REVIEW

CURRENT
OPINION Respiratory complications, management and
treatments for neuromuscular disease in children
MyMy C. Buu

Purpose of review
To summarize current literature describing the respiratory complications of neuromuscular disease (NMD)
and the effect of respiratory interventions and to explore new gene therapies for patients with NMD.
Recent findings
Measurements of respiratory function focus on vital capacity and maximal inspiratory and expiratory
pressure and show decline over time. Management of respiratory complications includes lung volume
recruitment, mechanical insufflation-exsufflation, chest physiotherapy and assisted ventilation. Lung
volume recruitment can slow the progression of lung restriction. New gene-specific therapies for
Duchenne muscular dystrophy and spinal muscular atrophy have the potential to preserve respiratory
function longitudinally. However, the long-term therapeutic benefit remains unknown.
Summary
Although NMDs are heterogeneous, many lead to progressive muscle weakness that compromises the
function of the respiratory system including upper airway tone, cough and secretion clearance and chest
wall support. Respiratory therapies augment or support the normal function of these components of the
respiratory system. From a respiratory perspective, the new mutation and gene-specific therapies for
NMD are likely to confer long-term therapeutic benefit. More sensitive and standard tools to assess
respiratory function longitudinally are needed to monitor respiratory complications in children with NMD,
particularly the youngest patients.
Keywords
lung, neuromuscular disease, respiratory complications, respiratory insufficiency, respiratory therapy

INTRODUCTION is important to develop and describe respiratory end points

Neuromuscular disease (NMD) is a heterogeneous group of
disorders that affect the motor neuron, neuromuscular
junction and muscle fibers, with variable onset of illness,
presentation, natural history and prognosis. For many
NMDs, progressive muscle weakness compromises
function of the respiratory system including lowering upper
airway tone, impairing cough and secretion clearance and
weakening chest wall support [1]. Thus, children with
NMD are prone to upper airway obstruction, pulmonary
aspiration, recurrent respiratory infec-tions, sleep
disordered breathing, hypoventilation and respiratory
failure. Respiratory impairment is the leading cause of
morbidity and mortality.
New therapies for NMD target the genetic defect in
specific NMDs and hold the promise of effective long-term
treatment for the diseases. These thera-pies are being
studied with motor function end points because of lack of
respiratory outcome measures especially in preschool aged
children. It
for patients with NMD. To accomplish this goal,
understanding both the natural progression of NMD and
the mechanism and clinical implications of therapies
designed to maintain the respiratory health of patients with
NMDs is necessary.
The purpose of this review is to summarize current
literature in NMD patients that outlines the respiratory
complications, the impact of respir-atory interventions on
pulmonary health and new disease-modulating therapies.
Department of Pediatrics, Stanford University School of Medicine,
Stanford, California, USA
Correspondence to MyMy C. Buu, Department of Pediatrics,
Stanford University School of Medicine, 770 Welch Rd. Suite 350,
Stanford, CA 94304, USA. Tel: +1 650 723 8325; fax: +1 650 723
5201; e-mail: mymybuu@stanford.edu
Curr Opin Pediatr 2017, 29:326–333
DOI:10.1097/MOP.0000000000000498

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 Respiratory complications of neuromuscular disease in children Buu
KEY POINTS
The respiratory complications of NMDs include low
upper airway tone, abnormal chest wall compliance,
weak inspiratory muscles and dysphagia resulting
in abnormal pulmonary function.
Measures of respiratory function include pulmonary
function testing (vital capacity and respiratory muscle
strength), measurement of blood gases (pulse
oximetry and capnography) and polysomnography.
Lung volume recruitment has been shown to slow down
the decline in vital capacity from 4.5%-predicted per year
to 0.5%-predicted per year for patients with DMD.
MI-E is used to augment cough during respiratory
illness but can also assist with extubation of patients
with acute respiratory failure.
The respiratory phenotype of patients treated with
gene-specific therapies for DMD (eteplirsen) and
spinal muscular atrophy (nursinersen) is not yet known
nor described.
METHODS
Relevant, peer-reviewed research articles published in
January 2015–December 2016 were identified using
MEDLINE and Scopus databases using search terms
‘neuromuscular disease,’ ‘respiratory,’ ‘pulmonary,’ and
limited to studies of children.
RESPIRATORY COMPLICATIONS OF
NEUROMUSCULAR DISEASE
Although NMDs are heterogeneous, the respiratory
complications of these disorders overlap and include
ineffective airway clearance, recurrent respiratory
infections and respiratory failure. The onset and
progression of respiratory complications depend on the
region of muscle weakness and the underlying NMD
(Table 1) [2]. NMD causes low upper airway tone,
abnormal chest wall compliance, weak inspiratory muscles
and dysphagia resulting in abnormal pulmonary function
(Fig. 1). Low upper airway tone leads to upper airway
obstruction and obstructive sleep apnea. Abnormal chest
wall com-pliance and spinal support cause a restrictive
lung defect, chest wall deformity and scoliosis. Weak
inspiratory muscle strength leads to ineffective air-way
clearance and recurrent respiratory infections. These
deficiencies lead to ineffective ventilation. Dysphagia and
poor swallow coordination can lead to chronic pulmonary
aspiration that can cause atelectasis, bronchiectasis and
fibrosis that affects the lung’s ability to exchange gas. In
the presence of chronic respiratory insufficiency, a child
with NMD
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is at increased risk for acute respiratory failure in the
presence of infection or volume overload as well as
progressive chronic hypercapnic respiratory failure.
IDENTIFYING CHILDREN AT RISK FOR
RESPIRATORY COMPLICATIONS
Measures of respiratory function include pulmonary
function testing, measurement of blood gases (pulse
oximetry and capnography) and polysomnography.
Pulmonary function testing includes spirometry for vital
capacity, tests of respiratory muscle strength including
maximal inspiratory and expiratory pres-sure (MIP and
MEP), peak cough flow and peak expiratory flow (PEF).
Close and recurrent measure-ment of respiratory function
in patients with NMD is important in order to detect
disease progression and onset of pulmonary compromise
that might result in chronic respiratory insufficiency.
Accurate and reliable measurement of respiratory function,
with minimal interobserver variability, is necessary to
assess the efficacy of therapies such as in clinical trials.
Clinical trials for patients with NMD have focused on
muscle strength or functional status [3], such as the
NorthStar Ambulatory Assessment, a validated tool for
patients with Duchenne muscular dystrophy (DMD) [4].
There have been a number of recent studies describing the
natural history of lung function in patients with NMD.
These studies attempt to characterize pulmonary function
measurements as potential study end points for clinical
trials. In a study of 60 patients with DMD, Mayer et al.
[5 ] showed that the per-centage predicted forced vital
&&
capacity (FVC) and PEF declined linearly by
approximately 5% per year from ages 5 to 24. This finding
is in agreement with other studies looking at the natural
history of DMD. However, this study also showed that the
rate of decline was unaffected by the patients’ ambulatory
status nor treatment with steroids.
MEP and MIP have also been described in patients
with NMD to correlate with functional status, but the
measurement is problematic as it is not reliably
reproducible. There was a study describ-ing lung function
in 14 patients with centronuclear myopathies (CNMs)
attending a conference for CNM [6]. All required assisted
ventilation with 13 treated by invasive mechanical
ventilation. The ability to tolerate time off (>1 h/day)
mechanical ventilation was associated with higher MIP,
com-pared to patients on continuous (24 h) support [33.7
(11.9–42.3) vs. 8.4 (6.0–10.9) cm H2O, P < 0.05]. Years of
mechanical ventilation dependence corre-lated inversely
with MEP (r ¼ –0.715, P < 0.01).
www.co-pediatrics.com 327
 328

Pulmonology
Table 1. Respiratory features of neuromuscular diseases

Condition Respiratory failure Secretion clearance difficulty Recurrent pneumonia Progression Disease-specific features

SMA
com.pediatrics-co.www

Type 1 All by 2 years Marked All Rapid All require full-time respiratory support
Type 2 40% in childhood Early 25% in first 5 years Slow
©Copyright

Type 3 Rare in childhood Rare in childhood Rare in childhood Slow

SMA with respiratory All by 6 months Marked All Rapid in first year, All require full-time respiratory support
distress type 1 then slows
DMD/severe childhood After loss of ambulation After loss of ambulation Late Cardiomyopathy usually occurs after
onset limb-girdle respiratory problems but may precede
muscular dystrophy them
Facioscapulohumeral When onset < 20 years With infantile onset With infantile onset Slow Severe infantile onset type is frequently
muscular dystrophy associated with sensorineural deafness
Congenital muscular dystrophy
.reservedrightsAll.IncHealth,KluwerWolters2017

All types Any age depending on severity Any age depending on severity Any age depending on Slow
severity
Ullrich 70% in adolescence Mild Infrequent Proximal contractures with marked distal
laxity
Rigid spine muscular Early while ambulation preserved Mild Infrequent Hypoventilation may occur in ambulant
Dystrophy children with relatively preserved vital
capacity
Congenital myopathy
Central core Uncommon except in severe recessive Uncommon Uncommon Slow Susceptible to malignant hyperthermia
type
Minicore Early while ambulation preserved
Nemaline Early in severe neonatal form, mild later In severe form In severe form Slow
onset form may develop early while
ambulation preserved
Myotubular 85% in severe X-linked form In severe form In severe form Slow Ophthalmoplegia, rare coagulopathy and
liver hemorrhage
Fiber-type disproportion Depends on genotype Uncommon Uncommon
Myotonic dystrophy
Myotonic dystrophy 1 Common in severe congenital onset, Common in severe congenital Common in severe Initial improvement, Prominent learning difficulty, somnolence
usually improves onset congenital onset later slow and central hypoventilation
deterioration
Number29Volume 3

Myotonic dystrophy 2 Uncommon Uncommon Uncommon

Congenital myasthenic Often in neonatal period, may occur Especially during intercurrent Possible if weakness Weakness may fluctuate, episodic apnea in
Syndromes during intercurrent illnesses illnesses severe and persistent some. Congenital stridor in those with
DOK7 mutations
Mitochondrial myopathy Common Possible Possible Acute deterioration
possible
Charcot–Marie–Tooth With severe early onset, especially with With severe early onset With severe early onset Stridor, especially with GDAP1 mutation
GDAP1 mutation
Pompe Infantile onset, may be early in later Infantile onset Infantile onset Infantile rapid, late Variable relationship between motor and
2017June

onset while ambulation preserved onset slow respiratory progression

DMD, Duchenne muscular dystrophy; SMA, spinal muscular atrophy.

Originally from [2].
 Respiratory complications of neuromuscular disease in children Buu

FIGURE 1. Respiratory complications of neuromuscular disease. Compromise of upper airway tone, chest wall compliance
and inspiratory muscles lead to ineffective ventilation. Dysphagia and recurrent respiratory infections lead to gas-exchange
dysfunction. Together, these contribute to chronic respiratory insufficiency. Source: Original.

Diaphragm function can be affected in patients with DIAGNOSIS OF NEUROMUSCULAR

NMD. Electromyography measurements of dia-phragm
function in eight patients with late onset Pompe disease
compared with healthy controls demonstrated that the
evoked diaphragm response could distinguish patients with
Pompe disease from control individuals [7]. Maximal
Twitch transdiaph-ragmatic pressure responses were lower
in patients with Pompe (1.4–17.1 cm H2O, P < 0.001).
Com-pound muscle action potential amplitude distin-
guished patients who needed or did not need ventilator
support, with lower amplitudes in patients who used
ventilator support.
DISEASE
The diagnosis of NMDs is often based on clinical
presentation, physical examination, examinations of the
muscle and motor neuron and genetic testing if available.
In recent years, there has been an emphasis on genetic
diagnosis for certain NMDs, as correct diagnosis is
essential for family planning and new mutation-specific
therapies [8].
There has been consideration of newborn screening for
NMDs such as DMD and spinal mus-cular atrophy (SMA)
because of the potential impact on early initiation of
recommended treatments

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Pulmonology

Table 2. Management of respiratory complications of neuromuscular disease

Physiologic compromise Respiratory complication Treatment

Low upper airway tone Upper airway obstruction Consideration of tonsillectomy

Obstructive sleep apnea and/or adenoidectomy
Noninvasive ventilation
Abnormal chest wall compliance Lung restriction Lung volume recruitment
Atelectasis Scoliosis surgery
Scoliosis
Weak inspiratory muscles Lung restriction Respiratory muscle training
Atelectasis Lung volume recruitment
Ineffective airway clearance Airway clearance therapies
Dysphagia Pulmonary aspiration Feeding therapy
Recurrent respiratory infections Enteric tube feeding
Bronchiectasis and fibrosis Airway clearance therapies
Impaired oxygenation
Respiratory insufficiency Acute or chronic respiratory failure Noninvasive ventilation
Tracheostomy tube placement
and invasive ventilation

(such as corticosteroids for DMD) and genetic-based
therapies for these disorders. In the case of DMD, the first
trial newborn screening programs used creatine kinase
levels in blood spots followed by confirmation in serum
and then clinical follow up or muscle biopsy. These
programes lead to early diagnosis of boys with DMD, but
the majority of programs were terminated because of lack
of funding [9]. With the availability of strategies that
inline one-way valve and mask or an MI-E machine set to
insufflation only. Sequential positive pressure breaths (3–
5) are delivered to achieve maximal inspiratory capacity
sequentially, repeated 3–5 times, two times a day. Lung
volume recruitment has been shown to slow down the
decline in vital capacity from 4.5%-predicted per year to
0.5%-pre-dicted per year over a 6-year period in 16
patients with DMD [10 ].
&&

permit early, effective intervention, it may be reasonable to

revisit the issue of newborn screen-ing for these disorders.

MANAGEMENT OF RESPIRATORY
COMPLICATIONS
The principles of managing respiratory compli-cations in
patients with NMD include maintaining vital capacity,
TREATMENT OF RESPIRATORY
COMPLICATIONS
MI-E is used to augment cough. MI-E use in the home was
associated with a lower rate of emergency room use in 37
patients with NMD [11]. The MI-E has been used to assist
patients toward extubation after intubation. Bach et al.
[12 ] describe a protocol that allowed them to extubate 97
&

mobilization of secretions and treat-ment of aspiration,
airway obstruction and respir-atory insufficiency (Table 2).
Lung volume recruitment and respiratory muscle training
can prevent lung restriction and atelectasis. Treatment of
ineffective airway clearance and aspiration con-sists of
mechanical insufflation-exsufflation (MI-E), chest
physiotherapy and airway clearance therapies. Treatment
of upper airway obstruction or chronic respiratory failure
includes assisted ventilation.
patients who had been intubated for an average of 25 days
and failed extubated at least once.
Chest physiotherapy is used to mobilize secretions.
Airway clearance with high-frequency chest wall
oscillation (HFCWO) reduces outpatient and inpatient cost
[13]. Using an insurance claims database from 2007 to
2011, 426 patients with NMD had a reduction in total
medical claims cost per member per month by $1949 and
reduction in inpatient admission cost by $2392 after
initiation of HFCWO.

PREVENTION OF RESPIRATORY Patients with chronic respiratory failure may need to

COMPLICATIONS be treated with assisted ventilation that is delivered
Lung volume recruitment is achieved by using a manual noninvasively (NIV) or invasively. In a descriptive study
self-inflating resuscitation bag with an of Korean patients with DMD

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 Respiratory complications of neuromuscular disease in children Buu
and myotonic muscular dystrophy, they developed the need
for assisted ventilation when sitting FVC was 23.5 and
39.9%-predicted, respectively, and sitting MIP was 24 and
41 mmHg, respectively
[14]. Even children below 1 year of age can be effectively
treated with NIV at home [15 ]. NIV is usually delivered
& identi-fied as barriers, but this did not affect the rate of
via a nasal or face mask. Volume-controlled ventilation can
also be deliv-ered by a mouth piece if patients have good
bulbar strength. Carlucci et al. [16] describe tidal volume
and inspiratory time settings to avoid nuisance alarms.
Scoliosis contributes to restrictive lung defect. Prior
case series and studies have shown that spinal fusion in
patients with DMD results in both improvement in rate
decline of vital capacity and no effect on future need for
assisted ventilation and survival [17]. One retrospective
study of 29 patients with DMD and 11 patients with SMA
in Singapore after spinal fusion with follow up for 11.6
years showed reduction in rate of decline in FVC from 7.8
to 4.26% per year and 5.31 to 1.77% per year, respectively
[18]. Of note, this improvement is not better than the
described natural history of decline in vital capacity for all
patients with DMD described above.
PRACTICE GUIDELINES
Practice guidelines are developed with the intent to reduce
morbidity and mortality in patients with NMD. Societies
and provider groups have been creating them for each
primary NMD group. In the last 2 years, new practice
guidelines were pub-lished for congenital muscular
dystrophy [19 ] and home invasive ventilation for patients
&&
with chronic respiratory failure [20 ,21 ]. Despite the
& &
availability of care guidelines for specific NMDs, there are
bar-riers to implementation of recommended care.
The American Thoracic Society published a consensus
statement for the respiratory care of patients with DMD in
2004 [22], and there are newer guidelines by the US
Centers for Disease Control and Prevention from 2010
[23,24]. Andrews et al.
[25] looked at participants in the Muscular Dystrophy
Surveillance, Tracking, and Research Network from 2000
to 2010. They showed that for the sickest patients who
ended up needing tracheostomy, all patients were evaluated
by a pul-monologist, more than 80% were treated by MI-E
and NIV in 2009–2010, which greatly improved from 2001
to 2002. However, for all other DMD patients,
measurements of respiratory function occurred less than
50% and the use of respiratory assist devices occurred less
than 67% than recom-mended by the guidelines.
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A study of children with congenital muscular
dystrophy at multiple centers showed 40–44% adherence to
lung volume recruitment, but more than 50% of individuals
and their families could not identify barriers to adherence
[26 ]. Social distractions and family obligations were
&
adherence.
NEW THERAPIES AND FUTURE
DIRECTIONS
It is an exciting time in the field of NMD as mutation and
gene-specific therapies are becoming available for DMD
and SMA. In the last year, two therapies were approved by
the US Food and Drug Administration (FDA) based on
muscle or motor outcomes.
For DMD, eteplirsen is a small molecule that induces
skipping of exon 51 of the dystrophin gene in DMD pre-
mRNA resulting in functional dystrophin protein [27].
Eteplirsen was FDA approved in 2016. In a pharmaceutical
sponsored small study of 12 patients with DMD amendable
to exon 51 skipping, there was no change in MIP, MEP or
FVC over a 3-year follow-up period, but the rate of decline
in the 6-min walk test was attenuated and the incidence of
loss of ambulation was diminished compared with
historical controls [28].
Nusinersen is an antisense oligonucleotide that alters
the splicing of SMN2 mRNA to create SMN protein
production in patients with SMA. The phase 1 study of
patients with type 2 and 3 SMA showed a good safety
profile and increase in a clinical motor scale,
Hammersmith Functional Motor Scale Expanded [29 ]. &&
The phase 2 study of 20 patients with infantile-onset SMA
less than 7 months old showed that patients achieved motor
milestones, improved motor scores and increased muscle
action potential [30 ]. Nusinersen was FDA approved in
&
December 2016.
These therapies target the genetic mutation or
defective gene and produce near normal protein correcting
the molecular defect. In effect, these therapies may change
the disease course depending on when therapy is initiated.
It is likely that these therapies will alter the clinical course
of the disease, creating, arguably, a new clinical phenotype.
Lessons can be learned from the experience in patients
with cystic fibrosis and the cystic fibrosis transmembrane
conductance regulator protein potentiator, ivacaftor, which
was first FDA approved in 2012 [31,32], including
respiratory effects in young patients, long-term effects on
decline of respiratory function, changes to treatment
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Pulmonology
paradigms and clinical and socioeconomic factors affecting
prescription and adherence to therapy.
The absence of reliable and reproducible respir-atory
outcome measures especially in preschool aged children
confounds our collective ability to assess the response to
therapy. There is a critical need to derive respiratory end
points for patients with NMD. It is a crucial time to
understand the natural progression of respiratory function
in early life. It seems as adherence to clinical care
guidelines for patients with NMD has been focused on
treating respiratory insufficiency rather than preventing
decline. Given the advent of disease-modulating therapies,
treatment can now be focused upon maintaining respiratory
health.
These therapies are very costly. In 2016, ete-plirsen
costs $300,000 per year of treatment and nusinersen is
$125,000 per injection, an annual cost of $750,000 for the
first year, for the medication alone. This does not include
the cost of intrathecal injection of the medication. Whether
all the chil-dren who might benefit from the medication
will gain access to the treatment remains uncertain given
multiple payer systems that exist in the United States and
the world.
CONCLUSION
Although NMDs are heterogeneous, many lead to
progressive muscle weakness that compromises the
function of the respiratory system including upper airway,
cough and secretion clearance and chest wall support.
Respiratory therapies augment the function of the
respiratory system. Lung volume recruitment can slow the
progression of lung restriction.
The new gene-specific therapies are likely to change
the respiratory phenotype for these dis-orders. These
therapies highlight the importance of developing tools to
measure respiratory compli-cations in young patients. It is
important for early initiation of respiratory therapies to
preserve life and function.
Acknowledgements
I would like to thank Johnny Liu for illustrative assist-ance.
Financial support and sponsorship
M.B. received travel reimbursement from Parent Project
Muscular Dystrophy to attend Pulmonary Outcome
Workshop in April 14–15, 2016.
Conflicts of interest
There are no conflicts of interest.
332 www.co-pediatrics.com
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 Respiratory complications of neuromuscular disease in children Buu
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