R. Ted Abresch

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, ∼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 (R2 = 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. Muscle Nerve, 2010

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. Muscle Nerve 48: 343–356, 2013

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. Muscle Nerve, 2010

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. Muscle Nerve 48: 357–368, 2013

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

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. Muscle Nerve, 2013

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

Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials.

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

Abstract 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, 1 7.5 ± 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.

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.

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

Abstract Background: lndividuals 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 Iead to secondary complications associated with diminished physical activity and obesity. Methods: This study used dual energy X-ray absorptiometry (DXA) to estimate the totallean tissue mass (L TM), 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 (1 0-21 years of age) who had a SCI in the previous 1 to 3 years andin 27 age-and sex-matched controls. Results: Children with SCI had significantly lower mean LTM than control subjects (3 7.6 ± 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 (1 8.9 ± 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.