The assisted 6‐minute cycling test to assess endurance in children with a neuromuscular disorder

Introduction: For late‐ or non‐ambulant children with a neuromuscular disorder no suitable endurance tests are currently available. We developed the assisted 6‐minute cycling test (A6MCT) for the legs and arms and investigated its psychometric properties in healthy boys and boys with Duchenne muscular dystrophy (DMD). Methods: Ninety‐nine healthy boys and 30 boys with DMD (12 wheelchair‐dependent) performed the A6MCT. Seventy healthy boys also performed the 6‐minute walk test (6MWT), and 23 boys performed the A6MCT twice within 2 weeks. Boys with DMD also performed the Motor Function Measure (MFM). Results: The A6MCT was feasible for >90% of all boys. Boys with DMD achieved fewer cycling revolutions than controls. The A6MCT was positively correlated with the 6MWT and was reproducible in healthy boys, and it correlated with disease severity in boys with DMD. Conclusions: The A6MCT is a promising outcome measure for the follow‐up of non‐ambulant children with a neuromuscular disorder. Muscle Nerve 46: 520–530, 2012     

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     

Assisted 6‐minute cycling test: An exploratory study in children

Introduction: The 6‐minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neuromuscular disease. Because this submaximal endurance test is not feasible for nonambulatory patients, the motor‐assisted 6‐minute cycling test (A6MCT) was developed. Methods: Nineteen children with neuromuscular disorders and children with OXPHOS‐dysfunction performed the a6MCT and the 6MWT to explore feasibility and construct validity. Test–retest reproducibility was evaluated within 3 weeks. Results: The assisted 6‐minute cycling test was feasible in 90% and 78% of the patients with a neuromuscular disorder and OXPHOS‐dysfunction, respectively. The A6MCT for legs correlated with the 6MWT in both patient groups. The assisted 6‐minute cycling showed good reproducibility for both legs and arms. Conclusions: This exploratory study indicates that the assisted 6‐minute cycling test is a promising outcome measure for patients with a neuromuscular disorder and patients with OXPHOS‐dysfunction. Muscle Nerve, 2015. Muscle Nerve 54 : 232–238, 2016     

Validity of the 6 minute walk test in facioscapulohumeral muscular dystrophy

Introduction: In preparation for future clinical trials, we determined the reliability, relationship to measures of disease severity, and consistency across sites of the 6 Minute Walk Test (6MWT) in patients with facioscapulohumeral muscular dystrophy (FSHD). Methods: Genetically defined and clinically affected FSHD participants at 2 sites performed the 6MWT, the Timed Up and Go, and the 30 foot Go/Timed 10 meter test as measures of mobility using standard procedures. Results: Eight‐six participants representing the full range of severity performed the 6MWT. The mean 6MWT distance was 404.3 meters (SD 123.9), with no difference between sites. The 6MWT was reliable (n = 25; intraclass correlation coefficient = 0.99) and demonstrated moderate to strong correlations with lower extremity strength, functional outcomes, and FSHD Clinical Score. Conclusions: The 6MWT is reliable and is associated with other measures of FSHD disease severity. Future directions include assessing its sensitivity to disease progression. Muscle Nerve 55 : 333–337, 2017     

Reliability of the walking energy cost test and the six-minute walk test in boys with Duchenne muscular dystrophy

The walking energy cost test (WECT) is a useful tool when measuring ambulatory function in children with motor disorders. However, data on the reliability of this test in Duchenne muscular dystrophy (DMD) is not available. In this study we established the reliability of the WECT and the commonly used six-minute walk test (6MWT) in 19 boys with DMD, aged 6–12 years. Participants performed the WECT and 6MWT twice within three weeks. Reliability was determined for walking distance (D, m) and gross energy cost (EC, J kg⁻¹ m⁻¹), using the intraclass correlation coefficient (ICC_2,1) and smallest detectable change (SDC).Reliability for walking distance was good, with an ICC of 0.92 [95% CI: 0.81–0.97] and 0.83 [CI: 0.53–0.94] for the 6MWT and WECT, respectively, and an ICC of 0.85 [CI: 0.64–0.94] for gross EC. SDCs were 12.2% for D_6MWT, 12.7% for D_WECT and 18.5% for gross EC. In conclusion, in young boys with DMD, the reliability of both the WECT and 6MWT for assessing walking distance is adequate. Gross EC, as assessed with the WECT is also reliable and sufficiently sensitive to detect change in walking strain following interventions at group level.     

Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. Because the progression of SBMA is slow, it is plausible to identify biomarkers that monitor disease course for therapeutic development. To verify whether the 6-min walk test (6MWT) is a biomarker of SBMA, we performed the 6MWT in 35 genetically confirmed patients and in 29 age-matched healthy controls. The walk distance covered within 6 min (6MWD) was significantly less in SBMA than it was in controls (323.3 +/- 143.9 m and 637.6 +/- 94.2 m, respectively; P < 0.001). In test-retest analysis, the intraclass correlation coefficient for the 6MWD was high in SBMA patients (r = 0.982). In a 1-year follow-up the 6MWD significantly decreased at a rate of 11.3% per year. Our observations suggest that the 6MWT is a biomarker that can be used to monitor progression of motor impairment in SBMA.     

Outcome reliability in non‐Ambulatory Boys/Men with duchenne muscular dystrophy

Introduction: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non‐ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. Methods: Non‐ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. Results: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9‐hole peg test, and Jebsen‐Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. Conclusions: Reliable assessment of non‐ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use. Muscle Nerve 51: 522–532, 2015     

Myostatin inhibitor ACE‐031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized,placebo‐controlled clinical trial

Introduction: ACE‐031 is a fusion protein of activin receptor type IIB and IgG1‐Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). Methods: ACE‐031 was administered subcutaneously every 2–4 weeks to DMD boys in a randomized, double‐blind, placebo‐controlled, ascending‐dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. Results: ACE‐031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6‐minute walk test (6MWT) distance in the ACE‐031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. Conclusion: ACE‐031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non–muscle‐related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55 : 458–464, 2017     

Body weight‐supported training in Becker and limb girdle 2I muscular dystrophy

Introduction: We studied the functional effects of combined strength and aerobic anti‐gravity training in severely affected patients with Becker and Limb‐Girdle muscular dystrophies. Methods: Eight patients performed 10‐week progressive combined strength (squats, calf raises, lunges) and aerobic (walk/run, jogging in place or high knee‐lift) training 3 times/week in a lower‐body positive pressure environment. Closed‐kinetic‐chain leg muscle strength, isometric knee strength, rate of force development (RFD), and reaction time were evaluated. Results: Baseline data indicated an intact neural activation pattern but showed compromised muscle contractile properties. Training (compliance 91%) improved functional leg muscle strength. Squat series performance increased 30%, calf raises 45%, and lunges 23%. Conclusions: Anti‐gravity training improved closed‐kinetic‐chain leg muscle strength despite no changes in isometric knee extension strength and absolute RFD. The improved closed‐kinetic‐chain performance may relate to neural adaptation involving motor learning and/or improved muscle strength of other muscles than the weak knee extensors. Muscle Nerve 54 : 239–243, 2016     

Cardiopulmonary dysfunction in patients with limb‐girdle muscular dystrophy 2A

Introduction: Little is known about the frequency of cardiopulmonary failure in limb‐girdle muscular dystrophy type 2A (calpainopathy) patients, although some studies have reported severe cardiomyopathy or respiratory failure. Methods: To clarify the frequency of cardiopulmonary dysfunction in this patient population, we retrospectively reviewed the respiratory and cardiac function of 43 patients with calpainopathy. Results: Nine of the 43 patients had forced vital capacity (FVC) < 80%, and 3 used noninvasive positive pressure ventilation. Mean FVC was significantly lower in patients who were nonambulant and had normal creatine kinase levels. Only 1 patient had a prolonged QRS complex duration. Echocardiography revealed that 1 patient had very mild left ventricular dysfunction. Conclusions: These findings suggest that patients with calpainopathy may develop severe respiratory failure, but cardiac dysfunction is infrequent. Muscle Nerve 55 : 465–469, 2017     

Inflammation in muscular dystrophy and the beneficial effects of non‐steroidal anti‐inflammatory drugs

Introduction: Glucocorticoids are the only drugs available for the treatment of Duchenne muscular dystrophy (DMD), but it is unclear whether their efficacy is dependent on their anti‐inflammatory activity. Methods: To address this issue, mdx mice were treated daily with methylprednisolone and non‐steroidal anti‐inflammatory drugs (NSAIDs: aspirin, ibuprofen, parecoxib). Results: NSAID treatment was effective in ameliorating muscle morphology and reducing macrophage infiltration and necrosis. The percentage of regenerating myofibers was not modified by the treatments. The drugs were effective in reducing COX‐2 expression and inflammatory cytokines, but they did not affect utrophin levels. The effects of the treatments on contractile performance were analyzed. Isometric tension did not differ in treated and untreated muscle, but the resistance to fatigue was decreased by treatment with methylprednisolone and aspirin. Conclusions: NSAIDs have a beneficial effect on mdx muscle morphology, pointing to a crucial role of inflammation in the progression of DMD. Muscle Nerve, 2012     

Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids

In order to understand contemporary natural history of Duchenne muscular dystrophy (DMD), we report 6-minute walk distance (6MWD) and its change over time from a large single centre population of corticosteroid treated DMD boys. Sixty-five boys on daily corticosteroid treatment were identified with a mean (SD) age of 9.5 (2.3) years at first observation. 6MWD was described for 1 year age groupings. In addition, changes in 6MWD at 1, 1.5 and 2 years (±12 weeks) of follow-up were evaluated. The same evaluations were applied to 6MWD data converted to percent predicted values based on the Geiger equation. 6MWD showed an increase from age group 4.5–5.5 years to age group 6.5–7.5 years, followed by a decline, which became precipitous from 12.5 years onwards. From 15.5 years, all boys were unable to perform the 6-min test. Changes in 6MWD demonstrated a mean (median, SD) decline of ?43 (?14, 90) m at 1 year (N = 25, mean baseline age 9.5 years), ?64 (?56, 99) m at 1.5 years (N = 18, mean baseline age 9.6 years), ?125 (?106, 139) m at 2 years (N = 14, mean baseline age 10.0 years). Conversion to percent predicted values showed the same pattern of evolution.This study provides data on the ambulatory capacity and its changes over time in a homogenous cohort of 65 DMD boys on daily corticosteroids. The variability, the age-related aspects and the slope of decline of the 6MWD should be considered in the design and interpretation of therapeutic trials in ambulant DMD patients.     

Assessment of regional body composition with dual‐energy X‐ray absorptiometry in Duchenne muscular dystrophy: Correlation of regional lean mass and quantitative strength

The purpose of this study was to assess regional body composition and its correlation with regional strength in Duchenne muscular dystrophy (DMD) subjects and able‐bodied controls. Regional dual‐energy X‐ray absorptiometry (DEXA) measurements and isometric strength were obtained for 23 DMD subjects and 23 control subjects. DMD subjects showed a decreased regional lean mass (P < 0.001). The correlation between regional strength and regional lean mass was stronger for controls than for DMD subjects. DMD subjects had decreased regional lean mass, increased regional fat mass, and decreased strength. Muscle Nerve 39: 647–651, 2009