V. Tiffreau

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.

Intrathecal Baclofen in Subjects With Spastic Hemiplegia: Assessment of the Antispastic Effect During Gait

OBJECTIVE To determine whether leg muscle stiffness is measurably reduced after intrathecal baclofen (ITB) in subjects with spastic hemiplegia. DESIGN Nonrandomized trial. SETTING Inpatient multidisciplinary rehabilitation unit in France. PARTICIPANTS Seven consecutive subjects with spastic hemiplegia having Ashworth Scale scores for their quadriceps and triceps greater than 2. INTERVENTION Subjects were given ITB by lumbar puncture after a dose-selecting test period. MAIN OUTCOME MEASURES Triceps and quadriceps Ashworth scores, gait analysis at preferred and maximal speed measured by a motion analysis system with 2 forceplates, and electromyographic recording of leg muscles before and 4 hours after ITB. The slopes of the moment-angle curves were measured on the hemiplegic side at the onset of ankle and knee flexion to assess muscle stiffness during walking. Pre- and post-ITB spatiotemporal, kinetic, and kinematic data were compared by using a nonparametric test (Wilcoxon signed-rank test). RESULTS Ashworth scores of the quadriceps and triceps of all subjects decreased significantly after ITB. Maximal walking speed increased significantly, with a significant increase in stride length, but the preferred walking speed was unchanged. Minimal knee extension and maximal ankle flexion were the only kinematic data significantly different (increased) after ITB. The slope of the ankle moment-angle curve decreased significantly after ITB at preferred gait speed; it also decreased at maximal gait speed in all but 1 subject. Of the 4 available moment-angle curves, 3 showed decreased knee extensor muscle stiffness. The duration of the bursts of spastic muscles decreased after ITB. CONCLUSION Acute ITB improved walking and reduced muscle stiffness at both the ankles and knees on the spastic hemiplegic side of our subjects. Electromyographic findings suggest that some of the post-ITB reduction in muscle stiffness might be attributed to decreased spasticity.

Natural evolution of weight status in Duchenne muscular dystrophy: a retrospective audit

The life expectancy of patients with Duchenne muscular dystrophy (DMD) has increased. A cross-sectional study of DMD patients showed that 54 % of 13-year-old patients are obese and that 54 % of 18-year-old patients are underweight. We aimed to describe the natural evolution of weight status in DMD. This retrospective multi-centre audit collected body-weight measurements for seventy DMD patients born before 1992. The body-weight:age ratio (W:A) was used to evaluate weight status in reference to the Griffiths and Edwards chart. At the age of 13 years, 73 % were obese and 4 % were underweight. At maximal follow-up (age 15-26 years, mean 18·3 (sd 2·3) years), 47 % were obese and 34 % were underweight. Obesity at the age of 13 years was associated with later obesity, whereas normal weight status and underweight in 13-year-old patients predicted later underweight. A W:A ≥ 151 % in 13-year-old patients predicted later obesity, and a W:A ≤ 126·5 % predicted later underweight. Our audit provides the first longitudinal information about the spontaneous outcome of weight status in DMD. Patients (13 years old) with a W:A ≥ 151 % were more likely to become obese in late adolescence, but obesity prevented later underweight. These data suggest that mild obesity in 13-year-old DMD patients (W:A between 120 and 150 %) should not be discouraged because it prevents later underweight.

Efficacy and tolerance of gastrostomy feeding in Duchenne muscular dystrophy.

Undernutrition occurs often in individuals with Duchenne muscular dystrophy (DMD). Between 1997 and 2007, a gastrostomy was placed in 25 patients with DMD (median: 23 years old; range, 11-38 years) for weight loss (n=22) and/or swallowing disorders (n=13). We evaluated nutritional status using the weight-for-age (W/A) ratio, comparing the values to the reference curve for DMD patients. During the first 9 months, nutritional status improved: the W/A ratio increased and reached a plateau. The W/A ratio was 69% (range, 45-128%) at the start and increased to 87% (range, 49-164%) at the maximal follow-up of 22 months (P<0.001). However, the W/A ratio did not reach the median value for age. Complications occurred in 21 patients (84%), but caused no mortality. Our data suggest that gastrostomy is well tolerated by, and effective for improving the nutritional status of, individuals with DMD.

Post-polio syndrome and rehabilitation

Post-polio syndrome (PPS) is the commonly affected term to describe the symptoms that may develop many years after acute paralytic poliomyelitis. The etiology of PPS is still unclear. An overuse of enlarged motor units is suspected causing denervation again due to distal degeneration of axons. Metabolic and functional changes has been described in muscle fibers of partially denervated muscles. Nevertheless, submaximal aerobic training and low intensity muscular strengthening have shown positive effects on muscular strength and cardiorespiratory system in patients affected by PPS. Aquatic therapy has a positive impact on pain and muscle function. In patients with severe fatigue, it is recommended to adapt the daily exercise routine to their specific case.

Upper limb strength and function changes during a one-year follow-up in non-ambulant patients with Duchenne Muscular Dystrophy: an observational multicenter trial.

Introduction Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking. Patients and Methods We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 – 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 patients used non-invasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch, and MoviPlate). Results Our study confirmed preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages. Trial Registration ClinicalTrials.gov NCT00993161 NCT00993161

Post-polio syndrome: Pathophysiological hypotheses, diagnosis criteria, medication therapeutics

Post-polio syndrome (PPS) refers to a clinical disorder affecting polio survivors with sequelae years after the initial polio attack. These patients report new musculoskeletal symptoms, loss of muscular strength or endurance. PPS patients are tired, in pain and experience new and unusual muscular deficits, on healthy muscles as well as deficient muscles initially affected by the Poliovirus. Once a clinical diagnosis is established, the therapeutic options can be discussed. Some pathophysiological mechanisms have been validated by research studies on PPS (inflammatory process in cerebrospinal fluid [CSF] and cytokines of the immune system). Several studies have been conducted to validate medications (pyridostigmine, immunoglobulin, coenzyme Q10) or physical exercises protocols. This article focuses on the relevance and efficacy that can be expected from these therapeutics. Very few studies reported some improvements. Medications combined to individual and supervised exercise training programs are promising therapeutic strategies for PPS patients care management.

Isokinetic muscle testing for weak patients suffering from neuromuscular disorders: a reliability study.

Precise, sensitive muscle strength testing methods are needed to investigate muscle function in patients with neuromuscular disorders (NMD). Here, we describe an isokinetic knee flexor and extensor testing procedure using the Biodex 3s continuous passive motion (CPM) mode. The torque values recorded during passive isokinetic motion were subtracted from the torque values obtained for the same movement with maximal, concentric effort. The aims of the present study were to (i) evaluate the methods reliability in NMD patients presenting mild to severe muscle weakness and (ii) study the relationship between manual muscle testing (MMT) and isokinetic dynamometry. The fifteen participating patients were tested twice; the respective intraclass correlation coefficients (ICCs) for the two sessions ranged from 0.91 to 0.99 for the peak torque, work and power and from 0.50 to 0.90 for the angle at peak torque. The Spearman rho correlation coefficients comparing isokinetic values and MMT values ranged from 0.67 to 0.74 (p<0.01). This reliable, dynamic method appears to be of great value in NMD evaluation when sensitive strength measurement at the knee is required.

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

Background Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. Methods We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). Results Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. Conclusion Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

Phenotypical transitions and Ca2+ activation properties in human muscle fibers: effects of a 60-day bed rest and countermeasures

Muscle biopsies were taken from soleus and vastus lateralis before and after a 60-day bed rest (BR) to examine expression changes in the regulatory proteins of the thin filament and in contractile function. Twenty-four women separated in three groups were submitted to BR or a combined protocol of resistance and aerobic exercises during BR or received a supplementation of amino acids during BR. Ca(2+)-tension relationships were established in single skinned fibers identified by their myosin heavy chain and troponin C isoform expressions. Expression patterns of regulatory proteins were analyzed on muscle pieces. For both muscles, BR produced similar decreases in slow and fast fiber diameters but larger decreases in P(0) maximal forces in slow than in fast fibers. Specific forces were decreased in slow soleus and vastus fibers, which displayed a reduction in Ca(2+) affinity. These changes were accompanied by slow-to-fast transitions in regulatory proteins, with troponins C and T appearing as sensitive markers of unloading. Exercises prevented the changes in fiber diameters and forces and counteracted most of the slow-to-fast transitions. The nutrition program had a morphological beneficial effect on slow fibers. However, these fibers still presented decreases in specific P(0) after BR. Phenotypical transitions due to BR were not prevented by amino acids. Finally, in vastus lateralis muscle, BR induced a decrease in O-glycosylation level that was prevented by exercise and attenuated by nutrition. In conclusion, this study has addressed for the first time in women the respective efficiencies of two countermeasures associated with BR on muscle properties and regulatory protein expression.