REVIEW

CURRENT
OPINION Neuromuscular disease and the pulmonologist
Nanci Yuan

Purpose of review
The heterogeneous nature of neuromuscular disorders (NMDs) continues to promote slow but steady
advances in diagnosis, classification, and treatment. This review focuses on the updates in the general
management and treatment of NMDs, with emphasis on key updates in muscular dystrophy, myotonic
dystrophy, mitochondrial myopathy, spinal muscular atrophy, and hereditary neuropathies.
Recent findings
Current research shows that improvements in morbidity and mortality in various NMDs may be possible.
Key components include advances in identification and classification of individual NMDs; attention to
anesthetic and surgical risks; aggressive pulmonary care; and implementations of a proactive,
multidisciplinary, standard-of-care approach. Innovative molecular and pharmaceutical therapeutic options
are being investigated in many of these disorders, but unfortunately no new intervention has borne out.
Summary
Important advances were made in the last year in the field of neuromuscular disease. However, because of
their heterogeneous nature and rarity, diagnosis and treatment of these disorders either as a single disorder
or as a group continue to be both a clinical and a research challenge. It is of utmost importance that
clinicians and researchers be aware of these disorders to aid in identification and treatment.
Keywords
muscular dystrophy, myopathy, myotonic dystrophy, neuromuscular disorders, spinal muscular atrophy

INTRODUCTION decrease in chest wall compliance and unequal lung

Neuromuscular disorders (NMDs) are a hetero-
geneous group of inherited or acquired diseases
characterized by progressive muscle weakness and
wasting which may affect either one or all of
the major respiratory muscle groups (inspiratory,
expiratory, and bulbar). Thus, respiratory deteriora-
tion is often a primary cause of both morbidity
and mortality in children with NMD. As muscle
weakness and wasting progress, NMD patients
may develop ineffective cough and clearing of
respiratory secretions, aspiration of salivary and oral
contents, atelectasis, frequent recurrent respiratory
infections, pneumonias, airway obstruction, gas
exchange abnormalities (hypercapnea and hypo-
xemia), and sleep-disordered breathing (SDB) [1–4].
NMD patients frequently have other major
systemic dysfunction. Malnutrition and failure-to-
thrive [1–4] is an issue due to increased caloric
needs and metabolic demands secondary to chronic
respiratory failure, which requires intervention.
Malnutrition can contribute to respiratory failure
by further decreasing ventilatory muscle strength.
Significant scoliosis may develop because of
unequal muscle tone and gravity, leading to
expansion that further promotes pulmonary
compromise [1–4]. Finally, NMD patients may also
develop cardiac dysfunction negatively impacting
respiratory function, further accentuating both car-
diac and respiratory dysfunction [5,6]. Each of these
comorbidities needs thoughtful intervention.
Because of the heterogeneous nature of NMD,
the onset and severity of pulmonary manifestations
will vary depending on the particular muscle and
nerve involvement and the overall health of the
individual. For example, a patient with myotonic
dystrophy may not have difficulty with respiratory
clearance with mild upper respiratory infections
Division of Pediatric Pulmonary and Sleep Medicine, Lucile Salter
Packard Children’s Hospital at Stanford, Stanford University, Palo Alto,
California, USA
Correspondence to Nanci Yuan, MD, D, ABSM, Division of Pediatric
Pulmonary and Sleep Medicine, Lucile Salter Packard Children’s Hos-
pital at Stanford, 770 Welch Road, Suite 350, Palo Alto, CA 94304-
5786, USA. Tel: +1 650 723 8325; fax: +1 650 723 5201; e-mail:
nyuan@stanford.edu
Curr Opin Pediatr 2012, 24:336–343
DOI:10.1097/MOP.0b013e3283531bb0

www.co-pediatrics.com Volume 24  Number 3  June 2012

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

KEY POINTS
 Important advances have been made in the last year in
the field of neuromuscular disease.
 Because of their heterogeneous nature and rarity,
identification and treatment of these disorders either as
a single disorder or as a group continue to be both a
clinical and a research challenge.
 It is of utmost importance that clinicians and
researchers be aware of these disorders to aid in
identification and treatment.
but may have significant difficulty with lower
airway infections requiring the initiation of chest
physiotherapy. Therefore, current research in the
field of NMD recognizes the importance of updates
in the general management and treatment of NMD
but also acknowledges the importance of tailoring
specific treatments to specific NMD groups.
PULMONARY TREATMENTS AND
CONSIDERATIONS
The clinical and respiratory demise in chronic
medical diseases such as cystic fibrosis had once
been considered inevitable [7]. Advances in manage-
ment and treatment over the last 30 years, and
the willingness to prescribe the said therapies,
have dramatically improved the overall morbidity
and mortality in cystic fibrosis and in NMD [7–10].
Key hallmarks of medical care management
include the judicious usage of various airway
clearance techniques and noninvasive mechanical
ventilation.
AIRWAY CLEARANCE
Pediatric airway clearance techniques promote
cough and enhance mucociliary clearance. Airway
clearance management has been a mainstay treat-
ment of NMD patients during episodes of acute
respiratory decompensation and is now being used
proactively [8,9,11,12].
The gold standard is manual percussion and
postural drainage. Percussion and postural drainage
are most effective when applied by a physically
abled and responsible caregiver to all positions in
a stepwise reproducible fashion. Certain positions
which promote regurgitation and aspiration should
be avoided, such as prone head-down. Positions
are prohibited when patients have contractures or
scoliosis, are uncooperative, and too heavy or fragile
to move. High-frequency oscillatory devices may
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Neuromuscular disease and the pulmonologist Yuan
be a useful alternative in these cases. Assisted-cough
techniques and glossopharyngeal breathing are
effective recreations of a natural cough. Both require
patient cooperation and reliable coordination
between patient and caregiver. Hand-held mobiliz-
ation devices can be manual or electronic. Manual
devices are feasible when patients are able to create
a tight mouth seal, intellectually and physically
able to perform the proper maneuver, and have
the physical strength to operate the devices them-
selves. Electronic devices are initiated when manual
devices have failed or are not feasible, as they are
less patient state dependent. Disadvantages include
bulkiness of the device, inability to tolerate pressures
achieved, need for electricity, and unavailability
of the device. Multiple studies have demonstrated
the benefit of mechanical insufflation/exsufflation
in NMD [8,9,11,12]. Clinical settings should be
tailored to the individual irrespective of age,
weight, and baseline neuromuscular strength and
continuously reevaluated and adjusted based on
clinical needs.
Various techniques are available and techniques
may be applied in combination. The choice of
methodology is state dependent and may vary with
time within the same individual. Care must be given
for both under and over-utilization.
NONINVASIVE MECHANICAL
VENTILATION
Noninvasive negative pressure ventilation origi-
nated in the 1800s [13]. Its zenith was during the
polio epidemics. Modern negative pressure devices
are more portable, but restrictions on positioning
and access to patients, problems with correct
fitting, and a tendency to potentiate obstructive
sleep apneas have promoted the use of noninva-
sive positive airway pressure ventilation (NIPPV).
The successful use of NIPPV for NMD began in
the1980s. NIPPV has expanded in both acute and
chronic settings and in disease states [8–12]. Patient
selection criteria include location and severity of
respiratory compromise, the ability to cooperate
and synchronize with support, and availability of
appropriate machinery and patient interface. Mehta
and Hill [14] summarized the short-term and long-
term goals for NIPPV. NIPPV can be applied with
both hospital and outpatient bi-level devices and
pressure and volume ventilators. Choice of modality
in both the acute and the chronic setting should
be based on patient state, optimal achievement of
ventilation goals, patient comfort, and availability
of device.
Multiple models of bi-level devices with various
clinical options and accessories are available. Food
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 Pulmonology
and Drug Administration (FDA) approval of certain
devices based on weight (either >5 kg or >13 kg)
have both increased and hindered the availability of
bi-level devices to the pediatric population based on
the practices of local durable medical equipment
providers. Most bi-level devices provide the ability
to choose multiple modes of ventilation, choices of
alarms, downloadable memory card, in one device.
Some provide the ability to set two program settings,
an internal battery, ability to blend in supplemental
oxygen, and built-in pulse oximetry. Bi-level devices
are not approved for 24-h continuous use and are
not licensed in the USA as a ventilator, so back-up
devices are generally not approved by insurance
companies.
Multiple models of home pressure and volume
ventilators with various clinical options and acces-
sories are available. These devices also provide many
of the options and accessories available in bi-level
devices. Ventilators are effective to provide support
both invasively and noninvasively. To date, no
studies have definitively proven the efficacy of
either pressure or volume ventilation.
Successful application of NIPPV requires patient
preparation and cooperation, airway secretion man-
agement, optimal patient–ventilator synchrony,
and appropriate interface.
When clinically applicable, nonurgent age
appropriate introduction during the day should be
done in a controlled fashion with patient and
caregiver to optimize cooperation. Scheduled airway
clearance management may be done prior to,
during, and after NIPPV usage. Individualization
of modality and ventilation settings maximizes
the synchrony. FDA-approved pediatric interfaces
are available, but fitting remains problematic.
Concerns regarding skin breakdown and develop-
ment of midfacial hypoplasia warrant alternating
a minimum of two interfaces. Directed NIPPV
via a mouthpiece can be used with responsible
patients who are mentally and physically capable
of obtaining an appropriate mouth seal and strong
enough to trigger the ventilator-assisted breath with
reliable frequency.
LONG-TERM HOME INVASIVE
MECHANICAL VENTILATION
Invasive mechanical ventilation via tracheostomy
has been an increasing treatment option for patients
with NMDs in various countries over the past
30 years [15,16]. This is because of a combination
of factors including advancements in technology,
improved access to technology and medical care,
increased clinical expertise, and a paradigm shift
in patients’, caregivers’, and physicians’ attitudes
338 www.co-pediatrics.com
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toward quality of life and long-term care. Histori-
cally, these patients resided in hospital or postacute
care skilled nursing facilities. However, because of
increasing healthcare costs and shortage of skilled
nursing facilities, long-term home ventilation
programs have been created. Analysis of data over
the last 20 years highlights the complex factors
regarding the decision to consider tracheostomy
and home invasive mechanical ventilation: quality
and adequate home care, patients’ and caregiver
needs, community financial resources, and tran-
sition to adult medical care [17–20].
MULTIDISCIPLINARY APPROACH/
STANDARD-OF-CARE CLINICAL PRACTICE
GUIDELINES
A coordinated multidisciplinary team approach
improves the suboptimal medical care coordination
and increases the social support for caregivers
[21–26]. A dedicated pediatric palliative care team
addresses the needs of children with advanced
life-threatening conditions, their families, and the
hospital staff, with specific emphasis on symptom
relief, logistics and care coordination, and psycho-
social and decision-making support. This is especi-
ally important in pediatric NMD patients, who,
unlike their adult counterparts, are more likely
to be alive for more than a year after initiating
palliative care [21–26].
Clinical practice guidelines improve patient
care, provide a baseline standard for future clinical
studies, and serve as educational tools for medical
personnel, patients, and caregivers [27]. Practice
guidelines have already been published and updated
for the most commonly identified and treated
NMD populations: Duchenne muscular dystrophy
(DMD) and spinal muscular atrophy (SMA) [28,29].
Research continues to evaluate how the DMD
and SMA guidelines have shaped clinical practice
nationally and internationally [30–33]. Standard-
of-care consensus statements have also been pub-
lished for congenital muscular dystrophies, and
one has been accepted for publication in 2012 for
&& &&
congenital myopathies [34 ,35 ].
SCOLIOSIS
Patients with NMD are at risk for developing
musculoskeletal complications, of which the most
frequently encountered are scoliosis, bony rotational
deformities, and hip dysplasia [36–38]. Because of
the added negative impact on respiratory function,
surveillance for scoliosis is recommended in
NMD patients. However, in many cases, the first
indications for evaluation and treatment are
Volume 24  Number 3  June 2012

musculoskeletal complaints due to pelvic obliquity,
dislocation of the hip, limited balance or ability to
sit, and back pain [36–38]. Treatment options for
scoliosis include bracing and surgery.
Scoliosis surgery decreases lung volumes, expir-
atory flow rates, and oxygenation postoperatively
as a result of the site of surgery itself, anesthesia,
pain, and mobilization. A thorough preoperative
pulmonary evaluation can obviate postoperative
morbidity.
Preoperative pulmonary function measurements
and nutritional status have been validated in multi-
ple studies as reliable predictors of postoperative
respiratory morbidity [39,40]. Polysomnography
(PSG) is the gold standard for documentation
of SDB (nocturnal hypoventilation, hypoxemia,
and obstructive sleep apnea). Although PSG has
not yet been shown to be a reliable preoperative
marker, the detection of SDB demonstrates existing
pulmonary compromise and the necessity of initiat-
ing therapy such as NIPPV preoperatively and post-
operatively [41,42,43]. Preoperative cardiac studies
have aided anesthetic management intraoperatively
in patients with DMD [44].
A variety of surgical approaches have been used
in patients with NMD, the type and timing of which
require careful thought because of the increased
risk of anesthetic and surgical complications (post-
operative wound infections, bleeding, respiratory
compromise, etc.) [36–42,44–50]. Assessment
includes an understanding of the primary disease
and its prognosis, the preoperative risk factors (i.e.
poor baseline pulmonary function measurements,
nonambulatory status, preoperative curve magni-
tude, and the presence of a ventriculoperitoneal
shunt), and the goal for surgical correction (pre-
servation of lung function versus performance and
function in activities of daily living) [36–42,44–50].
The immediate and long-term effects of neuro-
muscular scoliosis surgery do not have a significant
impact on respiratory decline but can improve
quality of life via improvement in pelvic obliquity
and sitting balance [36–42,44–50].
SLEEP-DISORDERED BREATHING
The impact of SDB in NMDs has been reviewed
[51–53]. The current gold standard for evaluating
SDB is PSG; however, there was no current consen-
sus on when children 2–18 years of age are recom-
mended to have PSG. In 2011, both the American
Academy of Sleep Medicine (AASM) and The
American Academy of Otolaryngology – Head and
Neck Surgery Foundation have published evidence-
based recommendations for using PSG, especially in
assessing children with complex medical conditions
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Neuromuscular disease and the pulmonologist Yuan
&& &&
such as NMDs [54 ,55 ]. Although both statements
recommend obtaining a PSG before determining the
need for tonsillectomy, the AASM parameters go
further. The AASM recommends PSG to evaluate
postsurgical residual SDB (Standard), positive airway
pressure (PAP) titration (Standard), sleep-related
hypoventilation (Guideline), noninvasive positive
pressure ventilation (NIPPV) titration (Option),
mechanical ventilation (Option), tracheostomy,
and after decannulation (Option). Follow-up PSG
is indicated to determine whether pressure require-
ments have changed as a result of the child’s growth
and development, if symptoms recur while on PAP,
or if additional or alternate treatment is instituted
(Guideline).
INDIVIDUALIZED TREATMENT
Advances in diagnosis of NMD both clinically
and through molecular genetics have shown the
necessity of tailoring clinical and research endeavors
to a particular NMD type.
Myopathies
Muscular dystrophies are a heterogeneous group of
inherited myopathic disorders resulting in charac-
teristic patterns of progressive muscle weakness,
wasting, and myofiber degeneration. The traditional
classification into subgroups is based on clinical
parameters (the distribution of predominate muscle
weakness). Clinically, there are at least eight
major subgroups: Emery-Dreifuss (humeroperoneal)
muscular dystrophy, facioscapulohumeral (Land-
ouzy-Déjèrine) muscular dystrophy, the limb girdle
dystrophies, oculopharyngeal muscular dystrophy,
distal muscular dystrophy, and the congenital
muscular dystrophies [56,57].
Myotonic dystrophy encompasses a group of
genetic disorders that share specific clinical and
genetic features. There are currently two clinically
and molecularly defined types of myotonic dystro-
phy: DM1 and DM2. Pediatric onset forms (congen-
ital DM1 and childhood onset DM1) are associated
with developmental delay, ophthalmologic dys-
function, cardiac conduction defects, recurrent
aspiration pneumonia, hypersomnolence, insulin
resistance, and thyroid disorders [58,59].
Congenital myopathies are a distinct but
markedly heterogeneous group of muscle disorders
that present with muscle weakness and typically
appear at birth or in infancy. These myopathies
have characteristic histopathologic abnormalities
on muscle biopsy. Advances in molecular genetics
have allowed classification of congenital myo-
pathies into nemaline myopathy, myotubular
www.co-pediatrics.com 339
 Pulmonology
myopathy, centronuclear myopathy, central core
myopathy, multiminicore myopathy, congenital
fiber-type disproportion myopathy, and hyaline
body myopathy [60].
Pediatric patients with any form of myopathy
may frequently require dental and surgical pro-
cedures. These procedures may be delayed or fore-
gone because of anesthetic risks of malignant
hyperthermia, cardiomyopathy, and decreased
pulmonary function [61–63]. However, there is
little or no data on outcomes for nonscoliosis
surgeries. Research has shown that surgical correc-
tion for scoliosis and kyphoscoliosis may be success-
fully performed with careful assessment and
preparation [64,65].
Duchenne and Becker muscular dystrophy
The most common, well known, and severe myo-
pathy affecting respiratory function is DMD. Becker
muscular dystrophy is considered a late-onset form
of X-linked muscular dystrophy [1]. DMD has an
estimated birth prevalence of 1 : 3300 and Becker
1 : 18000. Of all the pediatric NMD disorders, the
most clinical and research investment has been in
the identification, treatment and management of
DMD since it was first described in the 1800s [1].
However, racial, ethnic, and socioeconomic dis-
parities exist in the diagnostic process for Duchenne
and Becker muscular dystrophy. Black and Hispanic
children are initially evaluated at older ages than
white children, and the disparity increases at later
steps in the diagnostic process [66]. Even after
diagnosis, clinical heterogeneity and phenotypic
variability exist which may dictate both clinical
and research considerations [67].
As has been stated previously, scoliosis manage-
ment is an intricate component of DMD patient
care. Surgical intervention studies demonstrate
both positive and negative short-term and long-
term results. Patients and caregivers have reported
postoperative satisfaction because of perceived
improved function, sitting balance, and quality of
life [68].
Retrospective reviews show that surgical
treatment is associated with declines in forced vital
capacity (FVC) independent of other treatment
variables, and that subsequent pulmonary and car-
diac function decline are not significantly improved
[69].
Steroids have been shown to temporarily
decrease muscle weakness progression and enhance
function and have become a mainstay treatment
for DMD. As patients with DMD often require
scoliosis repair, there is data to suggest steroid treat-
ment decelerates scoliosis curvature and may delay
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the time to spinal surgery. However, patients on
steroids were also more likely to require cataract
surgery [70].
Respiratory clinical practice guidelines for DMD
have been established since 2004 [29]. However,
many questions regarding respiratory management
remain.
Reliable, reproducible, simple, and cost-effective
markers still need to be identified as surrogates
for respiratory compromise. Possible candidates
include measurements of volume variations of
rib cage and abdominal compartments; various
lung function parameters including ratios of
tidal volume, vital capacity, respiratory rate, total
lung capacity (TLC), forced expiratory volume in
one second [FEV(1)], maximal inspiratory pressure
(Pimax); the average contribution of abdominal
volume change in relation to tidal volume; and
nocturnal hypoventilation with normocapnia
during daytime [71–75].
Of the therapeutic options currently available,
studies demonstrate the positive influence of non-
invasive mechanical ventilation, assisted coughing,
and cardioprotective medications [76]. Early dias-
tolic dysfunction and focal fibrosis in patients with
DMD proceed to dilated cardiomyopathy, compli-
cated by heart failure and arrhythmia. The specific
mechanisms resulting in heart failure in patients with
DMD are poorly understood. Current treatments are
not targeted to DMD-associated cardiomyopathy,
but rely on approaches that are considered standard
for dilated cardiomyopathy. These approaches
include angiotensin-converting enzyme inhibitors
and b-adrenoceptor antagonists [6].
The combination treatment of steroids with
bisphosphonates seems to be associated with signifi-
cantly improved survival compared with treatment
with steroids alone [77]. The most exciting potential
treatments are molecular therapeutic approaches
currently under investigation in both in vitro and
clinical trials: gene replacement therapy, mutation
suppression, and exon skipping [78].
Spinal muscular atrophy
SMA is caused by degeneration of anterior horn
cells of the spinal cord, which leads to progressive
muscle weakness. The incidence of SMA is 1 : 15 000
live births. The clinical classification of SMA is based
on age at onset and maximum function achieved.
The three classic forms are type I, who will never be
able to sit without support and usually die by the age
of 2 years, type II, who do not develop the ability
to walk without support and have a shortened life
expectancy, and type III, who develop the ability to
walk and have a normal life expectancy [1].
Volume 24  Number 3  June 2012

Several studies have validated the use of a
protocol that includes bi-level positive airway
pressure, mechanically assisted coughing, oxygen,
and suctioning to improve morbidity and mortality
in patients with SMA. This protocol can be used
by trained caregivers for children with SMA type I
under 3 years of age to avoid episodes of acute
respiratory failure and hospitalization and increase
survival time [8,79]. Feeding and swallowing
difficulties cause respiratory compromise in SMA
type I as well as failure-to-thrive and aspiration
pneumonia in type II and type III [80]. Laparoscopic
gastrostomy tube placement coupled with Nissen
fundoplication and noninvasive positive pressure
ventilation can be successfully used as a treatment
option to optimize quality of life in type I and severe
type II SMA patients [81].
The decision to undergo surgical correction
of scoliosis in patients with SMA is difficult because
of concerns of pulmonary failure as a direct
consequence of surgery. Recent studies show that
the placement of growing rod instrumentation
improves trunk height and the space-available-for-
lung ratio, while controlling curve and pelvic
obliquity in patients with SMA with severe scoliosis.
However, surgical correction does not halt rib
collapse. In addition, correction of scoliosis in
patients with SMA was associated with improve-
ment in self-image [82,83].
Several interventional therapeutic trials were
completed in 2011 to study the effect on disease
progression of SMA type I, II, and III, and safety
of drug treatments. Unfortunately, no study to date
has demonstrated a benefit in improving strength
or function in SMA [84–88]. However, there are
ongoing studies in gene replacement therapy and
stem cell transplant [88].
CONCLUSION
This review on NMD provides a current clinically
focused summary of the various NMD disorders.
The advances in molecular technology have sub-
stantially increased clinical and research investi-
gation in NMD disorders, leading to improved
diagnosis and possible new targets of therapy. This
summary demonstrates that current clinical care
must be focused on the basics of a multidisciplinary,
clinical, standard-of-care approach.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
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Neuromuscular disease and the pulmonologist Yuan
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