Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study

Esther S Veldhoen,Feline E V Scheijmans,Marloes Stam,W Ludo Van Der Pol,Bart Bartels,Cornelis K Van Der Ent,Camiel A Wijngaarde,Ruben P A Van Eijk,Roelie M Wösten-Van Asperen,Michael A Gaytant,Laura P Verweij-Van Den Oudenrijn,Inge Cuppen,Louise A M Otto,Erik H J Hulzebos,Renske I Wadman,Fay Lynn Asselman

doi:10.1186/s13023-022-02227-7

Abstract

BackgroundRespiratory complications are the most important cause of morbidity and mortality in spinal muscular atrophy (SMA). Respiratory muscle weakness results in impaired cough, recurrent respiratory tract infections and eventually can cause respiratory failure. We assessed longitudinal patterns of respiratory muscle strength in a national cohort of treatment-naïve children and adults with SMA, hypothesizing a continued decline throughout life.MethodsWe measured maximal expiratory and inspiratory pressure (PEmax and PImax), Sniff Nasal inspiratory pressure (SNIP), peak expiratory flow (PEF), and peak cough flow (PCF) in treatment-naïve patients with SMA. We used mixed-models to analyze natural history patterns.ResultsWe included 2172 measurements of respiratory muscle function from 80 treatment-naïve patients with SMA types 1c-3b. All outcomes were lower in the more severe phenotypes. Significant differences in PEF were present between SMA types from early ages onwards. PEF decline was linear (1–2%/year). PEF reached values below 80% during early childhood in types 1c-2, and during adolescence in type 3a. PEmax and PImax were severely lowered in most patients throughout life, with PEmax values abnormally low (i.e. < 80 cmH2O) in virtually all patients. The PEmax/PImax ratio was < 1 throughout life in all SMA types, indicating that expiratory muscles were most affected. All but SMA type 3b patients had a lowered PCF. Patients with types 2b and 3a had PCF levels between 160 and 270 L/min, those with type 2a around 160 L/min and patients with type 1c well below 160 L/min. Finally, SNIP was low in nearly all patients, most pronounced in more severely affected patients.ConclusionsThere are clear differences in respiratory muscle strength and its progressive decline between SMA types. We observed lower outcomes in more severe SMA types. Particularly PEF may be a suitable outcome measure for the follow-up of respiratory strength in patients with SMA. PEF declines in a rather linear pattern in all SMA types, with clear differences at baseline. These natural history data may serve as a reference for longer-term treatment efficacy assessments.

Highlights

Respiratory complications are the most important cause of morbidity and mortality in spinal muscu‐ lar atrophy (SMA)
Respiratory muscle weakness is associated with decreased pulmonary compliance, lung underdevelopment, decreased ability to cough, and it may lead to respiratory failure [11]
We evaluated whether the rate of decline over age was significantly different between SMA types using a likelihood ratio test

Summary

Introduction

Respiratory complications are the most important cause of morbidity and mortality in spinal muscu‐ lar atrophy (SMA). Improved understanding of the natural history of SMA has facilitated improvements of standards for supportive care and clinical trial design [1, 3,4,5,6] Respiratory complications, such as hypoventilation and impaired secretion clearance, are the most important cause of morbidity and mortality in SMA [1, 2] but respiratory outcome measures have not yet been used as primary outcomes in clinical trials. This is, at least partially, caused by a lack of reference data [7, 8]. Respiratory muscle weakness is associated with decreased pulmonary compliance, lung underdevelopment, decreased ability to cough, and it may lead to respiratory failure [11]

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