Sleep in pediatric neuromuscular disorders.

Sleep disordered breathing (SDB) is prevalent among children with neuromuscular disorders (NMD). The combination of respiratory muscle weakness, altered drive, and chest wall distortion due to scoliosis make sleep a stressful state in this population. Symptomatology can range from absent to snoring, nocturnal awakenings, morning headaches, and excessive daytime sleepiness. Sequelae of untreated SDB includes cardiovascular effects, metabolic derangements, and neurocognitive concerns which can be compounded by those innate to the NMD. The clinician should have a low threshold for obtaining polysomnography and recognize the nuances of individual disorders due to disproportionately impacted muscle groups such as hypoventilation in ambulating patients from diaphragm weakness. Non-invasive or invasive ventilation are the mainstay of treatment. In this review we explore the diagnosis and treatment of SDB in children with various NMD.

Sleep disordered breathing: Assessment and therapy in the age of emerging neuromuscular therapies.

The term neuromuscular disease (NMD) encompasses a large variety of disorders that result in abnormal muscle function. Although it may be conventional to relate the use of this term to the most common muscular diseases (Duchenne muscular dystrophy [DMD], spinal muscular atrophy [SMA], and amyotrophic lateral sclerosis, etc), it is important to extend the term to pathologies manifested by severe neurologic (brain and spinal cord) malformations and injuries. In many of these scenarios, there are common mechanisms that contribute to sleep disordered breathing (SDB) and respiratory insufficiency although comorbidities may be somewhat different. Advances in the understanding of these diseases and their natural history, and increasing availability of mechanical ventilation to these patients have improved survival. The development of novel genetic and molecular therapies (as in the cases of DMD, SMA, and X-linked myotubular myopathy) provides an opportunity to use SDB as a reasonable outcome measure while also allowing the use of polysomnography as a validation tool in the assessments of effectiveness of therapies. We seek to provide an understanding of SDB in NMDs, and in the same light, would like to begin the conversation of thinking about weaning respiratory support when possible.

Randomized trial of lung hyperinflation therapy in children with congenital muscular dystrophy.

OBJECTIVE: Respiratory compromise in congenital muscular dystrophy (CMD) occurs, in part, from chest wall contractures. Passive stretch with hyperinsufflation therapy could reduce related costo-vertebral joint contractures. We sought to examine the impact of hyperinsufflation use on lung function and quality of life in children with CMD. STUDY DESIGN: We conducted a randomized controlled trial on hyperinsufflation therapy in children with CMD at two centers. An individualized hyperinsufflation regimen of 15 minutes twice daily using a cough assist device over a 12 months period was prescribed. We measured lung function, quality of life, and adherence. To demonstrate reproducibility, pulmonary function was measured twice on the same day. A mixed-effects regression model adjusting for confounders was used to assess the effects of hyperinsufflation. RESULTS: We enrolled 34 participants in the study; 31 completed the trial (n = 17 treatment group and n = 14 controls). Participants in the treatment group demonstrated a relative gain in lung volume measured at 4 and 8 months, but not at 12 months. The control group required increases in the maximum insufflation pressures to achieve maximum lung volumes while the treatment group did not. Adherence was best early in the study, peaking at the first visit and decreasing at subsequent visits. Caregiver-reported quality of life was higher in the treatment group. CONCLUSION: Hyperinsufflation therapy is effective in increasing and sustaining lung volume over time. Adherence, however, was inconsistent and difficult to maintain. Further research should determine if improved adherence leads to sustained benefits of hyperinsufflation.

Sleep-Disordered Breathing in Pediatric Patients With Rett Syndrome.

STUDY OBJECTIVES: Although respiratory abnormalities occurring during wakefulness are well recognized in patients with Rett syndrome (RS), less has been reported regarding sleep-disordered breathing (SDB) in this population. This study aims to characterize the presenting complaints, types and severity of SDB, and treatment modalities of patients with RS and sleep concerns. METHODS: Retrospective chart review of pediatric patients with RS referred to our academic tertiary care institution from January 2007 to July 2017. RESULTS: Thirteen patients were identified, 11 female (84.6%); mean age at polysomnography (PSG) was 10.3 years (standard deviation 4.94). Eleven were white (84.6%), 2 were black (15.4%). The most common presenting symptoms were snoring (10/13, 77%) and witnessed apnea (7/13, 53.8%). On baseline PSG, all patients (100%) exhibited hyperapneas followed by a central apnea during wake. Nine (69.2%) had obstructive sleep apnea (OSA) (obstructive apnea-hypopnea index (oAHI) > 1); four had severe OSA (oAHI ≥ 10). One had central sleep apnea (central apnea index > 5) and severe OSA. No patients exhibited hypoventilation on baseline PSG. Mean AHI of all patients was 8.77 ± 8.82 (oAHI 6.51 ± 6.91) events/h. Mean oxyhemoglobin nadir was 88.52 ± 5.6%. Treatment modalities included observation: 5 (38%), acetazolamide: 2 (15%), nasal mometasone: 1 (7.7%), adenotonsillectomy: 3 (23.1%), and positive airway pressure: 2 (15%). CONCLUSIONS: Regarding patients with RS referred to the sleep medicine clinic, snoring and witnessed apneas were the most common presenting complaints. In addition to breathing abnormalities during wake, OSA was very common in our cohort. Further studies are needed to examine the pathogenesis of OSA in RS and relationships between disease genotype and respiratory abnormality phenotype.

Understanding adherence to noninvasive ventilation in youth with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked, progressive neuromuscular disorder that results in chronic respiratory insufficiency and subsequently failure requiring noninvasive ventilation (NIV). Adherence to NIV in neuromuscular disorders and related barriers are poorly described. The aim of the current study was to assess NIV adherence, adherence barriers, and identify psychosocial predictors of adherence in young boys with early DMD-related sleep disordered breathing and recommended nocturnal NIV. This cross-sectional study included 42 youth with DMD with prescribed nocturnal NIV, and their caregivers. Caregivers and youth completed questionnaires assessing adherence barriers, psychosocial symptoms (eg, anxiety and depressive symptoms), and stress. Medical information pertinent to cardiopulmonary health and neurologic status at both enrollment and initiation of NIV was reviewed. Adherence to NIV, defined as percent days used and days used ≥4 hours/day was 56.1 ± 38.7% and 46.2 ± 40.6%, respectively. Average duration of use on days worn was 5.61 ± 4.23 hours. NIV usage was correlated with the severity of obstructive sleep apnea but not cardiopulmonary variables. Mask discomfort was the most commonly reported adherence barrier followed by behavioral barriers (eg, refusing to use). Multiple regression analyses revealed that internalizing behaviors (eg, anxiety and depressive symptoms) and total adherence barriers significantly predicted NIV adherence. Adherence to NIV in DMD is poor and similar to other pediatric chronic diseases. Our data suggest interventions targeting adherence barriers and patient internalizing symptoms may improve adherence to NIV in DMD.

Adherence and barriers to hyperinsufflation in children with congenital muscular dystrophy.

BACKGROUND: Congenital muscular dystrophy (CMD) is a rare, inherited neuromuscular disease characterized by progressive muscle weakness, thoracic insufficiency, and ultimately respiratory failure. Adherence to respiratory therapies in children with neuromuscular disorders is unknown. This study examined the multimodal assessment of adherence and barriers to 15 min, twice daily hyperinsufflation in children with CMD. Adherence was hypothesized to be greater than 50% and discomfort, embarrassment, and difficulty finding time were hypothesized to be barriers. METHODS: Participants included 18 children with CMD. Personalized hyperinsufflation settings were determined based on pressure-volume measurements at each study visit. Adherence was measured by a daily phone diary (DPD) and by electronic data download from the hyperinsufflation device. The DPD was conducted twice over a 48-hr period to capture a weekend and weekday, with the goal being 60 min of hyperinsufflation over the 48 hr (100% adherence). The hyperinsufflation objective electronic data reflected daily use of hyperinsufflation for the same 48-hr period. Data from DPD and the corresponding hyperinsufflation device data were used for analyses. RESULTS: Adherence to hyperinsufflation was 40% via DPD and 44% for electronic data, with strong convergence between methods (r = 0.75, P < 0.001). Surprisingly, 53% of participants reported no barriers despite low adherence. Social distractions and family obligations were identified as barriers. There were no differences in adherence between those who did and did not endorse barriers to hyperinsufflation (DPD: t(13) = 0.44, P = n.s.; hyperinsufflation device: t(13) = -0.23, P = n.s.). CONCLUSION: Adherence to hyperinsufflation is a significant problem in children with CMD and families have difficulty identifying adherence barriers. An important next step is to encourage open dialog around adherence barriers and promote adherence behaviors via intervention. Pediatr Pulmonol. 2017; 52:939-945. © 2016 Wiley Periodicals, Inc.

Effects of mu, kappa, and delta opioid receptor agonists on the function of hypothalamic-pituitary-adrenal axis in monkeys.

Opioids can modulate neuroendocrine function. Less is known about the involvement of opioid receptor subtypes in the stimulatory effects of opioids on the primate hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the stimulatory effects of opioids selective for each receptor subtype on plasma adrenocorticotropic hormone (ACTH) and cortisol levels in both male and female monkeys. The blood collection procedure was conducted in home-caged and unanesthetized rhesus monkeys that showed low and stable basal ACTH and cortisol levels. Three opioid receptor agonists, fentanyl, U-50488H, and SNC80, were used in behaviorally active doses; they are highly selective for mu, kappa, and delta opioid receptors, respectively. Plasma samples were collected at multiple time points before and after IV administration of each compound and were quantified by radioimmunoassay. Neither fentanyl (0.0003-0.02mg/kg) nor SNC80 (0.03-0.3mg/kg) changed either ACTH or cortisol basal levels. In contrast, U-50488H (0.01-1mg/kg) dose-dependently stimulated ACTH and cortisol release in both male and female monkeys. Importantly, the stimulatory effects of U-50488H on the secretion of ACTH were blocked by a selective kappa opioid receptor antagonist, nor-Binaltorphimine. The antagonist effect of nor-binaltorphimine lasted up to 20 weeks. These results indicate that only synthetic kappa, but not mu or delta opioid receptor agonists stimulate HPA axis activity after acute administration in primates.