Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3.

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.

Relationship between respiratory function and need for NIV in childhood SMA.

BACKGROUND: Spinal muscular atrophy (SMA) causes progressive respiratory muscle weakness but respiratory function (RF) in those using noninvasive ventilation (NIV) is not well described. OBJECTIVE: To describe RF in childhood SMA and assess differences between those using and not using NIV. METHODS: A cross-sectional study of childhood SMA assessed polysomnography (PSG), spirometry, forced oscillation technique (FOT), lung clearance index (LCI), sniff nasal inspiratory pressures, peak cough flow, maximal inspiratory and expiratory pressure, and NIV use and indication. RESULTS: Twenty-five children (median age [interquartile range], 8.96 [5.63] years; 10 F) with SMA 1 (n = 3), 2 (n = 15), and 3 (n = 7) were recruited. Spirometry and FOT testing was feasible in children as young as 3 years. Ten (40%) required NIV, 5 for sleep-disordered breathing (SDB), and 5 initiated during lower respiratory tract infection (LRTI). Children requiring NIV were older (median, 10.52 vs 5.67 years; P < .02) with more abnormal forced vital capacity (FVC) z-score (-5.70 vs -1.39, P < .02), Rsr8 z-score (1.97 vs 0.50, P = .04), and LCI (8.84 vs 7.34, P = .01). Two had normal RF and SDB. For FVC z-score less than -2.5 and LCI greater than 7.5, the odds ratio for NIV was 10.70 (95% confidence interval [CI], 1.39-82.03) and 2 (95% CI, 0.40-10.31), respectively. All children with LCI greater than 8 used NIV. FVC z-score and LCI are associated with maximum transcutaneous carbon dioxide on PSG (r = 0.43, P < .001). CONCLUSION: NIV is common in SMA. Normal RF does not exclude SDB. Children with more abnormal FVC and LCI should be considered at risk of starting NIV during/following an LRTI.