Search

Highlights • Natural history changes in pulmonary function tests across time in Duchenne muscular dystrophy. • Treatment with glucocorticoids (steroids) > 1 year was compared to steroid naïve treatment. • Steroid treatment slowed the rate of pulmonary decline as measured by FVC%p in 7–9.9 year olds; • Steroid treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline. • Time to FVC < 1 liter was delayed by steroid treatment; FVC < 1 liter increased risk of death 4-fold. Abstract We describe changes in pulmonary function measures across time in Duchenne muscular dystrophy patients treated with glucocorticoids (GCs) > 1 year compared to GC naïve patients in the Cooperative International Research Group Duchenne Natural History Study, a multicenter prospective cohort study. 397 participants underwent 2799 pulmonary function assessments over a period up to 10 years. Fifty-three GC naïve participants (< 1 month exposure) were compared to 322 subjects with > 1 year cumulative GC treatment. Forced vital capacity (FVC), peak expiratory flow rate (PEFr), maximal inspiratory and expiratory pressures were performed and calculated as a percent predicted (%p). GC treatment slowed the rate of pulmonary decline as measured by FVC%p, in patients aged 7–9.9 years. GC treatment slowed 12 and 24-month progression of percent predicted spirometry to a greater degree in those with baseline FVC%p from < 80–34%. GC treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline. Progression to an absolute FVC < 1 liter was delayed by GC treatment. Patients who reached a FVC below 1 L were 4.1 times more likely to die (p = 0.017). Long-term glucocorticoid treatment slows pulmonary disease progression in Duchenne dystrophy throughout the lifespan. [ABSTRACT FROM AUTHOR]

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10–18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics. [ABSTRACT FROM AUTHOR]

Abstract: Chen Y, Anderson CJ, Vogel LC, Chlan KM, Betz RR, McDonald CM. Change in life satisfaction of adults with pediatric-onset spinal cord injury. Objectives: To examine the change in life satisfaction over time and potential contributing factors among adults with pediatric-onset spinal cord injury (SCI). Design: Prospective dynamic cohort study. Setting: Community. Participants: Individuals who sustained a SCI before age 19 years (N=278) were initially interviewed at age 24 years or older and followed on an annual basis between 1996 and 2006. Interventions: Not applicable. Main Outcome Measures: A structured telephone interview was conducted to obtain the measures of Satisfaction with Life Scale (SWLS), physical independence, participation, and psychologic functioning. The hierarchical linear modeling was performed to characterize individual person-specific time paths and estimate the average rate of change in SWLS over time. Results: A total of 1171 interviews were conducted among 184 men and 94 women (89% white; baseline age, 27.1±3.4y; baseline years since injury, 12.8±4.9). The initial SWLS score averaged 24.2 and was estimated to increase by 0.14 a year (P=.10). After adjusting for potential confounding factors, the overall life satisfaction was significantly higher for women and those who were married/living with a partner; were employed/students; did not use illicit drugs; and scored high in the FIM, the mental health component of the Short Form-12, and the social integration subscale of the Craig Handicap Assessment and Reporting Technique. The rate of change in life satisfaction did not differ significantly by any personal, medical, and psychosocial characteristics under investigation. Conclusions: The study findings suggest that people who feel unsatisfied with life initially are likely to stay unsatisfied over time if the critical determinant factors remain unchanged in their life. To minimize the risk of decreasing life satisfaction, several modifiable risk factors identified in the present study could be targeted for intervention. [Copyright &y& Elsevier]

Abstract: Werner BC, Skalsky AJ, McDonald CM, Han JJ. Convexity of scoliosis related to handedness in identical twin boys with Duchenne''s muscular dystrophy: a case report. The interplay between hand dominance and directionality of scoliosis in boys with Duchenne''s muscular dystrophy (DMD) is not clearly defined. We describe an extremely rare presentation of monozygotic twin boys with DMD and opposing hand dominance who developed major spine curvature with opposite convexities. The unique clinical presentation of progressive neuromuscular disease and scoliosis in monozygotic twins should allow for a unique evaluation of some of the contributory factors associated with the development of neuromuscular scoliosis in DMD. In this case report, we explore the pathophysiology involved in neuromuscular scoliosis, examine the role of conservative, surgical, and medical treatments, and discuss potential future avenues of research. [Copyright &y& Elsevier]

Abstract: Stoelb BL, Carter GT, Abresch RT, Purekal S, McDonald CM, Jensen MP. Pain in persons with postpolio syndrome: frequency, intensity, and impact. Objective: To describe the frequency, intensity, and impact of pain in persons with postpoliomyelitis syndrome (PPS). Design: Retrospective, cross-sectional survey. Setting: Community-based survey. Participants: Convenience sample of people with PPS. Interventions: Not applicable. Main Outcome Measures: Overall intensity and duration of pain, pain sites, pain interference, pain treatments, and relief provided by pain treatments. Results: A total of 91% (n=57) of the study participants (N=63) reported pain. The most frequently reported pain sites were the shoulders, lower back, legs, and hips. Participants reported pain intensity to be the greatest in the knees, legs, wrists, lower back, and head. Pain interfered most with sleep and with activities requiring a high level of musculoskeletal involvement. Respondents also reported pain problems that were more severe than those of the general population and than those of a sample of people with multiple sclerosis. Many treatments had been tried previously for pain, but continued use of treatments was reported by relatively few participants at the time of the survey. Conclusions: The findings indicate that pain is a persistent and common problem in persons with PPS, highlighting the need for effective and accessible pain treatments for this population. [Copyright &y& Elsevier]

Abstract: Jensen MP, Hoffman AJ, Stoelb BL, Abresch RT, Carter GT, McDonald CM. Chronic pain in persons with myotonic dystrophy and facioscapulohumeral dystrophy. Objective: To determine the nature and scope of pain in working-aged adults with myotonic muscular dystrophy (MMD) and facioscapulohumeral muscular dystrophy (FSHD). Design: Retrospective, cross-sectional survey. Setting: Community-based survey. Participants: Convenience sample of subjects with MMD and FSHD. Interventions: Not applicable. Main Outcome Measures: Overall intensity and duration of pain, pain inference, pain sites, pain treatments, and relief provided by pain treatments. Results: More subjects with FSHD (82%) than with MMD (64%) reported pain. The most frequently reported pain sites for both diagnostic groups were lower back (66% MMD, 74% FSHD) and legs (60% MMD, 72% FSHD). Significant differences in pain intensity were found between the diagnostic groups in the hands, legs, knees, ankles, and feet, with patients with MMD reporting greater pain intensity at these sites than patients with FSHD. Age was related to the onset of pain (participants reporting pain were younger than those not reporting pain in the FSHD sample), but pain severity was not significantly associated with age in those reporting pain. Respondents with both diagnoses that reported mobility limitations and used assistive devices (eg, wheelchair, cane) reported more pain severity than those with mobility limitations who did not use assistive devices, who, in turn, reported more pain severity than respondents who reported no mobility limitations at all. The treatments that were reported to provide the greatest pain relief were not necessarily those that were the most frequently tried or still used. Conclusions: The findings indicate that pain is a more common problem in persons with FSHD than in persons with MMD, although it is common in both populations. In addition, these pain problems are chronic, underscoring the need to identify and provide effective pain treatments for patients with these neuromuscular diseases. [Copyright &y& Elsevier]

Abstract: Jensen MP, Abresch RT, Carter GT, McDonald CM. Chronic pain in persons with neuromuscular disease. Arch Phys Med Rehabil 2005;86:1155–63. Objective: To examine the nature and scope of pain in persons with neuromuscular disorder (NMD). Design: Survey study. Setting: University-based rehabilitation research programs. Participants: Adults with NMD (N=193). Interventions: Not applicable. Main Outcome Measures: Pain presence or absence, pain severity, pain quality (Neuropathic Pain Scale), pain interference (Brief Pain Inventory), pain site, quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]), and pain treatment. Results: Seventy-three percent of the sample reported pain, with 27% of these reporting that this pain was severe (≥7 on a 0–10 scale), on average. “Deep,” “tiring,” “sharp,” and “dull” were the words used most frequently to describe NMD pain. Patients with amyotrophic lateral sclerosis and myotonic muscular dystrophies reported the greatest pain interference, and patients with Charcot-Marie-Tooth the least, among all NMD diagnoses. The most frequent pain site, overall, was back (49%), followed by leg (47%), shoulder (43%), neck (40%), buttock and hip(s) (37%), feet (36%), arm(s) (36%), and hand(s) (35%). The study participants reported significantly greater dysfunction than subjects in the SF-36 normative sample (persons without health problems) on a number of the SF-36 scales. However, we found no significant differences between the study participants and the US norms on the SF-36 role-emotional or mental health scales. A number of pain treatments were used by the study sample, but no treatment appeared to be effective for all participants, and some of the treatments reported as most effective (eg, chiropractic care) were used by very few participants. Conclusions: Pain is a common problem among patients with NMDs. There are many similarities, but also some important differences, between NMD diagnostic groups on the nature and scope of pain and its impact. More research is needed to identify and test effective treatments for NMD-related pain. [Copyright &y& Elsevier]

Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four through five years with a confirmed Duchenne muscular dystrophy (DMD)-causing mutation in the DMD gene. This therapy was developed to address the underlying cause of DMD through targeted skeletal, respiratory, and cardiac muscle expression of delandistrogene moxeparvovec micro-dystrophin, an engineered, functional dystrophin protein. Drawing on clinical trial experience from Study 101 (NCT03375164), Study 102 (NCT03769116), and ENDEAVOR (Study 103; NCT04626674), we outline practical considerations for delandistrogene moxeparvovec treatment. Before infusion, the following are recommended: (1) screen for anti-adeno-associated virus rhesus isolate serotype 74 total binding antibody titers <1:400; (2) assess liver function, platelet count, and troponin-I; (3) ensure patients are up to date with vaccinations and avoid vaccine coadministration with infusion; (4) administer additional corticosteroids starting one day preinfusion (for patients already on corticosteroids); and (5) postpone dosing patients with any infection or acute liver disease until event resolution. Postinfusion, the following are recommended: (1) monitor liver function weekly (three months postinfusion) and, if indicated, continue until results are unremarkable; (2) monitor troponin-I levels weekly (first month postinfusion, continuing if indicated); (3) obtain platelet counts weekly (two weeks postinfusion), continuing if indicated; and (4) maintain the corticosteroid regimen for at least 60 days postinfusion, unless earlier tapering is indicated. Although the clinical safety profile of delandistrogene moxeparvovec has been consistent, monitorable, and manageable, these practical considerations may mitigate potential risks in a real-world clinical practice setting. [ABSTRACT FROM AUTHOR]

• Domagrozumab at 5, 20, and 40 mg/kg was generally safe and well tolerated. • Primary endpoint of mean change from baseline in 4SC time at week 49 was not met. • Efficacy measures did not support a significant treatment effect with domagrozumab. • Nonsignificant increase in muscle volume was observed with domagrozumab vs placebo. We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619 [ABSTRACT FROM AUTHOR]

• Respiratory disease continues to be major cause of morbidity and mortality in DMD. • Cohort study with DMD patients treated with idebenone for up to six years. • Respiratory function evolution with/without idebenone in same patients assessed. • Annual rate of decline in FVC%p was reduced by approximately 50%. • Long-term data confirm disease modifying treatment effect of idebenone. Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with idebenone (900 mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean idebenone exposure in the EAPs was 4.2 (range 2.4–6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from −7.4% (95% CI: −9.1, −5.8) for the Off-Idebenone periods to −3.8% (95% CI: −4.8, −2.8) for the On-Idebenone periods (N = 11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was −5.9% (95% CI: −8.0, −3.9) for the Off-Idebenone periods (N = 9) and reduced to −1.9% (95% CI: −3.2, −0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of idebenone previously observed in randomized, controlled trials. [ABSTRACT FROM AUTHOR]

• The reachable workspace detects slowly progressive upper extremity change in FSHD. • Decline rates are more pronounced if subjects were challenged with wrist weights. • The reachable workspace is superior to existing scaled assessments over time. • The reachable workspace is useful for stratification for clinical trials. Facioscapulohumeral Dystrophy (FSHD) results in slowly progressive strength impairment, especially the upper extremities. Recent discoveries regarding pathophysiology have led to exciting novel therapeutic strategies. To further facilitate drug development, improved FSHD outcome measures that are functionally-relevant and sensitive to longitudinal change will be critical. Recently, a motion sensor (Kinect)-based upper extremity outcome called 'reachable workspace' that provides a quantitative reconstruction of an individual's reachability was developed. In this study, changes in reachable workspace were tracked upwards for five-years in 18 FSHD subjects. Results show -1.63 %/year decline in total reachable workspace (p = 0.144); with most notable decline in the above-the-shoulder level quadrants (upper-lateral Q3: -9.5 %/year, p < 0.001 and upper-medial Q1: -6.8 %/ year, p = 0.063) with no significant changes in the lower quadrants (Q2, Q4). Reachable workspace declined more significantly if the subjects were challenged with 500 g wrist weights: total reachable workspace: -1.82 %/year, p = 0.039; Q1: -7.20 %/year, p = 0.041; Q3: -8.09 %/year, p = 0.001. Importantly, reachable workspace outcome was also able to distinguish subgroups in FSHD: mildly- and severely-affected with essentially unchanging reachability over years, and moderately-affected who demonstrate the most detectable changes longitudinally. The study demonstrates utility for measuring declines in upper quadrant reachability, and provides enrichment/stratification of FSHD populations most likely to show treatment effects in clinical trials. [ABSTRACT FROM AUTHOR]

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference ( P  = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300–400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters ( P  = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder characterized by progressive proximal to distal muscle weakness. The success of randomized clinical trials for novel therapeutics depends on outcome measurements that are sensitive to change. As the development of motor skills may lead to functional improvements in young boys with DMD, their inclusion may potentially confound clinical trials. Three-dimensional gait analysis is an under-utilized approach that can quantify joint moments and powers, which reflect functional muscle strength. In this study, gait kinetics, kinematics, spatial-temporal parameters, and timed functional tests were quantified over a one-year period for 21 boys between 4 and 8 years old who were enrolled in a multisite natural history study. At baseline, hip moments and powers were inadequate. Between the two visits, 12 boys began a corticosteroid regimen (mean duration 10.8±2.4 months) while 9 boys remained steroid-naïve. Significant between-group differences favoring steroid use were found for primary kinetic outcomes (peak hip extensor moments (p=.007), duration of hip extensor moments (p=.007), peak hip power generation (p=.028)), and spatial-temporal parameters (walking speed (p=.016) and cadence (p=.021)). Significant between-group differences were not found for kinematics or timed functional tests with the exception of the 10m walk test (p=.03), which improves in typically developing children within this age range. These results indicate that hip joint kinetics can be used to identify weakness in young boys with DMD and are sensitive to corticosteroid intervention. Inclusion of gait analysis may enhance detection of a treatment effect in clinical trials particularly for young boys with more preserved muscle function. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of Duchenne muscular dystrophy starts before birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here, we report 6- and 12-month follow-up of two subsets of these boys. Patients: Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and 6 months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, 6, and 12 months. Results: Gross motor scores were lower at baseline compared with published controls (6.2 ± 1.7; normal 10 ± 3; P < 0.0001) and revealed a further declining trend to 5.7 ± 1.7 (P = 0.20) at 6 months. Repeated measures analysis of the 12 boys monitored for 12 months revealed that gross motor scores, again low at baseline (6.6 ± 1.7; P < 0.0001), declined at 6 months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (P = 0.11). Cognitive and language scores were lower at baseline compared with normal children (range, P = 0.002-<0.0001) and did not change significantly at 6 or 12 months (range, P = 0.89-0.09). Fine motor skills, also low at baseline, improved >1 year (P = 0.05). Conclusion: Development can reliably be measured in infants and young boys with Duchenne muscular dystrophy across time using the Bayley-III. Power calculations using these data reveal that motor development may be used as an outcome measure. [ABSTRACT FROM AUTHOR]