sign in sign up
<<
Home , Obstructive sleep apnea, Sleep apnea

Paediatric Respiratory Reviews 30 (2019) 49–57

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review Diagnosis, management and pathophysiology of central in children ⇑ Anya T. McLaren a, Saadoun Bin-Hasan b, Indra Narang a,c, a Division of Respiratory , The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G1X8, Canada b Department of Pediatrics, Division of Respiratory Medicine, Farwaniya Hospital, Kuwait c Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Educational aims

The reader will be able to:

 Identify the different types of pediatric central (CSA)  Describe the clinical presentation of CSA in children  Discuss the pathophysiology of CSA  Understand the evaluation of CSA in the pediatric population

article info summary

Keywords: (CSA) is thought to occur in about 1–5% of healthy children. CSA occurs more com- Central sleep apnea monly in children with underlying disease and the presence of CSA may influence the course of their dis- Sleep disordered ease. CSA can be classified based on the presence or absence of as well as the underlying Hypoventilation condition it is associated with. The management of CSA needs to be tailored to the patient and may Children include medication, non-invasive ventilation, and surgical intervention. Screening children at high risk will allow for earlier diagnosis and timely therapeutic interventions for this population. The review will highlight the pathophysiology, and diagnosis of CSA in children. An algorithm for the manage- ment of CSA in healthy children and children with underlying co-morbidities will be outlined. Ó 2018 Elsevier Ltd. All rights reserved.

INTRODUCTION significant when the number of central per hour (central apnea index, CAI) is 5/h [1]. CSA can occur in the presence or

Central sleep apnea (CSA) is a sleep-related disorder occurring absence of hypoventilation, defined as a CO2 >50 mmHg for >25% when there is diminished or absent respiratory effort. CSA is often of the total sleep time in the pediatric population [2]. associated with arterial oxygen desaturation, arousals, frequent The International Classification of Sleep Disorders (ICSD)-2 rec- nocturnal awakenings and sleep fragmentation [1]. In the pediatric ognizes six different forms of central sleep apnea including pri- population, the AASM defines a central apnea as the absence of mary CSA and CSA due to other causes such as Cheyne-Stokes chest and/or abdominal movement associated with a cessation of breathing (CSB), medical conditions, drugs or substances, high- airflow of more than 20 s or lasting more than 2 baseline respira- altitude periodic breathing and infancy [1]. In the pediatric popu- tory cycles if it is associated with an arousal, an awakening or an lation, CSA occurs more commonly in association with underlying oxygen desaturation of at least 3% [2]. In adults, CSA is considered medical conditions. These conditions include anatomical brain and brainstem abnormalities (such as Arnold–, foramen magnum stenosis), neurogenetic conditions such as Pra- ⇑ Corresponding author at: Division of Respiratory Medicine, The Hospital for der–Willi syndrome, upper airway abnormalities (laryngomalacia), Sick Children, 555 University Avenue, Toronto, ON M5G1X8, Canada. prematurity, gastroesophageal reflux, and hypothyroidism Fax: +1 4168136246. [3,4]. CSA can also occur in the context of other sleep disordered E-mail addresses: [email protected] (A.T. McLaren), Saadoun.binhasa- [email protected] (S. Bin-Hasan), [email protected] (I. Narang). breathing conditions such as OSA [5,6], emerge with the treatment https://doi.org/10.1016/j.prrv.2018.07.005 1526-0542/Ó 2018 Elsevier Ltd. All rights reserved. 50

Table 1 Central sleep apnea in healthy children and children with underlying conditions.

Study Patient Population Methods Findings 2 N Age (years) BMI (kg/m ) Underlying Definitions OAHI CSA SpO 2 condition Nadir (%)

w/CA 49–57 (2019) 30 Reviews Respiratory Paediatric / al. et McLaren A.T. CA CSA CAI Range %Reported CSA Marcus et al., 1992 [14] 50 9.7 ± 4.6 18.6 ± 3.2 Healthy 10 s NA 0.1 ± 0.5 NR NR NA 89 Schluter et al., 2001 681 1–24 mo NA Healthy 3 s NA NR 1 mo:8.8/h NR NA NR 2 mo: 5.0/h  Uliel et al., 2004 [19] 70 8.0 ± 4.6 NR Healthy 10 s OR dec SaO2 >4% or 92% NA 0.37 (SD NR) 0.4 (SD NR) NR NA 88 Traeger et al., 2005 [18] 66 6.6 ± 1.9 NR Healthy 20 s OR <20 s + dec SaO2 3% NA 0.01 ± 0.03 0.08 ± 0.14 0–6 NA 81 Montgomery et al., 2006 [16] 153 4.9 ± 0.69 16.7 ± 2.8 Healthy At least 2 breaths NA 0.03 ± 0.1 0.82 ± 0.73 0–3.6 NA NR 388 6.8 ± 0.48 17.1 ± 3.4 0.05 ± 0.11 0.45 ± 0.49 0–3.4 Verhulst et al., 2007 [17] 66 11.7 ± 2.6 NR Healthy 10 s OR dec SaO2 >3% NA 0.06 ± 0.16 0.85 ± 1.06 0–5.5 NA 82 Scholle et al., 2011 [15] 209 1–18 y NR Healthy At least 2 breaths NA **0.1–0.3 **0.4–2.8 0–6.9 NA NR Brockman et al., 2013 [12] 37 1 mo NA Healthy >20 s OR 2 breaths + dec SaO2 3% or HR changes NA 0.8/h 5.5/h 0.9–44.3 NA NR 3mo 0.8/h 4.1/h 1.2–27.3 White et al., 2016 [35] 17 2.4 ± 3.6 NR Ach NR >5/h 24.61 ± 23.63 3.32 ± 4.15 0–10.4 4.2 69 Waters et al., 1998 [23] 83 8.9 ± 5.6 NR ACM 20 s OR dec SaO2 4% 5/h NR NR NR 17 NR Kirk et al., 2000 [24] 73 1–>18 y NR ACM NR >5/h 17 (10.3–32.6) 16.6 (7.7–46.4) 34 67 ± 14 Amin et al., 2015 (22) 68 7.3 ± 4.0 (z-score) ACM AASM 5/h 1.9 (0.7–5.7) 2.4 (0.63–8.95) NR 18 NR Patel et al., 2015 [21] 52 8.3 ± 0.9 NR ACM 10 s 5/h NR NR NR 29 NR Cohen et al., 2014 [26] 44 1.9 (0.3, 15.6) (z-score) PWS AASM 5/h 4 (1.5–57) 10.6 (5–68.3) 5–68.3 14 52 Khayat et al., 2017 [27] 28 0.9 (0.5–1.1) 16 (14.3–16.8) PWS AASM 5/h 0.5 (0.2–33) 6.6 (2.6–12.1) 2.6–12.1 53 NR Al-Saleh et al., 2016 [36] 21 (10.7, 0.5–17.7) (z-score) DCM AASM 5/h 1.2 (0–26) 1.1 (0–17.6) 0–17.6 24 NR

Values represented as mean ± standard deviation (where reported) or median (range or Interquartile range). All studies were retrospective. NR = not reported; NA = not applicable; dec = decreased. AASM: AASM Criteria for central apnea; Ach = ; ACM = Arnold–Chiari malformation; PWS = Prader–Willi syndrome; DCM = Dilated cardiomyopathy; OAHI = obstructive apnea– index; CAI-central apnea index A full overnight, laboratory PSG was used in all these studies except Brockman et al which used polygraphic recordings. CAI presented as mean ± SD, median (IQR) or range. ** In this study, the median CAI across the different age groups is reported as a range. Please refer to the study for more detail. A.T. McLaren et al. / Paediatric Respiratory Reviews 30 (2019) 49–57 51 of OSA [7] or hypoventilation disorders such as congenital central Central sleep apnea in children with underlying disorders hypoventilation syndrome (CCHS). CCHS is a rare genetic disorder of ventilatory control that is marked by alveolar hypoventilation The prevalence of CSA ranges between 4 and 6% in children [8]. CCHS is caused by a genetic defect in PHOX2B (paired-like [3,4]. Studies that have looked at CSA (using a cut-off of >5/h) in homeobox 2B gene). Mutations in this gene are known as polyala- children with underlying conditions is summarized in Table 1. nine repeat mutations (PARMs) or non-polyalanine repeat muta- In their retrospective chart review, Kritzinger et al. [3] reviewed tions (nPARMs) [8]. 969 children aged between 3 months to 13 years (median age 19 months) who underwent an overnight PSG. Of these, 52/969 (5.4%) patients had a CAI of >5/h. The commonest cause of CSA in Diagnosis of pediatric CSA patients who were not preterm was an underlying neurologic dis- order. In another retrospective study, Felix and colleagues [4],in A full-night in-laboratory is the gold stan- their cohort of 441 patients found that 18/441 (4.1%) had a CAI dard diagnostic test for central apneas [2]. A finding of 5 central of >5/h. Neurosurgical disorders particularly Arnold–Chiari malfor- events per hour is considered clinically significant [3]. However, mations were the most common cause of CSA in their cohort and the minimum number of events required to cause a specific disor- occurred in four of the eighteen patients. Arnold–Chiari malforma- der or syndrome remains elusive and may be different in different tions are one of the most frequently reported neuroanatomical patient populations. As such, there is no threshold of the number of conditions with a frequency of CSA that ranges between 17 and central apneas associated with disease. Normative data are dis- cussed in more detail below. Table 2 Pediatric classification of central sleep apnea, adapted from [9].

Physiologic CSA Epidemiology of central sleep apnea in children Post-arousal Healthy children Post-sigh Central apneas during sleep are common in the preterm, new- Phasic REM sleep Body movement born period and during infancy [10]. All preterm infants born at Sleep-wake transition less than 29 weeks gestation have apnea of prematurity and up Idiopathic CSA to 25% of these events are central in origin [11]. In healthy children, CSA with possible hypoventilation short duration (<20 s) central apneas in sleep are considered phys- Arnold–Chiari malformation iologic particularly in the context of a sigh, movement and/or REM CNS tumors sleep [10]. There is an age-related decrease in central apneas that is Neuromuscular disorders Thoracic cage disease thought to be related to maturation of the central nervous system Chronic renal failure and patients on dialysis [10]. CSA with genetic conditions Specifically, polysomnographic recordings in healthy term Achondroplasia infants estimate the median CAI at one month of life to vary CCHS between 5.5/h [12] and 8.8/h [13] with a duration ranging between LO-CCHS 3.1 and 20.1 s [12,13] when the definition of a CA was a central pause lasting for greater than 3 s. [13]. Central apneas after sighs Rett Syndrome Vici Syndrome were not included in these indices but accounted for 18% of all Smith–Magenis syndrome CAs in one study [12]. A reduction in central apneas occurs by CSA with other sleep disordered breathing conditions the second and third month of life [12,13] and central apneas con- tinue to reduce in frequency in the second year of life [13]. In sub- CPAP emergent CSA jects beyond infancy, Marcus et al found that in otherwise healthy CSA with heart conditions 1–18 year olds (n = 50), the prevalence of central apneas that lasted between 10 and 18 s was 30% and central apneas 20 s were Idiopathic pulmonary arterial found to be rare in another study [14,15]. In other studies, the CSA with congenital craniofacial abnormalities mean CAI in healthy children older than one year is less than 1/h but CAIs as high as 6/h have been measured [16–18]. Pierre–Robin Sequence Normative data from several studies across North America and CSA with neurogenetic/neurological conditions Europe are summarized in Table 1 below. These studies show that Prader–Willi Syndrome in healthy children, CAs are not associated with significant oxygen desaturation [16–19] and arousals caused by central apneas are CSA with endocrine conditions Obesity rare in this population [15]. It is important to note that healthy Hypothyroidism term infants that are born and reside at high altitude have a higher CSA with upper airway abnormalities prevalence of total central indices (median of 12.4/h for 1 month Laryngomalacia olds) and a high frequency of oxygen desaturation episodes occur- Choanal atresia ring with obstructive and central respiratory events [20]. CSA with other medical conditions Gastroesophageal reflux Prematurity Bronchopulmonary dysplasia SUMMARY Tetralogy of Fallot Based on the normative data shown, the authors recommend that a CSA with miscellaneous conditions CAI greater than 5/h, with CAs occurring in non-REM sleep, associated Behavioral hyperventilation with significant oxygen desaturations and of greater 10 s duration Epilepsy require further investigation High Altitude 52 A.T. McLaren et al. / Paediatric Respiratory Reviews 30 (2019) 49–57

34% [21–24]. Surgical decompression may improve the CAI in these pathophysiologic mechanisms of OSA and CSA. In obese children, patients [25]. Similarly, White and colleagues assessed sleep in 17 BMI may be predictive of central apnea [32,33]. CSA is also a com- children with achondroplasia who had an MRI study. A CAI >5/h plication of brain tumors and it has been reported in children with was found in 6/17 children. CSA is also common in infants with gangliomas and CNS tumors of the medulla [4,34]. PWS, occurring in up to 53% in one cohort [26,27]. Central apneas occur mostly in REM sleep and in some infants can cause marked Pediatric classification of CSA [28]. Beyond two years of age, CSA is less common and OSA predominates in this population [26]. In adults, CSA is commonly categorized based on wakefulness

In Down syndrome, the of CSA and hypoventilation CO2 levels into hypercapnic and non-hypercapnic CSA based on are increased [29,30]. CSA correlates with very young age (0–3 the steady-state PaCO2 (normal range is 35–45 mmHg) being above years) [29] and central apneas may occur in long and regular the upper limit of normal or within the low range respectively [9]. sequences showing a periodic pattern and accompanied by signif- For the purposes of this review, pediatric CSA can be divided into icant oxygen desaturation in the absence of upper airway pathol- physiologic, idiopathic and CSA with specific medical conditions ogy [30]. In children with Down syndrome and adenotonsillar as illustrated in Table 2 [9]. Physiologic CSA is considered normal hypertrophy, adenotonsillectomy may improve the incidence of sleep phenomena. This category includes central apneas that occur CSA [31]. This has been found to be the same for healthy children with sleep onset, post-arousal, post-sigh, phasic REM sleep and that undergo adenotonsillectomy [5,6] suggesting overlapping body movement. The majority of central apneas in healthy children

Fig. 1. Schematic explanation of the different mechanisms contributing to CSA. The gray central shapes with large dashed lines represent the plant system. The dashed boxes represent the different disorders with CSA. The central pentagonal shape represents CSA with the three primary mechanisms leading to its occurrence; controller defect, ventilatory defect and PaCO2 changes. CHF = Congestive heart failure, NMD = Neuromuscular disease, CCHS = Congenital central hypoventilation syndrome, ROHHAD = Rapid- onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation. A.T. McLaren et al. / Paediatric Respiratory Reviews 30 (2019) 49–57 53 occurs after a movement or sigh and will not be scored on an over- Patients can present either in childhood, adolescence or adulthood night polysomnogram (PSG) [37]. Idiopathic central sleep apnea with unexplained during sleep, respiratory (ICSA) occurs when there are symptoms of sleep disordered with or after anesthesia and further, with unexplained breathing such as restless sleep, daytime sleepiness, frequent persistent [8]. night-time awakenings and daytime sleepiness and PSG features In summary, CSA in children cannot be reliably identified or diag- of CSA without Cheyne-Stokes breathing (CSB), hypoventilation nosed on the basis of history, nor a specific set of or an underlying medical condition [1]. Central apneas occur as part of a central hypoventilation syndrome which can either be Consequences of pediatric CSA inherited as in CCHS and late-onset congenital central hypoventila- tion (LO-CCHS). It can also be acquired, for example in children CSA-associated complications are not as well defined as in OSA. with Arnold–Chiari malformations [9]. CSA can co-occur with other However, it has been suggested that the pathologic effect of multi- sleep disorders particularly OSA in both healthy children and chil- ple episodes of hypoxia, reoxygenation, apnea and arousals in OSA dren with other underlying conditions. can be extrapolated to CSA [43]. These effects include but are not limited to sympathetic nervous system activation; oxidative stress and systemic inflammation. In adults, an important CSA-associated Clinical presentation of pediatric CSA is the increased risk of adverse cardiovascular out- comes likely mediated by sympathetic nervous system activation The clinical presentation of CSA can vary from an incidental and impaired cardiac autonomic control [1]. In one study with 53 finding in an asymptomatic child to frank apneas and hypersomno- otherwise healthy children, mean age of 9.4 years, O’Driscoll and lence in others [3,4]. Many children with a PSG diagnosis of CSA colleagues observed that movement-related central apneas were have been found to be asymptomatic such as children with chronic associated with significant changes in heart rate (HR) and blood kidney disease, Arnold–Chiari malformations [ACM], achon- pressure (BP) measurements during the occurrence of central droplasia and Down syndrome [3,4,38]. On the contrary, in some events in sleep. Children with OSA had increased movement cases, a child may present with symptoms of a sleep related related central apneas compared to children without OSA. In a sep- breathing disorder that is not supported by PSG findings. This arate study in children with cardiomyopathy, (n = 21, median age was illustrated in children with dilated cardiomyopathy that 10.7 years), the number of central events correlated with left ven- snored significantly more than controls but had no increased OAHI tricular indices but the consequence of CSA in children with co- or CAHI scores or SDB frequency [36]. existing heart conditions is unclear [38]. In children with ICSA, sleep complaints are common and include , respiratory pauses, gasping, restless sleep, fre- quent night-time awakenings and daytime sleepiness [39]. Similar Pathophysiology of central sleep apnea symptoms have been reported in patients with Chiari malforma- tions [40,41] sometimes in the context of a normal neurological The control of breathing during wakefulness, sleep transition examination [41,42]. and stable sleep is a highly integrated process. This process can In patients with CCHS, presentation is usually in the neonatal be simplified by the controller theory [44] (Fig. 1). As in any system period with infants exhibiting shallow breathing, and (plant), there is a reference (thermostat) that determines the ideal frank central apneas suggestive of hypoventilation and hypoxemia set point of the system (e.g., PaCO2), the sensor, and the central [8]. Sleep disordered breathing can range in severity. In the milder controller that acts through the system’s effectors (e.g., respiratory presentation, patients have hypoventilation during non-REM sleep muscles) where the information is executed. with adequate ventilation during wakefulness. More severe venti- latory abnormalities are complete apnea during sleep and severe hypoventilation during wakefulness. In the latter case, patients tend to have longer PARMs and NPARMs [8]. The ventilatory abnor- During wakefulness, PaCO2, is tightly controlled by various malities in Individuals with LO-CCHS usually have a milder pheno- inputs from neural and chemical receptors to keep PaCO2 levels type and a particular genotype (PHOX2B PARM 20/24 or 20/25) [8]. near 40 mmHg [45]. Chemoreceptors provide tonic stimulus to

Fig. 2. Schematic summary of the physiological changes in ventilation during sleep. As shown, with progression in sleep, new PaCO2 level will be established that is different from wakefulness. Post arousal CSA will occur if the PaCO2 crosses the apnea threshold upon returning back to sleep state. 54 A.T. McLaren et al. / Paediatric Respiratory Reviews 30 (2019) 49–57

breathe in order to minimize PaCO2 fluctuation [46]. The central lesser extent to hypercapnia and acidosis [49]. Signals from those chemoreceptors play an important role in adjusting ventilation in chemoreceptors rapidly transfer to the controller (medulla) via response to the acid–base changes within the brain. One of the the glossopharyngeal nerve resulting in a change in the minute major sites of the CO2 chemoresponsiveness is the parafacial retro- ventilation [50]. trapezoid nucleus (RTN), where paired-like homeobox 2B gene (PHOX2B) is strongly expressed by glutamatergic interneurons Wakefulness drive and sleep transition [47]. This gene has a strong implication in the pathogenesis of some CSA syndromes like congenital central hypoventilation syn- The wakefulness stimuli to breathe mainly function through the drome (CCHS) [48]. This will be discussed in more detail below. involuntary excitation involving the suprapontine systems [51].It The peripheral chemoreceptors, carotid bodies and aortic bod- can influence wakefulness breathing patterns irrespective of the ies, above and below the aortic arch, are the primary sensors for varying degrees of PaCO2 values [52]. However, during sleep tran- changes in the partial pressure of arterial oxygen (PaO2), and to a sition difference in breathing control during wakefulness and sleep

Fig. 3. Algorithmic approach to management of pediatric CSA. In healthy children, diagnostic testing should be performed in a step-wise manner and the authors would recommend a brain and spine MRI as the primary investigation following a PSG diagnosis of CSA. Personalized and targeted therapeutic interventions are required for the treatment of CSA, depending on the patients’ medical condition, symptoms, and severity of CSA and long-term goals of care. Ancillary diagnostic testing needs to be targeted to the specific underlying medical condition. Complex high-risk patients require special as they are at higher risk for developing CSA, e.g., Down Syndrome, Prader– Willi Syndrome, neuromuscular disease, congenital heart disease, achondroplasia, Arnold–Chiari malformation and pulmonary arterial hypertension. ECHO = Echocardio- graphy, TFT = Thyroid function test, NIPPV = Non-invasive positive pressure ventilation, PFT = Pulmonary function test, MIPS = Maximum inspiratory pressures, MEPS = Maximum expiratory pressures, ECG = Electrocardiogram, EEG = Electroencephalogram, PHOX2B = Paired-like homeobox 2b, Trach = Tracheostomy, OHS = Obesity hypoven- tilation syndrome, ROHHAD = Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation. A.T. McLaren et al. / Paediatric Respiratory Reviews 30 (2019) 49–57 55

Fig. 3 (continued) may result in ventilatory instability (Fig. 2). With sleep onset, there duced leading to hyperventilation. Upon resumption of sleep the is a loss in the behavioral and wakeful stimuli as well as metabolic arousal induced-ventilatory response leads to reduced PaCO2 such regulation. As the sleep deepens and transitions into REM sleep, that central apnea may ensue, if the hypocapnea is sufficient to there is widespread muscle atonia and a reduction in upper airway cross the apnea threshold. dilator muscle tone leading to instability of ventilatory control with further reduction in ventilatory response to hypoxia and Loop gain hypercapnia [53]. This will cause a gradual rise in PaCO2 (3–8 mmHg above the wake eucapnic level); establishing a new sleep Is an engineering concept adopted in the early 1980s [55] to  specific PaCO2 set point ( 45 mmHg) [45]. Central apneas will describe a feedback system, through the plant gain (i.e., PaCO2 ensue if the PaCO2 falls below, which is usually 2–6 mmHg lower changes in response to ventilation) and the controller gain (i.e., than the eucapnic sleeping level (apnea threshold) [54].Fig. 3. ventilatory response to PaCO2). As described by Younes et al., indi- viduals with high loop gain are more prone to ventilatory instabil- Arousals ity, hence periodic breathing [56]. To further explain the loop gain model, Malhotra et al. [57], used the thermostat analogy; in a room

With arousal, the sleeping PaCO2 set point (45 mmHg) rapidly with an excessively sensitive thermostat, there will be a significant shifts to the wakefulness level (40 mmHg) creating a state of rel- fluctuation in the room temperature with a minimal change in set ative hypercapnia and the wakefulness drive to breathe is reintro- point. As in humans, chemosensitivity is variable between individ- 56 A.T. McLaren et al. / Paediatric Respiratory Reviews 30 (2019) 49–57 uals and this might lead to respiratory disturbances in people with [17] Verhulst SL, Schrauwen N, Haentjens D, Van Gaal L, De Backer WA, Desager KN. more robust system [58]. Reference values for sleep-related respiratory variables in asymptomatic European children and adolescents. Pediatr Pulmonol 2007;42(2):159–67. [18] Traeger N, Schultz B, Pollock AN, Mason T, Marcus CL, Arens R. Polysomnographic values in children 2–9 years old: additional data and Summary and recommendations review of the literature. Pediatr Pulmonol 2005;40(1):22–30. [19] Uliel S, Tauman R, Greenfeld M, Sivan Y. Normal polysomnographic respiratory values in children and adolescents. Chest 2004;125(3):872–8. CSA is relatively rare in healthy children. When it does occur, it [20] Duenas-Meza E, Bazurto-Zapata MA, Gozal D, Gonzalez-Garcia M, Duran- is usually in the context of an underlying medical condition, most Cantolla J, Torres-Duque CA. Overnight Polysomnographic Characteristics and common of which are neuroanatomical abnormalities. A CAI of >5/ Oxygen Saturation of Healthy Infants, 1 to 18 Months of Age, Born and Residing At High Altitude (2,640 Meters). Chest 2015;148(1):120–7. h is a reasonable threshold to define clinically significant CSA. [21] Patel DM, Rocque BG, Hopson B, Arynchyna A, Bishop ER, Lozano D, et al. Because children may be asymptomatic, those at high risk for Sleep-disordered breathing in patients with myelomeningocele. J Neurosurg CSA should be screened. In healthy children with a PSG diagnosis Pediatr. 2015;16(1):30–5. of CSA, we suggest MRI evaluation to assess for neuroanatomical [22] Amin R, Sayal P, Sayal A, Massicote C, Pham R, Al-Saleh S, et al. The association between sleep-disordered breathing and magnetic resonance imaging findings abnormalities. In other children with specific underlying medical in a pediatric cohort with Chiari 1 malformation. Can Respir J. 2015;22 conditions, further testing should be directed to the specific (1):31–6. condition. [23] Waters KA, Forbes P, Morielli A, Hum C, O’Gorman AM, Vernet O, et al. Sleep- disordered breathing in children with myelomeningocele. J Pediatr 1998;132 (4):672–81. [24] Kirk VG, Morielli A, Gozal D, Marcus CL, Waters KA, D’Andrea LA, et al. DIRECTIONS FOR FUTURE RESEARCH Treatment of sleep-disordered breathing in children with myelomeningocele. Pediatr Pulmonol 2000;30(6):445–52. [25] Pomeraniec IJ, Ksendzovsky A, Yu PL, Jane Jr JA. Surgical History of Sleep Apnea Although CSA is relatively uncommon in childhood, it is likely in Pediatric Patients with Chiari Type 1 Malformation. Neurosurg Clin N Am under diagnosed. Future research should be directed at identifying 2015;26(4):543–53. risk factors for CSA and promoting timely screening of at risk [26] Cohen M, Hamilton J, Narang I. Clinically important age-related differences in sleep related disordered breathing in infants and children with Prader-Willi patient populations. While there have been some studies looking Syndrome. PLoS One 2014;9(6):e101012. at the pathophysiology of CSA in specific conditions in children, [27] Khayat A, Narang I, Bin-Hasan S, Amin R, Al-Saleh S. Longitudinal evaluation of further studies are needed to define the mechanisms of CSA. sleep disordered breathing in infants with Prader-Willi syndrome. Arch Dis Child 2017;102(7):638–42. Finally, it would be important to understand the natural course [28] Urquhart DS, Gulliver T, Williams G, Harris MA, Nyunt O, Suresh S. Central of CSA from childhood to adulthood and to identify the outcomes sleep-disordered breathing and the effects of oxygen therapy in infants with of treatment of CSA downstream. Prader-Willi syndrome. Arch Dis Child 2013;98(8):592–5. [29] Fan Z, Ahn M, Roth HL, Li L, Vaughn BV. Sleep apnea and hypoventilation in patients with down syndrome: analysis of 144 polysomnogram studies. Children (Basel) 2017;4(7). REFERENCES [30] Ferri R, Curzi-Dascalova L, Del Gracco S, Elia M, Musumeci SA, Stefanini MC. Respiratory patterns during sleep in Down’s syndrome: importance of central apnoeas. J Sleep Res 1997;6(2):134–41. [1] AASM. Central Sleep Apnea Syndromes. International Classification of Sleep [31] Thottam PJ, Choi S, Simons JP, Kitsko DJ. Effect of Adenotonsillectomy on Disorders. Darien, IL: American Academy of ; 2014. pp. 69–107. Central and Obstructive Sleep Apnea in Children with Down Syndrome. [2] Berry R, Brooks R, Garnaldo C, Hardig S, Lloyd R, Quan S, et al. The AASM Otolaryngology–head and surgery: official journal of American Academy manual for the scoring of sleep and associated events: rules, terminology and of Otolaryngology-Head and Neck. Surgery. 2015;153(4):644–8. technical specifications. 2017. [32] Verhulst SL, Schrauwen N, Haentjens D, Suys B, Rooman RP, Van Gaal L, et al. [3] Kritzinger FE, Al-Saleh S, Narang I. Descriptive analysis of central sleep apnea Sleep-disordered breathing in and obese children and adolescents: in childhood at a single center. Pediatr Pulmonol 2011;46(10):1023–30. prevalence, characteristics and the role of fat distribution. Arch Dis Child [4] Felix O, Amaddeo A, Olmo Arroyo J, Zerah M, Puget S, Cormier-Daire V, et al. 2007;92(3):205–8. Central sleep apnea in children: experience at a single center. Sleep Med [33] Kohler M, Lushington K, Couper R, Martin J, van den Heuvel C, Pamula Y, et al. 2016;25:24–8. Obesity and risk of sleep related upper in Caucasian [5] Baldassari CM, Kepchar J, Bryant L, Beydoun H, Choi S. Changes in central apnea children. Journal of clinical sleep medicine: JCSM: official publication of the index following pediatric adenotonsillectomy. Otolaryngology Head Neck Surg American Academy of Sleep Medicine. 2008;4(2):129–36. 2012;146(3):487–90. [34] Rosen GM, Bendel AE, Neglia JP, Moertel CL, Mahowald M. Sleep in children [6] Boudewyns A, Van de Heyning P, Verhulst S. Central apneas in children with with neoplasms of the central nervous system: case review of 14 children. obstructive sleep apnea syndrome: prevalence and effect of upper airway Pediatrics 2003;112(1 Pt 1):e46–54. surgery. Sleep Med 2016;25:93–7. [35] White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V. Is there a correlation [7] Waters KA, Everett FM, Bruderer JW, Sullivan CE. Obstructive sleep apnea: the between sleep disordered breathing and foramen magnum stenosis in children use of nasal CPAP in 80 children. Am J Respir Crit Care Med 1995;152 with achondroplasia? Am J Med Genet A 2016;170(1):32–41. (2):780–5. [36] Al-Saleh S, Kantor PF, Chadha NK, Tirado Y, James AL, Narang I. Sleep- [8] Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, disordered breathing in children with cardiomyopathy. Annals of the Trang H. An official ATS clinical policy statement: congenital central American Thoracic Society. 2014;11(5):770–6. hypoventilation syndrome: genetic basis, diagnosis, and management. Am J [37] O’Driscoll DM, Foster AM, Ng ML, Yang JS, Bashir F, Wong S, et al. Central Respir Crit Care Med 2010;181(6):626–44. apnoeas have significant effects on and heart rate in children. J [9] Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3 Sleep Res 2009;18(4):415–21. (1):141–63. [38] Amin R, Sharma N, Al-Mokali K, Sayal P, Al-Saleh S, Narang I, et al. Sleep- [10] Carroll JL, Donnelly DF. Respiratory physiology and pathophysiology during disordered breathing in children with chronic kidney disease. Pediatr Nephrol sleep. In: Sheldon SH, Ferber R, Kryger M, Gozal D, editors. Principles and 2015;30(12):2135–43. Practice of Pediatric Sleep Medicine. Elsevier; 2014. [39] Gurbani N, Verhulst SL, Tan C, Simakajornboon N. Sleep Complaints and Sleep [11] Stokowski LA. A primer on Apnea of prematurity. Adv Neonatal Care 2005;5 Architecture in Children With Idiopathic Central Sleep Apnea. J Clin Sleep Med (3):155–70. quiz 71–74. 2017;13(6):777–83. [12] Brockmann PE, Poets A, Poets CF. Reference values for respiratory events in [40] Keefover R, Sam M, Bodensteiner J, Nicholson A. Hypersomnolence and pure overnight polygraphy from infants aged 1 and 3 months. Sleep Med 2013;14 central sleep apnea associated with the Chiari I malformation. J Child Neurol (12):1323–7. 1995;10(1):65–7. [13] Schlüter B, Buschatz D, Trowitzsch E. Polysomnographic reference curves for [41] Murray C, Seton C, Prelog K, Fitzgerald DA. Arnold Chiari type 1 malformation the first and second year of life. Somnologie. 2001. presenting with sleep disordered breathing in well children. Arch Dis Child [14] Marcus CL, Omlin KJ, Basinki DJ, Bailey SL, Rachal AB, Von Pechmann WS, et al. 2006;91(4):342–3. Normal polysomnographic values for children and adolescents. Am Rev Respir [42] Losurdo A, Dittoni S, Testani E, Di Blasi C, Scarano E, Mariotti P, et al. Sleep Dis. 1992;146(5 Pt 1):1235–9. disordered breathing in children and adolescents with Chiari malformation [15] Scholle S, Wiater A, Scholle HC. Normative values of polysomnographic type I. J Clin Sleep Med 2013;9(4):371–7. parameters in childhood and adolescence: cardiorespiratory parameters. Sleep [43] Costanzo MR, Khayat R, Ponikowski P, Augostini R, Stellbrink C, Mianulli M, Med 2011;12(10):988–96. et al. Mechanisms and clinical consequences of untreated central sleep apnea [16] Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographic in heart failure. J Am Coll Cardiol 2015;65(1):72–84. characteristics in normal preschool and early school-aged children. Pediatrics 2006;117(3):741–53. A.T. McLaren et al. / Paediatric Respiratory Reviews 30 (2019) 49–57 57

[44] Batzel JJ, Tran HT. Stability of the human respiratory control system. I. Analysis [51] Moosavi S, Paydarfar D, Shea S. Suprapontine control of breathing. LUNG of a two-dimensional delay state-space model. J Math Biol 2000;41(1):45–79. BIOLOGY IN HEALTH AND DISEASE. 2005;202:71. [45] Skatrud JB, Dempsey JA, Badr S, Begle RL. Effect of airway impedance on CO2 [52] Fink BR. Influence of cerebral activity in wakefulness on regulation of retention and respiratory muscle activity during NREM sleep. J Appl Physiol breathing. J Appl Physiol 1961;16(1):15–20. 1988;65(4):1676–85. [53] Fogel RB, Trinder J, White DP, Malhotra A, Raneri J, Schory K, et al. The effect of [46] Blain GM, Smith CA, Henderson KS, Dempsey JA. Contribution of the carotid sleep onset on upper airway muscle activity in patients with sleep apnoea body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog. versus controls. The Journal of physiology. 2005;564(2):549–62. J Appl Physiol 2009;106(5):1564–73. [54] Dempsey JA. Crossing the apnoeic threshold: causes and consequences. Exp [47] Nattie E, Li A. Central chemoreceptors: locations and functions. Compr Physiol Physiol 2005;90(1):13–24. 2012. [55] Khoo M, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing periodic [48] Amiel J, Laudier B, Attié-Bitach T, Trang H, de Pontual L, Gener B, et al. breathing in humans: a general model. J Appl Physiol 1982;53(3):644–59. Polyalanine expansion and frameshift mutations of the paired-like homeobox [56] Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemical gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet control stability in patients with obstructive sleep apnea. Am J Respir Crit Care 2003;33(4):459–61. Med 2001;163(5):1181–90. [49] Dempsey JA, Smith CA, Blain GM, Xie A, Gong Y, Teodorescu M. Role of central/ [57] Malhotra A, Owens RL. What is central sleep apnea? Respiratory care. 2010;55 peripheral chemoreceptors and their interdependence in the pathophysiology (9):1168–78. of sleep apnea. Arterial Chemoreception: Springer; 2012. p. 343–9. [58] Weil J. Variation in human ventilatory control—genetic influence on the [50] Burton MD, Kazemi H. Neurotransmitters in central respiratory control. Respir hypoxic ventilatory response. Respir Physiol Neurobiol 2003;135(2):239–46. Physiol 2000;122(2):111–21.