Ryth Grychtol^a, Francois Abel^a, Dominic A. Fitzgerald^b,c

Summary

Spinal muscular atrophy (SMA) is a degenerative motor neurone disorder causing progressive muscular weakness. Without assisted ventilation or novel therapies, most children with SMA type 1 die before the second year of life due to respiratory failure as the respiratory muscles and bulbar function are severely affected. Active respiratory treatment (mechanically assisted cough, invasive or non-invasive ventilation) has improved survival significantly in recent decades, but often at the cost of becoming ventilator dependent. The advent of a new oligonucleotide based therapy (Nusinersen) has created new optimism for improving motor function. However, the long-term effect on respiratory function is unclear and non-invasive respiratory support will remain an important part of medical management in patients with SMA.

This review summarises the existing knowledge about sleep-disordered breathing and respiratory failure in patients with SMA, especially type 1, as well as the evidence of improved outcome and survival in patients treated with non-invasive or invasive ventilation. Practical considerations and ethical concerns are delineated with discussion on how these may be affected by the advent of new therapies such as Nusinersen.

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive degenerative motor neurone disorder caused by a mutation in the survival motor neurone 1 (SMN1) gene (5q11.2-q13.3) [1]. The approximate incidence is 1:11,000 and the untreated, most severe form is the leading genetic cause of infant mortality in the developed world [2]. The mutation causes degeneration of the α-motor neurones in the anterior horn of the spinal cord and nuclei of the lower brainstem with progressive truncal and proximal limb weakness. There is associated bulbar dysfunction with poor feeding and abnormal swallow function with risk of aspiration pneumonia [3]. Clinical presentation ranges from symptom onset at birth with neonatal respiratory failure to onset in adulthood with little impact on survival (see Table 1). The severity is mostly inversely correlated to the amount (copy numbers) of functional protein transcribed by a nearly identical gene called SMN2 [4].

Survival is predominantly linked to respiratory failure caused by progressive weakness of the respiratory muscles aggravated by impaired cough and bulbar dysfunction. Children with SMA type 1 can survive until childhood or rarely even until adult age with the help of invasive or non-invasive ventilation but all patients remain paralysed from early childhood onwards in the absence of disease modifying therapy [5], [6], [7].

A new intrathecal drug, Nusinersen, which aims to increase the amount of functional SMN2 coded protein via an antisense oligonucleotide, might change this course in the future. Nusinersen has been shown to improve survival, prevent disease progression and even allow for motor development. However, the proportion of patients developing ventilator dependency was not significantly different in symptomatic infants [8]. There is at this point in time no experience about the long-term course of respiratory function in Nusinersen treated patients. Treatment of respiratory failure will therefore continue to play an important part in the management of symptomatic patients with SMA type 1.

Younger age of commencing treatment appears to offer a better prognosis for both motor development and independent breathing in symptomatic patients treated with a single dose of AVXS-101 gene replacement therapy and in pre-symptomatic infants treated with nusinersen [9], [10].

Nonetheless, it remains likely that clinical decisions regarding the extent of respiratory support will remain difficult in many patients with SMA type 1. In reality, many patients will not have access to these expensive pharmacologic treatments. Furthermore, while non-invasive ventilation is now widely accepted, invasive ventilation is still a matter of individual decision making [11]. However, it remains to be seen how Nusinersen will influence the perception about tracheostomy and invasive ventilation in children, especially in those who have already been started on this treatment.

This review aims to delineate the current knowledge about respiratory failure in patients with SMA, how it is diagnosed and the current treatment guidelines regarding ventilation support.

Section snippets

Respiratory failure

To understand the pathophysiology of SDB in patients with SMA it is necessary to appreciate respiration of healthy children during wakefulness and sleep and the specific abnormalities seen in infants and young children with SMA.

In healthy individuals, respiratory drive and the “respiratory pump” i.e., the respiratory muscles are able to meet the demands (“respiratory load”) for ventilation at rest, during exertion as well as during sleep. Conversely, patients with neuromuscular diseases are at...

Practical considerations of non-invasive ventilation

Non-invasive ventilation refers to the provision of positive pressure ventilation via a non-invasive interface, e.g., a nasal mask. In patients with neuromuscular diseases, NIV aims at supporting the weak respiratory muscle by delivering a positive inspiratory pressure that can supplement the patient’s own breathing effort or substitute it when absent.

NIV can be successfully established in infants, with careful consideration of age and disease-specific issues. Mask fit is always crucial for...

Summary

Diagnosis and management of respiratory failure in patients with SMA type 1 has progressed over the years from a palliative approach to a more proactive approach while still recognising SMA type 1 as a life limiting condition.

There is however variability of practice in implementing this approach and that includes the introduction of non-invasive ventilation (NIV) amongst other things. Polysomnography remains a useful diagnostic tool for respiratory failure; however some patients will develop a...

Educational aims

The reader will be able to:

• Understand the origins of respiratory failure and sleep-disordered breathing in patients with SMA
• Understand the role of sleep studies in the management of patients with SMA and the current recommendations
• Understand the practical considerations around implementing non-invasive ventilation in patients with SMA

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Directions for future research

• Prospective and sufficiently statistically powered long-term assessment of the effect of Nusinersen on respiratory function of children with SMA type 1
• Adequate and clinically relevant tools to assess respiratory outcomes in the SMA type 1 cohort
• Development of useful markers to assess quality of life in young neuromuscular patients with special focus on impact of respiratory morbidity and ventilator dependency on quality of life.

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