and 17). CONCLUSIONS For multidimensional scales designed to measure patient abilities in various diseases, a Rasch analysis might not be the most convenient, whereas a CFA is able to establish the scale construct validity and provide weights to adapt the item scores to a specific disease.

Clinical practices in intrathecal baclofen pump implantation in children with cerebral palsy in France.

Cerebral palsy (CP) encompasses an array of permanent movement and posture disorders leading to activity limitations caused by events or non-progressive pathologies affecting the developing brain. In CP, motor disorders are often associated with sensory, perception, cognitive, communication and behavioral disorders, epilepsy and secondary musculoskeletal problems [1]. One of the commonly used therapeutics in CP is baclofen [2], which inhibits presynaptic and excitatory neurotransmitters [2]. The 2009 guidelines of the French healthcare safety agency Agence Nationale de Sécurité du Medicament recommend intrathecal baclofen (ITB) therapy via pump infusion for patients with widely distributed spasticity of the lower limbs diffusing to the trunk (Grade A recommendation) [3]. Studies with a high level of scientific evidence demonstrated that ITB was the most effective treatment for spasticity in CP patients with Gross Motor Function Classification System (GMFCS) grades IV and V [2,4]. A European consensus [5] has been established on the appropriate use of ITB mainly for non-ambulatory children with CP (GMFCS grade IV or V) [2,4]. However, in France, because of the great heterogeneity of patient conditions and medical practices, no standard of care has been established for ITB therapy. We performed a survey of the current use of ITB via pump infusion in children seen in pediatric physical medicine and rehabilitation (PMR) departments in France to describe practices and to establish specific guidelines. We also surveyed the literature for practices. The evaluation involved a questionnaire survey about clinical practices, specifically pump implantation and follow-up after ITB, with 108 closed questions regarding full management of ITB from patient selection to post-implantation follow-up. In May 2012, the questionnaire was sent by email to 29 heads of pediatric PMR departments all over France to be distributed via the French society for research in patients with disabilities (SFERHE) network to all physicians (PMR physicians, child neurologists) and surgeons