Non-invasive ventilation usage and adherence in children and adults with Duchenne muscular dystrophy: A multicenter analysis.

INTRODUCTION/AIMS: Non-invasive ventilation (NIV) is routinely prescribed to support the respiratory system in Duchenne muscular dystrophy (DMD) patients; however, factors improving NIV usage are unclear. We aimed to identify predictors of NIV adherence in DMD patients. METHODS: This was a multicenter retrospective analysis of DMD patients prescribed NIV and followed at (1) The Hospital for Sick Children, Canada; (2) Rady Children's Hospital San Diego, USA; and (3) University of California San Diego Health, USA, between February 2016 and October 2020. The primary and secondary outcomes were 90-day period NIV adherence and clinical and socioeconomic predictors of NIV adherence. RESULTS: We identified 59 DMD patients prescribed NIV (mean ± SD age = 20.1 ± 6.7 y). Overall, percentage of nights used, and average nightly usage, were 79.9 ± 31.1% and 7.23 ± 4.12 h, respectively. Compared with children, adults had higher percentage of nights used (92.9 ± 16.9% vs. 70.4 ± 36.9%; P < .05), and average nightly usage (9.5 ± 4.7 h vs. 5.3 ± 3.7 h; P < .05). Non-English language (P = .01), and absence of deflazacort prescription (P = .02) were significantly associated with higher percentage of nights used while Hispanic ethnicity (P = .01), low household income (P = .02), and absence of deflazacort prescription (P = .02) were significantly associated with higher nightly usage. Based on univariable analysis, older age and declining forced vital capacity were associated with increased percentage of nights used and increased average nightly usage. DISCUSSION: Certain clinical and socioeconomic determinants had a significant impact on NIV adherence in DMD patients, providing insight into those at risk for high versus low compliance with respiratory therapy.

Screening Intrathecal Baclofen Pump Systems for Catheter Patency via Catheter Access Port Aspiration.

OBJECTIVES: To screen all of our patients being treated with intrathecal baclofen (ITB) therapy for catheter patency. METHOD: Catheter patency was examined by performing a catheter access port study in 91 pediatric and adult patients undergoing ITB therapy at our institution. RESULTS: Despite no preoperative clinical suspicion of a problem with the ITB system in all but one case, 16.5% of the catheters in our patient population were not patent. After replacement, prerevision and stable postrevision dosage was examined to determine the impact system replacement had on the daily dosage. There was a significant 65% reduction in the daily ITB dosage from before catheter exploration (M = 823.8 mcg/day, SD = 390.51) to stable post replacement/revision dosage after catheter replacement or revision (M = 289.43 mcg/day, SD = 187.76), t11 = 4.09, p = .002, 95% CI [246.80, 822.00]. CONCLUSIONS: These results suggest that catheters need to be routinely screened for patency. Routine maintenance and screening can minimize or more quickly detect nonpatent systems and ensure proper functioning of the ITB system.

Comparing Deflazacort and Prednisone in Duchenne Muscular Dystrophy.

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-hoc analyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone. 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.

Multimodal assessment of spasticity using a point-of-care instrumented glove to separate neural and biomechanical contributions.

Accurate assessment of spasticity is crucial for physicians to select the most suitable treatment for patients. However, the current clinical practice standard is limited by imprecise assessment scales relying on perception. Here, we equipped the clinician with a portable, multimodal sensor glove to shift bedside evaluations from subjective perception to objective measurements. The measurements were correlated with biomechanical properties of muscles and revealed dynamic characteristics of spasticity, including catch symptoms and velocity-dependent resistance. Using the biomechanical data, a radar metric was developed for ranking severity in spastic knees and elbows. The continuous monitoring results during anesthesia induction enable the separation of neural and structural contributions to spasticity in 21 patients. This work delineated effects of reflex excitations from structural abnormalities, to classify underlying causes of spasticity that will inform treatment decisions for evidence-based patient care.

A population-based study of dystrophin mutations in Canada.

INTRODUCTION: We carried out a population-based study of dystrophin mutations in patients followed by members of the Canadian Paediatric Neuromuscular Group (CPNG) over a ten-year period. OBJECTIVES: We aimed to describe the changes in diagnostic testing for dystrophinopathy and to determine the frequency of dystrophin mutations from 2000 to 2009. METHODS: De-identified data containing the clinical phenotypes, diagnostic methods, and mutational reports from dystrophinopathy patients followed by CPNG centres from January 2000 to December 2009 were analyzed using descriptive statistics. RESULTS: 773 patients had a confirmed diagnosis of dystrophinopathy based on genetic testing (97%), muscle biopsy (2%), or family history (1%). 573 (74%) had complete deletion/duplication analysis of all 79 exons or whole gene sequencing, resulting in 366 (64%) deletions, 64 (11%) duplications, and 143 (25%) point mutations. The percentage of patients who were diagnosed using currently accepted genetic testing methods varied across Canada, with a mean of 63% (SD 23). 246 (43%) mutations involved exons 45 to 53. The top ten deletions (n=147, 26%) were exons 45-47, 45-48, 45, 45-50, 45-55, 51, 45-49, 45-52, 49-50, and 46-47. 169 (29%) mutations involved exons 2 to 20. The most common duplications (n=29, 5.1%) were exons 2, 2-7, 2-17, 3-7, 8-11, 10, 10-11, and 12. CONCLUSION: This is the most comprehensive report of dystrophin mutations in Canada. Consensus guidelines regarding the diagnostic approach to dystrophinopathy will hopefully reduce the geographical variation in mutation detection rates in the coming decade.

Determinants of usage and nonadherence to noninvasive ventilation in children and adults with Duchenne muscular dystrophy.

STUDY OBJECTIVES: Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to chronic respiratory insufficiency and failure. Use of home noninvasive ventilation (NIV) has been linked to improved outcomes including reduced mortality. Despite the importance of NIV, factors promoting optimal NIV usage and determinants of nonadherence have not been rigorously examined. Moreover, given that respiratory issues in DMD span between childhood and adulthood, examination across a broad age group is needed. The objectives of this study were to (1) evaluate NIV usage across a broad spectrum of patients with DMD, including both children and adults, and (2) identify biological and socioeconomic determinants of NIV usage and NIV nonadherence. METHODS: We performed a retrospective review of all patients with DMD from February 2016 to February 2020 who underwent evaluation at associated pediatric and adult neuromuscular disease clinics. NIV use was determined objectively from device downloads. A priori, we defined nonadherence as < 4 hours use per night, quantified as the percentage of nights below this threshold across a 30-day period within 6 months of a clinic visit. We also assessed the average hours of NIV usage over this time period. Predictors examined included demographics, social determinants, and pulmonary function. RESULTS: 33 patients with DMD were identified, 29 (87%) of whom were using NIV (13 age < 21 years). Mean age was 22.9 ± 6.6 years (range 13-39 years), body mass index was 23.4 ± 10.4 kg/m2, and seated forced vital capacity was 23% ± 18% predicted. Mean nightly NIV usage was 7.4 ± 3.8 hours and mean percentage of nonadherent nights was 13% ± 30%. In univariable analysis, age did not predict use. Those with lower forced vital capacity had higher NIV usage hours (P = .01) and a trend toward less nonadherence (P = .06). Higher estimated household income demonstrated a trend toward increased usage hours and less nonadherence (both P = .08). Multivariable analysis found increased usage hours were predicted best by higher income, higher inspiratory positive airway pressure, and higher bicarbonate. Nonadherence was higher in those with lower income or higher forced vital capacity. CONCLUSIONS: In this cohort of adult and pediatric patients with DMD, most individuals were using NIV. While usage hours were higher with lower lung function, substantial variability remains unexplained by examined factors. Nonadherence was observed in some individuals, including those with advanced disease. Further investigations should focus on evaluating patient-oriented outcomes to define optimal NIV usage across the spectrum of disease and determine strategies to counteract issues with nonadherence. CITATION: Hurvitz MS, Bhattacharjee R, Lesser DJ, Skalsky AJ, Orr JE. Determinants of usage and nonadherence to noninvasive ventilation in children and adults with Duchenne muscular dystrophy. J Clin Sleep Med. 2021;17(10):1973-1980.

Nusinersen treatment of older children and adults with spinal muscular atrophy.

The purpose of this study was to determine how effective administration of nusinersen was at improving motor function in older adolescent and adult patients with spinal muscular atrophy, using standardized motor outcome measures. Data were gathered through a retrospective chart review of older spinal muscular atrophy patients (ages 5-58) being treated at Rady Children's Hospital and the University of California, San Diego with nusinersen from April 2017-June 2019. Linear mixed effects analyses found that, for older children and adult patients with SMA 1, 2, and 3, motor scores as measured by the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for non-sitters improved by 6 points (p = .01) and the Hammersmith Infant Neurological Examination-2 by 2.6% (p = .008) over the 22-month study period. Over the same period, sitters improved on the Revised Upper Limb Module by 4.4 points (p = .02) and on the Hammersmith Functional Motor Scale-Expanded by 3.3% (p = .00005) post treatment with nusinersen. Older spinal muscular atrophy patients (5-58 years) being treated with nusinersen at our institutions are improving. Not only have symptoms stabilized, but their motor function has shown incremental improvements. Based on the results of this study, we suggested that nusinersen is well-tolerated and efficacious when treating older children and adult patients with spinal muscular atrophy 1, 2, and 3.

The relationship between regional body composition and quantitative strength in facioscapulohumeral muscular dystrophy (FSHD).

This study determines in facioscapulohumeral muscular dystrophy (FSHD) and able-bodied controls (1) the regional body composition and (2) the correlation between regional lean tissue mass and the corresponding regional strength. This is a cross-sectional, criterion standard, case-control study at a university based neuromuscular disease clinic. A dual-energy X-ray absorptiometry (DEXA) scanner was used to obtain regional body composition measurements in 14 FSHD and anthropometrically matched control pairs. A dynamometer determined peak isometric strength for the elbow and knee. Compared to controls, FSHD subjects showed increased regional fat tissue mass (p < 0.001-0.017), decreased regional lean tissue mass (p < 0.001-0.010), and decreased strength (p < 0.001-0.020). There was a correlation between quantitative strength and lean tissue mass for both FSHD and controls (r = 0.791-0.906; p < 0.001). FSHD subjects have higher regional fat tissue mass and lower regional lean tissue mass despite similar BMI and anthropometrics. Regional lean tissue mass correlates with strength.

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.

Common complications of pediatric neuromuscular disorders.

Children with pediatric neuromuscular disorders experience common complications, primarily due to immobility and weakness. Musculoskeletal complications include hip dysplasia with associated hip subluxation or dislocation, neuromuscular scoliosis, and osteoporosis and resulting fractures. Constipation, gastroesophageal reflux, and obesity and malnutrition are commonly experienced gastrointestinal complications. Disordered sleep also is frequently observed, which affects both patients and caregivers.

Intrathecal baclofen bolus dosing and catheter tip placement in pediatric tone management.

Intrathecal baclofen (ITB), administered by an implanted pump, has emerged as an efficacious therapy for the treatment of hypertonicity in pediatrics. Although ITB has been used for more than 20 years clinically, much is still unknown about the most optimal dosing regimens and intrathecal catheter tip placement. Clinician experience, animal research, and advanced imaging is guiding the use of ITB. The rationale for high cervical catheter tip placement and pulsating flex dosing is described.

Evaluation of phrenic nerve and diaphragm function with peripheral nerve stimulation and M-mode ultrasonography in potential pediatric phrenic nerve or diaphragm pacing candidates.

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.

Shunted hydrocephalus has a significant impact on quality of life in children with spina bifida.

OBJECTIVE: To determine which clinical (health status) and nonclinical (demographic) factors may affect perceptions of quality of life in children with spina bifida and their parents. DESIGN: A prospective study by using a validated questionnaire. SETTING: A multidisciplinary spina bifida clinic at a pediatric tertiary referral center. PATIENTS: Thirty-three children with spina bifida aged 5-18 years and 41 parents of children with spina bifida aged 2-18 years completed questionnaires after informed consent was obtained. METHODS: The Peds QL 4.0 Short Form 15 questionnaire was administered to children with spina bifida and their parents. Additional data were collected, including socioeconomic status, self-reported ethnicity, insurance status, ambulatory status, presence of shunted hydrocephalus, and continence. All completed questionnaires were included in the final analysis. RESULTS: Self-reported physical and psychosocial health scores for patients in our study were lower than previously published scores from healthy children. Patients with a shunted hydrocephalus had significantly lower self-reported physical health scores compared with those without shunted hydrocephalus (61.4 versus 39.3; P = .015). Self-reported physical health score in those with shunted hydrocephalus improved with age (Spearman ρ = 0.42; P = .017). Shunted hydrocephalus remained significant on multivariate analysis. Ethnicity, insurance, socioeconomic status, ambulatory status, and urinary and fecal continence were not associated with self-reported physical or psychosocial scores. Parent-reported scores were not associated with any of the variables of interest. There was excellent correlation between parent-reported and self-reported psychosocial health scores (Spearman ρ = 0.636; P < .001) but not physical health scores (Spearman ρ = 0.023; P = .905). CONCLUSIONS: Shunted hydrocephalus has a negative impact on the perception of quality of life, an effect that may be attenuated by age. Further study and more-specific measurement tools are needed to better understand health-related quality of life in children with spina bifida.

Prevention and management of limb contractures in neuromuscular diseases.

Limb contractures are a common impairment in neuromuscular diseases. They contribute to increased disability from decreased motor performance, mobility limitations, reduced functional range of motion, loss of function for activities of daily living, and increased pain. The pathogenesis of contractures is multifactorial. Myopathic conditions are associated with more severe limb contractures compared with neuropathic disorders. Although the evidence supporting the efficacy of multiple interventions to improve range of motion in neuromuscular diseases in a sustained manner is lacking, there are generally accepted principles with regard to splinting, bracing, stretching, and surgery that help minimize the impact or disability from contractures.

Current pharmacologic management in selected neuromuscular diseases.

For generations, the neuromuscular disorder care community has focused on establishing the correct diagnosis and providing supportive care. As the pathophysiology and genetics of these conditions became better understood, novel treatments targeting the disease mechanism were developed. This has led to some significant disease-modifying and supportive treatments for several neuromuscular disorders. The current treatments for amyotrophic lateral sclerosis (ALS), neuromuscular junction disorders, inflammatory myopathies, and myotonia are reviewed. Additionally, investigational treatments for ALS, Duchenne muscular dystrophy, and spinal muscular atrophy are discussed.

Mobility-assistive technology in progressive neuromuscular disease.

Mobility-assistive technologies allow patients with neuromuscular disease to interact with peers and the community. In children, they also serve to facilitate development. Lack of access to appropriate assistive technology, especially in regards to mobility, can have adverse developmental consequences. There are multiple options for mobility devices and methods for their control. These devices can be integrated with other electronics to facilitate the control of a variety of devices in the environment. The clinician should assess which devices are best based on the patient's, caregivers', and medical team's goals.

Regional and whole-body dual-energy X-ray absorptiometry to guide treatment and monitor disease progression in neuromuscular disease.

Dual-energy x-ray absorptiometry (DEXA) is a safe, noninvasive, inexpensive tool for managing patients with neuromuscular diseases. Regional and whole-body DEXA can be used to guide clinical treatments, such as determining body composition to guide nutritional recommendations, as well as to monitor disease progression by assessing regional and whole-body lean tissue mass. DEXA can also be used as an outcome measure for clinical trials.

The natural history of cardiac and pulmonary function decline in patients with duchenne muscular dystrophy.

STUDY DESIGN: Retrospective review of scoliosis progression, pulmonary and cardiac function in a series of patients with Duchenne Muscular Dystrophy (DMD). OBJECTIVE: To determine whether operative treatment of scoliosis decreases the rate of pulmonary function loss in patients with DMD. SUMMARY OF BACKGROUND DATA: It is generally accepted that surgical intervention should be undertaken in DMD scoliosis once curve sizes reach 35° to allow intervention before critical respiratory decline has occurred. There are conflicting reports, however, regarding the effect of scoliosis stabilization on the rate of pulmonary function decline when compared to nonoperative cohorts. METHODS: We reviewed spinal radiographs, echocardiograms, and spirometry, hospital, and operative records of all patients seen at our tertiary referral center from July 1, 1992 to June 1, 2007. Data were recorded to Microsoft Excel (Microsoft, Redmond, WA) and analyzed with SAS (SAS Institute, Cary, NC) and R statistical processing software (www.r-project.org). RESULTS: The percent predicted forced vital capacity (PPFVC) decreased 5% per year before operation. The mean PPFVC was 54% (SD = 21%) before operation with a mean postoperative PPFVC of 43% (SD = 14%). Surgical treatment was associated with a 12% decline in PPFVC independent of other treatment variables. PPFVC after operation declined at a rate of 1% per year and while this rate was lower, it was not significantly different than the rate of decline present before operation (P = 0.18). Cardiac function as measured by left ventricular fractional shortening declined at a rate of 1% per year with most individuals exhibiting a left ventricular fractional shortening rate of more than 30 before operation. CONCLUSION: Operative treatment of scoliosis in DMD using the Luque Galveston method was associated with a reduction of forced vital capacity related to operation. The rate of pulmonary function decline after operation was not significantly reduced when compared with the rate of preoperative forced vital capacity decline.