Stabilization of respiratory function in pediatric spinal muscular atrophy treated with nusinersen

Abstract

Rationale: Nusinersen is widely used for Spinal Muscular Atrophy (SMA), however respiratory effects are largely unknown. Aim: Assess change in respiratory function in pediatric SMA during first year of nusinersen treatment and compare to previous function. Methods: 12-month prospective study of all childhood SMA type 1- 3 in Queensland, Australia from June 2018. Muscle strength testing (Revised Hammersmith Functional Motor Scale for SMA, Hammersmith Infant Neurological Examination or Children's Hospital of Philadelphia Infant Test of Neurological Disorders) performed prior to commencement and 4 occasions during study period. Respiratory investigations also attained: Spirometry, Forced Oscillation Technique (FOT), Sniff Nasal Inspiratory Pressure (SNIP), Mean Inspiratory Pressure (MIPS), Mean Expiratory Pressure (MEPS), Lung Clearance Index (LCI). Full Polysomnography (PSG) conducted initially and study completion. Lung function 2 years prior to study commencement collected retrospectively. Lung function decline and PSG parameters pre- and post-treatment compared. Muscle strength responders/non-responders compared for respiratory function change. Results: 31 children (18 males, 0.25-18.8 years) included; 6 (19%) SMA type 1, 16 (52%) type 2 and 9 (29%) type 3. For all lung function parameters, stability noted throughout first year treatment (Table 1). Type 2 annual rate of decline in Forced Vital Capacity (FVC) z-score reduced from -0.5 per annum (p=0.001, 95%CI 0.26-0.72) to +0.002 (p=0.5, 95%CI -0.08-0.006), p=0.009; for type 3 SMA,-0.4 per annum (p=0.008 95%CI 0.1-0.6) to -0.001 (p=0.4, 95%CI -0.005-0.002), p=0.3. Mean total apnea-hypopnea index (AHI) reduced following treatment for type 1 [12.3 events/hour to 3.7], type 2 [4.5 (SD 3.0 95% CI 1.8-7.3) to 2.9 (SD 3.0 CI 0.1-5.6) p=0.1] and type 3 [5.3 (SD 2.2 95% CI0.14-10.8) to 2.5 (SD 19.98 95%CI 4.34) p=0.4]. Motor muscle response attained in 5/11 (45%) type 2, 6/9 (67%) type 3. No change in FVC z-score between responders/non-responders (FVC z-score 0.5 p=0.5 95%CI -1.2-2.1 r<0.001/0.1 p=0.9 95%CI -2.4-2.6 r=0.01 respectively). Conclusion: Nusinersen halts respiratory function decline seen before treatment and stabilizes lung function during first treatment year in type 2 and 3 SMA, and seen even in those without peripheral muscle strength response. Improvements in sleep disordered breathing in all types SMA seen in first year of treatment.L6323763332020-07-27 <br />