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Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMDmutation type and location, and variants in other genes.Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (–0.80%) and SF (–0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (–11.01?mL/m2, p?=?0.03) while for dp116 were correlated with decreased EF (–4.14%, p?=?<0.001). The rs10880 genotype in the LTBP4gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p?=?0.002, and –10.62?mL/m2, p?=?0.008) with a recessive model.Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4genotype of DCM in DMD.

Background: Duchenne muscular dystrophy (DMD) exhibits substantial variability in rates of disease progression and response to treatment. This has hindered treatment development and complicated interpretation of drug effects in clinical trials.Objective: We hypothesized that a multivariate combination of early-age clinical outcome measurements can explain differential disease progression.Methods: Data on boys with DMD (ages 4–<10 years), both treated with steroidal anti-inflammatories and untreated, were obtained from CINRG Duchenne Natural History Study (n?=?209) and vamorolone VBP15-002/003/LTE (n?=?46) studies. Velocities from three timed function tests (TFTs; stand from supine, run/walk 10 meters, and climb 4 stairs) were simultaneously modeled in a longitudinal latent class analysis.Results: Three classes of differentially progressing early age DMD motor trajectories were identified. Quicker decline/progression was associated with lower baseline TFT velocities, earlier loss of ability to finish a TFT, and lower predicted velocities. Earlier substantial steroid exposure was associated with greater TFT velocities while the moderate progression class was observed to have the largest difference in performance between boys treated early with steroids vs. not. Sample size calculations with the class showing the largest treatment response showed a large reduction in required sample size as compared to using summaries from all participants. Gene mutations were also investigated in post-hocanalyses, with mutations near the beginning of the DMDgene (Dp427 absent and Dp140/Dp71 present) found to be enriched in the slowest progressing class.Conclusions: This study provides insight into the variation in DMD progression through a latent class analysis. Our findings show class-related trajectories of motor outcomes and pharmacological response to corticosteroids, and suggest that enrichment strategies and/or subgroup analyses could be considered further in design of therapeutic interventions in DMD.

Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of?>?4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]).Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD.Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to?

Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited. Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD. Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models. This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 [deflazacort], n = 29 [prednisone], n = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p < 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p < 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p < 0.05 vs. no steroids). Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone.

Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. A cohort of 83 patients with Becker muscular dystrophy (5–75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Deletion mutations of dystrophin exons 45–47 or 45–48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

IMPORTANCE: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. OBJECTIVE: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. INTERVENTIONS: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. MAIN OUTCOMES AND MEASURES: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)–challenge test. RESULTS: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo −0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, −1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. CONCLUSIONS AND RELEVANCE: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03439670

Studies 4658-201/202 (201/202) evaluated treatment effects of eteplirsen over 4 years in patients with Duchenne muscular dystrophy and confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405) further followed these patients while receiving eteplirsen during usual clinical care. To compare long-term clinical outcomes of eteplirsen-treated patients from Studies 201/202/405 with those of external controls. Median total follow-up time was approximately 6 years of eteplirsen treatment. Outcomes included loss of ambulation (LOA) and percent-predicted forced vital capacity (FVC%p). Time to LOA was compared between eteplirsen-treated patients and standard of care (SOC) external controls and was measured from eteplirsen initiation in 201/202 or, in the SOC group, from the first study visit. Comparisons were conducted using univariate Kaplan-Meier analyses and log-rank tests, and multivariate Cox proportional hazards models with regression adjustment for baseline characteristics. Annual change in FVC%p was compared between eteplirsen-treated patients and natural history study patients using linear mixed models with repeated measures. Data were included from all 12 patients in Studies 201/202 and the 10 patients with available data from 405. Median age at LOA was 15.16 years. Eteplirsen-treated patients experienced a statistically significant longer median time to LOA by 2.09 years (5.09 vs. 3.00 years, p < 0.01) and significantly attenuated rates of pulmonary decline vs. natural history patients (FVC%p change: –3.3 vs. –6.0 percentage points annually, p < 0.0001). Study 405 highlights the functional benefits of eteplirsen on ambulatory and pulmonary function outcomes up to 7 years of follow-up in comparison to external controls.

Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group. To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy. This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations. Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy.

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder, that is characterized by progressive muscle degeneration and loss of ambulation between 7–13 years of age. Novel pharmacological agents targeting the genetic defects and disease mechanisms are becoming available; however, corticosteroid (CS) therapy remains the standard of care.Objective: The purpose of this longitudinal study was to elucidate the effect of CS therapy on the rate of muscle strength and gross motor skill decline in boys with DMD and assess the sensitivity of selected outcome measures.Methods: Eighty-four ambulatory boys with DMD (49–180 months), 70 on CS, 14 corticosteroid naïve (NCS), participated in this 8-year multi-site study. Outcomes included; isokinetic dynamometry, the Standing (STD) and Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure (GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures determined the rate of change with age and the influence of steroids.Results: Despite CS therapy the rate of decline in strength with age was significant in all muscle groups assessed. CS therapy significantly slowed decline in knee extensor strength, as the NCS group declined at 3x the rate of the CS group. Concurrently, WRJ skills declined in the NCS group at twice the rate of the CS group. 4-stair climb and 10 meter walk/run performance was superior in the boys on CS therapy.Conclusion: CS therapy slowed the rate of muscle strength decline and afforded longer retention of select gross motor skills in boys on CS compared to boys who were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may prove informative in assessing the efficacy of new therapeutics in ambulatory boys with DMD.

Aim:We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods:Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion:Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov registration: NCT01557400.

Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle strength, improve timed motor function, delay loss of ambulation, improve pulmonary function, reduce the need for scoliosis surgery, delay onset of cardiomyopathy, and increase survival. Both have been used off-label for many years (choice dependent on patient preference, cost, and geographic location) before FDA approval of deflazacort for DMD in 2017. In this review, we compare deflazacort and prednisone/prednisolone in terms of their key pharmacological features, relative efficacy, and safety profiles in patients with DMD. Differentiating features include lipid solubility, pharmacokinetics, changes in gene expression profiles, affinity for the mineralocorticoid receptor, and impact on glucose metabolism. Evidence from randomized clinical trials, prospective studies, meta-analyses, and post-hocanalyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone, with the strongest evidence being for improved muscle strength with deflazacort. Regarding side effects, weight gain and behavior side effects appear to be greater with prednisone/prednisolone than with deflazacort, whereas bone health, growth parameters, and cataracts appear worse with deflazacort.

Background: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-?B and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD).Objective: This international, randomized 2?:?1, placebo-controlled, phase 3 study in patients =4?–?

Myelomeningocele is a form of spina bifida in which a portion of the spinal cord and membranes protrude; it is a congenital disorder that can be crippling. Whether children suffering from myelomeningocele are able to walk has been found to depend, in part, on the extent of the damage and the strength of the muscles in the lower body. There are no consistent data, however, that allow easy prediction of outcome with regard to mobility. Some investigators have reported that the most important muscle groups for walking (ambulation) are those in the knees, hips, and the quadriceps. In the present study, 291 children with myelomeningocele were grouped by their ability to ambulate: community ambulators, partial ambulators (able to ambulate in the home, but not in the community), and nonambulators. Muscle strength was assessed and graded as well. The purpose of the study was to determine the degree to which different muscles influence ambulation. The best predictor of ambulation was the strength of the pelvic muscles in conjunction with the quadriceps, the tibia, (a bone between the ankle and the knee), and the muscles in the buttocks. Deterioration of the strengths of these muscles was not age-related. The results provide useful information for the surgical correction of mobility problems in children suffering from myelomeningocele. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMDgene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD.Objective: Compare long-term ambulatory function in eteplirsen-treated patients versus controls.Methods: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries.Results: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p?=?0.015] at Year 3 and 159?m [95%CI (66, 253), p?=?0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p?=?0.020). At Year 3, eteplirsen-treated patients demonstrated milder NSAA decline versus controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available.Conclusion: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.

Eteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production. To report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort. Ambulatory patients aged 7–16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled. 78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoccomparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: –68.9 m; phase 2 studies: –67.3 m; external controls: –133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: –3.3%, phase 2 studies: –2.2%, external controls: –6.0%; p <  0.001). Adverse events were generally mild to moderate and unrelated to eteplirsen. Most frequent treatment-related adverse events were headache and vomiting; none led to treatment discontinuation. This large, multicenter study contributes to the growing body of evidence for eteplirsen, confirming a positive treatment effect, favorable safety profile, and slowing of disease progression versus natural history.

Aim:Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials & methods:Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300–<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Results:Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2–34.1) m, p = 0.0473; ≥300–<400 m (n = 143), +43.9 (18.2–69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4–49.0) m, p = 0.0109. Conclusion:These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300–<400 m (the ambulatory transition phase), thereby informing future trial design.

IMPORTANCE: An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019. INTERVENTIONS: Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion. MAIN OUTCOMES AND MEASURES: Primary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants’ biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function. RESULTS: Of the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: −0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: −0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: −65.3 m) at the week 25 visit. CONCLUSIONS AND RELEVANCE: Systemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02740972

IMPORTANCE: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. OBSERVATIONS: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. CONCLUSIONS AND RELEVANCE: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMDgene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1)gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.

Aim:Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype–phenotype/–ataluren benefit correlations and ataluren safety. Patients & methods:Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion:Kaplan–Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p ≤ 0.05). There were no DMD genotype–phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier:NCT02369731. ClinicalTrials.gov identifier:NCT02369731.

Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. FVC% p annual change was greater for CINRG DNHS Exon 51 controls (– 6.00) versus patients in studies 201/202, study 204, and study 301 (– 2.19, P < 0.001; – 3.66, P0.004; and – 3.79, P0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (– 5.67) and All CINRG DNHS (– 5.56) cohorts (P < 0.05, all comparisons). Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.

Loss of pulmonary function is a main cause of early morbidity and mortality in patients with Duchenne muscular dystrophy (DMD). Standard of care guidelines recommend regular assessment of pulmonary function by hospital-based spirometry to detect onset and monitor progression of pulmonary function decline. To assess the feasibility of home-based monitoring of pulmonary function by a hand-held device (HHD) in adolescent and adult patients with DMD over a period of 12 months. In the phase III randomized placebo-controlled DELOS trial in 10–18 year old DMD patients, peak expiratory flow (PEF) measurements were collected weekly at home by the patient (assisted by parent/caregiver) using a peak flow meter HHD. Adherence to the use of the HHD was assessed and 12-month changes in PEF as percent of predicted (PEF% p) for the idebenone (N = 31) and the placebo treatment groups (N = 33) from HHD-derived data were compared to results from hospital-based spirometry. A total of 2689 individual HHD assessments were analysed. Overall adherence to the use of the HHD over the course of the 12-month study duration was good (75.9%, SD 21.5%) and PEF% p data obtained at the same day by HHD and standard spirometry correlated well (Spearman’s rho 0.80; p < 0.001). Several analysis methods of HHD-derived data for PEF% p consistently demonstrate that idebenone treatment slowed the decline in PEF% p compared to placebo, which supports the statistically significant difference in favour of idebenone for PEF% p measured by standard spirometry. This study demonstrates that home-based monitoring of pulmonary function in adolescent patients with DMD using a HHD is feasible, provides reliable data compared to hospital-based spirometry and is therefore suitable for use in clinical practice and for clinical trials.

Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD.

Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field of therapeutics for dystrophic cardiomyopathy.

Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids.

Assessing phrenic nerve function in the setting of diaphragmatic paralysis in diaphragm pacing candidates can be challenging. Traditional imaging modalities and electrodiagnostic evaluations are technically difficult. Either modality alone is not a direct measure of the function of the phrenic nerve and diaphragm unit. In this article, the authors present their method for evaluating phrenic nerve function and the resulting diaphragm function. Stimulating the phrenic nerve with transcutaneous stimulation and directly observing the resulting movement of the hemidiaphragm with M-mode ultrasonography provides quantitative data for predicting the success of advancing technologies such as phrenic nerve pacing and diaphragm pacing.

Traumatic brain injury is a major cause of morbidity in children and accounts for more than 100,000 admissions to hospital per year. Children who survive moderate and severe head trauma [...]

AbstractObjectives: To compare body composition in patients aged 11 to 21 years with spinal dysfunction due to spinal cord injury (SCI) and spina bifida (SB) vs able–bodied control (CTRL) and able–bodied overweight (OW) groups and to examine the relationships between resting energy expenditure (REE) and total lean mass (TLM) in the SCI, SB, CTRL, and OW groups.Methods: Two hundred fifteen subjects, including 85 CTRL, 31 OW, 33 SCI, and 66 SB, were evaluated. Body composition was estimated by dual energy x-ray absorptiometry (DXA). Measurements included height, weight, total lean mass (TLM), fat tissue mass (FTM), body mass index (BMI), BMI percentile (BMI%tile), and %fat. Resting energy measurements were obtained in fasting subjects with an open-circuit indirect calorimeter.Results: There were gender differences in height, weight, BMI, TLM, fat mass,%fat, and REE. The REE in the SCI and SB groups was significantly different from that in the CTRL and OW groups, but no significant difference was found between the SCI and SB groups. The SB group had significantly higher REE/TLM ratios than did the other groups. The %fat was significantly higher in the SB and OW groups as compared to the CTRL and SCI groups. TLM was significantly higher in CTRL and OW groups as compared to SCI and SB groups, with the lowest TLM found in the SB group.Conclusion: Patients aged 11 to 21 years with SB or SCI have significant lean tissue mass deficits by DXA as compared to able–bodied CTRL and OW groups, with the greatest deficits in total lean mass measured in SB. The absolute REE values were significantly reduced in both SCI and SB groups in association with their lean tissue deficits. Interestingly, REE/TLM ratios were remarkably constant in the CTRL, OW, and SCI groups but significantly elevated in the SB group. One would expect an even greater degree of adiposity in the SB group if their REE/TLM ratios were not elevated relative to those without congenital paralysis.

AbstractBackground/Objective: The purpose of this study is to report the results of rater agreement for the International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI) motor and sensory scores before and after training in the testing technique.Methods: Six raters performed sequential motor and sensory examinations on 5 adolescents with SCI according to the ISCSCI manual. After completion of the first examinations, all raters were provided with a half-day formal training session on testing techniques, after which the raters repeated the examinations. lntraclass correlation coefficients (ICCs) and 95% confidence intervals (Cis) were calculated to provide parameters for ICC interpretation: > 0.90 = high agreement; 0.75 to 0.90 = moderate agreement; < 0.75 = poor agreement.Results: After training, there was improvement in rater agreement of summed motor scores (MS) from ICC = 0.809 to 0.862 and discrimination scores from ICC = 0.786 to 0.892. There was moderate rater agreement for light touch scores (LTS) before and after training. After training, there was improvement in 95% Cis except for ICCs for LTS, but for all ICCs, the lower 95% Cl value remained less than 0.75.Conclusions: Training improved rater agreement on MS and discrimination, but 95% Cis remained unacceptably wide. The positive effect of training in motor and sensory testing techniques is supported by the study data. Unlike previous studies that have suggested the ISCSCI has acceptable reliability for clinical trials, the results of this study do not fully support the use of the ISCSCI for clinical trials without better standardization to establish a lower 95% Cl value of at least 0.75.

AbstractBackground/Objective: Determine the effects of a nutrition education and exercise intervention on the health and fitness of adolescents with mobility impairment due to spinal cord dysfunction from myelomeningocele and spinal cord injury. Subjects participated in a 16-week intervention consisting of a behavioral approach to lifestyle change, exercise, and nutrition education to improve fitness (BENEfit) program. Participants were given a schedule of aerobic and strengthening exercises and attended nutrition education and behavior modification sessions every other week along with their parent(s).Subjects: Twenty adolescents (aged 11–18 years, mean 15.4 ± 2.2 years) with spinal cord dysfunction.Methods: Subjects were tested immediately prior to starting and upon completion of the program. Aerobic fitness was measured using a ramp protocol with an arm ergometer. Heart rate and oxygen uptake were measured. Values at anaerobic threshold and maximum oxygen uptake were recorded. Peak isokinetic arm and shoulder strength were determined with a dynamometer. Body composition was estimated with dual–energy x–ray absorptiometry. Serum chemistry included measures of cholesterol, high–density lipoprotein, low-density lipoprotein, and triglycerides.Results: Fourteen individuals completed all testing sessions. There was no significant overall change in weight, body mass index, body mass index z–scores, or serum chemistry. Overall, there was a significant increase in whole body lean tissue without a concomitant increase in whole body fat. Fitness measures revealed a significant increase in maximum power output, work efficiency as measured by the amount of power output produced aerobically, and resting oxygen uptake. Strength measurements revealed a significant increase in shoulder extension strength and atrend towards increased shoulder flexion strength. There were no significant changes in high–density lipoprotein, low–density lipoprotein, total cholesterol, or triglycerides.Conclusions: The BENEfit program shows promise as a method for improving the health and fitness of adolescents with mobility impairments who are at high risk for obesity and obesity-related health conditions.

AbstractBackground/Objective: To determine the body composition of adolescents with spinal cord injury (SCI) and to assess whether established cutoff values for obesity determined by body mass index (BMI) are valid for this population.Methods: Sixty patients, aged 10–21 years, with traumatic SCI (50 with paraplegia and 1 0 with tetraplegia) were compared with 60 gender–, age–, and BMI-matched controls (CTRL). Dual–energy x–ray absorptiometry was used to estimate regional and total bone mineral content, lean tissue mass, fat tissue mass, and body fat percentage. BMI was calculated from measured weight and stature (kg/m2) .Results: Total percent body fat was significantly higher in the paraplegia group (31.4%±1.2%; mean±SE) than in the tetraplegia and CTRL groups (25.7%±2.7% and 22.9%±1.1 %, respectively). This change in percent total body fat was associated with a reduction of lean tissue mass in the paraplegia (37.6±1.1 kg; mean±SE) and tetraplegia (32.8±2.5 kg) subjects as compared to the CTRL group (46.2±1.0 kg; P<0.001 ). Total fat mass was significantly greater in the paraplegia group (19.3±1.3 kg) than the CTRL and tetraplegia groups (14.9±1.2 kg and 11.7±3.0 kg, respectively). Regional measurements revealed thatthe greatest reduction of lean tissue mass in the SCI subjects occurred in the lower extremities, followed by the trunk. As a result of these changes in body composition, the optimal BMI for classifying obesity (trunk fat percen>0 in males and>35 in females) in subjects with SCI was 19 kg/m2 as compared to 25 kg/m2 in able–bodied subjects.Conclusions: Patients aged 10 to 21 years with SCI have significantly decreased lean tissue mass and bone mineral content, and increased fat mass. As a result, traditional BMI cutoff criteria significantly underestimate obesity in this population. New clinically applicable criteria to define obesity should be established for SCI children and adolescents with SCI.

AbstractObjective: To determine whether the aerobic fitness, upper extremity strength, and body composition in groups of adolescents with mobility impairment due to thoracic and upper lumbar spinal cord injury (SCI) or spina bifida (SB) are significantly different from those in groups of adolescents without mobility impairment who are of normal weight (CTRL) or overweight (OW). Subjects: One hundred fifteen total subjects were evaluated including 59 female (19 SB, 9 SCI, 17 OW, and 14 CTRL) and 56 male (18 SB, 1 0 SCI, 8 OW, and 20 CTRL) participants aged 11 to 21 years.Methods: Aerobic fitness was assessed using a ramp protocol with a magnetically braked arm ergometer. Heart rate and oxygen uptake (V02) were recorded. Peak isokinetic upper arm and shoulder strength values were determined with a dynamometer. Body composition was estimated using dual energy x–ray absorptiometry (DEXA). Male and female subjects were categorized as overweight if their percent body fat by DEXA exceeded 25% and 30%, respectively. Results were analyzed with an ANOVA using the Bonferroni correction. Significance was accepted at P<0.05.Results: The percent body fat of both the male and female SB and SCI subjects was significantly higher than CTRL but was not different than OW. In general, the shoulder extension and flexion strength in both the SB and SCI males and females was significantly lower than that of the CTRL and OW. The SCI and SB subjects had significantly reduced aerobic capacity (VO2/kg) compared to the CTRL subjects but were not different than the OW subjects. During the maximal exercise test, the SB and SCI subjects reached exhaustion at significantly lower workloads than the CTRL and OW subjects.Conclusions: Patients age 11 to 21 years with SB and SCI had reduced aerobic capacity that was associated with being overweight and having reduced upper extremity strength. These data suggest that interventions to increase strength and fitness and to manage weight should be recommended in this population.

AbstractStudy design: Interview survey.Objective: To assess depression in adults with pediatric–onset spinal cord injuries (SCI) and to determine demographic and injury–related factors, and outcomes associated with depression, and to determine which other outcomes are associated with depression.Methods: Subjects were adults with pediatric-onset SCI who sustained SCI at age =18 years and were interviewed at age =24 years. This is part of a longitudinal study for which there were 864 eligible participants; 353 (41%) were interviewed. Of these, 232 were assessed for depression. A telephone interview was conducted that included a structured questionnaire and standardized measures (Functional Independence Measure, Craig Handicap Assessment and Reporting Technique, Short-Form 12 measure of healthrelated quality of life, Satisfaction with Life Scale, and Patient Health Questionnaire–9 to screen for depression).Results: Twenty–seven percent reported depressive symptoms ranging from mild to severe, and 7% reported having suicidal thoughts within the last 2 weeks, and 3= reported symptoms consistent with probable major depressive disorder (MDD). Depression was not significantly associated with any demographic factors but it was associated with incomplete injury (P = 0.013). Depression was also associated with many participation outcomes, health–related quality of life, life satisfaction, and medical complications.Conclusions: Depression is a significant problem among adults with pediatric–onset SCI and is associated with poorer outcomes and lower quality of life. These findings should be addressed as clinicians prepare children and adolescents with SCI to transition to adulthood

AbstractBackground/Objective: The purpose of this study is to assess the impact of a thoracolumbosacral orthosis (TLSO) on children with spinal cord injuries (SCI) in terms of functional independence and time requirements for performance of functional activities and to ascertain the children's preference for TLSO use.Methods: Fourteen subjects with thoracic SCI, ages 6 to 14 years, were studied. All subjects had previously been prescribed and were using a TLSO to prevent the progression of scoliosis. Functional activities included in the Functional Independence Measure and 6 additional wheelchair and transfer skills were scored by level of assistance required. The timed motor test (TMT) included 6 activities involving dressing, transfers, and wheelchair propulsion. Subjects completed the activities of the functional activities scale (FAS) and TMT while wearing a TLSO and without a TLSO. Subjects were asked their preference for wearing or not wearing the TLSO during each of the activities.Results: For the TMT, subjects were slower with a TLSO when donning a shirt or pants, with even and uneven transfers and hallway propulsion (P < 0.05). The majority of subjects preferred not wearing the TLSO during the TMT activities. Lower functional activity scores were recorded while wearing a TLSO for upperextremity dressing (P < 0.05), lower-extremity dressing, bladder management, transferring to bed, and reaching for objects on the floor. Subjects preferred not wearing a TLSO for the following activities: lowerextremity dressing, bladder management, reaching for an object on the floor, and transfer from a supine to a sitting position.Conclusions: Wearing a TLSO adversely affected independence level and time requirements for selected functional activities. Subjects preferred not wearing a TLSO while performing the activities. Activities that required hip flexion, such as donning pants or transitioning from a supine to a sitting position were restricted by the TLSO. Future studies with larger sample sizes should explore the relationships between functioning with a TLSO as related to a patient’s age, level of injury, and TLSO design.

AbstractBackground/Objective: Wheelchair users often use trunk motion to facilitate or augment their upper extremity reach. Children with spinal cord injury (SCI) are often prescribed thoracic lumbar sacral orthoses (TLSO) to delay or prevent spinal curve progression. The impact of wearing a TLSO while reaching has not been studied. Therefore, the purpose of this study was to see the quantitative effect of the TLSO on reachable workspace volumes and reach of children with SCI.Methods: Twenty children with SCI aged 5 to 18 years participated in the present study. Three-dimensional upper extremity motion analysis was used to assess the reachable workspace patterns of children reaching for targets at varying heights. Volumes in and out of TLSO and kinematic ranges of reach were statistically analyzed using paired Student’s t tests with a P value set at 0.05.Results: Reachable workspace volumes were significantly greater for the non-TLSO condition compared with the TLSO condition (112,836 vs 80,711 cm3; P = 0.0002; a decrement of 28%). Anterior posterior and medial lateral ranges of reach were statistically greater in the non-TLSO condition (P = 0.002, P = 0.01 ). Nondominant hand medial lateral reaches were statistically greater in the non-TLSO condition (P = 0.003). Dominant hand anterior posterior reaches were greater in the non-TLSO condition (P = 0.009).Conclusions: Results suggest the reachable workspace of children with SCI is lessened with the use of a TLSO. This may be an important negative factor for brace compliance in children with SCI. The TLSO interferes with their ability to reach; therefore, children may prefer not to wear the orthosis.

AbstractObjective: The purpose of this study was to determine the prevalence of components of the metabolic syndrome in adolescents with spinal cord injury (SCI) and spina bifida (SB), and their associations with obesity in subjects with and without SCI and SB.Methods: Fifty-four subjects (20 SCI and 34 SB) age 11 to 20 years with mobility impairments from lower extremity paraparesis were recruited from a hospital-based clinic. Sixty able-bodied subjects who were oversampled for obesity served as controls (CTRL). Subjects were categorized as obese if their percent trunk fat measured by dual x-ray absorptiometry (DXA) was>30.0> for males and>35 .0> for females. Ten SCI, 24 SB, and 19 CTRL subjects were classified as obese. Fasting serum samples were collected to determine serum glucose, insulin, and lipid concentrations. Metabolic syndrome was defined as having #x003D;3 of the following components: (a) obesity; (b) high-density lipoprotein (HDL) <45 mg/dl for males;<50 mg/dl for females; (c) triglycerides #x003D;100 mg/dl; (d) systolic or diastolic blood pressure95th percentile for age/ height/gender, and (e) insulin resistance determined by either fasting serum glucose 100-125 mg/dl; fasting insulin #x003D;20 μU /ml; or homeostasis model assessment of insulin resistance #x003D;4.0 .Results: Metabolic syndrome was identified in 32.4>of the SB group and 55> of the SCI group. Metabolic syndrome occurred at a significantly higher frequency in obese subjects (SB = 45 .8>, SCI = 100>, CTRL = 63.2>) than nonobese subjects (SB = 0>, SCI = 10>, CTRL = 2.4>).Conclusions: The prevalence of metabolic syndrome in adolescents with SB/ SCI is quite high, particularly in obese individuals. These findings have important implications due to the known risks of cardiovascular diseases and diabetes mellitus associated with metabolic syndrome in adults, particularly those with spinal cord dysfunction.

AbstractBackground/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.

AbstractBackground:Autonomie dysreflexia (AD) is a well-documented complication of spinal cord injury (SCI) at or above the T6 Ievei. However, research into AD has focused primarily on the adult. Because research that involves children with SCI is scarce, current guidelines may not be appropriate for children. Therefore, many episodes of AD may be unrecognized or inappropriately treated. To address this issue, Shriners Hospitals for Children undertook the development of a protocol specific to children and adolescents.Method:A task forcewas developed to Iook at current Iiterature on AD and blood pressure in children. Utilizing this Iiterature and consensus among the task force members, the tools necessary to treat children with SCI at risk for AD were developed.Results:The task force developed several products intended to assist in the recognition and management of AD. These include an event flow sheet for recording incidents of AD, a Ietter for the child 's school or primary care physician that provides abrief summary of AD and the child's baseline blood pressure, and a policy/protocol with 2 age-specific algorithms to standardize interventions across the 3 Shriners Hospitals in the United States with SCI programs (California, lllinois, and Pennsylvania).Conclusion:The Shriners Hospitals for Children Task Force on Autonomie Dysreflexia in Children with Spinal Cord lnjury has developed several tools specific to children. However, many questions remain tobe answered concerning blood pressure norms and the clinical presentation of AD in children.

AbstractBackground: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.

Disease of the peripheral nerves often causes muscle wasting, weakness, and loss of sensation in children. Unlike polyneuropathies in adulthood, which most commonly are acquired, peripheral neuropathies occurring in childhood are predominantly of the inherited variety This review focuses on the most common inherited and acquired peripheral neuropathies of childhood.

The purpose of the study is to further assess the usefulness of short TI (time to inversion) recovery (STIR) magnetic resonance imaging (MRI) in detecting denervation of skeletal muscle compared to needle electromyography (EMG). Ninety subjects with clinical evidence of peripheral nerve injury or radiculopathy underwent STIR MRI and EMG of the affected limb. In 74 (82%) of these subjects, a positive correlation was found between STIR MRI and EMG (P< 0.009). STIR MRI has a relative sensitivity of 84% and specificity of 100% for detecting denervation. A subset of 28 subjects underwent quantitative assessments of signal intensity ratio (SIR) from the STIR MRI. The rank order correlation coefficient between the SIR and abnormal spontaneous activity on EMG was 0.70 (P< 0.001). Increased signal intensity on STIR MRI corresponds closely with spontaneous activity on EMG in denervated muscle. Although less sensitive than EMG in detecting muscle denervation, STIR MRI may be a useful adjunctive diagnostic tool in this setting. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 1431‐1434, 2000

Severe spinal deformity in progressive neuromuscular disease (NMD) leads to multiple problems, including poor sitting balance, difficulty with upright seating and positioning, pain, difficulty in attendant care, and potential exacerbation of underlying restrictive respiratory compromise. Severe scoliosis and pelvic obliquity can in some instances completely preclude upright sitting in a wheelchair. This article reviews the prevalence, natural history, and management of scoliosis in neuromuscular diseases at greatest risk for progressive spinal deformity.

Limb contractures are common impairments in selected progressive neuromuscular disease (NMD) conditions and can lead to such increased disabilities as worsening motor performance, decreased mobility, loss of ADL skills, and pain. This article reviews the pathogenesis of joint contractures in NMD, the prevalence of specific contractures among many common NMD conditions, and the role of optimal positioning, stretching, upright ambulation, orthotics, and splinting, as well as surgery in the prevention and management of contractures.

This article reviews the clinical approach to the diagnostic evaluation of progressive neuromuscular diseases with an emphasis on relevant neuromuscular history, family history, clinical examination findings, laboratory studies, and the role of muscle biopsy. In some instances, a precise diagnosis is not medically possible; however, the accurate characterization of an individual patient within the most appropriate NMD clinical syndrome often allows the clinician to provide the patient and family with accurate prognostic information and anticipatory guidance for the future.

We retrospectively reviewed 39 patients with a tethered spinal cord to evaluate whether surgical release positively influenced urological symptoms or urodynamic findings.

A coordinated, interdisciplinary, team approach is the most effective way to provide optimal care, and prevent complications, to the array of problems resulting from spinal dysraphic lesions. This article reviews health care maintenance issues unique to the child. Rehabilitation goals and treatment strategies are presented in the contexts of mobility, toilet training, skin management, cognitive functioning, fine motor skills, school and vocational integration, adjustment to disability, and transition from adolescence to adulthood. Such rehabilitation interventions strive for improved function, independence, and quality of life.