Disorders of Respiratory Control and Sleep-Disordered Breathing

David Gozal and Leila Kheirandish-Gozal

While the neuronal and musculoskeletal components of the respiratory system mature postnatally, the systems governing respiratory control in general, and more specifically rhythmogenesis, must be mature and functional by birth to enable the successful transition from fetus to infant. The respiratory controllers must have the necessary components to generate a rhythm that allows gas exchange in a highly compliant chest wall and to integrate swallowing, crying, vocalization, and other behaviors with breathing. Premature infants display deficiencies of central respiratory rhythmogenesis or of activation of respiratory musculature. However, such problems are not restricted to this particular stage of life, and alterations in the control of breathing may play a role in many conditions that become apparent throughout childhood and adolescence, particularly during sleep. During sleep, the clinical manifestations of many diseases of respiratory control as well as other conditions affecting the respiratory system in general are more likely to emerge. Thus, understanding the pathogenesis of breathing problems is an important component of the clinical evaluation of any child with respiratory symptoms.

DEVELOPMENT OF RESPIRATORY CONTROL AND NORMAL FUNCTION

It has become apparent that at least in mammals, and more particularly in humans, the respiratory control system undergoes substantial maturation during the first few years of life. The progress in our understanding of the intricate neural networks of respiration has been tremendous, and the identity of several of the genes that control the development and maturation of multiple neurally controlled respiratory functions is now emerging.^1-10

THE RESPIRATORY RHYTHM GENERATOR

The presumed neural region underlying the generation of respiratory rhythmic activity has now been recognized,¹¹ and specific markers such as neurokinin and opioid receptors in these neurons have revealed that this uniquely important neural center consists of a small cluster of only 150 to 200 neurons in the brainstem region designated as pre-Bötzinger complex.¹² These relatively few rhythmically firing neurons appear both necessary and sufficient to generate most of the complex normal respiratory behaviors that we currently recognize, such as eupnea, sigh, and gasping.^13-15 Several genes, such as Phox2a, Hox paralogs, and Hox-regulating genes kreisler/mafB and Krox20, have been recently identified as important players in the embryonic generation of respiratory centers and their intrinsic connectivities.^16,17 These and probably other yet unknown genes govern the regulation of brainstem functional ontogeny.

SLEEP AND BREATHING DURING DEVELOPMENT

Respiratory activity is chaotic in nature, with nonrandom, nonlinear properties governing its moment-to-moment variability.^18,19 For example, short apneic episodes lasting less than 5 seconds are extremely common in preterm infants, and their frequency is reduced progressively with maturation. These episodes occur predominantly during REM sleep, although they may emerge during any transitional state. To understand the high probability for sleep-associated disruption of normal gas exchange in early postnatal life, it is useful to identify some of the developmental differences between the infant and the adult respiratory systems that contribute to the occurrence of infantile apnea:

• The majority of young infants can be considered as obligatory or near obligatory nasal breathers, such that any increased resistance to airflow in the nasal passages or congenital size reduction in the nasal orifices (eg, choanal atresia) may translate into major disruption of breathing and inability to sustain adequate gas exchange.

• In early postnatal life, the reflexes that originate in the upper airway (ie, laryngeal chemoreflex) are stronger and may provoke the onset of profound apnea and bradycardia. This respiratory depressant component of the laryngeal chemoreflex slowly declines with maturation.²⁰ Thus, frequent events such as gastroesophageal reflux or even swallowing can trigger this reflex, and manifest as apnea and bradycardia events in the nursery.

• Chest wall compliance is higher in infants and therefore requires dynamically active maintenance of the functional residual capacity (FRC) of the lungs. Furthermore, younger infants have barrel-shaped rib cages, which makes the rib cage contribution to tidal breathing less effective when compared to older children and adults. As a corollary of this developmental issue, situations that reduce or compromise the ability to maintain FRC (eg, REM sleep) may promote the occurrence of oxyhemoglobin desaturations, even in the absence of apnea.

• Asynchronous breathing is very common in sleeping newborns because of the discoordinated interactions between chest and abdominal respiratory muscles. It usually improves as postnatal age increases such that it is rarely present after 3 years of age.²¹

• The basal respiratory rate is much higher in the neonatal period and decreases during infancy and early childhood. Respiratory rate decreases exponentially with increasing body weight and is faster during REM sleep.

• Short apneic episodes (less than 5–10 s) are extremely common in neonates, are more frequent in REM sleep, and are mostly central (ie, absence of respiratory effort during cessation of airflow). The frequency of these events decreases with age. Obstructive and mixed apneas are also more frequently seen in preterm infants.

• Periodic breathing, defined as 3 episodes of apnea lasting longer than 3 seconds and separated by continued respiratory activity over a period of 20 seconds or less, is extremely common in preterm infants and in some full-term infants.^22,23 Generally, the frequency and duration of periodic breathing decreases over time during the first year of life. Despite initial concerns about the implications of periodic breathing, this breathing pattern is currently not considered to bear any pathological significance. However, environmental factors such as sleep state transitions, arousals, hypoxia, and hyperthermia can all enhance the probability and severity of periodic breathing in infants and can ultimately lead to significant hypoxemia and bradycardia.

• Apneas during sleep in infants are associated with a fall in heart rate, particularly during nonrapid eye movement (NREM) sleep, and the presence of hypoxemia enhances the reflex bradycardic response during apnea.

• The ability to arouse from sleep is considered one of the most important components leading to the termination of an apneic episode.²⁴ Not surprisingly, arousal deficits have been implicated in the pathophysiology of the sudden infant death syndrome. However, fewer than 10% of apneic events are terminated by an electroencephalographic arousal in infants. Autonomic arousals (ie, changes in heart rate and blood pressure) are nevertheless very frequent during the period surrounding the termination of an apneic event but are associated with vastly different autonomic responses.²⁵ Moreover, while hypercapnia is a very potent stimulus for arousal, hypoxia, and particularly rapidly developing hypoxia, is much less effective. Finally, prone position, sleep deprivation, and prenatal/postnatal exposure to cigarette smoking are all accompanied by decreased arousability in infants, thereby providing the putative link between arousal deficits and sudden infant death syndrome.

• It is important to emphasize that decreases in oxyhemoglobin saturation below 92% during sleep in the first 4 weeks of life is an extremely rare occurrence among full-term infants. Normative blood oxygen levels reach lowest levels during the first week of life and subsequently increase over the next 1 to 3 months, at which time values of 97% to 100% are the rule. Baseline values for arterial carbon dioxide tension during sleep are generally between 36 and 42 mm Hg in newborns and infants.

The implications of REM sleep on breathing are substantial; the loss of muscle tone during REM is particularly influential to the upper airway muscles and airway patency. A frequently overlooked aspect of breathing control is the close interaction of breathing and blood pressure regulation. The continuous interactions between the 2 systems can be readily recognized (eg, respiratory sinus arrhythmia), with inspiratory efforts being associated with accelerated heart rate and expiratory efforts with cardiac frequency decelerations, all of which are the result of reflex activity from pulmonary afferents and vagal outflow, with coupling between breathing and heart rate being particularly prominent during NREM sleep.²⁶ Therefore, assessment of heart rate variability can provide important information about state (REM, NREM sleep, or awake) and also about the respiratory status.

CENTRAL CHEMORECEPTORS AND THEIR DEVELOPMENT

While the concept developed to understand central chemoreception has now been revised and reformulated, it is noteworthy that hypercapnia (particularly transient changes in carbon dioxide tension above the apneic threshold) will also activate the peripheral chemoreceptors and accounts for up to one third of peripheral chemoreceptor activity. Activation of either central or peripheral chemoreflexes exerts powerful effects on sympathetic activity in both health and disease and may be an important contributor to pathophysiology of sleep apnea.

In marked contradistinction with classic theory, neurons exhibiting intrinsic chemosensitive properties (ie, the ability to sense changes in extracellular pH and to contribute to the ventilatory response) are diffusely located in the central nervous system. Indeed, brain regions such as the posterior hypothalamus, cerebellum, locus ceruleus, raphe, and multiple nuclei within the brainstem are all contributors to the hypercapnic ventilatory response.^27-29 The immediate clinical relevance and importance of these discoveries resides in the fact that the severity of a condition such as central alveolar hypoventilation, particularly when occurring secondarily to other disorders (eg, myelomeningocele, tumors, stroke), cannot be adequately explained by either the location or the magnitude of the brain lesions in these patients.

As with other respiratory control functions, central CO₂ chemosensory mechanisms are not fully functional or mature at birth. For example, exogenous hypercapnic challenges will elicit a relatively sustained ventilatory increase in term infants that is almost entirely due to an increase in tidal volume without consistent change in respiratory frequency. In contrast, the ventilatory response to hypercapnia in premature infants is attenuated and can even become inhibitory at higher concentrations of inhaled CO₂, with the ventilatory increase being characterized by progressive increases in expiratory duration and consequent reductions in frequency over time, both of which appear to be associated with diaphragmatic recruitment during expiration (respiratory braking or grunting). This unique response aims to preserve a high end-expiratory lung volume, such as to optimize gas exchange and promote respiratory stability. Of note, prepubertal children also exhibit enhanced ventilatory responses to hypercapnia when compared to adults, perhaps due to differences in weight-adjusted metabolic rates.³² Similarly, significant developmental differences in CO₂ responses are present when the CO₂ stimulus is presented in either a step (sudden increase) or ramp (slow progressive increase) fashion.³³ These findings in older children indicate that during transition from infancy to childhood and on to adulthood, major changes occur in the relative contributions and integration of peripheral and central chemoreceptor inputs.

PERIPHERAL CHEMOREFLEXES

The ventilatory responses related to changes in blood oxygen levels represent complex interactions between peripheral and central components. However, peripheral chemoreceptors are uniquely positioned to sense rapid changes in blood oxygenation changes, and activation of these peripherally located chemosensory cells (ie, glomus cells within the carotid bodies), leads to a fast, transient increase in minute ventilation after inhalation of gases containing low concentrations of oxygen. Several strategies to measure peripheral chemoreceptor function have been developed and include progressive isocapnic hypoxic responses (over a period of 2–3 min), sudden 5 tidal breaths of pure nitrogen,^34-36 or assessment of the ventilatory decline following inhalation of 100% oxygen (Dejours test).³⁷ However, these tests may be quite variable over time.

THE UPPER AIRWAY

UPPER AIRWAY CONTROL

Snoring and obstructive sleep apnea (OSA) represent opposite ends of a severity spectrum associated with increased upper airway resistance. Some basic principles are enumerated and should provide the conceptual framework of this important function. The upper airway consists of the nose, pharynx, larynx, and extrathoracic trachea and is designed for the multiple functions of vocalization, ingestion, airway protection, and respiration. Maintenance of a rigid and patent upper airway is therefore mandatory for achieving adequate respiration and represents the balance between forces promoting airway closure and dilatation. Thus, inherent collapsibility of the pharynx predisposes to the occurrence of impaired respiration, particularly when the regulation of the pharyngeal muscles is impaired (eg, during sleep).

The smaller the cross-sectional area of the upper airway, the less the ability to maintain upper airway patency will be. Because the upper airway behaves as a collapsible tube, increased inspiratory effort may only result in more collapse of the airway rather than increased flow.^44-46 Hence, snoring and obstructive apnea can become worse during a common cold (increased nasal upstream resistance), which provokes more inspira-tory effort.

During sleep, upper airway tone is consistently reduced. It is unknown whether children with OSA obstruct because of a relatively larger decrease in airway tone during sleep, in comparison to controls, or whether the decrease in tone is similar but those with OSA have an increased structural load. The upper airway muscles are accessory muscles of respiration and, as such, are activated by stimuli such as hypoxemia, hyper-capnia, and upper airway subatmospheric pressure. When upper airway muscle function is decreased or absent (eg during anesthesia), the airway is prone to collapse.⁴⁷ Pharyngeal airway neuromotor responses are prominently present in normal children but are lacking in children with OSA, most likely because of habituation to chronic respiratory abnormalities during sleep, mechanical damage to the upper airway, or genetically determined differences in these upper airway protective reflexes.^54-56

In addition, children with OSA demonstrate impaired arousal responses to inspiratory loads during REM and NREM sleep compared to healthy children.⁵⁷

While dynamic functional factors such as those discussed previously have been implicated in the pathophysiology of upper airway obstruction during sleep in children, the important contributions of either anatomical elements or genetic factors must be emphasized as well. While micrognathia or severe retrognathia are clearly associated with an increased risk for upper airway obstruction, the mandibular dimensions of otherwise healthy children with OSA appear to be within the normal range.⁵⁸ However, a detailed analysis of the upper airway using magnetic resonance imaging (MRI) techniques suggested that the upper airway in children with OSA is narrowest where adenoids and tonsils overlap and that such narrowing spans over the upper two thirds of its length rather than being restricted to a discrete region adjacent to either the adenoids or tonsils.^59,60 Moreover, it is imperative to dispel previous beliefs that proposed a higher prevalence of OSA in children 2 to 8 years old because of increased growth rate of lymphadenoid tissue within the upper airway compared to other upper airway structures.^61,62

UPPER AIRWAY DYSFUNCTION

OSA may occur in up to 10% of infants, is more frequent in premature infants, and is associated with hypoxemia. It is more frequent in male infants than in females, which may be attributable to sex-related differences in the anatomy of the upper airway or to a protective role of female hormones. The main risk factors for OSA in the first year of life include (1) craniofacial abnormalities (eg, micrognathia, cleft palate, Pierre Robin syndrome, Treacher-Collins syndrome, choanal atresia, mucopolysaccharidoses, Down syndrome); (2) soft tissue infiltration, which may result from infection, inflammation, laryngomalacia, subglottic stenosis, and also, as in older children, adenotonsillar hypertrophy^65,66; (3) neurologic disorders accompanied by pharyngeal hypotonia, such as Arnold-Chiari malformation, cerebral palsy, and poliomyelitis. Although the anatomic site of obstruction in infants is widely believed to be the retroglossal region,⁶⁷ recent evidence utilizing MRI and airway manometry suggests that upper airway obstruction with clinically significant OSA occurs in the retropalatal region 80% of the time and only 20% of the time in the retroglossal region.⁶⁸ While the laryngeal chemore-flex aims to prevent aspiration of food, it is enhanced by upper airway viral infections, particularly respiratory syncytial virus (RSV) infection, and this may explain the inordinately high prevalence of apnea among young babies with RSV infection.⁶⁹ Similarly, prenatal exposure to maternal smoking, which potentiates the laryngeal chemoreflex, also increases the frequency of OSA in infants.^70,71

GENETIC AND NONGENETIC DISORDERS AFFECTING CONTROL OF BREATHING

CENTRAL APNEA AND HYPOVENTILATION SYNDROMES

Insufficient central respiratory drive is a primary cause of alveolar hypoventilation. The presence of a hypoventilation syndrome is suggested by the medical history as well as examination of the patient during wake and sleep. When evaluating alveolar hypoventilation in a child, all disorders that could explain this condition must be evaluated and progressively excluded to narrow the scope of the diagnosis; at the same time, a polysomnographic evaluation that includes measurements of tidal volume and carbon dioxide should be conducted. The measurement of spontaneous resting tidal volumes and noninvasive assessments of blood gas exchange across all sleep states should be sufficient to establish the presence and severity of alveolar hypoventilation. In the subsequent subsections, several prominent conditions leading to alveolar hypoventilation in children are reviewed.

CONGENITAL CENTRAL HYPOVENTILATION SYNDROME

Central hypoventilation syndromes can be primary (congenital central hypoventilation syndrome and late-onset central hypoventilation syndrome) or secondary (Table 508-1). Primary congenital central hypoventilation syndrome (CCHS) is a relatively rare entity, with less than 1000 cases reported in the medical literature worldwide. It was originally described in 1970⁷² and is traditionally defined as the idiopathic failure of automatic control of breathing.^72,73 CCHS is a life-threatening disorder primarily manifesting as sleep-associated respiratory insufficiency and markedly impaired ventilatory responses to hypercapnia and hypoxemia.⁷⁴ Ventilation is most severely affected during quiet or NREM sleep, a state during which automatic neural control is predominant. Abnormal respiratory patterns also occur during active sleep and even during wakefulness, although to a milder degree. The spectrum of disease in CCHS cases is far reaching, ranging from relatively mild and often asymptomatic hypoventilation during quiet sleep with fairly good alveolar ventilation during wakefulness to recurrent and severe apneic episodes during sleep also accompanied by severe alveolar hypoventilation during waking. The increased awareness leading to recognition and earlier clinical management of CCHS patients has also revealed the presence of wide-ranging structural and functional impairments of the autonomic nervous system.^75-77 In particular, Hirschsprung disease⁷⁵ and tumors of autonomic neural crest derivatives such as neuroblastoma, ganglioneuroblastoma and ganglioneuroma^78,79 are noted in 20% and in 5% to 10% of CCHS patients respectively. In addition, abnormal regulation of body temperature responses or even moment-to-moment heart rate variability is consistently documented in these patients. In recent years, 3 major advances in our understanding of the pathophysiology and treatment of CCHS have occurred: (1) paired-like homeobox 2B (PHOX2b) identification as the putative gene underlying CCHS; (2) functional imaging of neural structures in patients with CCHS, enabling major insights into the respiratory and autonomic disturbances of this syndrome; and (3) implementation of noninvasive mechanical ventilatory support among many patients leading to improved quality of life without detriment to survival and other medical outcomes.

Table 508-1. Conditions Associated with Central Alveolar Hypoventilation in Children

The identification of PHOX2b mutations in the vast majority of patients with CCHS (> 95% of afflicted patients) has enabled genetic counseling and prenatal diagnosis for this condition. At the same time, the prevalence of sudden infant death syndrome is high in CCHS families suggests that the 2 disorders may share common abnormalities in the embryogenesis of respiratory control.⁹⁸

Functional and advanced structural MRI studies have further revealed disruptions in the connectivity of brain regions underlying autonomic functions.^99-102 As a corollary to these anatomical findings, decreased heart rate beat-to-beat variability is consistently found in Holter recordings, and the circadian patterning of such variability further suggests major imbalances in sympathetic/parasympathetic regulation in patients with CCHS.^103-106 Furthermore, alterations in blood pressure regulation during simple daily activities or during sleep further provide evidence for autonomic nervous system abnormalities.^107-109 Neuroocular findings are also frequently identified in children with CCHS,¹¹⁰ and marked reduction in the size of arterial chemoreceptors, carotid bodies, and intrapulmonary neuroepithelial bodies with decreased staining for tyrosine hydroxylase and serotonin¹¹¹ support the extensive and diffuse nature of autonomic nervous system involvement.¹¹²

DIAGNOSIS AND CLINICAL MANAGEMENT

The clinical presentation of CCHS is extremely variable and therefore requires a high index of suspicion. For example, some infants will not breathe at birth and will require assisted ventilation in the newborn nursery. Such infants may or may not develop adequate breathing during wakefulness over time, but it will almost universally manifest either apnea or severe alveolar hypoventilation during sleep that will persist and become a lifelong problem. The apparent improvement that may occur over the first few months of life is most likely accounted for by the normal maturation of the respiratory system and, as such, does not represent a true change in the severity of the disorder.¹¹³ Other infants may present at a later age with cyanosis, edema, and signs of right heart failure and may be mistaken for patients with cyanotic congenital heart disease. However, cardiac catheterization reveals only pulmonary hypertension. Infants with even less severe CCHS may present with tachycardia, diaphoresis, and/or cyanosis during sleep, and others may present with unexplained apnea or an apparent life-threatening event. Finally, other a priori asymptomatic children will manifest sleep-associated alveolar hypoventilation following a respiratory infection or an intercurrent illness at a much later age, and therefore be assigned to the diagnostic entity of late-onset CCHS.^114-115

Although other symptoms indicative of brainstem or autonomic nervous system dysfunction may be present, the criteria for diagnosis of CCHS usually include (1) persistent evidence of sleep hypoventilation (PaCO₂ greater than 60 mm Hg), particularly during quiet sleep (best measured by overnight polysomnography); (2) usually, albeit not exclusively, presentation of symptoms occurring during the first year of life; and (3) absence of cardiac, pulmonary, or neuromuscular dysfunction that could explain the alveolar hypoventilation.^90,116 Furthermore, hypercapnic ventilatory challenges are an important component for the diagnosis of CCHS. Steady-state or rebreathing incremental carbon dioxide challenges are similarly valid and will usually reveal absent or near-absent responses. Confounding variables, including asphyxia, infection, trauma, tumor, and infarction, must be discarded from CCHS by appropriate assessments. Currently, there are no specific guidelines regarding the use of genetic testing for CCHS. However, identification of mutations in genes such as RET, HASH, BDNF, GDNF, the endothelin gene family, and more particularly the PHOX2b gene, in the context of clinical manifestations supporting central alveolar hypoventilation, is highly supportive of the diagnosis of CCHS.^117,118

Congenital central hypoventilation syndrome is a lifelong condition, and depending on the severity of clinical manifestations, patients may require ventilatory support while asleep or as long as 24 hours a day. As such, a multidisciplinary approach to provide for comprehensive care and support of every child is needed. The treatment of CCHS should aim to ensure adequate ventilation when the patient is unable to achieve adequate gas exchange while breathing spontaneously. Since CCHS does not resolve spontaneously, chronic ventilatory support is required, such as positive pressure ventilation (either via a tracheotomy or nasal mask bilevel positive airway pressure) or negative pressure ventilation. The majority of children with CCHS initially require positive pressure ventilation through a permanent tracheotomy, although successful transition to noninvasive ventilation has been now extensively reported,⁷⁵ with a trend toward earlier transition to noninvasive ventilation.^119-124 However, families may opt for negative pressure ventilation as well. Daytime diaphragm pacing is usually reserved for children with CCHS who exhibit 24-hour mechanical ventilation dependency, since this approach provides greater ability to ambulate during daytime. In recent years, improved pacer technology has prompted many adolescent and young adult patients to transition to this modality as well. As a rule, the diaphragm pacer settings should provide adequate alveolar ventilation and oxygenation during rest as well as during daily activities such as exercise, while major disadvantages of diaphragm pacing include cost, discomfort associated with surgical implantation, and potential need for repeated surgical revisions due to pacer malfunction.^125-128

LATE-ONSET ALVEOLAR HYPOVENTILATION WITH HYPOTHALAMIC DYSFUNCTION

In recent years, a series of cases presenting with alveolar hypoventilation during sleep developing later during childhood and associated with clinical manifestations of hypothalamic dysfunction were reported.^129-131 Although underlying congenital brainstem abnormalities have not been extensively confirmed or excluded, the most characteristic manifestations in these patients consist of rapid-onset obesity in the first 10 years of life, followed by hypothalamic dysfunction, and then by the onset of symptoms of autonomic dysregulation with later onset of alveolar hypoventilation around the age of 6 years. Intriguingly, this distinct entity does not show evidence of abnormalities in candidate genes such as PHOX2b or necdin.^130,131

SECONDARY CENTRAL HYPOVENTILATION SYNDROMES

Patients with myelomeningocele and/or with Arnold-Chiari type II malformation frequently exhibit sleep-disordered breathing, and such respiratory control disturbances are frequently suspected as causative mechanisms in the sudden unexpected deaths that occur in this population. Moderate or severe breathing disturbances occur in approximately 20% of cases.^132,133 The largest proportion of cases exhibit central apnea, while others show obstructed breathing; obstructed cases are seldom resolved with surgical intervention for tonsillectomy, suggesting that the primary dysfunction is due to damage to central neural structures. The possible damage to vermis cerebelli structures from foramen magnum herniation in Arnold-Chiari type II malformation has the potential to interfere with both blood pressure and breathing regulation, particularly under extreme challenges of hypotension or prolonged apnea. Compression of ventral neural surfaces is also a major concern. The presence of thoracic or thoracolumbar myelomeningocele or the addition of severe brainstem malformations has been shown to enhance the potential for manifesting sleep-disordered breathing. Support for affected patients with Arnold-Chiari II syndrome must consider the needs for recovery from pronounced hypotension during sleep, the overall respiratory disturbances that are present, and the surgical interventions required for decompression of neural structures. As such, a multidisciplinary approach is necessary and yields optimal outcomes.¹³⁴ Of note, alveolar hypoventilation can also be acquired in a child with previously normal control of breathing following an event resulting in brainstem injury, such as severe asphyxia, stroke, brainstem tumors, encephalitis, and infectious encephalopathies.

PRADER-WILLI SYNDROME

Prader-Willi syndrome (PWS) was first described in 1956 by endocrinologists Prader, Lab-hart, and Willi (see Chapter 176). They reported on several patients with poor feeding in infancy, underdeveloped sexual characteristics, short stature, hypotonia, small hands and feet, cognitive impairment, and the onset of gross obesity after infancy. It was not until 1981 that PWS became the first recognized microdeletion syndrome identified by high-resolution chromosome analysis.¹³⁵ Prader-Willi syndrome is now known to be one of the most common microdeletion syndromes. It is the first known human genomic imprinting disorder and is the leading known genetic cause of obesity. Prader-Willi syndrome is also associated with growth deficiency, abnormal body composition, hyperghrelinemia,¹³⁶ hypogonadism, and specific behavioral and learning issues. PWS syndrome results when there is an absence of the normally active paternally inherited genes on the proximal long arm of chromosome 15 and, consequently, no active copy of this genetic information. In approximately 75% of cases, the absence is due to a de novo deletion of the paternally contributed chromosome 15 between bands 15q11 and 15q13.2. Most of these cases involve the same breakpoints on the chromosome, resulting in the same 4 megabyte deletion. The remaining patients with PWS (approximately 20% of the cases), have 2 maternal copies of chromosomes 15 but no paternal chromosome 15, a phenomenon known as maternal uniparental disomy.¹³⁷ Consensus diagnostic criteria for PWS were developed in 1993 to aid in early recognition and diagnosis and have since been confirmed using molecular and cytogenetic techniques.^139,140

Patients with PWS present a unique combination of sleep- and breathing-related manifestations.^141-143 Excessive daytime sleepiness and increased frequency of REM sleep periods occurs in a subset of PWS patients, while others show disturbances in circadian rhythmicity with a tendency for multiple microsleep periods. In addition, the combination of obesity and hypotonia favors the occurrence of OSA. Patients with PWS also display significant alterations in central and peripheral elements of respiratory control that, although not immediately related to the obesity, can be severely modified and exacerbated by the mechanical consequences of increased adiposity, ultimately leading to ventilatory failure. A unique and almost universal feature of these patients is the absence of ventilatory responses to peripheral chemoreceptor stimulation; this deficiency leads to abnormal arousal patterns during sleep.^144-147 When untreated, obesity progressively reduces central chemosensitivity as well, with the latter being ameliorated by growth hormone therapy and increased muscle mass.^148,149 However, growth hormone therapy has also been associated with reports of sudden unexpected death, the mechanisms of which remain to be elucidated.^150,151

RETT SYNDROME

Rett syndrome is a severe neurodevelopmental disorder primarily affecting females and has an incidence of 1:10,000 female births by the age of 12 years, making it one of the most common genetic causes of severe mental retardation in females (see Chapter 575).¹⁵² The postnatal neurodevelopmental disorder Rett syndrome is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a transcriptional repressor involved in chromatin remodeling and the modulation of RNA splicing.^153,154

The autonomic features of Rett syndrome include abnormalities in cardiorespiratory patterns and the presence of abnormal blood pressure responses. The typical respiratory abnormalities include hyperventilation, apnea, breath-holding, and rapid shallow-breathing during wakefulness and occasionally during sleep.^160-162 During wakefulness, breathing abnormalities are associated with behavioral agitation as well as with other stereotypic motor functions. During sleep, an increased frequency of desaturation events and periodic breathing has been reported. Girls with Rett syndrome who demonstrate hypoxemia without hypercarbia, awake or asleep, need to be treated with supplemental oxygen, while those patients who demonstrate evidence for OSA, usually without a treatable cause, need to be treated with mask bilevel positive airway pressure during sleep, such as to prevent some of the morbidities associated with repeated desaturation episodes. Of note, recent reports using desipramine in mice suggest a potentially promising role for this pharmacological approach in patients with Rett syndrome.^163,164

JOUBERT SYNDROME

Joubert syndrome is an autosomal recessive condition characterized by hypotonia, ataxia, psychomotor delay, and variable occurrence of oculomotor apraxia and neonatal breathing abnormalities. The neuroradiologic hallmark of this unusual and rare condition is a complex midbrain-hindbrain malformation known as the molar tooth sign that is related to the association of cerebellar vermis hypoplasia or aplasia, horizontally oriented and thickened superior cerebellar peduncles, and a deepened interpeduncular fossa.¹⁶⁵ The most typical respiratory manifestations of Joubert syndrome consist in the occurrence of episodes of marked hyperpnea occasionally followed by severe alveolar hypoventilation and respiratory failure, potentially necessitating mechanical ventilation.^166,167

FAMILIAL DYSAUTONOMIA (RILEY-DAY SYNDROME)

Familial dysautonomia (FD) is one of the multiple hereditary diseases associated with insensitivity to pain. It is an autosomal recessive disorder with extensive central and peripheral autonomic abnormalities associated with abnormal development and survival of unmyelinated sensory and autonomic neurons, with the sympathetic system being more extensively affected.¹⁶⁸ Patients with FD display inappropriate cardiovascular or catecholamine responses to physical stress, position changes, or exercise. The gene encoding for this disorder has been identified as IKBKAP (IκB kinase–associated protein gene), and more than 99% of individuals with FD are homozygous for a mutation in intron 20, which leads to marked reductions in the correctly spliced messenger RNA in neuronal tissues and consequently to absent expression of the normal protein.^169,170 It should be noted that although central autonomic symptoms are present, no consistent central neuro-pathology has been described. Many of the respiratory disturbances have been attributed to dysfunction of both chemoreceptors and baroreceptors.^171,172 Typically, patients develop severe and prolonged breath-holding episodes, usually following emotional outbursts, that can result in decerebrate posturing. In addition, periodic breathing and central apnea during sleep, lack of appropriate reflexive tachypnea with respiratory infections, and inability to adapt to low-oxygen environments are all frequently reported. When sustained hyperventilation occurs, it is usually followed by prolonged apnea or even respiratory arrest, further emphasizing the abnormal chemoreceptor functions in these patients. Therefore, sleep studies and more extended cardiorespiratory recordings appear to be necessary in the evaluation and potential treatment of the respiratory disturbances frequently encountered in patients with familial dysautonomia.¹⁷³

APNEA OF PREMATURITY

Apnea in infants has been traditionally defined as a pause in breathing of greater than 20 seconds or an apneic event of less than 20 seconds associated with bradycardia and/or cyanosis. Reduced respiratory drive and impaired pulmonary function due to lung immaturity as well as a variety of mechanical factors adversely affecting respiratory mechanics will predispose the premature infant to apnea and hypoventilation, which, in turn, may precipitate oxyhemoglobin desaturations and/or bradycardia. Alternatively, excessive peripheral chemoreceptor sensitivity can lead to destabilization of the respiratory system by creating exaggerated ventilatory responses to small fluctuations in oxyhemoglobin saturation, which then may lead to hypocapnia below the apneic threshold and reduced respiratory drive, thereby promoting apnea. Although apneic episodes can occur spontaneously and be attributable to the interactions of prematurity and sleep state alone, such apneic events can also be provoked or worsened if there is some additional insult, such as infection, underlying hypoxemia, hyperthermia, or any evolving intracranial pathology. Although most of the apneic events are self-resolving and seldom prompt medical recognition or intervention, apneic events associated with hypoxemia and reflex bradycardia may require active resuscitative efforts to reverse this condition.

Idiopathic apnea of prematurity (AOP) is a common, albeit often unsuspected, problem in the clinical setting¹⁷⁴ and seems to be primarily related to the immaturity of the infant neurological and respiratory systems. Premature infants breathe irregularly during sleep, with markedly greater breath-to-breath variability during all sleep and waking states, and this enhanced irregularity in their pattern of breathing renders them susceptible to apnea. Both central and obstructive apneas are frequently reported in preterm infants, although the most common form of apnea is mixed apnea (ie, the occurrence of an initial central apnea that then develops an obstructive pattern as respiratory effort begins in the context of a collapsed airway). Mixed apnea typically accounts for more than half of all clinically relevant apneic episodes, followed in decreasing frequency by central and obstructive apnea. By definition, there is no airway obstruction in central apnea, although some studies suggest that the central airways frequently will progressively reduce their cross-sectional area and even collapse during the course of a central apnea, with a rule of thumb proposing that such airway occlusion will be more likely as the duration of the event is prolonged.^175-178 Such apneic events have also been termed silent obstruction due to the lack of respiratory effort. Apnea of prematurity generally resolves by about 36 to 40 weeks postconceptional age. However, in the most premature infants (born at 24–28 weeks of gestation), apnea may frequently persist beyond 40 weeks postconceptional age, finally resolving by 43 to 44 weeks postconceptional age.^179,180 Beyond this developmental stage, the incidence and severity of cardio-respiratory events does not appear to differ between babies born at term and those born prematurely.

PATHOPHYSIOLOGY

Immaturity of central respiratory control and of the various ventilatory muscles and ribcage is the key element in the pathogenesis of AOP.^181,182 Since breathing patterns are more disorganized during REM sleep, the predominant mode of sleep in preterm infants, it is not surprising that apneic events will be more common, longer, and more frequently associated with profound bradycardia during active or REM sleep than during quiet or NREM sleep.^183,184 Premature infants have altered responses to increased CO₂ and decreased O₂ and will, for example, reduce rather than mount an increased respiratory effort response when exposed to elevated CO₂.^185,186 This remarkably different response of respiratory timing during hypercapnia is associated with prolongation of expiratory duration,^187,188 which appears to be centrally mediated within the brainstem,¹⁸⁹ especially via the inhibitory neurotransmitter γ-aminobutyric acid (GABA).^190,191 It is also well established that premature infants exhibit a biphasic ventilatory response to decreases in inspired oxygen concentration: a rapid increase in minute ventilation associated with peripheral chemoreceptor stimulation is subsequently followed by a decline in ventilation to levels that fall below those in normoxia. The decrease in ventilation, also termed hypoxic ventilatory depression,^192,193 may persist for several weeks and even months postnatally. Administration of adeno-sine receptor antagonists such as theophylline or caffeine is routinely used for the treatment of AOP.

The site of obstruction during either mixed or obstructive apneic events in the upper airways of premature infants suffering from AOP is mostly within the pharynx; however, it may also occur at the level of the larynx, and possibly at both locations.^199-201 Integrated pharyngeal muscle dilator functions are reduced during sleep and will result in airway collapse and subsequent apnea in susceptible infants. In addition, the airway may be compromised by postural changes, such as flexing of the neck, such that spontaneous obstructive apnea in the absence of a positional issue is uncommon. Reflexes originating in the upper airway may alter the pattern of respiration and play a role in the initiation and termination of apneas.²⁰² Stimulation of the laryngeal mucosa, either by chemical (ie, milk water, saliva) or mechanical (eg, swallowing) stimuli, may induce reflex inhibition of breathing and apnea. There appears to be a maturational change in this type of reflex-induced apnea.²⁰³ Preterm infants have an exaggerated laryngeal inhibitory reflex, which may elicit prolonged apnea in response to instilling saline in the oropharynx, gastroesophageal reflux, or during the course of respiratory syncytial virus infection.^204-207

DIAGNOSIS

AOP can be diagnosed only after a thorough evaluation has been completed and all other potential causes of apnea have been ruled out (eTable 508.2 ). These include prematurity, infection, impaired oxygenation, central nervous system problems such as intracranial hemorrhage or brain malformation, metabolic disorders such as hypoglycemia, electrolyte imbalance, fatty acid disorders and metabolic acidosis, temperature instability, and drugs such as narcotics or anticonvulsants. Often, apnea is attributed to the occurrence of coexisting gastroesophageal reflux (GER),^209,210 but studies assessing the timing of reflux in relation to apneic events do not support this association.^211-213 Furthermore, there is no clear evidence that treatment of GER will affect the frequency or severity of apnea in most pre-term infants. Thus, even the presence of GER, as shown by esophageal pH monitoring in an infant with proven apnea in a sleep study, should not necessarily assign the cause of the respiratory disturbance during sleep to GER. When a high level of suspicion is present, simultaneous assessment of sleep measures and of esophageal pH and, if possible, impedance esophageal recordings are necessary to establish that GER and apnea are present and enable formulation of a more effective management plan in these infants.

As a reminder, alveolar hypoventilation, oxygen desaturation, and even frank apnea and bradycardia may occur in premature infants during nutritive sucking as the result of immaturity. In the normal healthy infant, as fluid enters the pharynx or larynx, breathing will be discontinued to protect the airway and prevent aspiration. However, this protective reflex is excessive in some premature or even full-term infants and may promote prolonged apnea. With advancing maturation, feeding-associated apneic events become less frequent and eventually disappear.²¹⁴

TREATMENT

Treatment is usually with either pharmacologic therapy or continuous positive airway pressure (CPAP) ventilation, although other supportive measures, such as placing the infant with the head in the midline and the neck in the neutral position to minimize upper airway obstruction are clearly recommended. Methylxanthines have been the mainstay of pharmacologic treatment of apnea of prematurity.²¹⁵ Both theophylline and caffeine citrate can be used and are effective possibly through multiple physiologic and pharmacologic mechanisms of action. A likely major mechanism of action for xanthine therapy is through competitive antagonism of adenosine receptors, because adenosine acts as an inhibitory neuroregulator in the central nervous system.

It is important to rule out systemic conditions (sepsis), seizure disorders, and severe GER before initiation of methylxanthine therapy, since these compounds will lower the seizure threshold and decrease muscle tone of the esophageal sphincter.²¹⁶ Caffeine has clear advantages over other methylxanthines because it more effectively stimulates the central nervous and respiratory systems and has a higher therapeutic index; as such, central nervous system toxicity is less of a concern. A recent meta-analysis on the use of methylxanthines in AOP concluded that both theophylline and caffeine are effective in reducing the frequency and severity of apneic episodes and are also of value in reducing the need for mechanical ventilation.²¹⁸ Elimination of methylxanthines is prolonged in infants when compared to children and adults and is especially prolonged in preterm infants. Thus, serum measurement of theophylline should be monitored whenever aminophylline or theophylline are used. Caffeine levels are less critical but should also be followed at least during the initial phases of treatment.

The decision to discontinue xanthine therapy is largely empirical, although it is to be encouraged at least 1 to 2 weeks prior to discharge from the nursery. Toxic levels of xanthines may cause tachycardia, cardiac dysrhythmias, feeding intolerance, diuresis, and seizures, although these side effects are less commonly seen with caffeine at commonly prescribed therapeutic doses. Although recent concerns about potential long-term side effects of methylxanthines on the neurodevelopmental outcomes of low-birth-weight infants have been recently dispelled, discontinuation of treatment as soon as possible should be pursued.^219,220

Role of Continuous Positive Airway Pressure

Among the nonpharmacologic strategies widely used in the treatment of AOP, CPAP is relatively safe and effective and usually requires relatively low pressures to achieve the desired effect (3–6 cm H₂O).^221,222 CPAP appears to be effective by splinting the upper airway with positive pressure and decreasing the risk of pharyngeal or laryngeal obstruction, and also by increasing functional residual capacity and improving oxygenation. Studies have also compared nasal CPAP to nasal intermittent positive pressure ventilation (NIPPV) in the treatment of AOP and found that NIPPV reduces the frequency of apneas more effectively than nasal CPAP, particularly when apnea is frequent or severe.^223,224 In addition, high-flow nasal cannula therapy seems to be equivalently efficacious to nasal CPAP but allows for greater mobility of the infant by parents and caretakers.^225,226 Of course, endotracheal intubation and artificial ventilation may be needed as a last resort when extremely severe or refractory episodes are present.

The effect of supplemental oxygen on cardio-respiratory events and sleep architecture in premature infants has also been examined, and low-flow supplemental oxygen via a nasal cannula will lead to resolution of AOP and periodic breathing.^227-229 As mentioned earlier, AOP generally resolves by 36 to 40 weeks postconceptional age, and beyond 43 to 44 weeks, the risk appears to be similar to that of term infants, such that the majority of premature infants should be AOP-free by the time they are discharged home.²³² In this context, the safe minimum apnea-free observation period before discharge has been suggested as 8 apnea-free days.²³³ However, accurate and thorough monitoring in the neonatal intensive care unit is critical because clinically significant apneas with either bradycardia and/or desaturation will likely go unnoticed.^234-236

The clinical significance and long-term consequences of persistent apnea, bradycardia, or desaturation are still under considerable debate, particularly because idiopathic apnea is most often seen in high-risk preterm infants, such that separation of the consequences of premature birth from the specific effects of AOP is difficult.^237,238 Premature infants who were followed until early school age showed that AOP was one of the predictors of poor neurodevelopmental outcomes, but this issue requires more extensive and comprehensive studies before a definitive conclusion can be reached.

OBSTRUCTIVE SLEEP APNEA

The spectrum of sleep-disordered breathing (SDB), which includes obstructive sleep apnea (OSA), upper airway resistance syndrome, and primary snoring, occurs in children across the complete age spectrum. OSA is characterized by repeated events of either partial or complete upper airway obstruction during sleep, resulting in disruption of normal gas exchange and sleep patterns.²³⁹

Common nighttime symptoms and signs of SDB include snoring, paradoxical chest and abdomen motion, retractions, witnessed apnea, snorting episodes, enuresis, frequent nightmares and night terrors, difficulty breathing, cyanosis, sweating, and restless sleep. Daytime symptoms can include morning headaches, mouth breathing, difficulty in waking up, moodiness, nasal obstruction, daytime sleepiness and tiredness, hyperactivity, and cognitive problems, with severe cases of OSA associated with cor pulmonale, failure to thrive, developmental delay, or even death.

It is clear that the classic clinical syndrome of OSA in children is a distinct disorder from the condition that occurs in adults, particularly with respect to gender distribution, clinical manifestations, polysomnographic findings, and treatment approaches.^242,243 OSA in children is frequently diagnosed in association with adenotonsillar hypertrophy and is also common in children with obesity, craniofacial abnormalities, and neurological disorders affecting upper airway patency.

EPIDEMIOLOGY

OSA occurs in all pediatric age groups. Although accurate prevalence information is missing in infants, OSA is particularly common in young children (preschool and early school years) with a peak prevalence around 2 to 8 years of age and subsequent declines in frequency,²⁴⁴ the latter probably related to age-related reductions in viral loads that contribute to adenotonsillar lymphoid tissue proliferation.^245,246 Habitual snoring, the hallmark indicator of increased upper airway resistance during sleep, is an extremely frequent occurrence and affects up to 27% of children, with median frequencies revolving around 10% to 12%.^247-254 While specific clinical and sleep study–based criteria that link polysomnographically defined thresholds with OSA-associated morbidity are only now being developed, the current diagnosis of OSA relies on several consensus guidelines²⁵⁵ and is currently estimated to affect approximately 2% to 3% of children.²⁵⁶ Thus, the odds for identifying OSA vary between 1 of every 4 to 6 snoring children. Unfortunately, reliable identification of habitually snoring children who have OSA, on the basis of medical history and physical examination, is particularly arduous and error prone.^257,258 Therefore, at this time, overnight sleep studies remain the only objective and validated diagnostic approach for establishing the diagnosis of OSA in children.

PATHOPHYSIOLOGY

OSA occurs when the upper airway collapses during inspiration, a dynamic process that involves interactions between sleep state, pressure-flow airway mechanics, and respiratory drive. When resistance to inspiratory flow increases or when activation of the pharyngeal dilator muscle decreases, negative inspiratory pressure may collapse the airway.⁴⁷ Both functional and anatomic factors may tilt the balance toward airway collapse. For example, the site of upper airway closure in children with OSA is at the site where the tonsils and adenoids overlap in the upper airway, whereas in children with OSA in the absence of hypertrophied adenoids and tonsils, collapse is more likely to occur at the level of the soft palate.⁴³ The size of the tonsils and adenoids increases from birth to approximately 12 years of age, with the greatest increase occurring in the first few years of life, albeit proportionately to the growth of other upper airway structures.⁴³ However, the mass of upper airway lymphadenoid tissue will particularly proliferate in children exposed to cigarette smoking,^249,259 children with allergic rhinitis,^260,261 asthmatic children,²⁶² and obviously in children exposed to a variety of upper airway respiratory infections, particularly viruses.²⁶³

It is important to remember that although childhood OSA is associated with adenotonsillar hypertrophy, the presence of the latter does not mandatorily imply that OSA will be present. OSA is clearly the combined result of structural, anatomical, and neuromuscular factors within the upper airway, since patients with OSA do not obstruct their upper airway during wakefulness, and the correlation between upper airway adenotonsillar size and OSA is only modest at best. In addition, a small percentage of children with adenotonsillar hypertrophy but no other known risk factors for OSA will not be cured by surgical removal of tonsils and adenoids, while in others, postsurgical improvements may be only temporary,^264,265 Therefore, childhood OSA is a dynamic process resulting from the combination of structural and neuromotor abnormalities rather than from structural abnormalities alone. These predisposing factors occur as part of a spectrum: In some children (eg, those with craniofacial anomalies), structural abnormalities predominate, whereas in others (eg, those with cerebral palsy), neuromuscular factors predominate. In otherwise healthy children with adenotonsillar hypertrophy and OSA, neuromuscular abnormalities are subtle.

ASSOCIATED CONDITIONS

OSA also occurs in children with upper airway narrowing due to craniofacial anomalies and in those with neuromuscular abnormalities such as hypotonia (eg, muscular dystrophy) or muscular discoordination (eg, myelomeningocele). In addition to craniofacial anomalies and abnormalities of the central nervous system, altered soft tissue size may result from obesity, infection of the airways, allergy, supraglottic edema, adenotonsillar hypertrophy, mucopolysaccharide storage disease, laryngomalacia, subglottic stenosis, neck tumors, or enlarged thyroid gland in the context of hypothyroidism. Of particular emphasis, the global epidemic increase in obesity around the world is leading to marked increases in the proportion of obese symptomatic children referred for evaluation of habitual snoring. Genetic factors clearly also play a role in the patho-physiology of OSA, as demonstrated by studies of family cohorts,^266,267 but it remains unclear whether this is due to the modulating influence of genetic factors on ventilatory drive, anatomic features, or both. Ethnicity is also important, with OSA occurring more commonly in African American and Hispanic children.^253,268,269

CLINICAL EVALUATION AND DIAGNOSIS

The clinical presentation of a child with suspected OSA syndrome is usually very nonspecific and therefore requires not only increased awareness but also consistent and periodic assessments using specific questions on sleep during physician visits. If symptoms are present, a thorough history should be obtained and should include detailed information pertaining to the sleep environment (Table 508-2). In the otherwise normal child, the principal parental complaint will be snoring during sleep, such that even when the clinical consultation is conducted by a sleep specialist, the predictive accuracy of OSA based on history alone is poor, and an overnight polysomnographic assessment is required. The routine physical examination of a snoring child is usually not likely to demonstrate significant and obvious findings. Attention to the size of the tonsils^270,271 with careful documentation of their position and relative intrusion into the retropalatal space should be conducted. In addition, the presence of allergic rhinitis, nasal polyps, nasal septum deviation, or any other factor likely to increase nasal airflow resistance should be sought. The relative size (ie, micrognathia) and positioning of the mandible (ie, retrognathia) should also be documented. Finally, attention should be paid to systemic blood pressure values and to the presence of auscultatory findings suggestive of increased pulmonary artery pressures.

Table 508-2. Pertinent Clinical Findings in Pediatric Obstructive Sleep Apnea

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