Sleep and neuromuscular disorders in children

Sleep Medicine Reviews (2009) 13, 133e148

www.elsevier.com/locate/smrv

CLINICAL REVIEW

Sleep and neuromuscular disorders in children Rosana S.C. Alves a,*, Maria B.D. Resende a, Robert P. Skomro b, Fabio J.F.B. Souza a, Umbertina C. Reed a a

Department of Neurology, University of Sa~o Paulo Medical School, HCeFMUSP, Sa~o Paulo, SP, Brazil Division of Respirology, University of Saskatchewan, Ellis Hall, Royal University Hospital, Saskatoon, Saskatchewan, Canada b

KEYWORDS Sleep in children; Neuromuscular disorders; Sleep disorders; Sleep-related hypoventilation

Summary Children suffering from neuromuscular diseases are at an increased risk of sleep-related breathing disorders (SRBD) such as obstructive sleep apnea syndrome (OSAS) and hypoventilation as well as central sleep apnea, which is frequent in these patients due to diaphragmatic weakness. They are at higher risk for developing complications of nocturnal hypoxemia, including pulmonary hypertension, cor pulmonale and neurocognitive dysfunction. Neuromuscular disorders and OSAS are both prevalent disorders and frequently overlap. Sleep-related hypoventilation/hypoxemia due to neuromuscular diseases may be exacerbated in the presence of OSAS; these children are likely to experience greater severity and duration of sleep-related hypoxemia than are children with either disorder alone. Additionally, some of these children have reduced central neural chemoresponsiveness. The development of SRBD in these patients further impairs their quality of life and worsens their respiratory status. We review the literature on the diagnosis and treatment of SRBD in children with a variety of neuromuscular disorders. ª 2008 Elsevier Ltd. All rights reserved.

Introduction Children with sleep-related hypoventilation and hypoxemia due to neuromuscular disorders are at risk for developing complications of nocturnal

* Corresponding author. Address: Rua Capote Valente 231, CEP ~o Paulo, SP, Brazil. Tel.: þ55 11 7646 2532; fax: 05409-000, Sa þ55 11 3061 2661. E-mail address: [email protected] (R.S.C. Alves).

hypoxemia, including pulmonary artery hypertension, cor pulmonale and neurocognitive dysfunction. Neuromuscular disorders and sleep apnea (obstructive or central apneas) are both prevalent disorders and frequently overlap. Sleep-related hypoventilation/hypoxemia due to neuromuscular diseases may be exacerbated in the presence of obstructive sleep apnea syndrome (OSAS). Additionally, some of these children have reduced central neural chemoresponsiveness. Thus, these children are likely to experience greater severity

1087-0792/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2008.02.002

134 Nomenclature AHI BiPAP CFTD CMD CPAP DMD EEG FEV1 FVC FSMD

apnea-hypopnea index bilevel positive airway pressure congenital fiber- type disproportion congenital muscular dystrophy continuous positive airway pressure Duchenne muscular dystrophy electroencephalogram forced expiratory volume in 1 second forced vital capacity fascioscapulohumeral muscular dystrophy fR respiratory frequency ICSD 2 International Classification of Sleep Disorders-2005

and duration of sleep-related hypoxemia than are children with either disorder alone. In this review we will focus specifically on diagnosis and treatment of sleep-related breathing disorders (SRBD) in children with neuromuscular disorders; other sleep disorders which may also be present in this population such as insomnia or narcolepsy will not be discussed.

Overview The onset of sleep is associated with a diminished responsiveness of the respiratory center to chemical and mechanical inputs, and with a major reduction in the stimulant effects of cortical inputs. Ventilatory responsiveness to both hypoxia and hypercapnia is diminished. Furthermore, responsiveness of the respiratory muscles to respiratory center outputs is also diminished during sleep, particularly during rapid eye movement (REM) sleep. The diaphragm is less affected than the accessory muscles in this respect during nonrapid eye movement (NREM) sleep, when breathing is remarkably regular both in amplitude and frequency. There is a decrease in minute ventilation (V0 E) during NREM sleep, predominantly due to a reduction in tidal volume (VT), which is associated with a rise in end-tidal carbon dioxide tension (PETCO2). Part of this hypoventilation during sleep is likely to be a response to the lower metabolic rate, since oxygen consumption and carbon dioxide production diminish during sleep compared to wakefulness. During REM sleep, both VT and respiratory frequency (f R) are much more variable than in NREM sleep, particularly during phasic REM sleep,

R.S.C. Alves et al. LGMD limb-girdle muscular dystrophy NIPPV noninvasive intermittent positive pressure ventilation NIV noninvasive ventilation NREM nonrapid eye movement OSAS obstructive sleep apnea syndrome PImax maximal inspiratory pressure PSG polysomnography REM rapid eye movement oxygen saturation SaO2 SMAs Spinal muscular atrophy SRBD sleep-related breathing disorders V‘E minute ventilation VT tidal volume

characterized by bursts of REM, as opposed to tonic REM sleep, where eye movements tend to be absent. Phasic REM activity may have an influence distinct from that encountered in general REM sleep. Upper airway resistance increases during sleep compared to wakefulness, which predisposes to upper airway occlusion and obstructive sleep apnea (OSA) in susceptible individuals. The loss of stimulant input from the cerebral cortex is an important contributor to the hypoventilation of sleep described above, but in addition, during REM sleep, there is a marked loss of tonic activity in the tongue, pharyngeal, laryngeal, and intercostal muscles. There appears to be supraspinal inhibition of g-motoneurons (and to a lesser extent amotoneurons), in addition to presynaptic inhibition of afferent terminals from muscle spindles. The diaphragm, being driven almost entirely by amotoneurons and with far fewer spindles than intercostal muscles, has little tonic (postural) activity and, therefore, escapes reduction of this particular drive during REM sleep. This helps to explain the increase in abdominal contribution to breathing in REM sleep. Neuromuscular disorders, particularly Duchenne muscular dystrophy (DMD), other types of muscular dystrophies and spinal muscular atrophies (SMAs), are associated with hypoventilation, which becomes more severe as the disease progresses, particularly during sleep. DMD is associated with respiratory insufficiency due to progressive respiratory muscles degeneration leading to respiratory failure, which is the major cause of death in this condition, although cardiomyopathy due to degeneration of cardiac muscle is also a common finding. The deterioration in awake blood gas values has been found in several reports to parallel

Sleep and neuromuscular disorders in children the decline in lung function as measured by spirometry and maximum inspiratory pressures, although other reports have not shown such a relationship. Although DMD is a progressive and ultimately fatal condition, patients with the disease can be kept alive for many years by appropriate modalities of assisted ventilation, once respiratory failure has developed. Sleep-related hypoxemia in muscular dystrophy is predominantly found in REM sleep, because of the loss of accessory muscle contribution to breathing in the setting of diaphragmatic weakness. REM-related desaturation is also frequently associated with recurring apnea and hypopnea. These apneas are most commonly central in nature, but obstructive apnea could develop if upper airway muscle contraction is impaired. Traditional noninvasive methods of distinguishing obstructive from central apneas in this condition may be inadequate because of the reduced respiratory effort associated with muscle weakness, and it is possible that some apparently central apneas are obstructive in origin, but appear central because of poor respiratory effort. Coexisting OSA is particularly likely in obese patients, and in patients with associated macroglossia, which is seen in DMD1 or in patients with craniofacial abnormalities such as in myotonic dystrophy (Steinert’s disease). Diagnostic sleep studies may be necessary to characterize the etiology of sleep related hypoxemia, depending on the clinical features. Sleep may have major adverse effects on gas exchange in patients with respiratory insufficiency. These effects relate largely to a reduction in various excitatory inputs to the brainstem respiratory center. Conditions that may be associated with sleep-related respiratory insufficiency range from pulmonary disorders to central respiratory insufficiency (such as central alveolar hypoventilation), neurological and neuromuscular disorders (such as muscular dystrophy and SMA), and thoracic cage disorders (such as kyphoscoliosis). All these conditions have in common the finding of hypoxemia and hypercapnia, which become more pronounced during sleep. The relative hypoventilation, which is common to each condition, is due to varying combinations of an inadequate respiratory drive and an increase in the work of breathing. Most children with neuromuscular disease eventually require assistance with airway clearance and with breathing, especially during sleep.2 Nocturnal sleep-related ventilatory alterations may occur in disproportion to the severity of the neuromuscular disorder. Failure to thrive,

135 daytime tiredness, and incapacitating fatigue may be the result of a correctable sleep-related abnormality, not the result of a progression of the neuromuscular disorder.3 Progressive ventilatory restriction in neuromuscular diseases correlates with respiratory muscle weakness and results in progressive sleep-disordered breathing which, by pattern and severity, can be predicted from daytime lung and respiratory muscle function.4

Neuromuscular disorders Sleep-disordered breathing is common in children with a wide variety of neuromuscular disorders, and may be observed at the time when muscle weakness is still mild, and diurnal respiratory dysfunction is not evident. The child may manifest diverse, often isolated, symptoms such as excessive daytime sleepiness, tiredness and fatigue, failure to thrive, complaints of insomnia and bad sleep quality, morning headaches, changes of mood, attention deficit, and learning difficulties as well as hypoxia-induced nocturnal seizures. Polycythemia, hypertension, and signs of heart failure may also be seen.5 To prevent these complications, nocturnal symptoms such as air hunger, intermittent snoring or breathing, orthopnea, cyanosis, restlessness, and insomnia must be recognized early. The impairment of respiratory muscles may occur in different neuromuscular disorders, particularly in those that share a progressive deterioration to a nonambulatory stage. Regardless of the pathogenesis of each of these conditions sleep-related breathing disorders may occur especially in REM sleep. Since 1990 the utilization of nocturnal noninvasive intermittent positive pressure ventilation (NIPPV) has increased, decreasing the need for invasive procedure such as tracheostomy and mechanical ventilation. The utilization of nocturnal polysomnograms was facilitated by the use of portable equipment and the simplicity of bilevel positive airway pressure (BiPAP) delivered by nasal mask.6 Since 2000, many reviews concerning sleep and neuromuscular disorders have been published,7e16 but most consider adult patients only. The treatment of respiratory failure with NIPPV in children with neuromuscular disease leads to an improvement of symptoms, quality of life, and reduction in hospitalizations and health care costs.17 Panitch2 emphasized that the physiological differences and small size of infants and young

136 children with neuromuscular disease require special consideration concerning the procedures of airway clearance and noninvasive ventilation (NIV). In this age group, the appropriate time to begin airway clearance assistance and to introduce NIV that can preserve or enhance lung growth and chest wall mobility must be better discussed and defined. Due to the high prevalence of DMD and SMA among children with neuromuscular disorders, many studies are specifically directed at these two disorders.18e21 Beside these two common neuromuscular disorders, nocturnal respiratory failure may occur in patients with other types of muscular dystrophies such as limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSMD), and congenital muscular dystrophy (CMD), as well as in patients with myasthenia gravis, myotonic dystrophy, congenital myopathies, metabolic myopathies, and hereditary sensorymotor polyneuropathies. Most of these conditions manifest phenotypical variability with different degrees of clinical severity and progression, which must be considered when deciding on the most appropriate time for initiating mechanical ventilation. A greater clinical severity is generally associated with scoliosis, sedentariness, early wheel-chair dependence, and obesity, which can contribute to a worsening of respiratory function during sleep. In addition, craniofacial dysmorphism, prominent in certain neuromuscular diseases, may increase the risk of nocturnal sleeprelated ventilatory disorders. The World Muscle Society adopts a classification of the neuromuscular disorders based on genetic data. Its official journal ‘‘Neuromuscular Disorders’’ includes periodically a printed format of the gene table (established in 1991) and an online gene table which is available at http://194.167.35.195: 3000/. In the printed or in the online version there are 16 categories of diseases: 1. muscular dystrophies, 2. congenital muscular dystrophies, 3. congenital myopathies, 4. distal myopathies, 5. other myopathies, 6. myotonic syndromes, 7. ion channel muscle diseases, 8. malignant hyperthermias, 9. metabolic myopathies, 10. hereditary cardiomyopathies, 11. congenital myasthenic syndromes, 12. SMAs, 13. hereditary ataxias, 14. hereditary motor and sensory neuropathies,

R.S.C. Alves et al. 15. hereditary paraplegias, and 16. other neuromuscular disorders.

Progressive muscular dystrophies Duchenne muscular dystrophy DMD is an X-linked form of muscular dystrophy caused by mutation in the gene encoding dystrophin that leads to a progressive degeneration of muscles and, in approximately 90% of the patients, to myocardium involvement.22 The clinical manifestations are apparent between three and four years of age, wheelchair dependence usually occurs by the age of 12 years; after the introduction of the palliative steroid therapy the median age for the loss of ambulation has increased by two years but the prognosis depends also on the respiratory care offered to these boys. Before implementation of ventilatory support death was usually caused by respiratory failure. Currently, heart failure is becoming the leading cause of death.23,24 Over the last 15 years, the improvement in ventilatory support methods has highlighted the importance of an adequate treatment of the cardiac symptoms in an attempt to improve the survival of DMD patients.25,26 Signs of early respiratory insufficiency are usually first detectable in sleep, so the importance of the polysomnography for assessing sleep hypoventilation must be emphasized.27 In general, sleep-disordered breathing is evident when forced vital capacity (FVC) declines to <65% of predicted value. Therefore, most specialists consider this value for recommending annual monitoring of sleep-disordered breathing. Despite the high incidence of sleep-disordered breathing in boys with DMD, the optimal timing and the methodology for such testing has not been established. The determination of the parameters of daytime lung function in patients with DMD may provide a clue to the presence of sleep hypoventilation. In children who are able to cooperate, (i.e. from five years of age), lung volumes, maximal inspiratory and expiratory pressures, arterial blood gases, and polysomnography must be considered. In patients with nocturnal hypoventilation the development of daytime hypercapnia is expected within two years of the progressive course; it is recommended that nocturnal NIV be introduced before daytime hypercapnia ensues.28 DMD is associated with a gradual loss of muscle function over time. Loss of respiratory muscle strength, with ensuing ineffective cough and decreased ventilation, leads to pneumonia, atelectasis, and respiratory insufficiency in sleep and

Sleep and neuromuscular disorders in children while awake. These complications are generally preventable with careful serial assessment of respiratory function. Respiratory evaluation of individuals with DMD includes a thorough history and physical examination, measurement of pulmonary function, and evaluation for sleepdisordered breathing. Measurement of respiratory function and respiratory muscle strength allow the clinician to predict who will require assisted coughing and ventilation. Various levels of impairment of pulmonary function and gas exchange have been reported to be associated with an increased risk of respiratory complications and death. Although the optimal frequency of physician follow-up of DMD patients is unknown, in our Institution we recommend that our patients visit a pediatric respirologist twice a year after confinement to a wheelchair, after a fall in vital capacity below 80% of the predicted and/or after the age of 10 years. After 7 years of age we also recommend that all patients have FVC and respiratory muscle strength measured (PI/PEmax) twice a year. All patients with DMD should undergo pulmonary and cardiac evaluations before surgeries and should receive the pneumococcal vaccine and an annual influenza vaccination. Objective evaluation at each clinic visit should include: oxyhemoglobin saturation by pulse oximetry, spirometric measurements of FVC, FEV1, and maximal mid-expiratory flow rate, maximum inspiratory and expiratory pressures, and peak cough flow. Peak cough flows correlate directly with the ability to clear secretions from the respiratory tract, and values below 160 L/min have been associated with ineffective airway clearance. Additional measures of pulmonary function and gas exchange, including lung volumes, and maximum inspiratory capacity may be useful. Carbon dioxide tension with the patient awake should be evaluated at least annually in conjunction with spirometry. Where available, capnography is good for this purpose, but is limited by the alveoloarterial gradient. Transcutaneous CO2 measurement may also be used. If capnography is not available, then a venous or capillary blood sample should be obtained to assess for the presence of alveolar hypoventilation. These patients should also be evaluated for evidence of other respiratory disorders, such as OSA and central apnea, oropharyngeal aspiration, gastroesophageal reflux, and asthma. Annual laboratory studies in patients should include a complete blood count, serum bicarbonate concentration, and a chest radiograph. Quality of life judgments should be made with the informed participation of the patient and his

137 family, and long-term mechanical ventilation should be considered even when the treating physician predicts that quality of life on long-term ventilation will be poor. As respiratory failure in DMD can occur either suddenly, in association with a respiratory tract infection, or gradually, education about ventilatory and palliative options should be provided before either of these scenarios occurs. The patient’s and family’s views on quality of life should be sought. The care team should involve a nutritionist who can facilitate maintenance of ideal body weight, because both obesity (which can lead to OSA) and malnutrition are detrimental to respiratory health. Malnutrition and obesity appear to be equally common in young adults with DMD, each occurring in about 44% of individuals. Systemic steroid therapy also has nutritional implications, with potentially increased risks of osteoporosis and obesity, necessitating dietary manipulation. Evaluation for dysfunctional swallowing should be performed if there is a history of choking or dysphagia. Video-fluoroscopy may be used to confirm the presence of aspiration, and to assist the clinician in prescribing safer swallowing techniques. DMD is associated with sleep-disordered breathing and alveolar hypoventilation. Onset of respiratory insufficiency can be subtle. Symptoms of sleep hypoventilation include gradually increasing numbers of nocturnal awakenings, daytime sleepiness, morning headache, and, rarely, vomiting. Patients with DMD are also at risk for upper airway obstruction. The timing of polysomnography to detect sleep hypoventilation has not been determined in patients with DMD. In one study, sleep hypoventilation correlated with an awake PaCO2 of >45 mmHg and a base excess >4 mmol/L. Another study suggested that an unattended sleep study in the home could identify sleep-disordered breathing in patients with DMD, who did not undergo polysomnography. Simple oximetry at home can be a useful screen for sleeprelated oxyhemoglobin desaturation. Impaired ventilatory drive is a possible mechanism for respiratory failure in these patients, as the NIVassociated decrease in awake PaCO2 occurs despite a further decline in ventilatory capacity, suggesting continuing deterioration in respiratory muscle function.20 The prevalence of SRBD in DMD is significant. There is a bimodal presentation of SRBD, with OSA found in the first decade and hypoventilation more commonly seen at the beginning of the second decade.27 Annual evaluation for sleep-disordered breathing should be performed in patients with

138 DMD starting from the time they are wheelchair users and/or when clinically indicated. The annual repetition of polysomnography with continuous CO2 monitoring is ideal where available. In areas where full polysomnography is not readily available, overnight pulse oximetry with continuous CO2 monitoring provides useful information about nighttime gas exchange, although sleep-disordered breathing not associated with desaturation or CO2 retention will not be detected. A simple capillary blood gas upon arousal in the morning can demonstrate CO2 retention, although not as sensitively as continuous capnography. Cardiac involvement is almost universal in patients with DMD, with 10e20% of individuals dying of cardiac failure. Dilated cardiomyopathy primarily involves the left ventricle, and can lead to dyspnea and other symptoms of congestive heart failure, evolving to central apnea. Conversely, right ventricular failure can result from respiratory failure and pulmonary hypertension. Patients with DMD have increased risk for sleepdisordered breathing, including hypopnea, central and obstructive apnea, and hypoxemia. Treatment of these pulmonary complications with noninvasive ventilatory support may improve quality of life and reduce the high morbidity and early mortality associated with DMD. These patients can evolve to a state of hypoventilation and may require 24-h ventilatory support. Daytime ventilation should be considered when awake PCO2 exceeds 50 mmHg or when hemoglobin saturation remains <92% while awake. Mechanical ventilation is usually initiated through NIV, tracheostomy is rarely indicated. The advantages of a tracheostomy are a more secure ventilatorepatient interface, the ability to provide higher ventilator pressures in patients with intrinsic lung disease or severe reductions in chest wall compliance (for example, secondary to scoliosis), and the ability to perform direct airway suctioning during respiratory infections. However, tracheostomy has many potential complications, including generating more secretions, impairing swallowing and increasing the risk of aspiration, bypassing of airway defenses, likely increasing the risk of infection. There is also a risk of airway occlusion by a mucus plug. Traditionally, tracheostomy also impairs oral communication. For many patients, communication may be restored using a relatively small tracheostomy tube allowing a ‘‘leak’’ around the airway, and a speaking valve. Loss of ventilator tidal volume due to a leak can be compensated by increasing the tidal volume. Many patients are concerned about the cosmetic and

R.S.C. Alves et al. potential communication implications of tracheostomy, and this needs to be addressed with sensitivity during discussions about continuous ventilation. Although the above reports support a role for mechanical ventilation in patients with established or impending respiratory failure, there are no data to support a preventive role for mechanical ventilation. In a multicenter, prospective, controlled trial, patients with DMD who were normocapneic with FVCs between 20% and 50% of predicted were randomized to receive either six or more hours of nocturnal NIV or no ventilatory support.29 Although 15 of the 35 patients receiving NIPPV did not adhere to the protocol, survival was significantly decreased in the group receiving ‘‘preventive’’ nasal ventilation. This caused the authors to conclude that NIPPV for preventive purposes should be avoided in patients with DMD, and to speculate that a false sense of security with less diligent monitoring was associated with the use of NIPPV and was responsible for the increased death rate among users in the study. Imbalance between load and capacity of the respiratory muscles may lead to fatigue and respiratory failure, which is the most important cause of death in these patients. The inspiratory muscle training in patients with DMD can improve function parameters significantly after one month of training. Further improvements were seen after three and six months. Even six months after the end of training, those effects were sustained. The specific inspiratory muscle training is useful principally in the early stage of DMD. Among the other muscular dystrophies, like Becker, LGMD, and FSMD, respiratory failure is not common, and generally occurs in the more severe cases that have progressed to wheel-chair dependence.

Limb-girdle muscular dystrophy (LGMD) LGMD are highly heterogeneous both clinically and genetically. Many forms have childhood onset30 and may have an unfavorable severe course resembling DMD therefore presenting with the same types of sleep-disorder breathing. Most of the severe LGMD beginning in the first decade of life have an autosomal recessive type of inheritance. The following forms are the most frequent: LGMD type 2E that is caused by mutation in the gene on 4q12 encoding beta-sarcoglycan; LGMD type 2I that is caused by mutation in the gene encoding fukutin-related protein (FKRP); LGMD type 2C, also known as Duchenne-like muscular

Sleep and neuromuscular disorders in children dystrophy, that is caused by mutation in the gamma-sarcoglycan gene; LGMD type 2F, that is caused by mutation in the delta-sarcoglycan gene.

Facioscapulohumeral muscular dystrophy (FSMD) FSMD is an autosomal dominant progressive myopathy, characteristically associated with a 4q35 deletion.31 FSMD begins in late childhood or adolescence and has a slowly progressive course leading to variable disability only late in adulthood. However, in some families a severe infantile form of the disorder can be identified even in descendents of minimally affected parent. Infantile FSMD is rare, amounting to less than 10% of FSMD patients. The onset may be at birth or in infancy and all children manifest severe weakness and progressive clinical course leading to respiratory failure and even death in adolescence. Therefore, the prognosis of infantile FSMD may be as devastating as that of DMD and of the severe forms of LGMD. Coats’ retinopathy, mental retardation, and possible epilepsy can accompany the muscular involvement.32 The infantile-onset form of the disease may also present with sensorineural hearing loss, whereas in patients with typical lateonset FSMD hearing loss is not more prevalent than in the normal population.33

Emery-Dreifuss Emery-Dreifuss muscular dystrophy is a rare disorder characterized by childhood onset of contractures, humeroperoneal muscle atrophy, and cardiac conduction abnormalities. The onset of the disease is usually between the ages 5 and 15 years. The clinical findings consist of slowly progressive muscle weakness and atrophy, especially in the humeroperoneal region; muscle contractures, especially in the neck, elbows, and ankles; and cardiac conduction abnormalities. The patients and carriers are at risk of sudden death due to cardiac arrhythmias.

139 During the last 13 years the characterization and classification of many different forms of CMD have been established on the basis of their specific molecular and phenotypic aspects.34,35 Other clinical phenotypes remain to be identified but among those described practically all may have a severe course that leads to progressive muscular atrophy, chest deformities and respiratory failure, often accompanied by prominent scoliosis. Except for Walker-Warburg syndrome that is lethal, the patients with any of the other subtypes may be considered for evaluation and treatment of sleepdisordered breathing by means of oximetry periodic polysomnographic records, and nocturnal ventilatory support. In our experience, in patients with merosin-deficient CMD, Ullrich CMD, and rigid spine CMD the vigilance for early detecting and treating sleep-breathing disorders is crucial. In patients with merosin-deficient CMD, the associated facial dysmorphism can be an additional factor of risk. The reports on CMD 1C have recently become more common. The clinical severity of this subtype of CMD clearly deserves a continuous vigilance for sleepdisordered breathing. In one report among patients with CMD, none acquired independent ambulation and most had facial weakness, wasting of the shoulder girdle and hypertrophy of the lower limb muscles.36 In spite of the high prevalence (0.7/100 000) the literature focusing specifically the sleep-breathing disorders in CMD is scarce.37 Kryger et al.38 reported two sisters with CMD in whom central sleep apnea resulted in the isolated symptom of nocturnal seizures in one, and morning headaches in the other. Kahn et al.39 reported good results of supportive ventilatory treatment in eight ambulant children aged 6e13 years, four with congenital myopathy, two with CMD and two with the rigid spine syndrome. In conclusion CMD has a heterogeneous clinical course, which is at least moderate in most patients. Therefore, any patient must be carefully evaluated with the aim of early detecting and treating sleep-disordered breathing even in the absence of marked weakness or diurnal respiratory dysfunction.

Congenital muscular dystrophies Myotonic dystrophy (Steinert disease) The term CMD refers to a genetically and clinically heterogeneous group of autosomal recessive disorders that begin in the perinatal period or during the first year of life and is characterized by congenital hypotonia and slowly progressive muscle weakness. The muscular involvement may be isolated or included within a spectrum of central nervous system and eye involvement.

The autosomal dominant myotonic dystrophy (Steinert disease) is the most common form of muscular dystrophy in adults. The amplification of a trinucleotide repeat in an untranslated region of the protein kinase gene at 19q13.2 is the genetic defect that causes the disease whose clinical severity depends on the number of repeats.40

140 In patients with myotonic dystrophy the excessive daytime somnolence is common and may be present even before the deterioration of the respiratory muscles, suggesting a central nervous system involvement. Thalamic and hypothalamic dysfunctions have been associated with hypersomnia, apathy, mental slowness and behavioral changes. At least 13 of the patients have SRBD and some of them continue with daytime somnolence even after the adequate treatment of their sleepdisordered breathing.41 The addition of stimulant medication such as modafinil in these patients can offer a better symptom control.42 In childhood-onset myotonic dystrophy type 1 daytime somnolence and learning disabilities occur in most patients and must be evaluated by polysomnography to look for sleep apnea syndrome and/or periodic limb movement, which are present in 23 of this population.43 The congenital form of myotonic dystrophy is classically related to a maternal transmission and shows the greatest number of repeats. Polyhydramnios and reduced fetal movements are frequently reported by the mother. Facial diplegia and dysmorphic craniomandibular structures contribute to increase of the respiratory difficulty, which can be fatal. After a troubled neonatal period the babies who survive have a stable course and a mild motor delay but more than 50% have speech difficulties, learning disabilities, or mental retardation. By the second decade of life they develop characteristic myotonia and systemic organ involvement described in the childhood and adult-onset disease. As in the noncongenital form the amount of SRBD depends on the degree of thoracic muscles weakness and the abnormal craniofacial features which may lead to an increase in upper airway resistance in sleep. Mixed central and obstructive apneas have been reported in cases of congenital myotonic dystrophy.44

Spinal muscular atrophy SMA, due to recessive mutations in the survival motor neuron gene 1 (SMN1), is the second most common neuromuscular disorder in children with a frequency of 8 per 100 000 live births. SMA is characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. According to the age of onset it is classified into four subtypes from I to IV. Type I or Werdnig-Hoffman disease has onset at birth or during the first months of life and a severe course resulting in inability to sit without support. Type II or infantile/intermediate form has onset during the second semester of life and a severe

R.S.C. Alves et al. course: the affected children maintain the ability of sitting without support but remain nonwalkers for life. Type III or juvenile form (Wohlfart-Kugelberg-Welander disease) has onset from the second year of life typically after that the child has achieved independent walking; the course is greatly heterogeneous and the affected children may or not maintain the ability of walking without support. Type IV or adult-onset clinical form is also clinically hetrogeneous. In children with SMA who present with sleep disorders and hypercapnia, somnolence, morning headaches, and attention deficit during daytime, the initiation of NIV enhances the quality of life and normalizes sleep architecture.45 The management of restrictive lung disease, the most common and most serious complication in SMA, is focused on the utilization of NIV, on the awareness of the importance of identifying sleep-disordered breathing, and on the need to standardize a multidisciplinary approach to care. The optimal settings for the introduction of NIV have not been clearly established.46 This is particularly evident in patients under five years of age, who are not able to collaborate with spirometry and have to be referred for annual polysomnography and overnight oximetry which in some centers are not easily available. According to a recent consensus statement in nonsitters and sittersc NIV can be used palliatively even for short daytime periods to reduce work of breathing and to improve chest wall as well as lung development and pulmonary function, therefore, reducing ribcage and sternal deformity. In walkers NIV may be required during the day at the time of a respiratory infection and during sleep chronically. The need of a consensus statement for standard of care in SMA has increased recently due to the continuous advances in the field of possible therapeutic strategies. For some patients the decision to use NIPPV to prolong survival may represent an ethical dilemma. In situations where NIV does not extend survival, however, it may have a role in palliating symptoms and allowing the child to be cared for at home.47 In children with SMA sleep-disordered breathing may cause impairment of sleep and well being. Children affected by types I and II SMA have significantly higher apneaehypopnea indices than normal children. Thoracoabdominal asynchrony is present during the inspiratory and expiratory phases in both quiet and active sleep. Measures of c The terms sitters and nonsitters are related to the functional mobility status of the motor ability: the patient can be nonsitter, sitter, or walker.

Sleep and neuromuscular disorders in children thoracoabdominal coordination may be useful in the evaluation and monitoring of therapeutic interventions for these patients.48

Congenital myasthenic syndromes The congenital myasthenic syndromes represent a group of highly heterogeneous disorders that can be classified into presynaptic, synaptic, or postsynaptic according to the site of the transmission defect. Many different molecular and electrophysiological mechanisms have been proposed and different clinical phenotypes have been described.49 The manifestations can be severe from birth with weak cry, congenital hypotonia, generalized weakness and a feeble suck, or can combine in various degrees ptosis of the eyelids, ophthalmoparesis, easy fatigability, and proximal pattern of muscle weakness. In many patients the muscle weakness is restricted to ptosis while others may manifest a variable course with weakness and respiratory distress precipitated by respiratory infections. The presence of sleep hypoventilation syndrome even in children with no obvious changes in muscle strength or lung function tests has been reported. Therefore, polysomnographic evaluation and noninvasive positive pressure ventilation may be indicated even in the absence of abnormal daytime muscle function.

Congenital myopathies The congenital myopathies are clinically and genetically heterogeneous. The structural congenital myopathies such as nemaline, myotubular/centronuclear and protein aggregate myopathies are more predisposed to sleep-disordered breathing, because of the amount of muscle weakness, common involvement of the facial, bulbar, and respiratory muscle, facial dysmorphism and scoliosis. However, the nonstructural types such as congenital fiber-type disproportion (CFTD) may also be associated with sleep-disordered breathing. Nemaline myopathy has great genetic heterogeneity; so far seven different genes have been described with mutations in the nebulin gene (NEM2) being the most common.50 Independently of the gene involved the clinical manifestations range from a severe form of the disorder with marked hypotonia, weakness, feeding and respiratory troubles at birth to the most classical and benign form presenting at birth or during infancy with different degrees of hypotonia and muscle

141 weakness and a variable course. Late-childhood or adult onset can occur. Prognosis is dictated by the degree of scoliosis and restrictive lung disease. Sasaki et al.51 described four patients with nemaline myopathy, one with the severe infantile form and three with the benign congenital (classical) form, who exhibited significant respiratory problems. The three patients with the benign infantile form suddenly developed respiratory failure while still ambulant. The authors emphasized that careful monitoring of the respiratory status is recommended in patients with nemaline myopathy who may manifest a discrepancy between clinical motor weakness and respiratory involvement. Myotubular myopathy is also clinically and genetically heterogeneous. The X-linked form, with prenatal/neonatal onset, is particularly severe with most of patients surviving only with careful monitoring and ventilatory support. The autosomal forms are highly variable in relation to the age of onset and the clinical features. The weakness can be generalized or predominantly proximal; facial as well as the ocular muscles may also be involved. The occurrence of respiratory failure depends on the degree of disease progression. Protein aggregate myopathies are classified according to the morphologic phenomenon of aggregation of proteins within muscle fibers and according to mutations in proteins. Onset may occur at birth, at various stages of childhood or in adulthood. Some patients are severely floppy and rapidly progress to respiratory distress that requires ventilation. Others show a typical limb-girdle mild or moderate involvement and may present with ophthalmoplegia and cardiomyopathy. Like the other types of congenital myopathies already described, CFTD myopathy is a clinical and genetically heterogeneous disorder. In most cases, the clinical phenotype resembles limb girdle muscular involvement but some children may have generalized muscle weakness or a severe floppy infant phenotype with respiratory distress. Severe respiratory involvement occurs in about 15 of patients. Although most cases do not have a molecular definition, two distinct subtypes have already been associated with CFTD: one is caused by mutations of the actin gene52 and the other is an X-linked subtype.53 In the two subtypes, all the affected children except one have severe weakness, muscle hypotonia and respiratory failure from birth but only the latter subtype is associated with ophthalmoplegia. Other less common neuromuscular disorders in children which also may present with sleep-disordered breathing include: metabolic myopathies, such as mitochondrial myopathy and glycogen

142 storage disease, and inherited peripheral motorsensory neuropathies.54 Within the group of metabolic myopathies, Pompe disease (maltase acid deficiency) has recently received special attention because of therapeutic advances. Acid maltase is a lysosomal enzyme present in all tissues, which hydrolyses maltose to yield glucose. Glycogen storage disease II is a rare autosomal recessive disorder, caused by mutation in the gene encoding acid alpha-1,4glucosidase. The classic infantile form (Pompe disease) has a severe course with cardiomyopathy, marked hypotonia and enlarged tongue; the juvenile and adult forms are associated with variable degrees of severity including wheelchair or ventilator dependency. Replacement enzyme therapy has been shown to improve survival and quality of life but its high cost precludes a widespread utilization. Sleep-disordered breathing and respiratory failure can occur at different stages of the disease and require early intervention by means of NIV.55 It is therefore important to detect the disease soon since treatment with enzyme replacement can be offered. Respiratory symptoms in maltase acid deficiency can be one of the first clinical manifestations. In contrast to other neuromuscular diseases, diaphragm weakness with sleep disordered breathing frequently precedes global muscle weakness. Physicians treating this population should be aware that patients with Pompe disease may present with fatal central sleep apneas as well as hypoventilation.

Diagnostic-evaluation According to the International Classification of Sleep Disorders-2005 (ICSD-2), in the section sleeprelated breathing disorders,56 neuromuscular disorders are cited as ‘‘sleep related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders’’ and the diagnostic criteria are: (A) A neuromuscular or chest wall disorder is present and believed to be the primary cause of hypoxemia. (B) Polysomnography or sleeping arterial blood gas determination shows at least one of the following: (i) An SpO2 during sleep of less than 90% for more than 5 min with a nadir of at least 85%. (ii) More than 30% of total sleep time at an SpO2 of less than 90%. (iii) Sleeping arterial blood gas with PaCO2 that is abnormally high or disproportionately

R.S.C. Alves et al. increased relative to levels during wakefulness. (C) The disorder is not better explained by another current sleep disorder, another medical or neurological disorder, medication use or substance use disorder.

Polysomnography Diagnosis of obstructive, central, mixed apneas, hypopneas, and hypoventilation is best made using polysomnography.57 In one polysomnographic study of neuromuscular patients the following sleeprelated respiratory disturbances were observed: decrease in oxygen saturation (SaO2), cardiac arrhythmias, sleep disruption, apneas, tachypnea, tachycardia, and snoring. These patients presented with pulmonary restriction and thoracic deformities, some with tachypnea and/or hypoxemia. Snoring was observed in muscular dystrophy patients while tachypnea was observed in patients who had desaturations. Sleep architecture revealed an increase of stage 1 sleep coupled with a decrease or absence of REM sleep.58 In a recent study of adults with neuromuscular disease, sleep macrostructure was normal. The number of respiratory arousals per hour of sleep was above the upper limit observed in a control group (>2.1) in 71% of the patients. Nadir SaO2 <85% was the most common finding and was present in 80% of the patients. Noninvasive blood gas monitoring identified all but two patients with sleep-related respiratory abnormalities. The respiratory arousal index correlated with the oxygen desaturation index, but otherwise there were no significant correlations between sleep and nocturnal respiratory parameters. Vital capacity significantly correlated with AHI and daytime base excess with nadir oxygen saturation. Inspiratory activity in accessory respiratory muscles was present during REM sleep and/or slow wave sleep in 70% of the patients.59 Investigation of patients with neuromuscular diseases with a simple pulse oximeter during sleep may not be sufficient as an arousal response can be triggered much before a drop in SaO2 of 3% or more is seen. This arousal response will induce sleep fragmentation. Ambulatory monitoring may also miss this problem as few of these monitor EEG. When should polysomnography be performed? 1. Overnight polysomnography should be performed in all neuromuscular patients as early as possible as a baseline recording, and

Sleep and neuromuscular disorders in children

143

repeated depending on the course of the neuromuscular disease. 2. Polysomnography should be repeated periodically after treatment initiation to evaluate the effects of therapy (see Figure 1). 3. Follow-up polysomnography can allow detection and correction of poor treatment efficacy, which is generally due either to asynchrony between the patient and the ventilator (this is particularly true in patients receiving NIPPV, who are not yet entirely dependent on the ventilator) and/or to the occurrence of mouth leaks, which may induce sleep fragmentation. Bourke and Gibson60 emphasize the need for performing polysomnography in neuromuscular patients both before and after treatment. Early polysomnography ensures early detection of the criteria for NIPPV, such as episodes of nocturnal hypoxemia and hypercapnia. Polysomnography is valuable in ensuring adequate sleep and ventilation during NIPPV and after tracheostomy.61

Treatment The use of respirators in children started after the epidemic of poliomyelitis. Historically, after the end

of the Second World War and in 1950s, the poliomyelitis epidemic occurring in the western countries provided extraordinary challenges to the development of effective methods of ventilatory support for patients with neuromuscular disorders. West, in 2005, emphasized these aspects in a review of the 1952 Copenhagen poliomyelitis epidemic.62 Nowadays benefits of NIV on quality of life and survival in children with chronic neuromuscular disorders are well established, and have recently been documented even in patients with daytime normocapnia. Management of respiratory insufficiency during sleep should be directed first at optimizing the underlying disorder. Pharmacological therapy may be effective in some instances, but the choice of agent varies with the underlying disorder. Assisted ventilation is an important part of the management of advanced cases, and the recent development of NIPPV by nasal mask has been an important advance in this area. Use of nighttime NIPPV is associated with beneficial daytime effects: an improvement in awake gas exchange, respiratory muscle strength, dyspnea, and quality of life. Electrophrenic pacing of the diaphragm is helpful in highly selected cases, particularly patients with central respiratory insufficiency and high quadriplegia, but is frequently complicated by the development of OSA.63

Clinical evaluation PFT review ESS Capnography or gasometry Nocturnal PSG

PSG

Mean SaO2 < 92 and/or RDI >10

Normal

Repeat PSG in 1 year

Clinical visit every 3 months

Titration NIPPV

Clinical visit to adaptation and review NIPPV

Figure 1 Suggested approach to the child with neuromuscular disorder. PFT: pulmonary function tests; NIPPV: noninvasive positive pressure ventilation; ESS: Epworth Sleep Scale; PSG: polysomnography; RDI: Respiratory Disturbance Index.

144 Nocturnal nasal intermittent positive pressure ventilation is typically administered using BiPAP generator or volume-cycled ventilator and has been used successfully in the treatment of sleep-disordered breathing and nighttime hypoventilation in patients with DMD and other neuromuscular disorders. The level of positive pressure required to eliminate obstructive apneas or hypopneas and normalize ventilation should be determined in the sleep laboratory or with careful bedsides monitoring and observation. Serial evaluation and adjustment of NIPPV are necessary, as the patient’s requirements change with time. Nocturnal NIPPV in DMD has resulted in improved survival, well being, sleep quality, daytime gas exchange, decreased daytime sleepiness, and a slower rate of decline in pulmonary function compared with nonventilated controls. Complications of nasal intermittent positive pressure ventilation include eye irritation, conjunctivitis, skin ulceration, gastric distention, and emesis into a full-face mask. Facial complications can be avoided by regular follow-up to assess mask fit. Nasal steroids or humidification of the delivered air can help relieve nasal obstruction. Serious complications of NIPPV are not common. There has been a single case report of recurrent pneumothorax in a 26-year-old man with a nonDMD on nasal intermittent positive pressure ventilation who had subpleural blebs. In fragile patients, mask displacement can rapidly lead to severe hypoxemia and hypercapnia. Because most bilevel machines do not have built-in alarms, additional monitoring, such as pulse oximetry, is useful in this setting. There are four factors that may precipitate respiratory failure and the need for mechanical ventilation. First, upper-airway compromise due to weakness of the facial, oropharyngeal, and laryngeal muscles can interfere with swallowing and secretion clearance, placing the patient at risk for aspiration. In addition, weakness of those muscles may result in mechanical obstruction of the upper airway, particularly in the supine position. Second, weakness of the muscles of inspiration results in inadequate lung expansion, with microatelectasis, leading to ventilation/perfusion mismatch and consequent hypoxemia. Compensatory tachypnea exacerbates the atelectasis, which reduces the compliance of the respiratory system and increases the mechanical load on already weakened respiratory muscles. Third, expiratory muscle weakness prevents adequate cough and secretion clearance, increasing the risk of aspiration and pneumonia. Finally, acute complications of the illness, such as pneumonia or pulmonary

R.S.C. Alves et al. embolism, may further increase the ventilatory demands on an already failing respiratory system. The role of continuous positive airway pressure (CPAP) as a first line treatment in neuromuscular patients needs clarification. The distinction between the different causes of apneas during sleep should have been made at the diagnostic phase, before treatment is considered. If an upper airway occlusion during sleep is suspected in a neuromuscular patient, nasal CPAP may be helpful. But most commonly in neuromuscular patients, especially the DMD patients, where the thoracoabdominal impairment during sleep is the primary defect, nasal CPAP is ineffective. In cases of hypoxemia due solely or partially to hypoventilation, support with BiPAP or a volume ventilator should be considered. As hypoxemia in DMD is usually a manifestation of hypoventilation, treatment with oxygen without concurrent supplemental ventilatory support should be avoided. Negative pressure ventilators can lead to upper airway obstruction in patients with DMD, possibly due to the lack of synchrony between inspiration and vocal cord abduction and are rarely used. Simple oximetry provides, at best, only indirect information on ventilation, and may be used to assess need for ventilatory support only when better alternatives are unavailable. NIPPV is usually started when patients present with chronic daytime (wake) respiratory failure, when there is evidence of sleep hypoventilation, or when the illness is brought to medical attention secondary to an acute respiratory insufficiency. Bilevel positive pressure treatment delivered by nasal mask has been widely used in patients with OSA syndrome with or without hypoventilation, and in chronic obstructive pulmonary disease but may be underutilized as a treatment of patients with neuromuscular disease. Such patients commonly not only have impairment of chest bellows, which may be too weak to generate the negative pressure necessary to trigger the ventilator, but may also have an impairment of upper airway dilators. The NIPPV can be easily titrated during one night of polysomnographic recording. BiPAP has the advantages of simplicity and cost over classic volume-cycled home positive pressure ventilators. The specialist, however, must know the limits of this pressure based equipment and the type of follow-up that is necessary. The use of domiciliary nocturnal ventilation for the management of sleep-disordered breathing has had a major impact on clinical outcome of chronic respiratory failure in patients with neuromuscular or chest wall disease. The effectiveness of nocturnal ventilatory support in reversing daytime

Sleep and neuromuscular disorders in children respiratory failure and improving daytime function has been demonstrated by many groups.17,64,65 A common concern among patients and families, as well as referring medical practitioners, is that the patient may develop ventilator dependence. There is often a fear that once ventilation begins, muscle detraining and inability to be without the ventilator will leave the patient worse off, and that if the ventilator fails the patient may simply not wake up from sleep. There is no doubt that an improvement in respiratory muscle function occurred with the introduction of NIPPV, and this may explain the improvements in nocturnal gas exchange. The results from the study of Piper and Sullivan64 demonstrate that long-term nocturnal ventilation can reduce the severity of nocturnal hypoventilation. Fourteen patients with documented nocturnal respiratory failure, who had been treated with nocturnal NIPPV for at least 6 months, were reviewed with an all night polysomnograph on a night without ventilatory support. Spontaneous daytime blood gas values were significantly improved at follow-up compared to values obtained prior to nasal ventilation. Significant improvements in inspiratory muscle strength were also observed with maximal inspiratory pressure (PImax) increasing from a baseline value of 4118% to 6526% predicted (p<0.003). Spontaneous breathing during sleep after long-term treatment was markedly improved although still abnormal. During NREM sleep without ventilatory support, oxygen desaturation was significantly less severe compared to the initial study (arterial oxygen saturation (SaO2) 884% vs. 788%; p<0.001). Minimum SaO2 during REM sleep similarly improved from a mean value of 4914% during the diagnostic night to 7310% at review follow-up (p<0.001). In 12 patients, transcutaneous carbon dioxide was measured continuously during sleep on both occasions and demonstrated significantly less CO2 retention during follow-up compared to control studies both in NREM (p<0.003) and REM sleep (p<0.004). Long-term nocturnal ventilation produces improved respiratory drive both asleep and awake and improves arousal responses to abnormal blood gases.64 Previously, volume-cycled ventilation has been used successfully in neuromuscular syndromes associated with sleep-disordered breathing. BiPAP administered by nasal mask is usually less costly. This method of ventilatory support is less complicated to initiate than volume-cycled NIPPV. Undoubtedly, BiPAP given by nasal mask is not always as efficacious as traditional volume-cycled ventilation. However, for mild to moderate sleep-

145 disordered breathing this approach may be successful for several years. It has to be remembered, however, that these devices generate a maximum inspiratory pressure of 30 cm H2O and therefore may deliver lower Vt compared with volume-cycled home ventilators. The new generations of variable flow pressurecycled devices are equipped with a ‘‘rise time’’ as well as the expanded range of pressures; this functions as a rudimentary flow adjustment. Evaluation of different indices of quality of sleep while on NIPPV shows a significant improvement over time. There is a significant reduction in daytime sleepiness after treatment as measured by the Epworth sleepiness scale and multiple sleep latency test. Mellies et al. conducted a study to prospectively investigate the effects of nocturnal NIPPV in 30 children and adolescents with neuromuscular disorders. Long-term BiPAP improved or normalized mean SaO2 and PaCO2 and percent of sleep time spent in hypoxemia and hypercapnia. NIPPV improved gas exchange by increasing tidal volume, unloading respiratory muscles, and possibly by resetting respiratory center chemosensitivity. NIPPV effectively suppressed sleep-disordered breathing and improved sleep. During NIPPV respiratory disturbances and associated EEG arousals normalized, proportion of stage 1 and 2 decreased and slow wave sleep increased. Over the course of the study vital capacity decreased in five adolescents with DMD but remained stable in 25 children with other conditions. No patient died or experienced life threatening complications during 3 years of study. NIV should be recommended in children with sleep-disordered breathing when an initial trial is tolerated and symptoms improve, but it is mandatory once respiratory failure occurs.65 Ferguson and Gilmartin66 indicated that BiPAP may not always reduce hypercapnia (PaCO2). These authors found that CO2 may not be cleared adequately when using the standard exhalation device. Despite an increase in minute ventilation, a relative hypercapnia was noted due to rebreathing of exhaled gases and increased dead space. The replacement of the usual valve by a nonrebreather valve eliminated CO2 rebreathing and had no effect on the overall beneficial effect of BiPAP. This finding emphasises the need for regular follow-up of these patients with appropriate sleep recordings. Steroid therapy for DMD has had a positive influence on the natural history of the disease, with benefits on respiratory function, sleep quality and consequently an improvement in the quality of life of these patients.

146 In summary we recommend that children with neuromuscular disorders should be evaluated and followed with a multidisciplinary group, with pediatricians, pediatric neurologists, pediatric pulmonologists, sleep specialists, pediatric cardiologists, physiotherapists, orthopedic surgeons, nutritionists, psychologists, nurses, and social workers.

Practice points 1. Children with neuromuscular disease should be evaluated for SRBD since they are at risk for developing complications of nocturnal hypoxemia. 2. Clinicians caring for these patients should be aware of increased risk of OSA which may contribute to worsening of nocturnal hypoxemia. 3. The timing of such evaluation should be individualized depending on disease entity and progression, overall clinical condition, patient’s quality of life and wishes. 4. Children with neuromuscular disease should be evaluated and followed by a multidisciplinary group of health care professionals at a specialized tertiary center.

Research agenda For children with neuromuscular disease future research should focus on: 1. Development of predictors of respiratory failure in these patients. 2. Quality of life measures in children with nocturnal hypoventilation. 3. Quality of life measures in children who also have OSA and other sleep disorders.

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R.S.C. Alves et al. *65. Mellies U, Ragette R, Schwwake CD, Boehm H, Voit T, Teschler H. Long-term noninvasive ventilation in children and adolescents with neuromuscular disorders. Eur Respir J 2003;22:631e6. 66. Ferguson GT, Gilmartin M. CO2 rebreathing during BiPAP ventilatory assistance. Am J Respir Crit Care Med 1995; 151(4):1126e35.