Pulmonary Assessment and Management of Patients with Pediatric Neuromuscular Disease

Pulmonary Assessment and Management of Patients with Pediatric Neuromuscular Disease covers the broad medical problems and specific pulmonary conditions in patients with pediatric neuromuscular disease, ranging from the different types of neuromuscular disease, their pathophysiology, and assessment and management, including both novel disease modifying pharmacotherapies and state-of-the-art clinical management. This book provides evidence-based guidance for pediatric patients with neuromuscular disease, and is a valuable resource to pediatric pulmonologists, critical care physicians, and respiratory therapists who want an update and understanding on the cutting-edge therapies and standards of care for managing this population.

• Provides a single comprehensive source of information to properly guide pulmonary assessments of pediatric neuromuscular disease
• Discusses recent advancements in both medications and clinical respiratory management for pediatric patients
• Covers different types of neuromuscular disease, including spinal muscular atrophy, Duchenne muscular dystrophy, congenital muscular dystrophy, and more

• Language: English
• Publisher: Academic Press
• Release date: Apr 13, 2023
• ISBN: 9780323957489

Book preview

Preface

Pediatric-onset progressive neuromuscular disease has long been characterized and tracked by the inexorable progression toward respiratory insufficiency and related symptoms due to impaired airway clearance and respiratory failure. Through much of the last 70 years from the poliomyelitis epidemic of the 1950s through the introduction of true disease-modifying therapies in recent years, there have been many advances in the recognition and treatment of respiratory morbidity with a substantial impact on survival (Dubowitz, 2015; Eagle et al., 2007). There have been a number of seminal standard-of-care publications over the last two decades that have put some consistency both to the type of care needed and thankfully the need to be proactive and critical in introducing it (Birnkrant et al., 2018; Finder et al., 2004; Finkel et al., 2018; Hull et al., 2012).

As respiratory surveillance and introducing clinical support of airway clearance and ventilation in neuromuscular disease have become more widely offered, with the new reality of disease-modifying therapies that can substantially change the severity and timing of the onset of respiratory symptoms, modern clinical management of patients with neuromuscular disease needs to be dynamic. This new paradigm involves not only a deep understanding of disease and progression and when to introduce clinical support, but also when to consider weaning or discontinuing that support based on potentially improved clinical status.

Pulmonary Assessment and Management of Patients with Pediatric Neuromuscular Disease was written with the joint purpose of being a resource for the reader to learn about standard pulmonary management in patients with neuromuscular disease and a look toward the future in how the clinical standards of care in place now have changed and can change further over time. Each chapter has been matched with a recognized expert in the field to provide a high-quality and current approach to the spectrum of treatment options in neuromuscular disease. I hope you find this a useful resource for many years to come.

Oscar Henry Mayer, MD, Division of Pulmonology, Medical Director, Pulmonary Function Testing Laboratory, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States, Professor of Clinical Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

References

Birnkrant D.J. Diagnosis and management of Duchenne muscular dystrophy, part 2: Respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurology. 2018;17(4):347–361.

Dubowitz V. Unnatural natural history of Duchenne muscular dystrophy. Neuromuscular Disorders. 2015;25(12):936.

Eagle M. Managing Duchenne muscular dystrophy—The additive effect of spinal surgery and home nocturnal ventilation in improving survival. Neuromuscular Disorders. 2007;17(6):470–475.

Finder J.D. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. American Journal of Respiratory and Critical Care Medicine. 2004;170(4):456–465.

Finkel R.S. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscular Disorders. 2018;28(3):197–207.

Hull J. British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax. 2012;67(Suppl 1):i1–40.

Section 1

Introduction

Chapter 1: Types of neuromuscular disease

John F. Brandsema; Susan E. Matesanz    Division of Neurology, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States

Abstract

Neuromuscular disorders in childhood affect anterior horn cells, peripheral nerves, neuromuscular junction, or muscle; broadly, they can be categorized into genetic vs. acquired etiologies. Most have a progressive neurodegenerative course, with an optimal standard of care involving several disciplines to ensure the multisystemic complications are treated to minimize the impact on quality of life. Some acquired disorders and an increasing number of genetic disorders are treatable with targeted therapies, further increasing the importance of early diagnosis and interv

Keywords

Motor neuron disease; Neuropathy; Myopathy; Myasthenia

Introduction

Neuromuscular disorders in childhood can affect any of the branches of the peripheral nervous system (PNS). The PNS can be broken down into the following component parts: (1) anterior horn cell, (2) peripheral nerves, (3) neuromuscular junction, and (4) muscle cell. Localization of symptoms and signs to the corresponding area of the PNS is a key aspect of accurate neurologic diagnosis. Examples of relatively common pathologies localizing to each component of the PNS can be found in Table 1.1. Most pediatric neuromuscular disorders have a progressive neurodegenerative course, sometimes after a motor developmental delay and then a plateau phase before the decline phase, with optimal standard of care involving several disciplines to ensure the multisystemic complications are treated to minimize impact on quality of life. Broadly, pediatric neuromuscular disorders can be categorized into genetic vs. acquired etiologies—this chapter will discuss some of the more prevalent examples of both, with a focus on those who have pulmonary involvement in their most severe forms. Some acquired disorders and an increasing number of genetic disorders are also now treatable with targeted therapies, further increasing the importance of early diagnosis and intervention.

Table 1.1

Genetic neuromuscular disease

Spinal muscular atrophy

The most common inherited anterior horn disorder is SMA, with an incidence of approximately 1 in 10,000 live births. SMA is characterized by progressive flaccid weakness, atrophy, and diminished/absent reflexes, along with bulbar and respiratory insufficiency in the more severe forms; the most common form in about 2/3 of cases is unfortunately the most severe with infantile onset and has a natural history of never achieving the motor milestone of sitting and death by age 2 years unless feeding is supplemented and breathing is mechanically supported. 5q SMA results from homozygous deletions in about 96% of affected individuals, with the remainder having other mutations of the survival motor neuron 1 (SMN1) gene located on the long arm of chromosome 5. In humans, the SMN gene is present in two homolog genes, SMN1 and SMN2, formed from an inverted duplication. One of a handful of nucleotide changes that differentiate SMN2 from SMN1 creates an exon splicing site (ESS) in SMN2 leading to suppression of transcription of exon 7 the majority of the time, thus creating less functional SMN protein than its SMN1 counterpart (roughly 10%–20% of the levels of expression). People carry a varying number of SMN2 copies typically ranging from 0 (10%–15% of the population) to 4 (or more) copies; a genotype-phenotype correlation exists with increasing SMN2 copies signifying a less severe disease course, although exceptions to this correlation do occur (Darras, Markowitz, Monani, & De Vivo, 2015).

New genetically targeted treatments have led to a transformative impact on the disease course since the first, nusinersen, was approved in the United States in 2016. Both SMN1 and SMN2 expressions have been targeted, and currently in clinic discussions that were once primarily of a palliative nature are focused rather on potential for at minimum disease stabilization and often improved function in the majority with treatment.

Nusinersen is an antisense oligonucleotide (ASO), created to bind to SMN2 premessenger ribonucleic acid (RNA) (Finkel, Mercuri, Darras, et al., 2017). Nusinersen stabilizes transcription via increased inclusion of exon 7, leading to increased SMN protein production. It is administered intrathecally via repeated lumbar puncture and requires 4 loading doses over 2 months, followed by maintenance dosing every 4 months throughout the patient’s lifetime. Rare side effects include thrombocytopenia, coagulation abnormalities, and renal toxicity, which are monitored via laboratory work at each dose (Mercuri, Muntoni, Baranello, et al., 2021). Obtaining intrathecal access can be challenging in patients with severe scoliosis, especially with prior spinal fusion, and risks of lumbar puncture-related complications over time and also repetitive exposure to sedation for those who require it are additional factors to consider related to tolerability. A double-blinded, placebo-controlled, phase 3 study showed that nusinersen improved the event-free survival in SMA type 1 patients, defined as death or permanent assisted ventilation (Finkel et al., 2017). The initial trial data, now further supplemented by information from longer open label studies, as well as subsequent studies in phenotypically milder and later-onset patients, have shown significant functional improvement compared with placebo and/or natural history (Mercuri, Darras, Chiriboga, et al., 2018). Some infants who received early treatment have shown near-normal development (De Vivo, Topaloglu, Swoboda, et al., 2019). Real-world data has also shown promise in patient groups unlike those studied in the research trials (Hagenacker, Wurster, Günther, et al., 2020).

In mid-2020, risdiplam, an oral/gastrostomy tube administered selective SMN2 splicing modifier designed to modulate splicing of SMN2 to increase production of functional SMN protein, was approved in the United States for all SMA patients over 2 months of age. Given its mode of administration, risdiplam is taken up by both nervous system and systemic tissues; whether SMN repletion in peripheral tissues is of clinical significance is a subject of ongoing research. Data in an infantile-onset SMA cohort after 12 months of treatment showed that 1/3 were able to sit without support for at least 5 s, a milestone not attained in this disorder, and roughly twice the survival without permanent ventilation compared with a natural history cohort (Baranello, Darras, Day, et al., 2021). Additional trials in phenotypically milder and presymptomatic populations are accumulating data via several research protocols. This small molecule therapy has been well-tolerated in research trials although effects on male fertility and teratogenicity in pregnant females were described in preclinical studies, with no data yet available in humans. Effects of nonadherence to daily dosing in the context of interrupted supply or noncompliance or poor oral tolerance such as during viral gastrointestinal illnesses are also unclear at this time.

SMA is the first disease with an approved systemic in vivo gene therapy in the United States. Available since 2019, onasemnogene abeparvovec-xioi is a gene transfer therapy administered via an adeno-associated virus (AAV)-9 vector to patients under 2 years of age; in Europe, approval is up to 21 kg in weight. A transgene that manufactures SMN is in the genomic cassette, administered as a one-time intravenous infusion (Mendell, Al-Zaidy, Shell, et al., 2017). Side effects include thrombocytopenia, thrombotic microangiopathy, elevated troponin-I, and elevated aminotransferases (Mendell et al., 2017). To help mitigate some of the patient’s immune-based response to the viral load, concomitant oral daily steroids are given for at least a month and followed by a 4 week taper if safe to do so. Patients are required to have a baseline anti-AAV9 antibody titer of ≤1:50 prior to administration. Phase 3 open label data from the STR1VE study treating infantile-onset SMA patients with two copies of SMN2 showed 13 of 22 patients were independently sitting at 18 months of age, as well as improvements in other markers of motor, respiratory, and bulbar function (Mercuri et al., 2021). Ongoing trials are looking at benefit for those dosed at older ages with intrathecal gene transfer delivery; preclinical concerns for dorsal root ganglion toxicity led to a clinical hold on one study.

Real-world data on short- and long-term impact of all three approved SMA treatments continue to be collected. Combination therapy also is a reality, with research trials such as JEWELFISH accumulating data about risdiplam added after prior gene transfer treatment in a subset of subjects, and the RESPOND trial studying nusinersen after gene transfer; such data will be critical for evaluating the efficacy and tolerability of combination treatment, informing the ethical and economic considerations of access to these high-cost treatments across the spectrum of SMA severity.

It is likely that eventually a cocktail approach will be tailored with optimized timing of intervention to the individual SMA patient, based on genotype and age of diagnosis as well as symptom burden; this would ideally be informed by novel biomarkers of severity. Prenatal therapies are also under study. Given that both prenatal carrier screening and newborn screening focus on deletions of SMN1, silent carriers who are 2 + 0 SMN1 and the approximately 5% of 5q SMA diagnoses due to other genetic changes such as point mutations in SMN1 will be missed by screening and continue to present symptomatically, requiring urgent diagnosis and referral for treatment initiation. It is also important to include the large population living with symptomatic SMA in considerations for treatment approaches.

Charcot-Marie-tooth disease and other inherited neuropathies

Charcot-Marie-tooth disease (CMT) encompasses several hereditary motor-sensory neuropathies (HMSNs) and is one of the most common inherited neuromuscular diseases: estimated prevalence varies from 10 to 82 per 100,000 in different reports (Barreto, Oliveira, Nunes, et al., 2016). There are many rarer inherited neuropathies secondary to genetic and metabolic conditions, most of which may have pulmonary manifestations in their most severe forms.

CMT is often classified into autosomal dominant demyelinating (CMT1) and axonal (CMT2) forms, as well as autosomal recessive (CMT4) and X-linked forms. Most are slowly progressive and present in childhood or adulthood with primarily distal extremity weakness ± sensory loss. A severe infantile-onset phenotype is often referred to as Dejerine-Sottas syndrome and can have pulmonary involvement that is the cause of early death in the most severe cases.

Pulmonary manifestations are rare in CMT but if present are typically slowly progressive or static and include restrictive pulmonary impairment, sleep apnea, restless legs, and vocal cord dysfunction (Aboussouan, Lewis, & Shy, 2007). Restrictive pulmonary impairment has been described in association with phrenic nerve dysfunction, diaphragm dysfunction, or thoracic cage abnormalities. Vocal cord dysfunction, possibly due to laryngeal nerve involvement, is found in association with several CMT types and can often mimic asthma. Care for CMT is supportive at present; research trials are active in neurotropic and symptomatic medications as well as gene replacement and gene silencing.

Hereditary brachial plexopathy, also known as hereditary neuralgic amyotrophy, is a rare autosomal dominant disorder characterized by recurrent, painful brachial plexopathies, which can include the phrenic nerve and have incomplete recovery after flares. The condition is caused by pathogenic variants in the SEPT9 gene on chromosome 17q25. Characteristic somatic features include short stature, hypotelorism, a small face, unusual skin folds, and creases on the neck. Reported triggering events include physical exertion, anesthesia, surgery, pregnancy, and childbirth; attacks have been reported to be ameliorated/prevented in predictable triggers, such as planned surgery, with prophylactic steroid treatment (Van Eijk & Van Alfen, 2013).

Hereditary neuropathy with liability to pressure palsy (HNPP; tomaculous neuropathy), a recurrent, episodic demyelinating neuropathy, is an autosomal dominant disorder associated with PMP22 deletions and single nucleotide variant. Affected patients typically present with isolated nerve palsies in areas frequently affected by compression or mild trauma. Symptoms first appear in the second decade in most patients, but they can occur in younger children or be delayed until into the third decade. Brachial plexopathies and phrenic nerve involvement can be seen but are rare. Single nerve palsies typically appear sequentially, resolving in days to months and may be associated with persistent motor deficits in various nerve distributions (Potulska-Chromik, Sinkiewicz-Darol, Ryniewicz, et al., 2014).

Duchenne and Becker muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe X-linked neurodegenerative disorder that is the most common muscular dystrophy of childhood, affecting about 1 in 3500 male births (Darras, Menache-Starobinski, Hinton, & Kunkel, 2015). Natural history includes typical milestones such as loss of ambulation before age 13 years, progressive scoliosis with onset in school age, development of detectable and progressive cardiomyopathy in the late first or early second decade of life, need for pulmonary interventions related to chronic respiratory failure by teenage years, and death in the late second or early third decade of life (Darras, Menache-Starobinski, et al., 2015). Cognition does not decline but a significant proportion of patients may have cognitive symptoms ranging from behavioral issues such as anxiety or attention deficit disorder to more severe cognitive impairment and autism spectrum disorder. There are also milder forms of dystrophinopathy such as the Becker form defined by ambulation beyond age 16 years, which typically does not have pulmonary involvement until adulthood if at all (Darras, Menache-Starobinski, et al., 2015).

Before 2016, therapeutic options included optimized interdisciplinary supportive care as well as corticosteroids, the combination of which may increase lifespan into the fourth or rarely fifth decade of life for a larger proportion of patients. The typical impact is around 1–3 years of slower disease milestones in those treated with steroids, but this comes with a host of iatrogenic comorbidities, most prominently increased risk for behavioral issues, linear growth suppression, and obesity in younger patients and eventually poorer bone health with risk for cataracts in older patients (Mendell, Goemans, Lowes, et al., 2016). Options include prednisone/prednisolone versus deflazacort; the ideal steroid type and schedule are still not firmly established as dose reductions due to side effects or family preference, alternative dosing schedules (e.g., daily, weekend-only, 10 days on, and 10 days off), and heterogeneity in the disease phenotype among patients make even matched cohort comparisons have limitations (Chrzanowski & Poudyal, 2018).

The conditional approval of eteplirsen by the FDA in 2016 marked the first Duchenne-targeted therapy to receive a label in the United States. An antisense oligonucleotide (ASO) targeting skipping of exon 51, approximately 14% of DMD patients have an amenable mutation in dystrophin that may benefit from this approach (Bladen, Salgado, Monges, et al., 2015). The approval was based primarily on data from a phase IIb randomized-controlled clinical trial in 12 boys, 2 of whom lost ambulation soon after enrollment suggesting a more severe phenotype, treated for 24 weeks followed by an open label extension (Mendell, Rodino-Klapac, Sahenk, et al., 2013). Further evidence for efficacy in long-term follow-up was generated in comparison with a historical cohort (Mendell et al., 2016). The debate related to this approval hinged on surrogate marker data showing slightly increased dystrophin expression in muscle biopsies; among experts, the quantity and quality of dystrophin expression needed for clinically meaningful benefit remains ambiguous and is continuing to be studied (Charleston, Schnell, Dworzak, et al., 2018; Kesselheim & Avorn, 2016). Tolerability in the trial was similar to what has been seen in clinic since the 2016 approval, with minimal side effect burden—the trial reported rare side effects of balance disorder, vomiting, and contact dermatitis; renal monitoring is recommended in the context of ASO use (Mendell et al., 2013). Further studies have been ongoing with sparse additional data presented in peer-reviewed publications through 2022, although an effect on slowing pulmonary decline has been shown (Khan, Eliopoulos, Han, et al., 2019).

In December 2019, golodirsen achieved conditional approval to treat 53 skip-amenable patients, an additional 8% of the Duchenne population (Bladen et al., 2015), based primarily again on dystrophin expression data from muscle biopsies in a clinical trial. This was followed by approval of viltolarsen, also targeting 53 skip-amenable patients and subsequently casimersen for 45 skip-amenable patients; currently, approximately 25%–30% of DMD patients are eligible for exon-skipping treatments. Challenges regarding administration of exon-skipping therapies to DMD patients in clinic include the need for a weekly intravenous infusion, requiring central line (port) insertion in patients with challenging peripheral access—common in people living with weakness and especially those who are nonambulatory. With exon-skipping, the concept is one of slower decline; this is challenging to prove in an individual as their course without the intervention may not be clear at the time the medication is started.

As the size of the dystrophin gene precludes gene transfer with existing viral vector technology, several programs are underway, with data cuts being presented in 2021 and 2022, utilizing tailor-made micro-/mini-dystrophins incorporating the regions felt to be the most critical for function of DMD protein within the muscle fiber (Shieh, 2018). CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (CRISPR/Cas9)-mediated genome editing in mdx mice has been shown to partially restore dystrophin protein expression in cardiac and skeletal muscle; clinical development programs are on the horizon at time of writing; short- and long-term safety including potential for off-target effects will be closely monitored.

Myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by a triplet repeat expansion of the CTG sequence in the 3′ untranslated region of the DMPK gene on chromosome 19. Those with >50 triplet repeats develop disease, but there is a broad range of clinical phenotypes, correlating with the length of the repeat expansion. Anticipation often occurs when the disease is maternally inherited, with an expanded number of repeats present in the child. Individuals with >500 repeats can present with childhood onset of congenital DM1, with >1000 repeats typically presenting as the more severe congenital onset form (Johnson, 2019). The expanded repeat sequence leads to unstable RNA and abnormal protein splicing and affects many proteins throughout the body, leading to widespread multiorgan system involvement (Johnson, 2019; López-Martínez, Soblechero-Martín, De-La-puente-ovejero, Nogales-Gadea, & Arechavala-Gomeza, 2020). Prevalence has been estimated at approximately 1 in 8000 (Norwood et al., 2009; Siciliano, Manca, Gennarelli, et al., 2001), with a recent study estimating prevalence as high as 1 in 2100 in the United States (Johnson, Butterfield, Mayne, et al., 2021). Classically, the disease presents with myotonia, distal weakness, and cataracts, but a broad range of other symptoms are associated with the disease, including early baldness, cardiac conduction abnormalities, sleep apnea, learning difficulties, and endocrine disturbances (Johnson, 2019). In the congenital form, patients present with significant hypotonia, respiratory failure, feeding difficulties, and clubfoot/other musculoskeletal deformities. These children often have significant intellectual impairment and gastrointestinal problems (Johnson, 2019). The morbidity of respiratory failure in those with congenital DM1 is significant; one study showed that infants who required ventilation for >30 days had a 25% mortality in the first year of life (Campbell, Sherlock, Jacob, & Blayney,