Paediatric Respiratory Reviews 28 (2018) 18–25

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-Symposium: Spinal Muscular Atrophy

The role of sleep diagnostics and non-invasive ventilation in children

with spinal muscular atrophy
Ruth Grychtol a, Francois Abel a,⇑, Dominic A. Fitzgerald b,c
a
Department of Respiratory Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
b
Department of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney, NSW, Australia
c
Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

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

a r t i c l e i n f o s u m m a r y

Keywords: Spinal muscular atrophy (SMA) is a degenerative motor neurone disorder causing progressive muscular
Spinal muscular atrophy weakness. Without assisted ventilation or novel therapies, most children with SMA type 1 die before the
Polysomnography second year of life due to respiratory failure as the respiratory muscles and bulbar function are severely
Sleep-disordered breathing affected. Active respiratory treatment (mechanically assisted cough, invasive or non-invasive ventilation)
Lung function
has improved survival significantly in recent decades, but often at the cost of becoming ventilator depen-
Non-invasive ventilation
dent. 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 fail-
ure 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.
Ó 2018 Elsevier Ltd. All rights reserved.

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 a-
⇑ Corresponding author at: Paediatric Respiratory and Sleep Physician, Great
Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street,
London WC1N 3JH, UK.
E-mail address: francois.abel@gosh.nhs.uk (F. Abel).
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 feed-
ing and abnormal swallow function with risk of aspiration pneu-
monia [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 inver-
sely 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

https://doi.org/10.1016/j.prrv.2018.07.006
1526-0542/Ó 2018 Elsevier Ltd. All rights reserved.
 R. Grychtol et al. / Paediatric Respiratory Reviews 28 (2018) 18–25 19

Table 1
Classification of Spinal muscular atrophy (Adapted from Mercuri 2012 [84] and Finkel 2015 [65]).

Age of onset Maximal Defining clinical features1 SMN2 copy number (CN)2
milestone
achieved
Type 0 Birth, prenatal signs Nil Severe hypotonia, respiratory
failure at birth, congenital contractures
Type 1A First 2 weeks of life Nil Severe hypotonia, may require respiratory/feeding
support during neonatal period, no head control
Type 1B After neonatal period Never rolls or Severe hypotonia, no head control, paradoxical 1 or 2 CN in 80% of patients
but <3 months of life sits breathing pattern 3 CN in 20% of patients
Type 1C 3–6 months Never rolls or May gain head control, severe weakness
sits (proximal > distal, lower limbs > upper limbs)
Type 2 7–18 months Sitting, but See Finkel 2015 2 CN in 11% of patients, 3 CN in 82%
never stands and 4 CN in 7% of patients
Type 3 >18 months Stands and See Finkel 2015 1 CN in 0% of patients, 2 CN in 4% and
walks 3 or 4 CN in 96% of patients
Type 4 10–30 years Stands and See Finkel 2015 4 or more CN
walks

Key: CN = Copy number.

1
Adapted from Finkel 2015 [65]; only symptoms relevant for respiratory failure are listed. For comprehensive description of symptoms see Finkel 2015 [65].
2
Feldkotter 2002 [4].

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 [5–7].
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 manage-
ment 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 res-
piratory failure in patients with SMA, how it is diagnosed and the
current treatment guidelines regarding ventilation support.
PATHOPHYSIOLOGY OF RESPIRATORY FAILURE AND SLEEP-
DISORDERED BREATHING IN PATIENTS WITH SMA
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 risk for respiratory failure caused by imbalance between
inadequate muscle strength and often additionally increased respi-
ratory load, for example due to scoliosis and chest wall deformities
[12].
SMA type 1 is characterised by a progressive weakness of the
skeletal muscles, starting proximally but soon involving also the
distal muscles, sometimes with sparing of the fingers and facial
muscles. Involvement of the bulbar muscles causes swallowing
dysfunction with risk of aspiration and most children need intra-
gastric feeding by age 12 months [13]. Weakness affects all respi-
ratory muscles with initial sparing of the diaphragm [14].
Imbalance between the inspiratory intercostal muscles and the
diaphragm causes typical thoraco-abdominal asynchrony (‘‘para-
doxical breathing”) as the ribcage is not stabilised during the inspi-
ration against the negative pull generated by the diaphragm: the
upper ribcage is drawn inwardly during inspiration instead of
being elevated [15]. Reduced tidal volume, increased respiratory
load and greater energy expenditure are the immediate conse-
quences [16,17]. Failure of the intercostal muscles is additionally
aggravated by the high chest wall compliance of infants [18].
Chronic thoraco-abdominal asynchrony often causes chest defor-
mities in young children with SMA1 (‘‘bell-shaped” chest and pec-
tus excavatum) [19].
Other causes of increased respiratory load are micro-atelectasis
due to shallow breathing, reduced secretion clearance and reduced
elastic recoil of the lungs which usually helps to maintain airway
patency [20]. Older children with SMA type 1 often face increased
respiratory load due to chest deformities, scoliosis and stiffening of
the costovertebral joints as well as chronic parenchymal changes
due to atelectasis and recurrent chest infections [21].
Imbalance between increased respiratory load and reduced
muscle function is usually compensated by an increased respira-
tory drive but ultimately respiratory failure and hypoventilation
occurs [22–24]. Some patients develop reduced sensitivity of the
chemoreceptors to carbon dioxide with progressive hypoventila-
tion and consequently reduced respiratory drive [16]. This mecha-
nism might additionally aggravate hypoventilation including
during wakeful breathing. NIV sometimes reverts this process by
20 R. Grychtol et al. / Paediatric Respiratory Reviews 28 (2018) 18–25
guaranteeing normal gas exchange at night with ‘‘resetting” of the
chemoreceptors [25].
Sleep-disordered breathing
Patients with neuromuscular diseases are typically at risk for
SDB and hypoventilation as a result of their underlying disorder.
Sleep onset physiologically leads to a reduction in muscle tone
which is normally compensated for in healthy individuals.
Reduced muscle tone after sleep onset and supine position
cause a drop in tidal volume, functional residual capacity (FRC)
and consecutively oxygen reserve [24]. Additionally, chemorecep-
tors and central respiratory drive are less sensitive during sleep
and both lead to slightly lower oxygen saturation and higher arte-
rial carbon dioxide levels even in healthy individuals [26]. Small
children are additionally susceptible to oxygen desaturations due
to a physiologically lower FRC [27].
Maximum reduction in muscle tone occurs during periods of
REM (rapid eye movement) sleep and ventilation mostly depends
on the diaphragm during this period while its activity is also
reduced [28]. Hypotonia of the pharyngeal muscles can also cause
symptoms of upper airway obstruction during REM sleep however
this is rarely the case in children with SMA type 1 [29].
While healthy individuals are able to compensate for these
changes during sleep, patients with pre-existing muscular weak-
ness are at risk for SDB or hypoventilation due to aggravation of
the pre-existing imbalance between muscle function and respira-
tory load. Impaired secretion clearance might additionally con-
tribute to abnormal gas exchange.
SDB and nocturnal hypoventilation are often the first signs of
progressive respiratory decline. SDB first occurs during the most
vulnerable sleep stage of REM-sleep, progresses into REM-
associated hypoventilation and further into continuous nocturnal
hypoventilation and finally daytime respiratory failure [22,30].
Screening for SDB has therefore long been acknowledged as a
vital part of long-term management of neuromuscular diseases
to detect patients at risk for respiratory failure [11,31,32].
Untreated hypoventilation is associated with a high mortality
and respiratory morbidity [33] and causes daytime symptoms like
tiredness, morning headaches, poor concentration and sometimes
insufficient weight gain and can be effectively treated with NIV
[29].
Diagnostic gold-standard for SDB is a polysomnography or car-
diorespiratory polygraphy [31]. Scoring of respiratory events in
patients with muscular weakness requires some experience to
reach conclusive results. The most typical respiratory events seen
are hypopnoeas due to reduced muscle effort, with concomitant
reduction in nasal flow and abdominal and thoracic effort. These
events might be mistaken as being central in origin despite result-
ing from inadequate muscle activity and reduced FRC typically
during periods of REM-sleep [34]. In cases of overt thoraco-
abdominal asynchrony, as seen in patients with SMA, these events
can also sometimes be mistaken as obstructive [12].
Sleep disordered breathing (SDB) in patients with SMA type 1
Few studies about SDB have been published in SMA Type 1. This
paucity is likely explained by two factors. First, once a family deci-
des against life-prolonging treatment, unnecessary diagnostic pro-
cedures are consequently avoided. Secondly, many severely
affected children present with overt clinical signs of respiratory
distress or failure and the decision to start NIV is usually based
on clinical assessment only. One author even argues that sleep
studies are not helpful in SMA type 1 patients as indication and
titration of NIV are best done clinically with alleviation of
thoraco-abdominal asynchrony being the primary focus [35].
All published studies including infants (average age <1 year)
with SMA type 1 and severe forms of SMA type 2, predominantly
reported marked thoraco-abdominal asynchrony with only mild
signs of sleep disordered breathing [36–38]. Although the studies
are not directly comparable due to methodological reasons, the
average AHI was below 5/hr and the average oxygen desaturation
index below 3/hr with no oxygen desaturations <80%. Transcuta-
neous CO2 (TcCO2) was within normal limits in one study [36]
but was increased in some patients in another study with a median
TcCO2 of 46 mmHg ranging from 37 mmHg to 60 mmHg [37]. Due
to the limited data presented in these publications, it is difficult to
quantify the number of patients with SDB warranting initiation of
NIV and the authors of two studies recommended the use of NIV
predominantly for treatment of thoraco-abdominal asynchrony,
to rest the respiratory muscles and prevent chest deformity
[37,38].
Older patients with mild SMA type 1 or SMA 2 (average age
7.8 ± 1.9 years) have been shown to present with typical SDB dur-
ing REM sleep as first sign of respiratory failure [29].
To summarise, the limited data published as well as clinical
experience indicates that children with SMA type 1 might develop
obvious clinical symptoms of respiratory distress with the emer-
gence of bulbar palsy and pulmonary aspiration independently ini-
tially of the presence of SDB. The decision for respiratory support
with NIV might be solely based on treating dyspnoea and amelio-
rating more obvious clinical signs such as thoraco-abdominal asyn-
chrony, which are likely to be more significant in sleep because of
reduced muscle tone and hypoxaemia [11].
However, in children with slower respiratory decline, sleep
studies are a good tool to assess respiratory failure and regular
sleep studies are recommended [11]. Studies about non-
volitional lung function tests in infants as a screening tool are dif-
ficult and not used in clinical practice and sleep studies might fill
this gap. It is also possible that with more children receiving Nusin-
ersen, disparate SDB will become more prevalent as there may be
better motor development of the lumbar rather than cervical
innervated muscles and ventromedial motor neurones innervating
the superficial larger muscles rather than the dorsomedial motor
neurones connected to the small deep paraspinal muscles, related
to delivery method of Nusinersen [39]. This would reinforce the
value of polysomnography as a regular screening test for early
signs of Type I respiratory failure.
TREATMENT OF SDB AND RESPIRATORY FAILURE
Practical considerations of non-invasive ventilation
Non-invasive ventilation refers to the provision of positive pres-
sure 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 con-
sideration of age and disease-specific issues. Mask fit is always cru-
cial for success of NIV. Nasal masks are the interface of choice for
children with SMA type 1 due to bulbar dysfunction and risk of
aspirating oral secretions or gastric content. The choice of ventila-
tor is equally important and the chosen device should safely deli-
ver low tidal volumes and have a very sensitive flow trigger to
allow for patient synchrony with the ventilator. Weak children
might often not be able to trigger inspiration or cycle into expira-
tion even at the most sensitive settings and a back-up rate and a
fixed inspiratory time is therefore recommended [40]. To allow
effective ventilation in neuromuscular disorders, the back-up rate
 R. Grychtol et al. / Paediatric Respiratory Reviews 28 (2018) 18–25
should be set close to the spontaneous breathing rate (e.g., 2–3
breaths below the spontaneous breathing rate [41,42]) and usually
not higher than 30–35 breath per minute. Once effective ventila-
tion is achieved, many previously tachypnoeic children often
breathe at the back-up rate especially when asleep without the
need to trigger inspiration [43]. The ventilation mode of choice is
bilevel positive airway pressure (BIPAP), which supports the inspi-
ration by applying a positive inspiratory pressure (PIP). Continuous
positive airway pressure (CPAP) is rarely an option in weak
patients as little inspiratory support is given and as exhalation
against a positive end-expiratory pressure (PEEP) can be difficult
and uncomfortable for these patients. CPAP might only be cau-
tiously used in infants with SMA type 1 with mild respiratory fail-
ure who find it difficult to synchronise with NIV with the aim to
improve the FRC [11]. However, the authors’ experience would
argue that bilevel therapy is the treatment of choice.
Some authors advocate so-called high-span ventilation to pre-
vent or treat the typical bell-shaped chest deformity [44,45]. Pres-
sures settings aim at high amplitudes between inspiratory positive
airway pressure (IPAP) and expiratory positive airway pressure
(EPAP) of at least 10 cm H20 with further up-titration to com-
pletely abolish thoraco-abdominal asynchrony. Evidence for the
prevention of chest deformity is weak and based on observational
studies only [19,44] and clinical experience suggests that high
pressure amplitudes can be uncomfortable for the patient espe-
cially in the presence of mouth leak. Recently published recom-
mendations are more cautious about the prospect of preventing
chest deformities [11,31] and recommend titration of pressures
with focus on normalized gas exchange and reduced work of
breathing [11].
Titration of pressures and regular review of ventilator settings
can be best achieved with a polysomnography or cardiorespiratory
polygraphy which provides data about gas exchange or thoraco-
abdominal asynchrony but also helps identifying and improving
asynchrony between the child and the ventilator [31,46]. If not
available, clinical observation together with oxycapnography is
an alternative albeit less precise monitoring tool [31].
If NIV is started electively, careful acclimatisation to the mask is
crucial for later tolerance. Nocturnal NIV should ideally be set up in
hospital by an experienced team and with thorough training of the
parents. The child should be started on low pressure settings which
can then be titrated following clinical (correction of thoraco-
abdominal asynchrony and increase work of breathing) or
polysomnographic (correction of sleep disordered breathing and
normalisation of gas exchange) criteria. Some authors recommend
the use of an abdominal belt to counteract the thoraco-abdominal
asynchrony, improve ventilation of the upper lobes and prevent
abdominal bloating; however this is based on clinical observation
only [47,48].
Typical problems encountered when using NIV are pressure
sores caused by the interface and midface hypoplasia if used from
early age onwards [12]. Both are usually manageable by using
alternate masks with different pressure points [11]. Aerophagia
can in most cases be controlled by releasing gastric air via the gas-
trostomy or nasogastric tube. Bulbar palsy may be problematic
when using NIV as it can exacerbate pooling of oral secretions
and subsequent aspiration. The authors’ experience suggests that
regular suctioning of oral secretions, careful use of anticholinergic
secretion control medications such as glycopyrronium bromide,
use of nasal masks and lateral positioning can all be used to miti-
gate this risk.
Most patients with SMA type 1 develop respiratory failure in
the first year of life and often shortly after intragastric feeding
becomes necessary [13,49]. The timing of initiation of NIV in
patients with SMA type 1 is usually recommended in symptomatic
patients often in the following situations [11,31,32]: (1) symp-
21
tomatic patients with daytime respiratory failure, (2) treatment
of nocturnal hypoventilation or SDB, (3) as acute support during
an acute respiratory tract infection or after extubation and (4) as
an attempt to prevent the development of chest deformities
[19,44,45]. As patients with SMA type 1 often show clear signs of
respiratory distress and increased work of breathing while gas
exchange is still normal, some authors also suggest starting NIV
before respiratory failure develops to ameliorate dyspnoea
[9,11,32] and prepare the patient for acute decompensation which
may occur with inter-current infections and pulmonary aspiration
of secretions and or liquids with bulbar dysfunction.
Effects of non-invasive ventilation in patients with SMA type 1
Until the late 1990s, the only options for management of respi-
ratory failure in children with SMA type 1 were tracheostomy and
long-term invasive ventilation or palliation. Improved portable
ventilators and better choice of interfaces for small infants enabled
the use of NIV as a valuable alternative to tracheostomy and inva-
sive ventilation [43]. NIV proved to be useful for palliation and
symptom control as well as proactive and life-prolonging treat-
ment [50] – a dual role that can hardly be achieved by tra-
cheostomy and invasive ventilation.
The positive effects of NIV and augmented secretion clearance
on survival [51,52], prevention of chest infections [53,54], treat-
ment of SDB [29,51,54] and improvement of quality of life [55]
have long been demonstrated for neuromuscular patients. How-
ever, high quality evidence for children with SMA type 1 is sparse.
Nevertheless positive effects of NIV especially on survival have
consistently been shown in case series and historical comparisons
to justify the use in children with SMA type 1 [11].
The majority of children with untreated SMA type 1 who do not
receive respiratory support die before their second birthday. Med-
ian age at death in untreated children is 6–8 months [6,49,56–62]
and the probability of survival until 2 years of age ranges between
2% and 25% [6,63,64].
Survival improved with the introduction of supportive mea-
sures like NIV, mechanical insufflation-exsufflation (MI-E), naso-
gastric or gastrostomy feeds and with maximal care including
intubation during respiratory tract infections. A retrospective anal-
ysis covering 26 years showed that the chances of surviving until
the second year of life increased from 31% to 74% from the mid
1990s onwards due to active respiratory treatment [5] (see also
Table 2). Until the mid 1990 s, only 30.8% of all patients were ven-
tilated in this case series which rose to 82.1% from the mid 1990s
onwards. The percentage of patients with non-invasive ventilation
increased as well from 20% to 64% [5]. Improved survival of both
invasively as well as non-invasively ventilated patients was also
shown by other authors [6,7,60] (see Table 2).
Although there is consistent and valid evidence for the life-
prolonging effect of NIV, some caution in interpreting the data is
needed. The course of disease can vary dramatically in children
with SMA type 1 from neonatal onset of respiratory distress to
need for respiratory support in the second year of life. Defining
subgroups according to severity (SMA type 1a, b, c) [65] and anal-
ysis of SMN2 gene copy number [4] (see Table 1) are important
prognostic tools regarding survival but even within the same
patient groups, individual clinical courses can also be highly vari-
able. Study results comparing survival with and without ventila-
tion will therefore always be influenced by the proportion of
severely affected SMA type 1 patients in the patient groups and
this effect can be seen in the studies of Bach, Oskoui and Gregoretti
[5,6,60]. Parents and clinicians of severely affected children with
onset at birth or soon afterwards have previously been more likely
to consider a palliative route and this will further skew the survival
rates between treated and untreated patients [6] (Table 2).
22 R. Grychtol et al. / Paediatric Respiratory Reviews 28 (2018) 18–25

Table 2
Publication about survival of patients with SMA 1.

Author Country, study period Patients1 Outcome

Ignatius 1994 [56] Finland, 1960–1988 71 patients Age at death (n = 71): median 7 month (range 2 months–10 years)
Thomas 1994 [57] Great Britain, 1982–1990 30 patients Age at death (n = 29): median 7 month (range 1–24 months)
Zerres 1995 [85] Germany, 1995 –1994 197 patients Survival probability: 32% at 2 yrs, 18% at 4 yrs, 8% at 10 yrs, 0% at 20 yrs
Chung 2004 [86] Hong Kong, 1984–2002 22 patients Survival probability: 50% at 1 yrs, 40% at 2 yrs, 30% at 4 y, 30% at 10 y, 30% at 20 y.
Survivors (n = 6): IV 4, NIV 1, age not reported
Ioos 2004 [47] France, not reported 68 patients Onset <3 month (n = 33, NIV 2, IV 11): Age at death (n = 27): mean 18 month ± 29
months; Age at death of patients
with IV (n = 5): median 46 month, (range 9 month–10.5 yrs); Survivors with IV
(n = 6): range 8–17 yrs
Onset 3–6 months (n = 35, NIV 15, IV 20): Age at death (n = 9, NIV 6, IV 3):
4 ± 3.75 years
Oskoui 2007 [5] USA, 1980–2006 143 patients Born 1980–1994 (n = 65, NIV 4, IV 16):
Age at death (n = 52): mean 19.1 month, SD 38.7 month (median 7.3 month, range
1–193.5 month)
Survival probability: 37% at 12 month, 31% at 24 month, 26% at 48 month, 25% at
120 month
Born 1995–2006 (n = 78, NIV 41, IV 23):
Age at death (n = 28): mean 22.1 month, SD 28.6 month (median 10 month, range
2–112 month)
Survival probability: 79% at 12 month, 74% at 24 month, 65% at 48 month, 50% at
120 month
Banerias 2014 [58] France, 1989–2009 222 patients2 1989–1998 (n = 106): Age at death (n = 106): median 6 month (1–13 month)
1999–2009 (n = 116): Age at death (n = 116, NIV 8): median 7.5 month (1–24)
Mannaa 2009 [87] USA,1989–2005 13 patients Survival probability (NIV 7, IV 3): 62% at 2 yrs, 62% at 4 yrs, 8% at 10 yrs
Cobben 2008 [59] The Netherlands, 34 patients Age at death (n = 31, NIV/IV 0): 176 days (95% CI 150–214 days), 2 patients survived
1996–1999 >2 yrs
Gregoretti 2013 [6] Italy, 1992–2010 194 patients No treatment (n = 121, 68.5% with symptom onset <3 month):
Non-sitters Age at death (n = 113): median 6.95 month (IQR 5–10.1 month)
Age of survivors (n = 8): median 6.95 months (IQR 5–10.1 month)
IV (n = 42, 38% with symptom onset <3 month):
Age at death (n = 7): median 76.1 month (IQR 51.5–113.1 month)
Survival probability: >2 yrs: 95% (95% CI 81.8–98.8%); survival >4 yrs: 89.4%
NIV (n = 31, 32% with symptom onset <3 month):
Age at death (n = 14): median 28.6 month (IQR 12.8–41.4 month)
Survival probability: >2 yrs: 67.7% (95% CI: 46.7–82%); >4 yrs: 45%
Farrar 2013 [63] Australia 1995–2010 20 patients Age at death (n = 19, NIV 1): median 7.4 month (range 3–56 month)
Survival probability: 40% at 1 yr, 25% at 2 yrs, 6% at 4 yrs, 0% at 10 yrs
Bach 2007 [60] and USA, 1996–2008 92 patients, ‘‘Natural course” (n = 18): Age at death (n = 18) mean 9.6 ± 4 months
2009 [7] ‘‘non-sitters”, age at IV (n = 27): Age at death (n = 10): mean 61.6 month, SD 72.2 month
symptom onset not (range 16–270 month)
known Age of survivors (n = 17): mean 78.2 month, SD 36.1 month (range 5–179 month)
NIV (n = 75): Age at death (n = 12): mean 52.1 month (range 13–111 month)
Age of survivors with resp. failure <2 yrs of age (n = 56): mean 80.3 month
(range 13–196 month)
Age of survivors with resp. failure >2 yrs of age (n = 7): mean 11.6 yrs
(range 6–21 yrs)
D’Amico 2008 [64] Italy, 2001–2003 38 patients Survival probability (NIV/IV 0): 50% at 6 month (95% CI 33–65%), 21% at 1 yr (95%
35 non-sitters CI 10–35%), 5% at 2 yrs (95% CI 1–16%)
Rudnik-Schöneborn Germany, 2000–2005 66 patients 1 SMN2 copies (n = 4): Death after a few months, all needed mechanical ventilation
2009 [49] 2 SMN2 copies (n = 57): Age at death (n = 53): median 6.1 month
(range 0.5–19 month), Survivors (n = 4): NIV (1), IV (3)
3 SMN2 copies (n = 5): Age of non-ventilated survivors (n = 3): median
30.1 month (range 10–55 month)
Lemoine 2012 [61] USA, 2002–2009 49 patients NIV and MI-E device (n = 26): Age at death (n = 6): median 7.6 months
(IQR 6.5–10.5)
Supportive care (n = 23): Age at death (n = 16): median 8.8 months (IQR 4.7–23.7)
Finkel 2014 [13] USA, 2005–20093 34 patients4 Age at death (n = 9): median 11 months (range 2–177 months)
Age at death or ventilation >16 hrs/day: SMA 1B (n = 18): median 11.9 month
(IQR 7-229 mo);
SMA 1C (n = 16): median 13.6 month (IQR 8.8–20.1 month), 2 SMN2 copies (n = 23):
median 10.5 month (IQR 8.1–13.6)
Ottonello 2011 [66] Italy, 2006–2010 16 patients Age of survivors (n = 14, NIV 14): mean 40.5 ± 18.1 months
Age at death (n = 2, NIV 2): 30 days, 40 month
De Sanctis 2018 [62] Italy, 2011–2015 20 patients, non-sitters SMA 1a (n = 8, NIV/IV 0): all died within 6–14 months
SMA 1b (n = 8): Age at death (n = 5, NIV 4, IV1) between 12 and 48 month, 3
surviving patients (IV 2)
SMA 1c (n = 4, NIV 4): all patients alive (age range 39–48 month)

Key: Abbreviations: yrs = years, CN = copy number IQR = inter quartile range NIV = Non-invasive ventilation, IV = tracheostomy and invasive ventilation.
1
Clinical diagnosis of SMA 1 was defined as symptom onset <6 months of age and being not able to sit unsupported if not stated differently.
2
Study excluded patients with survival >2 years and ‘‘milder” forms of SMA type 1 without further specification.
3
Prospective study, all other studies retrospective.
4
14 patients with ventilation at inclusion (IV 3, NIV 11).
 R. Grychtol et al. / Paediatric Respiratory Reviews 28 (2018) 18–25
Additionally, general supportive measures such as improved nutri-
tion, consequent use of MI-E devices, vaccinations, early use of
antibiotics and improved management of exacerbations have influ-
enced survival over the past two decades as well. However, such
modest gains must been seen in a different light with availability
of Nusinersen and the likely additional pharmacologic therapies
on the horizon.
Prediction of survival with respiratory support remains difficult
for the individual patients especially in the most severely affected
children (i.e., SMA type 1a) and careful consideration of clinical
presentation at disease onset, course and progression of the dis-
ease and genetic predisposition is needed.
There is little published evidence that NIV prevents chest infec-
tions or hospitalisations. Generally, children with SMA type 1 are
very vulnerable to rapid decompensation even during minor upper
respiratory tract infections due to impaired cough, aspiration of
secretions and risk for mucus plugging with profound oxygen
desaturations. Intensified protocols for secretion clearance have
been proposed with aggressive use of MI-E devices together with
increased ventilation pressures at home to prevent hospitalizations
[43,66]. Early escalation of non-invasive ventilation (increased
inspiratory pressure and extension of ventilation up to 24-h usage)
during respiratory tract infection can be crucial in preventing intu-
bation [11]. NIV as well as intensive usage of MI-E devices also play
a decisive role in successful extubation [7,60]. In general, this
proactive management – with ventilation escalation and intensi-
fied airway clearance during respiratory decompensations – is
important as each intubation poses the risk of failure to wean from
invasive ventilation and consequently can confront the family with
the difficult decision between tracheostomy or palliation. Ideally,
parents should be prepared for these situations and acute manage-
ment plans should be made covering issues like intubation, resus-
citation and tracheostomy before the first severe decompensation
occurs [11].
Non-invasive ventilation versus tracheostomy and invasive ventilation
NIV is now widely accepted as first line treatment of respiratory
failure in children with SMA type 1 [9,67,68] and advantages com-
pared to tracheostomy and invasive ventilation have long been
acknowledged. NIV is easier to handle in patients with stable res-
piratory status and technologically less demanding. Additionally,
small and weak children often completely lose all ability to breathe
independently after tracheostomy while equally weak children on
NIV often retain some ability to breathe unsupported [60]. The
authors’ experience suggests that even children with dependency
on ventilation, i.e., need for respiratory support of more than
16h/ day might be able to breathe unsupported for a certain
amount of time according to their level of dependence and being
on NIV makes daily care easier and allows for some freedom from
the ventilator. Additionally, children with SMA type 1 and tra-
cheostomy almost always lose the ability to vocalize while chil-
dren on non-invasive support might be able to speak [7].
Tracheostomies also pose an intrinsic risk for complications them-
selves especially in young and completely dependent patients [65].
Finally, observational data also suggest, that long-term survivors
on NIV might eventually need less hospitalisations over time com-
pared to children with invasive ventilation [60]. All these aspects
are most likely contributing to better quality of life, although there
is no systematic evidence published.
Tracheostomies might be advantageous in emergency situation
caused by ‘‘mucus plugging” or aspiration of secretions with subse-
quent deep desaturations as they allow easy suctioning and bag
mask ventilation [6,60]. Gregoretti found a higher risk of death in
patients with NIV compared to tracheostomy, however general
recommendations cannot be drawn due to the retrospective nature
23
of this study. It remains highly controversial within the medical
profession if starting invasive ventilation is ethical in children with
a life-limiting disease that can lead to a state of complete paralysis
with none or very limited possibilities of communication in an
intellectually normally developed individual [69]. However, this
view might change with the advent of Nusinersen and additional
medical therapies, as well as gene therapy, which are undergoing
human clinical trials.
Tracheostomy might be an option in individual cases with
unmanageable secretion problems or failure of NIV after careful
consideration of the clinical status, dynamic of disease progression,
quality of life of the child and resources of the family and joint
decision making with the parents is crucial [9]. Ventilation for
>16 h/day is not necessarily an indication for tracheostomy in
patients with SMA1, as NIV can successfully be used in patients
who are nearly completely dependent on NIV [60].
Ethical considerations
Since technological advancement made life-prolonging respira-
tory support for children with SMA type 1 possible, strong opinions
existed among health care professionals about the ethics of provid-
ing such treatments [67,69–75] and considerable international dif-
ferences existed regarding recommendations [32,69,76] and use
especially of invasive ventilation [77].
The advent of new therapeutic options will most likely also
change the perception of SMA type1 as an inevitably fatal disease
at early age. However, even though the first clinical trial of Nusin-
ersen showed improved survival and motor function, there was no
difference in regard to ventilator dependent children [8]. Respira-
tory outcomes may end up better than the ones reported in the ini-
tial trial but it is likely that ethical considerations about the child’s
best interest regarding life-prolonging respiratory treatment will
remain an important issue.
The heart of the ethical concerns of using invasive or non-
invasive ventilation in children with SMA type 1 is the balance
between quality of life and prolongation of suffering. Clinicians
have been shown to perceive the quality of life of children with
SMA type 1 significantly worse than the parents and carers who
consequently also influenced their recommendation for ventilation
[78]. Life in a paralysed body, potentially with limited means of
communication but with normal cognitive development might
seem as ‘‘not worth living”. However, self-reported quality of life
of patients with similar degrees of disability and dependency can
be satisfactory or good [6,7,77,79,80] and assessment of quality
of life should therefore not simply focus on the ‘‘loss of physical
abilities”. More recent attitudes of clinicians about the happiness
of children with SMA type 1 and their quality of life reflect this
[67].
Conversely, clinical experience shows that children with pro-
active respiratory treatment are at risk of suffering and discomfort
as well. Use of MI-E devices and suctioning can be stressful, immo-
bility, contractures and scoliosis might be a source of chronic pain
and repeated decompensations with acute respiratory distress,
hospital and even intensive care admissions are likely frightening
and stressful. Recent data also show that quality of life is reduced
in children dependent on long-term ventilation and potentially
even more than in children with other chronic diseases [81,82].
Caring for a ventilated child with SMA type 1 also impacts on
the quality of life of the family. Parents have to cope with the
responsibility of being ‘‘the lifeline” of their children. The psycho-
logical burden of having a child with a life-limiting disease is huge
and on-going difficult decision making is required while trying to
offer the child the best quality of life as possible. Physical exhaus-
tion, social isolation and financial burden additionally contribute
to parental strain [83].
24 R. Grychtol et al. / Paediatric Respiratory Reviews 28 (2018) 18–25
Benefit and burden of active treatment always need to be con-
sidered carefully in respect to the patients’ clinical presentation
and course of the disease as well as the anticipated quality of life.
Inclusion of the parents in decision making is vital and principles
and scope of active treatment as well as solely symptom control
need to be discussed in an unbiased fashion.
Irrespective of the new therapies changing the prognostic out-
look of SMA type 1, the most recent recommendation also identi-
fies a need for redefining palliative care beyond the established
dichotomy of ‘‘end-of-life care” in opposition to active treatment.
Symptom control and improving quality of life are the main aims
of palliative care and do not oppose active treatment. Depending
on the context in an individual patient, NIV can sometimes be used
to facilitate life-supporting active treatment and sometimes as a
tool of symptom control.
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 venti-
lation (NIV) amongst other things. Polysomnography remains a
useful diagnostic tool for respiratory failure; however some
patients will develop a need for NIV prior to developing clear sign
of sleep-disordered breathing and hypoventilation on the
polysomnography.
Studies have shown that NIV improves survival and reduces the
burden of repeat hospitalisations and it currently remains the pre-
ferred ventilation support option over invasive ventilation via tra-
cheostomy. Tracheostomy has multiple downsides without
appearing at present to offer significant additional advantage,
however this may change with the new treatments and their effect
on the overall morbidity and mortality in this patient group.
The burden of care with ventilation can over time become quite
significant and constant attention to the patient’s needs and qual-
ity of life should remain at the centre of medical management deci-
sions in patients with SMA type 1 particularly if they require
increasing ventilation support. Consensus on meaningful respira-
tory outcomes in patients with SMA is required to evaluate the
impact of current and future ventilation strategies particularly
with the advent of new therapies such as Nusinersen.
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 out-
comes 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 respira-
tory morbidity and ventilator dependency on quality of life.
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