Chronic Neuromuscular Disease
Elena Cavazzoni
Jonathan Gillis
Monique M. Ryan
KEY POINTS
Clinical Management in Intensive Care
Neuromuscular diseases (NMDs) are a common cause of significant chronic neurologic morbidity in childhood. Recent advances have improved clinical and genetic characterization of many of these conditions.
Chronic NMDs are a common cause of admission to the pediatric intensive care unit. Most acute complications of pediatric NMDs relate to respiratory insufficiency.
It is important to consider the natural history in managing children with chronic NMDs. While some disorders are progressive, inevitably causing increasing weakness and respiratory insufficiency, in many children, strength and ventilatory function stabilize (and even improve) with increasing age.Ongoing Ventilatory Support
Most children recover from their acute episode and are discharged. In some cases, however, respiratory decompensation heralds a more permanent deterioration in the child’s condition and should trigger consideration of more aggressive respiratory support in the form of noninvasive ventilation or ventilation via tracheostomy.
Supportive care of children with chronic NMDs includes physical therapy for stretching and maintenance of range of motion, optimization of upper-limb function with occupational therapy, orthopedic management of contractures and scoliosis, and monitoring of swallow and nutrition.
A case manager should be assigned to each patient early in his/her admission in order to coordinate the multidisciplinary team and provide consistent, clear, and comprehensive care.Children with chronic neuromuscular diseases (NMDs) may have recurrent admissions to the pediatric intensive care unit (PICU) and may have a disproportionate impact on use of healthcare resources. For the staff, these admissions often engender discussion about the appropriate use of intensive care support and the patient’s quality of life. Management of these patients also highlights one of the major shortcomings of contemporary PICU practice: lack of continuity in care and longterm follow-up. In managing these patients, it is critical that the intensivist works with a neuromuscular neurologist who provides up-to-date information on diagnosis, disease trajectory, and prognosis, and who is able to develop a long-term care plan with the child and family. In most instances, this neurologist will remain the primary physician or an ongoing consultant to the general pediatrician after the child’s discharge from the PICU.
OVERVIEW OF CHRONIC NEUROMUSCULAR DISEASES
Clinical Presentation and Differential Diagnosis
The presentation of chronic NMDS relates largely to their pathophysiology (Table 54.1). Diagnosis is based on clinical findings and ancillary investigations (e.g., serum creatine kinase, neurophysiology, and muscle and nerve biopsy). In this chapter, chronic NMD will be discussed under the categories of disorders primarily affecting nerves, the neuromuscular junction, or muscles.
Nerve Disorders
Spinal Muscular Atrophy
Spinal muscular atrophy type 1 (SMA 1), the most common motor neuronopathy of childhood, is a devastating disease of childhood, with an incidence of 1 in 5000 live births. SMA is caused by recessive mutations in the survival motor neuron 
gene on chromosome 5. The four clinical subtypes of SMA are defined on the basis of disease severity and progression. Infants with SMA 1 never sit unsupported, children with SMA type 2 sit but never stand, those with SMA type 3 are able to walk without assistance, and SMA type 4 is of adult onset (1). All forms of SMA have the same genetic basis. The variable rate of disease progression relates to differential expression of modifying genes.
gene on chromosome 5. The four clinical subtypes of SMA are defined on the basis of disease severity and progression. Infants with SMA 1 never sit unsupported, children with SMA type 2 sit but never stand, those with SMA type 3 are able to walk without assistance, and SMA type 4 is of adult onset (1). All forms of SMA have the same genetic basis. The variable rate of disease progression relates to differential expression of modifying genes.Children with SMA type 1 present in the first months of life with hypotonia and decreased spontaneous movement. Progressive weakness causes loss of antigravity strength and increasing difficulty in breathing and feeding. Without ventilatory support, death from chronic respiratory insufficiency before the age of 2 is virtually universal (2,3). In some cases, noninvasive ventilatory support by nasal prongs or face mask has been successful in prolonging survival into the second
decade of life (3), although others report less success (4,5). Invasive mechanical ventilation via tracheostomy does lead to long-term survival in SMA 1, and this form of support is used in Asia, Europe, and the United States (5,6,7).
decade of life (3), although others report less success (4,5). Invasive mechanical ventilation via tracheostomy does lead to long-term survival in SMA 1, and this form of support is used in Asia, Europe, and the United States (5,6,7).
TABLE 54.1 CHRONIC NEUROMUSCULAR DISORDERS OF CHILDHOOD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Congenital Neuropathies
The congenital hypomyelinating or demyelinating neuropathies generally present in the first few years of life with hypotonia, weakness, and absent deep-tendon reflexes, often in association with congenital or acquired joint contractures. Complications include respiratory insufficiency, gastroesophageal reflux, and vocal cord paresis (8). These rare disorders are most often related to dominant or recessive mutations in genes for myelin proteins and represent an extreme of the Charcot-Marie-Tooth disease spectrum. Classification into congenital hypomyelinating neuropathy, Déjerine-Sottas syndrome, or other forms of Charcot-Marie-Tooth disease is contingent on age at presentation and findings on nerve biopsy.
Neuromuscular Junction Disorders
Muscle Disorders
Congenital Myopathies
The congenital myopathies are a heterogeneous group of rare disorders defined by distinctive histochemical or ultrastructural changes in muscle (9). The number of morphologically and genetically distinct congenital myopathies has grown rapidly in recent decades (Table 54.2). Clinical severity varies widely within each form of myopathy, and marked clinical overlap with other chronic NMDs is observed. All may be associated with early-onset weakness, hypotonia and hyporeflexia, poor muscle bulk, dysmorphic features secondary to muscle weakness (e.g., pectus carinatum, scoliosis, foot deformities, high-arched palate, and elongated facies), and a distinguishing morphologic abnormality on muscle biopsy. Affected patients may present later in life with delayed motor milestones, frequent falls, or disease complications such as contractures, scoliosis, and respiratory insufficiency.
Muscle weakness in the congenital myopathies is generally static. Facial weakness is common. Distal as well as proximal weakness may be present. The respiratory muscles are usually involved, but cardiac involvement is rare (10,11). Respiratory muscle involvement in the congenital myopathies generally parallels the extent of limb weakness. Some disorders (e.g., myotubular myopathy and nemaline myopathy) may present at birth with severe hypotonia, little spontaneous movement, and respiratory insufficiency. In severely affected infants, death from respiratory insufficiency, aspiration, or pneumonia is common during the first weeks or months of life (11). However, some severely hypotonic infants survive with little residual disability (12). Increasing weakness of the axial musculature may cause spinal deformities, which can progress rapidly during periods of rapid skeletal growth, particularly adolescence. Paraspinal muscle rigidity and kyphoscoliosis frequently result in significant restriction of lung capacity and respiratory insufficiency (10).
Congenital Muscular Dystrophies
Muscle disorders include the congenital muscular dystrophies, some of which affect only muscle. Others are associated with structural abnormalities of the brain and eyes (Table 54.3). The muscular dystrophies are generally caused by genetic
abnormalities of the muscle membrane. These conditions are associated with progressive weakness, elevated serum creatine kinase, and dystrophic changes in muscle. Respiratory insufficiency is common. Some congenital muscular dystrophies are associated with a characteristic pattern of axial weakness, spinal rigidity, and early respiratory insufficiency with relative sparing of the limb muscles.
abnormalities of the muscle membrane. These conditions are associated with progressive weakness, elevated serum creatine kinase, and dystrophic changes in muscle. Respiratory insufficiency is common. Some congenital muscular dystrophies are associated with a characteristic pattern of axial weakness, spinal rigidity, and early respiratory insufficiency with relative sparing of the limb muscles.
TABLE 54.2 CONGENITAL MYOPATHIES | ||||||||||||||||||||||||||||||||||||||||
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Myotonic Dystrophy
Myotonic dystrophy is caused by an abnormal expansion of a CTG trinucleotide repeat sequence in the myotonic protein kinase gene (DMPK) at 19q13. The size of the expanded repeat sequence corresponds with the severity of peripheral and respiratory muscle weakness. Normal individuals have 5-37 repeats; 50-350 repeats are seen in childhood- and adultonset myotonic dystrophy, and infants with severe congenital myotonic dystrophy may have more than 2000 repeats. The mother is the affected parent in cases of congenital myotonic dystrophy.
Infants with congenital myotonic dystrophy have congenital contractures, generalized hypotonia, and weakness. Facial weakness causes the characteristic tented upper lip and scaphoid temporal fossae. Swallowing difficulties are common; most children require gavage feeding. Respiratory insufficiency is common in children who present in the first few weeks of life and relates to lung hypoplasia caused by reduced intrauterine breathing movements, poor intercostal muscle action, and diaphragmatic hypoplasia (13). Bulbar weakness predisposes to aspiration. Preterm birth and asphyxia may exacerbate neonatal pulmonary hypertension and failure of central respiratory control. Approximately 50% of patients with congenital myotonic dystrophy require ventilation at birth (14). Poor prognostic factors include continued requirement for ventilatory support at 30 days of age, prematurity, pulmonary hypertension, and a large number of CTG repeats (15). Children who require ventilation beyond the first month of life have a 25% mortality in their first year (15). Most survivors eventually become ambulant, with improved respiratory function with increasing age, but remain at risk of later respiratory deterioration, cardiac arrhythmia, complications of poor gastrointestinal motility, diabetes, and mental retardation (9,15).
Duchenne Muscular Dystrophy
Duchenne and Becker muscular dystrophies are related muscle disorders caused by mutations in the gene for dystrophin at Xp21. Duchenne muscular dystrophy (DMD) affects 1 in 5000 boys and is the most common muscular dystrophy of childhood. DMD usually presents between 3 and 5 years of age with an abnormal (“waddling”) gait and frequent falls. Progressive muscle weakness causes loss of independent ambulation between ages 8 and 13. Becker muscular dystrophy is less common (affecting approximately 1 in 30,000 boys), generally presents between 5 and 15 years of age, and is more slowly progressive. Long-term corticosteroid treatment slows the progression of DMD (16). Loss of ambulation is followed by the development of scoliosis and muscle contractures. Other findings in DMD include muscle pseudohypertrophy, which most commonly affects the calves, and static intellectual impairment in 30% of patients. Most young men with DMD die before the age of 30, because of respiratory insufficiency
(90%) or cardiomyopathy (10%) (17
(90%) or cardiomyopathy (10%) (17
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