(-)-Epicatechin induces mitochondrial biogenesis and markers of muscle regeneration in adults with Becker muscular dystrophy.

INTRODUCTION: We conducted an open-label study to examine the effects of the flavonoid (-)-epicatechin in seven ambulatory adult patients with Becker muscular dystrophy (BMD). METHODS: Seven participants received (-)-epicatechin 50 mg twice per day for 8 weeks. Pre- and postprocedures included biceps brachii biopsy to assess muscle structure and growth-relevant endpoints by western blotting, mitochondria volume measurement, and cristae abundance by electron microscopy, graded exercise testing, and muscle strength and function tests. RESULTS: Western blotting showed significantly increased levels of enzymes modulating cellular bioenergetics (liver kinase B1 and 5'-adenosine monophosphate-activated protein kinase). Peroxisome proliferator-activated receptor gamma coactivator-1alpha, a transcriptional coactivator of genes involved in mitochondrial biogenesis and cristae-associated mitofilin levels, increased as did cristae abundance. Muscle and plasma follistatin increased significantly while myostatin decreased. Markers of skeletal muscle regeneration myogenin, myogenic regulatory factor-5, myoblast determination protein 1, myocyte enhancer factor-2, and structure-associated proteins, including dysferlin, utrophin, and intracellular creatine kinase, also increased. Exercise testing demonstrated decreased heart rate, maximal oxygen consumption per kilogram, and plasma lactate levels at defined workloads. Tissue saturation index improved in resting and postexercise states. DISCUSSION: (-)-Epicatechin, an exercise mimetic, appears to have short-term positive effects on tissue biomarkers indicative of mitochondrial biogenesis and muscle regeneration, and produced improvements in graded exercise testing parameters in patients with BMD.

Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary.

Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures.

UNLABELLED: introduction: Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. METHODS: The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2-28 years. A comprehensive battery of measures was obtained. RESULTS: A novel composite functional "milestone" scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4 ± 0.39 MMT unit/year, compared with -0.4 ± 0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. CONCLUSIONS: In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy.

The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study.

INTRODUCTION: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. METHODS: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate-determined energy expenditure index, and other exploratory endpoints. RESULTS: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. CONCLUSIONS: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression.

The cooperative international neuromuscular research group Duchenne natural history study--a longitudinal investigation in the era of glucocorticoid therapy: design of protocol and the methods used.

UNLABELLED: Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. METHODS: The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2-28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments. RESULTS: Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). CONCLUSIONS: Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics.

The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study.

INTRODUCTION: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints. METHODS: Evaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. RESULTS: Baseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation. CONCLUSION: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials.

mHealth application for upper extremity range of motion and reachable workspace.

We present mobile health (mHealth) applications utilizing embedded phone sensors as an angle-measuring device for upper-limb range of motion (ROM) and estimation of reachable workspace to assist in evaluation of upper limb functional capacity. Our results show that the phone can record accurate measurements, as well as provide additional functionalities for clinicians.

The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy.

Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6-minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, approximately 1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean +/- SD [range] 6-minute walk distance (6MWD) was lower in boys with DMD than in controls (366 +/- 83 [125-481] m vs. 621 +/- 68 [479-754] m; P < 0.0001; unpaired t-test). Test-retest correlation for boys with DMD was high (r = 0.91). Stride length (R(2) = 0.89; P < 0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease-related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials.

The 6-minute walk test in Duchenne/Becker muscular dystrophy: longitudinal observations.

In this study we used the 6-minute walk distance (6MWD) to characterize ambulation over time in Duchenne/Becker muscular dystrophy (DBMD). The 6MWD was assessed in 18 boys with DBMD and 22 healthy boys, ages 4-12 years, over mean [range] intervals of 58 [39-87] and 69 [52-113] weeks, respectively. Height and weight increased similarly in both groups. At 52 weeks, 6MWD decreased in 12 of 18 (67%) DBMD subjects (overall mean [range]: 357 [125-481] to 300 [0-510] meters; Δ -57 meters, -15.9%), but increased in 14 of 22 (64%) healthy subjects (overall mean [range]: 623 [479-754] to 636 [547-717] meters; Δ +13 meters, +2.1%). Two DBMD subjects lost ambulation. Changes in 6MWD depended on stride length and age; improvements usually occurred by 7-8 years of age; older DBMD subjects worsened, whereas older healthy subjects were stable. The 6MWD changes at 1 year confirm the validity of this endpoint and emphasize that preserving ambulation must remain a major goal of DBMD therapy.

Effectiveness of an upper extremity exercise device integrated with computer gaming for aerobic training in adolescents with spinal cord dysfunction.

BACKGROUND/OBJECTIVE: To determine whether a new upper extremity exercise device integrated with a video game (GameCycle) requires sufficient metabolic demand and effort to induce an aerobic training effect and to explore the feasibility of using this system as an exercise modality in an exercise intervention. DESIGN: Pre-post intervention. SETTING: University-based research facility. SUBJECT POPULATION: A referred sample of 8 adolescent subjects with spina bifida (4 girls, 15.5 +/- 0.6 years; 4 boys, 17.5 +/- 0.9 years) was recruited to participate in the project. All subjects had some level of mobility impairment that did not allow them to participate in mainstream sports available to their nondisabled peers. Five subjects used a wheelchair full time, one used a wheelchair occasionally, but walked with forearm crutches, and 2 were fully ambulatory, but had impaired gait. MAIN OUTCOME MEASURES: Peak oxygen uptake, maximum work output, aerobic endurance, peak heart rate, rating of perceived exertion, and user satisfaction. RESULTS: Six of the 8 subjects were able to reach a Vo2 of at least 50% of their Vo2 reserve while using the GameCycle. Seven of the 8 subjects reached a heart rate of at least 50% of their heart rate reserve. One subject did not reach either 50% of Vo2 reserve or 50% of heart rate reserve. Seven of the 8 subjects increased their maximum work capability after training with the GameCycle at least 3 times per week for 16 weeks. CONCLUSIONS: The data suggest that the GameCycle seems to be adequate as an exercise device to improve oxygen uptake and maximum work capability in adolescents with lower extremity disability caused by spinal cord dysfunction. The subjects in this study reported that the video game component was enjoyable and provided a motivation to exercise.

Modafinil to treat fatigue in amyotrophic lateral sclerosis: an open label pilot study.

An open label trial of modafinil was conducted to determine whether it would be tolerated and effective in treating fatigue for people with amyotrophic lateral sclerosis (ALS). Fifteen patients with ALS were treated for two weeks with either 200 mg or 400 mg of modafinil. Reported side effects of the medication were mild and included diarrhea, headache, nervousness, and insomnia. Side effects did not result in any study dropouts. Following treatment, mean scores on the Fatigue Severity Scale (FSS) decreased from 51.3 (SD 9.2) to 42.8 (SD 10.2). On the Epworth Sleepiness Scale (ESS), mean scores decreased from 8.2 (SD 2.0) to 4.5 (SD 2.4). Reductions in both the FSS and the ESS were significant at p < 0.001. Mean scores on the self-report version of the Functional Independence Measure (FIM-SR) increased from 115.2 (SD 5.6) to 118.1 (SD 5.4), with p < 0.01. This pilot study suggests that modafinil is well-tolerated and may reduce symptoms of fatigue in ALS. Further blinded, controlled studies of modafinil in larger numbers of ALS patients are warranted.

Validity and reliability of smartphone magnetometer-based goniometer evaluation of shoulder abduction--A pilot study.

BACKGROUND: Goniometers are commonly used by physical therapists to measure range-of-motion (ROM) in the musculoskeletal system. These measurements are used to assist in diagnosis and to help monitor treatment efficacy. With newly emerging technologies, smartphone-based applications are being explored for measuring joint angles and movement. OBJECTIVE: This pilot study investigates the intra- and inter-rater reliability as well as concurrent validity of a newly-developed smartphone magnetometer-based goniometer (MG) application for measuring passive shoulder abduction in both sitting and supine positions, and compare against the traditional universal goniometer (UG). DESIGN: This is a comparative study with repeated measurement design. METHODS: Three physical therapists utilized both the smartphone MG and a traditional UG to measure various angles of passive shoulder abduction in a healthy subject, whose shoulder was positioned in eight different positions with pre-determined degree of abduction while seated or supine. Each therapist was blinded to the measured angles. Concordance correlation coefficients (CCCs), Bland-Altman plotting methods, and Analysis of Variance (ANOVA) were used for statistical analyses. RESULTS: Both traditional UG and smartphone MG were reliable in repeated measures of standardized joint angle positions (average CCC > 0.997) with similar variability in both measurement tools (standard deviation (SD) ± 4°). Agreement between the UG and MG measurements was greater than 0.99 in all positions. CONCLUSION: Our results show that the smartphone MG has equivalent reliability compared to the traditional UG when measuring passive shoulder abduction ROM. With concordant measures and comparable reliability to the UG, the newly developed MG application shows potential as a useful tool to assess joint angles.

Altered body composition affects resting energy expenditure and interpretation of body mass index in children with spinal cord injury.

BACKGROUND: Individuals with spinal cord injury (SCI) typically undergo changes in their body composition (reduction in lean body mass and an increase in fat mass) that can lead to secondary complications associated with diminished physical activity and obesity. METHODS: This study used dual energy X-ray absorptiometry (DXA) to estimate the total lean tissue mass (LTM), total body fat, and total bone mineral content (BMC) to assess the relationship between body mass index (BMI), body composition, and resting metabolic rate (RMR) in a group of children with SCI who were matched with able-bodied controls for age and sex. Body composition and RMR were measured in 18 boys and 9 girls (10-21 years of age) who had a SCI in the previous 1 to 3 years and in 27 age- and sex-matched controls. RESULTS: Children with SCI had significantly lower mean LTM than control subjects (37.6 +/- 9.6 kg and 46.7 +/- 9.2 kg, respectively; P < 0.001) and higher percent body fat (26.4 +/- 7.9% and 20.2 +/- 8.5%, respectively; P < 0.02) as measured by DXA, despite their reduced BMI (18.9 +/- 3.8 kg/m2 and 21.2 +/- 2.9 kg/m2, respectively; P < 0.01). Children with SCI had lower RMR than the controls subjects (1213 +/- 334 kJ/d and 1511 +/- 257 kJ/d, respectively), but there was no difference in RMR when adjusted for LTM. CONCLUSION: Children with SCI have lower RMRs that are associated with their reduced LTM. The reduction in LTM and RMR may predispose children with SCI to relative gains in body fat. BMI significantly underestimates body fat in children with SCI.

Validity, Reliability, and Sensitivity of a 3D Vision Sensor-based Upper Extremity Reachable Workspace Evaluation in Neuromuscular Diseases.

INTRODUCTION: One of the major challenges in the neuromuscular field has been lack of upper extremity outcome measures that can be useful for clinical therapeutic efficacy studies. Using vision-based sensor system and customized software, 3-dimensional (3D) upper extremity motion analysis can reconstruct a reachable workspace as a valid, reliable and sensitive outcome measure in various neuromuscular conditions where proximal upper extremity range of motion and function is impaired. METHODS: Using a stereo-camera sensor system, 3D reachable workspace envelope surface area normalized to an individual's arm length (relative surface area: RSA) to allow comparison between subjects was determined for 20 healthy controls and 9 individuals with varying degrees of upper extremity dysfunction due to neuromuscular conditions. All study subjects were classified based on Brooke upper extremity function scale. Right and left upper extremity reachable workspaces were determined based on three repeated measures. The RSAs for each frontal hemi-sphere quadrant and total reachable workspaces were determined with and without loading condition (500 gram wrist weight). Data were analyzed for assessment of the developed system and validity, reliability, and sensitivity to change of the reachable workspace outcome. RESULTS: The mean total RSAs of the reachable workspace for the healthy controls and individuals with NMD were significantly different (0.586 ± 0.085 and 0.299 ± 0.198 respectively; p<0.001). All quadrant RSAs were reduced for individuals with NMDs compared to the healthy controls and these reductions correlated with reduced upper limb function as measured by Brooke grade. The upper quadrants of reachable workspace (above the shoulder level) demonstrated greatest reductions in RSA among subjects with progressive severity in upper extremity impairment. Evaluation of the developed outcomes system with the Bland-Altman method demonstrated narrow 95% limits of agreement (LOA) around zero indicating high reliability. In addition, the intraclass correlation coefficient (ICC) was 0.97. Comparison of the reachable workspace with and without loading condition (wrist weight) showed significantly greater RSA reduction in the NMD group than the control group (p<0.012), with most of the workspace reduction occurring in the ipsilateral upper quadrant relative to the tested arm (p<0.001). Reduction in reachable workspace due to wrist weight was most notable in those subjects with NMD with marginal strength reserve and moderate degree of impairment (Brooke = 2) rather than individuals with mild upper extremity impairment (Brooke = 1) or individuals who were more severely impaired (Brooke =3). DISCUSSION: The developed reachable workspace evaluation method using scalable 3D vision technology appears promising as an outcome measure system for clinical studies. A rationally-designed combination of upper extremity outcome measures including a region-specific global upper extremity outcome measure, such as the reachable workspace, complemented by targeted disease- or function-specific endpoints, may be optimal for future clinical efficacy trials.

Physical therapy evaluation and management in neuromuscular diseases.

Neuromuscular disorders (NMDs) are a group of myopathic or neuropathic diseases that directly or indirectly affect the functioning of muscle. Physical therapists (PTs) have extensive specialized training in musculoskeletal evaluation and assessment that gives them the tools to meet the significant needs of this population. This article reviews the role of PTs in treating the NMD population with a discussion of available evaluation techniques and interventions and with an effort to differentiate between treatments known to apply to this population and conventional practice of PTs. The status of currently available outcome measures used for research and their applicability to clinics are presented.

Exercise in neuromuscular diseases.

This article reviews the current knowledge regarding the benefits and contraindications of exercise on individuals with neuromuscular diseases (NMDs). Specific exercise prescriptions for individuals with NMDs do not exist because the evidence base is limited. Understanding the effect of exercise on individuals with NMDs requires the implementation of a series of multicenter, randomized controlled trials that are sufficiently powered and use reliable and valid outcome measures to assess the effect of exercise interventions-a major effort for each NMD. In addition to traditional measures of exercise efficacy, outcome variables should include measures of functional status and health-related quality of life.

Quality-of-life measures in children with neurological conditions: pediatric Neuro-QOL.

BACKGROUND: A comprehensive, reliable, and valid measurement system is needed to monitor changes in children with neurological conditions who experience lifelong functional limitations. OBJECTIVE: This article describes the development and psychometric properties of the pediatric version of the Quality of Life in Neurological Disorders (Neuro-QOL) measurement system. METHODS: The pediatric Neuro-QOL consists of generic and targeted measures. Literature review, focus groups, individual interviews, cognitive interviews of children and consensus meetings were used to identify and finalize relevant domains and item content. Testing was conducted on 1018 children aged 10 to 17 years drawn from the US general population for generic measures and 171 similarly aged children with muscular dystrophy or epilepsy for targeted measures. Dimensionality was evaluated using factor analytic methods. For unidimensional domains, item parameters were estimated using item response theory models. Measures with acceptable fit indices were calibrated as item banks; those without acceptable fit indices were treated as summary scales. RESULTS: Ten measures were developed: 8 generic or targeted banks (anxiety, depression, anger, interaction with peers, fatigue, pain, applied cognition, and stigma) and 2 generic scales (upper and lower extremity function). The banks reliably (r > 0.90) measured 63.2% to 100% of the children tested. CONCLUSIONS: The pediatric Neuro-QOL is a comprehensive measurement system with acceptable psychometric properties that could be used in computerized adaptive testing. The next step is to validate these measures in various clinical populations.

Rehabilitation management of neuromuscular disease: the role of exercise training.

This paper summarizes the current state of knowledge regarding exercise and neuromuscular diseases/disorders (NMDs) and reviews salient studies in the literature. Unfortunately, there is inadequate evidence in much of the NMDs to make specific recommendations regarding exercise prescriptions. This review focuses on the role of exercise in a few of the specific NMDs where most research has taken place and recommends future research directions.