AIM:To establish whether the initial positive effect of nusinersen (NUS) on respiratory outcomes in the first year of treatment was maintained in children with Spinal Muscular Atrophy (SMA) type 2 and to further define the effect on children with type 3 treated over 3 years. METHODS:A prospective observational study of children with type 2 and 3 beginning NUS in Queensland, Australia between June 2018-December 2020 was undertaken. Investigations conducted included age-appropriate lung function and polysomnography. Lung function data for two-years preceding NUS initiation was retrospectively collected. Change in lung function/polysomnography was assessed using mixed effects linear regression. RESULTS:24 of 30 children with type 2 and 3 SMA (14 males; 2.6-15.8) were included (type 2 n = 12; type 3 n = 12). No child had respiratory-related admissions during the period of study. For type 2, annual decline in FVC z-score pre-treatment was -0.75 (95 % CI: 1.14, -0.39, p < 0.001), and for the first 3 years on NUS was -0.20 ([95 % CI: 0.33, -0.06, p = 0.01] difference p = 0.008). For type 3 minimal change was seen: pre-NUS and post FVC z-scores -0.20 (95 % CI: 1.00, 0.61 p = 0.05) and -0.46 (95 % CI: 0.88, -0.04 p = 0.40) respectively (difference p = 0.46). Mean change in total apnoea-hypopnoea indices (total AHI) in type 2 tended to reduce -1.75 (95 % CI: 4.95-0.9, p = 0.24); type 3 appeared to remain stable (-0.39 [95 % CI: 1.1-0.33, p = 0.28). One child with type 2 ceased NIV due to normalisation of total AHI and gas exchange. CONCLUSION:Nusinersen lung function (FVC-z-scores) stability seen in the first year was maintained over 3 years and the total AHI tended to improve in type 2, but the long-term effects in type 3 are less clear.

Rationale: Pulmonary complications are common and significantly contribute to morbidity and mortality following pediatric hematopoietic stem cell transplantation (HSCT), and pulmonary function testing (PFT) is critical for early detection and treatment. This study evaluates the impact of a multidisciplinary respiratory-HSCT service on improving technically acceptable PFTs before transplantation. Methods: We retrospectively analyzed all PFTs from children undergoing HSCT at the Queensland Children's Hospital over 5 years prior to the COVID-19 pandemic (2015-2019 inclusive). Quality control grading was performed on pre-HSCT PFTs identified from existing electronic medical databases [spirometry (if ≥5 years), body plethysmography (if ≥8 years) and gas transfer (DLCO) (if ≥8 years)] using ATS/ERS criteria by an experienced pediatric respiratory scientist (KS). The same approach was used within a post-COVID 12-month period (August 2023-July 2024 inclusive) with multiple breath washout (MBW) scored by an experienced physician (PDR). Success rates between cohorts were compared using Fisher's exact test. Results: Between 2015-2019, 150 subjects received HSCT [median (range) age 5.49 (0.01-18.2 years) years] with 53% (79/150) eligible for any PFTs (i.e. ≥5 years). 86% of eligible patients (68/79) attempted baseline PFT [45% (68/150) of total cohort receiving HSCT]. Technical acceptability was achieved in 63% (50/79) for spirometry, 77% (46/60) for DLCO, and 70% (42/60) for body plethysmography, such that 73% (58/79) and 46% (36/79) achieved this for ≥1 or all eligible PFT tests [39% (58/150) and 24% (36/150) of total HSCT cohort], respectively. In 2023-24, of the 40 subjects receiving HSCT [5.15 (0.85-17.8) years], eligibility for PFTs (i.e. ≥3 years given MBW availability) increased to 65% (26/40) with 92% (24/26) attempted. Technical acceptability was achieved in 75% (15/20) for spirometry, 88% (15/17) for DLCO, 82% (14/17) for body plethysmography and 100% (23/23) for MBW, such that 88% (23/26, p=0.18 vs. 2015-19) and 69% (18/26, p=0.044 vs. 2015-19) achieved this for ≥1 or all eligible PFT tests [58% (23/40, p=0.047 vs. 2015-19) and 45% (18/40, p=0.017)] vs. 2015-19 of total HSCT cohort), respectively. Conclusions: Reliance of conventional lung function tests resulted in only half of subjects being eligible for baseline PFT prior to HSCT in our historical cohort. Of those eligible, only 73% achieved technical acceptability in at least one PFT measure and 46% in all eligible tests. Incorporation of MBW into pre-HSCT PFT screening as part of a formal respiratory-HSCT service increased not only eligibility, but also the proportion with a technically acceptable estimate of pre-HSCT lung function.

Introduction: Despite disease modifying treatments (DMT), assisted ventilation is commonly required in children with Spinal Muscular Atrophy (SMA). Guidelines suggest screening with oximetry and transcutaneous carbon dioxide (TcCO2) 2 ) for sleep disordered breathing (SDB). Aim: To determine the utility of pulse oximetry and TcCO2 2 as a screen for SDB and the need for Non-Invasive Ventilation (NIV) in children with SMA type 1-3. Methods: A prospective cohort study was conducted in Queensland, Australia. Full diagnostic PSG was completed in DMT na & iuml;ve children with SMA. Pulse oximetry and TcCO2 2 were extracted from PSG. Apnoea-hypopnoea indices (AHI) criteria were applied to PSG results to define the need for NIV. Abnormal was defined as: <= 3 months of age [mo] AHI>10 >10 events/hour; >3mo AHI >5 events/hour. Receiver operating characteristic curves were calculated for abnormal PSG and pulse oximetry/TcCO2 2 variables, and diagnostic statistics were calculated. Results: Forty-seven untreated children with SMA were recruited (type 1 n = 13; 2 n = 21; 3 n = 13) ranging from 0.2 to 18.8 years old (median 4.9 years). Oxygen desaturation index >4 % (ODI4) >20events/hour had sensitivity 82.6 % (95 % CI 61.2-95.0) and specificity of 58.3 % (95 % CI 36.6-77.9). TcCO2 2 alone and combinations of oximetry/TcCO2 2 had low diagnostic ability. The same methodology was applied to 36 children who were treated (type 1 n = 7; type 2 n = 17; type n = 12) and oximetry +/- TcCO2 +/- TcCO2 had low diagnostic ability. Conclusion: ODI4 >20events/hour can predict the need for NIV in untreated children with SMA. TcCO2 monitoring does not improve the PPV. If normal however, children may still require a diagnostic PSG. Neither oximetry nor TcCO2 2 monitoring were useful screening tests in the children treated with DMT.

Abstract Objectives to determine prevalence, patterns and clinical associations of sleep disordered breathing in a cohort of children with neuromuscular disorders. Methods children from three sites had a laboratory polysomnogram and clinical data collection. Sleep disordered breathing (SDB) was defined as the presence of obstructive sleep apnoea (OSA), hypoventilation and/or central sleep apnoea (CSA). Results 64 children aged 6.0-16.7 years (median 11.5) were included, 72% were male and diagnoses were Duchenne Muscular Dystrophy (DMD) (40%), spinal muscular atrophy (SMA) (28%), congenital muscular dystrophy (CMD) (13%) and congenital myopathy (CM) (19%). Scoliosis was present in 50%, 51% could ambulate and median BMI z-score was -0.23. Of the 13 (20%) who used non-invasive ventilation (NIV), 6 (46%) had SMA and 10 (77%) used NIV during the entire polysomnogram. Sleep disordered breathing was present in 48%, OSA in 31%, CSA in 14%, hypoventilation in 16% and mixed SDB in 23%. SDB was present in 50% of children with DMD, SMA and CM, most often OSA in DMD (70%) and SMA (78%). Hypoventilation was most common in children with CM (83%) and CMD (100%). SDB and OSA were associated with older age and OSA with inability to ambulate (OR 4.45). Hypoventilation was significantly more common in CM, CMD and those with lower BMI z-scores. Conclusions The prevalence of SDB was high and likely under-estimated due to use of NIV, particularly in those with SMA. The findings reflect the heterogeneity of the cohort and suggest individual risk factors for each type of SDB.

ObjectivesDisease-modifying agents (DMAs) for the treatment of spinal muscular atrophy (SMA) have evolved the SMA phenotype with improved survival. Ongoing oropharyngeal dysphagia and respiratory complications are reported. The extent of dysphagia and respiratory morbidity in this population, since DMAs' introduction, has not been well described.MethodsA whole-population study involved all children with treated SMA types 1-3 in our facility. Videofluoroscopic swallow studies (type 1 alone), chest CT scans, and clinical data were collected.ResultsThirty-six children were included (n = 9 type 1, n = 14 type 2, and n = 13 type 3; age range 0.3-15.4 years). Abnormal swallowing characteristics were demonstrated in all children with type 1 (n = 8; 100%). Bronchiectasis was found on chest CT: 3 of 9 (33.3%), 2 of 14 (14.3%), and 2 of 13 (15.4%) of type 1, 2, and 3, respectively. Atelectasis, mucus plugging, bronchial wall thickening, and parenchymal changes were common.DiscussionSwallow impairments were universal in children with type 1. Bronchiectasis was common in all pediatric SMA types, with a prevalence of 1 in 5. Routine monitoring and management of dysphagia/recurrent respiratory infection should be implemented for improvement in lung health.

Neuromuscular disorders can lead to nocturnal hypoventilation. Accurate diagnosis of hypoventilation is imperative to guide treatment decisions. This study determined interobserver agreement for a number of definitions of nocturnal hypoventilation in children and adolescents with neuromuscular disorders. Overall mean interobserver agreement was 89% (range 66–100%); however, reliability of agreement was moderate at best (Fleiss κ = 0.574, p < 0.001). When hypoventilation was present, the objective definition used most frequently was an average increase in partial pressure of carbon dioxide (pCO2) ≥ 3 mm Hg from NREM to REM. The appearance of the transcutaneous CO2 (TCO2) trend graph and an increase in pCO2 ≥ 10 mm Hg from awake to asleep were most often associated with a false positive diagnosis. The variation and at best moderate agreement between pediatric sleep physicians observed in this study when diagnosing hypoventilation in children with neuromuscular disorders may be partially explained by the existence of multiple definitions and failure to remove artifact and “drift” from the TCO2 data.

Abstract Background hypoventilation occurs in neuromuscular disorders with respiratory muscle weakness. There are numerous definitions of hypoventilation. This study aimed to determine which definitions of hypoventilation had the highest inter-observer agreement and sensitivity in children with neuromuscular disorders. Methods twenty polysomnograms from children with neuromuscular disorders were examined by six paediatric sleep physicians to determine whether hypoventilation was present and which definitions of hypoventilation were used. Inter-observer agreement for the diagnosis of hypoventilation was calculated, with sensitivity determined in an exploratory analysis. Results mean inter-observer agreement was excellent at 82% (κ=0.533), higher for the absence (84%) than the presence (70%) of hypoventilation. Some physicians used more than one definition to diagnose hypoventilation for the same polysomnogram. Even when agreement was substantial, the definitions chosen varied between physicians.The objective defiitions used most frequently when inter-observer agreement was substantial that hypoventilation was present were; average increase in pCO2 ≥3mmHg from NREM to REM (n=15), increase of ≥10mmHg from awake to asleep (n=10) and pCO2 >50mmHg >25% total sleep time (n=8). The sensitivity for these definitions was 83%, 67% and 50%. Conclusions even when inter-observer agreement was high that hypoventilation was present, there was a lack of consistency between physicians when defining hypoventilation. An average increase in pCO2 ≥3mmHg from NREM to REM sleep had the highest inter-observer agreement and sensitivity. Alternative definitions in cases without a rise of pCO2 in REM are pCO2 >50mmHg for 25% total sleep time and/or an increase of ≥10mmHg from awake to asleep.

Introduction Nusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown. Aim To assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment. Methods A prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019. Outcomes assessed were the age-appropriate respiratory investigations: spirometry, oscillometry, sniff nasal inspiratory pressure, mean inspiratory pressure, mean expiratory pressure, lung clearance index, as well as polysomnography (PSG) and muscle function testing. Lung function was collected retrospectively for up to 2 years prior to nusinersen initiation. Change in lung function was assessed using mixed effects linear regression models, while PSG and muscle function were compared using the Wilcoxon signed-rank test. Results Twenty-eight patients (15 male, aged 0.08–18.58 years) were enrolled: type 1 (n=7); type 2 (n=12); type 3 (n=9). The annual rate of decline in FVC z-score prior to nusinersen initiation was −0.58 (95% CI −0.75 to −0.41), and post initiation was −0.25 (95% CI −0.46 to −0.03), with a significant difference in rate of decline (0.33 (95% CI 0.02 to 0.66) (p=0.04)). Most lung function measures were largely unchanged in the year post nusinersen initiation. The total Apnoea–Hypopnoea Index (AHI) was reduced from a median of 5.5 events/hour (IQR 2.1–10.1) at initiation to 2.7 events/hour (IQR 0.7–5.3) after 1 year (p=0.02). All SMA type 1% and 75% of SMA types 2 and 3 had pre-defined peripheral muscle response to nusinersen. Conclusion The first year of nusinersen treatment saw reduced lung function decline (especially in type 2) and improvement in AHI.

Abstract Background there are numerous definitions of hypoventilation, the most commonly used for children being pCO₂ >50mmHg >25% total sleep time. There are concerns that a total sleep time threshold of >25% is not sensitive enough in children and individuals with neuromuscular disorders. Alternative thresholds of 2%, 5% and 10% total sleep time have been suggested. Methods the relationship between percentage of total sleep time with pCO₂ >50mmHg and the presence of hypoventilation (determined by physician diagnosis) was examined in a small exploratory analysis of children with neuromuscular disorders. ROC curves were constructed to determine the impact of changing cut-off thresholds for total sleep time with pCO₁ >50mmHg to define hypoventilation. Results the mean percentage of total sleep time that pCO₂ >50mmHg was higher for the studies with hypoventilation (50% vs.10%). The mean difference (40%) was not statistically significant, likely due to the small number of studies (n=6) with hypoventilation. The AUC for percentage of total sleep time with pCO₂ >50mmHg was 0.808 (p=0.035, CI 0.6 to 1.0). For thresholds of total sleep time with pCO₂ >50mHg to define hypoventilation of 20% and 27%, sensitivity was 50%. For thresholds of 11%, 5% and 3%, sensitivity was 67%, 100% and 100% respectively. Conclusions in this study the upper limit of total sleep time with pCO₂ >50mmHg in children with neuromuscular disorders without hypoventilation was 10%. Thresholds lower than 25% of total sleep time with pCO₂ >50mmHg to define hypoventilation had higher sensitivity for diagnosing hypoventilation in this population.