Sleep Complaints and Sleep Architecture in Children With Idiopathic Central Sleep Apnea

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1 pii: jc SCIENTIFIC INVESTIGATIONS Sleep Complaints and Sleep Architecture in Children With Idiopathic Central Sleep Apnea Neepa Gurbani, DO 1 ; Stijn L.Verhulst, MD, PhD 2,3 ; Chee Tan, MD 1 ; Narong Simakajornboon, MD 1 1 Division of Pulmonary and Sleep Medicine, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio; 2 Division of Pulmonary and Sleep Medicine, Antwerp University Hospital, Edegem, Belgium; 3 Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium Study Objectives: Idiopathic central sleep apnea (ICSA) is categorized as a type of nonhypercapnic central sleep apnea (CSA). Recurrent cessation and resumption of respiration leads to sleep fragmentation, which causes excessive daytime sleepiness, frequent nocturnal awakenings, or both. ICSA has been described in the adult population but there is limited information in children. The purpose of this study was to describe clinical manifestations and polysomnographic findings in children with ICSA. Methods: A retrospective review of medical records and polysomnograms was performed for 14 pediatric patients with ICSA, 9 from Cincinnati Children s Hospital Medical Center and 5 from Antwerp University Hospital. Polysomnographic features of patients with ICSA were compared with those of nine age-matched control group subjects. Patients with CSA caused by medical or neurological disorders, medication use, or substance use were excluded. Results: Sleep complaints were common in the 14 children with ICSA, including those with sleep-onset insomnia (7 children), frequent nighttime awakening (3 children), restless sleep (7 children), and daytime sleepiness (5 children). Symptoms of sleep-disordered breathing were noted in 11 of 14 subjects. Compared to that of the control group, sleep latency in the ICSA group was significantly prolonged (P <.05). The percentage of stage 2 sleep was significantly higher (P <.05), and slow wave sleep was significantly lower in patients with ICSA (P <.05). Conclusions: Similar to adult patients, children with ICSA present with complaints of insomnia, daytime sleepiness, and symptoms of obstructive sleep apnea. Analysis of polysomnograms reveals prolonged sleep latency, increased stage 2 sleep, and decreased slow wave sleep. Further studies are needed to assess mechanisms and the role of hypercapnic response in the pathogenesis of children with ICSA. Keywords: children, idiopathic central sleep apnea, insomnia Citation: Gurbani N, Verhulst SL, Tan C, Simakajornboon N. Sleep complaints and sleep architecture in children with idiopathic central sleep apnea. J Clin Sleep Med. 2017;13(6): INTRODUCTION Central sleep apnea (CSA) is characterized by a lack of drive to breathe during sleep. The condition leads to insufficient or absent ventilation and compromised gas exchange and is accompanied by a lack of respiratory effort during cessation of airflow. There are several manifestations of CSA, which is usually classified based on carbon dioxide (CO 2 ) levels during wakefulness as hypercapnic or nonhypercapnic CSA. Idiopathic central sleep apnea (ICSA) is categorized as nonhypercapnic CSA. Unlike patients with high-altitude periodic breathing, congestive heart failure, or neurologic diseases, patients with ICSA have central apneas during sleep, with normocapnia or hypocapnia during wakefulness without any underlying medical illness. 1 In adults with ICSA, common presenting features include sleep fragmentation, excessive daytime sleepiness, or insomnia. The true demographics and prevalence of ICSA in the general population are not known but within a sleep center population, the prevalence is reportedly 4% to 7%. 1 ICSA occurs most often in middle-aged to elderly individuals, and is more common in men than women. 2 Apneas are most commonly observed during the lighter stages of sleep, such as stages 1 and 2. Arousals typically occur at the termination of central apnea. 1 The BRIEF SUMMARY Current Knowledge/Study Rationale: ICSA has been described and studied in the adult population but little is known about children with the condition. Our literature review confirms there are no published case descriptions or clinical studies involving children with ICSA. Study Impact: The description of these cases of children with ICSA may help in increasing the understanding of common clinical presentations, pathophysiology of ICSA in children, and the effects of therapy on central respiratory events, sleep architecture, and quality of life. pathophysiology of ICSA is not fully understood. Suggested mechanisms include elevated hypercapnic ventilatory responses that lead to hypocapnia and respiratory control instability and further instability upon arousal with accompanying hyperventilation. These factors render the patient vulnerable to crossing the apnea threshold, which may be very close to the sleeping eucapnic partial pressure of CO 2. 1 Multiple modalities for the treatment of ICSA have been studied, mainly by observational studies in small numbers of adult patients. Literature on the management of CSA in adults suggests uses of supplemental oxygen, 3 inhaled CO 2, 4,5 nasal continuous positive airway pressure, 6 and medications including acetazolamide and zolpidem. 7,8 777 Journal of Clinical Sleep Medicine, Vol. 13, No. 6, 2017

2 ICSA has been described and studied in the adult population but little is known about children with this condition. Therefore, the purpose of our study was to describe the clinical manifestations, polysomnographic findings, and treatment pattern in children with ICSA. METHODS A retrospective review of medical records and polysomnograms was performed from January 2005 to April 2015 for pediatric patients with ICSA at Cincinnati Children s Hospital Medical Center (CCHMC) and Antwerp University Hospital. Patients received a diagnosis of ICSA based on the criteria by the International Classification of Sleep Disorders, which includes patient report of at least one of the following factors: (1) excessive daytime sleepiness, frequent arousals and awakenings during sleep or insomnia complaints, or shortness of breath upon awakening; (2) polysomnography (PSG) shows five or more central apneas per hour of sleep; (3) the disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use, or substance use disorder. 2 Patients with predominant obstructive sleep apnea were excluded from the study. The control subjects were normal asymptomatic subjects from our previous study, 9 and were age-matched to ICSA subjects. The study was approved by the Institutional Board Review at CCHMC and Antwerp University Hospital. PSG was performed using the Grass system at CCHMC (Grass Telefactor, West Warwick, Rhode Island, United States) and OSG system (OSG BVBA, Bussestraat 17, B-2840 Rumst, Belgium) at Antwerp University Hospital. The standard pediatric montage was used and the following parameters were recorded simultaneously: bilateral electrooculogram, electroencephalography (EEG; C3A2, C4A1, O1A2, O2A1), chin electromyogram, anterior tibialis electromyogram, tracheal microphone, electrocardiography, pulse oximetry and pulse waveform, thoracic and abdominal inductance plethysmography, nasal thermistor, nasal pressure transducer (Protech, Mukilteo, Washington, United States), end-tidal CO 2 (ETCO 2 ), (BCI Capnoguard, Dublin, Ohio, United States). PSG was performed in accordance with the American Academy of Sleep Medicine guidelines, 10 results scored by registered sleep technologists, and reviewed by board certified pediatric sleep specialists. American Academy of Sleep Medicine 2007 scoring rules were used to score CSA, including absent inspiratory effort associated with one of the following factors: (1) the event lasting 20 seconds or (2) the event lasting for duration of at least two breaths and associated with arousal, an awakening or 3% oxygen desaturation. An exception to this rule was made in 2 of 14 cases where a diagnosis of CSA was made with central apnea index 5 due to prolonged duration of central apneas greater than 20 seconds associated with severe oxygen desaturation, or significant frequent episodes of periodic breathing for which individual contributing apnea events did not meet desaturation criteria for scoring of central apnea. Central hypopneas were not scored, and therefore were not included in the central apnea index. Our data collection included patient demographics, medical diagnoses, presenting clinical features, medical and laboratory tests, medications, PSG results, and information on patients subsequent clinic visits and polysomnograms. Descriptive statistics were calculated for key demographic and PSG variables. Means and standard deviations are reported for continuous variables and frequencies and percentages are reported for categorical variables. The t test was also used for continuous variables such as age and PSG parameters. RESULTS A total of 14 pediatric patients with ICSA, 9 from CCHMC and 5 from Antwerp University Hospital, met criteria for entry into analysis. Descriptive data including age, body mass index percentile, presenting symptoms, and all investigations for each patient in the ICSA group are presented in Table 1. The demographic and polysomnographic features of the ICSA group and the nine patients in the age-matched control group are presented in Table 2. The mean ages of the patients in the ICSA and control groups were 9.6 years and 8.5 years, respectively. No significant difference was noted between the demographic features of the ICSA and control groups. There were nine males and five females in the ICSA group. Sleep complaints are common in the children in the ICSA group, including sleep-onset insomnia (7 patients), frequent nighttime awakening (3 patients), restless sleep (7 patients), and daytime sleepiness (5 patients). Symptoms of sleep-disordered breathing, including snoring, respiratory pauses, or gasping, were noted in 11 subjects. Comorbid conditions in the ICSA group included attention deficit hyperactivity disorder (6 patients), bipolar disorder (2 patients), mood disorder (1 patient), anxiety (1 patient), depression (1 patient), Asperger syndrome (1 patient), hypotonia (2 patients), rheumatoid arthritis (1 patient), Down syndrome (1 patient), obesity (1 patient), asthma (2 patients), allergic rhinitis (2 patients), eczema (1 patient), and gastroesophageal reflux (1 patient). There was no reported family history of CSA. Exposure to smoking was reported in four patients. Physical examination findings showed an average body mass index of 19.5 kg/m 2 in the ICSA group (range, 14 to 30 kg/m 2 ). Of nine patients in the ICSA group, Mallampati score was 2 in seven patients and 4 in two patients. Imaging and laboratory studies in the ICSA group included brain magnetic resonance imaging, serum amino acids, urine organic acids, echocardiogram, thyroid function tests, blood gas, and bicarbonate levels. The details of the workup for each patient in the ICSA group are summarized in Table 1. Brain magnetic resonance imaging studies were obtained and 11 of 14 were normal; of the 3 with abnormal findings unrelated to CSA, 1 showed incomplete myelination for age, another showed a bright spot in the posterior pituitary, and the third revealed an ectopic pituitary. Serum amino acid and urine organic acid levels in 5 of 14 patients were normal. Echocardiograms were obtained in 10 of 14 patients and were normal; 1 patient had mitral valve regurgitation. Thyroid function tests were normal in 9 of 14 patients. Capillary blood gas levels obtained in 6 of 14 patients were normal, with ph ranging from 7.31 to 7.41 Journal of Clinical Sleep Medicine, Vol. 13, No. 6,

3 Table 1 Demographics, presenting symptoms, and workup in idiopathic central sleep apnea group. ICSA Patient No. Age (y) Race BMI % ile Symptoms Comorbidities Brain MRI 1 5 Caucasian 29.2 Snoring, pauses Ehlers-Danlos Ectopic syndrome pituitary 2 10 Caucasian 24.6 Snoring, gasping, pauses, ADHD, anxiety, hyperactivity depression 3 14 Caucasian 95 Snoring, gasping, pauses, sleep onset and maintenance problems, restless sleep 4 18 African American 75 Snoring, gasping, pauses, sleep onset and maintenance problems, restless sleep, daytime sleepiness 5 8 Caucasian 77 Pauses, sleep onset problem, restless sleep and daytime sleepiness, hyperactivity ADHD, bipolar disorder, allergic rhinitis Asthma, allergic rhinitis, eczema, GER ADHD, bipolar disorder Serum Amino Echocardiogram Chest Xray Thyroid Function Tests Acids and Urine Organic Acids Normal N/A N/A N/A Normal Normal Normal Normal N/A Normal Mitral regurgitation N/A Normal N/A Normal Normal N/A N/A Normal Normal Normal N/A N/A Normal 6 5 N/A 50 Snoring none Normal N/A Normal Normal N/A N/A 15 Snoring, gasping, pauses none Normal Normal Normal Normal N/A 8 17 N/A 20.2 Snoring, pauses, sleep onset Down syndrome, Normal Normal N/A Normal N/A problem, restless sleep Rheumatoid Arthritis 9 7 N/A 30 Snoring, pauses, restless none Normal Normal Normal Normal Normal sleep 10 7 N/A 99 Restless sleep Obesity Normal Normal Normal Caucasian 94 Snoring, sleep onset problem, hyperactivity ADHD, hypotonia Incomplete myelination N/A N/A Normal N/A Caucasian 93 Gasping, pauses, sleep onset problem daytime sleepiness, hyperactivity 13 8 Caucasian 98 Snoring, pauses, daytime sleepiness and hyperactivity 14 4 Caucasian 17.4 Snoring, sleep onset and maintenance problem, restless sleep Asperger s syndrome, mood disorder Bright spot in posterior pituitary N/A N/A Normal N/A ADHD Normal N/A N/A N/A Normal asthma Normal Normal Normal N/A Normal ADHD = attention deficit hyperactivity disorder, BMI = body mass index, GER = gastroesophageal reflux, ICSA = idiopathic central sleep apnea, MRI = magnetic resonance imaging, N/A = not applicable. and PCO 2 ranging from 38 to 44 mmhg. The bicarbonate levels obtained from renal panels in 11 of 14 patients ranged from 20 to 33 mmol/l. The hypercapnic response performed in 1 of 14 patients showed an exaggerated hypercapnic response. Analysis of sleep architecture showed that the percentage of stage 2 sleep was significantly higher (49 ± 16% [ICSA] versus 40 ± 1% [control], P <.05), and the percentage of slow wave sleep was significantly lower in patients with ICSA (27 ± 1% [ICSA] versus 38 ± 3 % [control], P <.05) as shown in Figure 1. Compared to the control group, sleep latency was significantly prolonged in the ICSA group (66.5 ± 67 minutes [ICSA] versus 22.3 ± 9.52 minutes [control]; P <.05) as shown in Figure 2. There was no significant difference in percentage of rapid eye movement sleep (18.6 ± 10.7% [ICSA] versus 20 ± 2.8% [control]), sleep efficiency (71.7 ± 22.3% [ICSA] versus 86.2 ± 4% [control]) or arousal index (13.6 ± 10.8 [ICSA] versus 16.6 ± 3.6 [control]) between the two groups as shown in Figure 1 and Figure 2. A detailed description of the central events for the Table 2 Comparison of demographic and respiratory sleep parameters in the idiopathic central sleep apnea and control groups. Group Mean Age (y) Mean AHI (events/h) Control 8.5 ± ± 0.7 ICSA 9.6 ± ± 18.2 P value AHI = apnea-hypopnea index; ICSA = idiopathic central sleep apnea. patients in the ICSA group is presented in Table 3. Analyses of the respiratory sleep parameters showed that the apneahypopnea index (AHI) was significantly higher in the ICSA group (18.14 ± 18.2 versus 0.65 ± 0.7 [control], P <.05) as shown in Table 2. A majority of the respiratory events were central in origin in the ICSA group, with the central index ranging from 2.4 to 74.9 events/h and the average index of 16.9 events/h. The average duration of the central events was 11.5 ± 3.8 seconds, 779 Journal of Clinical Sleep Medicine, Vol. 13, No. 6, 2017

4 Figure 1 Comparison of non-rapid eye movement stage 1, 2, 3 and rapid eye movement sleep between the two groups (idiopathic central sleep apnea and control). ICSA = idiopathic central sleep apnea, NREM = non-rapid eye movement, REM = rapid eye movement, NS = nonsignificant. Figure 2 Comparison of sleep latency, sleep efficiency, and arousal index between the two groups (idiopathic central sleep apnea and control). ICSA = idiopathic central sleep apnea, NS = nonsignificant. with an average longest central apnea duration of ± 17.7 seconds. The obstructive index (OI) in the ICSA group ranged from 0 to 9 events/h with an average index of 1.44 events/h. The average oxygen saturation was significantly lower in the ICSA group than the control group (96.6 ± 1.4 [ICSA] versus 99.2 ± 0.7 [control], P <.001) as shown in Figure 3. There was no significant difference between the average ETCO 2 between the two groups as shown in Figure 3. ICSA was managed with supplemental oxygen in 3 of 14 patients, bilevel positive pressure support in 1 patient, and 7 of 14 patients were treated with acetazolamide. The remaining patients were monitored closely to determine if the ICSA Journal of Clinical Sleep Medicine, Vol. 13, No. 6,

5 Figure 3 Comparison of average oxygen saturation and average end tidal CO 2 between the two groups (idiopathic central sleep apnea and control). ICSA = idiopathic central sleep apnea, NS = nonsignificant. Table 3 Description of the central events in the idiopathic central sleep apnea group. ICSA Patient No. AHI (events/h) CAI (events/h) Central Apnea Average Duration (s) Central Apnea Longest Duration (s) Central Apnea Saturation Nadir (%) N/A N/A N/A N/A N/A N/A N/A N/A N/A 16 N/A AHI = apnea-hypopnea index, CAI = central apnea index, ICSA = idiopathic central sleep apnea, N/A = not applicable. improved or resolved. All patients responded to prescribed treatment. The duration of follow-up ranged from 2 to 9 years. Of the 14 ICSA patients, 8 had follow-up sleep studies to document treatment efficacy or resolution of CSA. Of these 8 patients, 6 experienced resolution of CSA, 1 patient had improvement of CSA, and 1 patient had persistent CSA. DISCUSSION This is the first study to describe clinical manifestations, polysomnographic findings, and treatment patterns in children with ICSA. Analyses of sleep architecture revealed alteration of sleep architecture including prolonged sleep latency, increased stage 2 sleep, and reciprocal decrease in slow wave sleep. Interestingly, children with ICSA had significantly lower average oxygen saturation, but had no significant difference in the average ETCO 2 when compared to a control group. The prevalence of ICSA is not known but it is expected to be rare in children, although most studies suggest that it is found in middle-aged to elderly adults. 2 Only nine cases were identified from 2005 to 2015 at the CCHMC. Among the clinical presentations, sleep complaints such as sleep onset insomnia, restless sleep, and nighttime awakening were common in the children with ICSA. Interestingly, most children with ICSA had symptoms of obstructive sleep apnea such as snoring, breathing pauses, and gasping. These findings are consistent with previous studies in the adult population. 8,11 Quadri et al. 8 studied 28 adults with ICSA, defined as central apnea-hypopnea index (CAHI) greater than or equal to 10 events/h and OI of less than or equal to 5 events/h, excluding patients with underlying cardiac disease, lung disease, obstructive sleep apnea, obesity hypoventilation syndrome, or neurologic disease. In this study, 14 subjects had excessive daytime sleepiness, 5 had difficulty initiating or maintaining sleep, 11 had a history of witnessed apneas, and 8 were habitual snorers. The similarity of symptoms 781 Journal of Clinical Sleep Medicine, Vol. 13, No. 6, 2017

6 between adults and children with ICSA suggests that in adults with ICSA, problems may have developed since childhood. Our study also revealed a significantly higher proportion of stage 2 sleep in patients with ICSA (49 ± 16%) compared to the control group (40 ± 1%). A previous study by Xie et al. 12 of adults with ICSA showed apneas occurred mostly in stages 1 and 2 sleep, with stage 1 accounting for 5.5% and stage 2 sleep representing 74.4% of total sleep time. The occurrence of central apneas in stages 1 and 2 sleep rather than slow wave or rapid eye movement sleep is probably related to greater arousability in the lighter stages of sleep. 12 Arousals can lead to hyperventilation with the waking stimulus and altered chemosensitivity, likely triggering hypocapnia in patients with ICSA. 1 Although our study did not show a significant difference in the arousal index between the ICSA and control groups, the possibility of increased microarousals or subcortical arousals cannot be excluded. Analysis of sleep architecture also showed prolonged sleep latency in children with ICSA that could be related to underlying comorbidities and may explain sleep onset issues in this population. Our study showed a mean AHI of ± 18.2 events/h and an average CAI of events/h in children with ICSA, which is lower than reported in previous studies in adult populations. Quadri et al. 8 reported a mean AHI of 30 ± 18.1 events/h and CAHI of 26 ± 17.2 events/h in adults with ICSA. Our study did not show any significant difference in the average ETCO 2 between ICSA and control subjects. This is in contrast to previous studies in adults that showed lower CO 2 level in patients with ICSA. 11,8 Xie et al. 11 reported a lower average CO 2 of 37.8 ± 1.2 mmhg in adults with ICSA compared 42.7 ± 0.9 mmhg in control subjects. A lower CO 2 level in patients with ICSA may play a role in the pathogenesis of CSA. The proposed mechanisms for the pattern of breathing in ICSA include abnormalities in CO 2 apnea threshold, ventilator control loop gain, and sleep instability or arousability. 8 The CO 2 apnea threshold aids in maintaining eucapnia during sleep. When the apneic threshold is close to the sleep eucapnia level, a small degree of hyperventilation can drive the PCO 2 to fall below the apnea threshold during sleep, resulting in central apnea. 8 The ventilatory control loop gain system is high in subjects with ICSA, so there is a higher degree of change in ventilation that occurs for a given change in PCO 2, leading to hypocapnia and central apneas. 8 These patients may also have a lower arousal threshold, which contributes to the breathing pattern in individuals with ICSA. 8 Although baseline CO 2 was not decreased in our children with ICSA, one subject who underwent a hypercapnic challenge was found to have an exaggerated hypercapnic response, indicating the presence of a high loop gain system. In addition, we found that the average oxygen saturation was lower in our ICSA group (96.6 ± 1.4%) compared to our control group (99.2 ± 0.7%). The reason for this is unknown because a previous study did not show any significant difference in oxygen saturation in adults with ICSA. 11 The lower baseline oxygen saturation may further contribute to high loop gain and respiratory instability in children with ICSA. Most of the patients in our study were treated with acetazolamide, with a few patients receiving supplemental oxygen and one patient receiving bilevel positive pressure support. Some patients were treated without any interventions (close clinical monitoring and repeat sleep studies). Many treatment modalities have been studied for the management of ICSA, mainly by observational studies in a few adult patients. ICSA patients with heightened chemosensitivity may benefit from the stabilizing respiratory control effects associated with oxygen therapy. 3 Studies have also demonstrated that mild increases in inspired CO 2 delivered directly or via face mask to increase dead space can be effective in treating ICSA. 4,5 Nasal CPAP has also been shown to be effective in some patients with ICSA. 6 Acetazolamide and zolpidem have also been shown to reduce total apneas and arousability in patients with ICSA. 7,8 The long-term prognosis in these patients is unknown. Our study has certain limitations. This is a retrospective study with a small number of pediatric subjects with ICSA. The diagnosis of ICSA is not very common in the pediatric population. Most children had CSA secondary to immaturity of respiratory control, congenital central hypoventilation, neuromuscular disease, or neurological disease, and were excluded from the study. Although it seems plausible, it is not clear whether the proposed mechanisms for ICSA in adults apply to children because there were no significant differences in the arousal index and average ETCO 2 between ICSA and control subjects, and the patients had normal baseline CO 2 with measurement of capillary blood gas. In addition, the patient group comprised children of a wide age range and coexisting comorbidities that may preclude accurate analysis of sleep architecture. Finally, only 8 of 14 subjects had follow-up sleep studies to document improvement of CSA after treatment. Larger studies in pediatric patients with ICSA are necessary to further validate our findings. ABBREVIATIONS ADHD, attention deficit hyperactivity disorder AHI, apnea-hypopnea index BMI, body mass index CAI, central apnea index CCHMC, Cincinnati Children s Hospital Medical Center CO 2, carbon dioxide CSA, central sleep apnea EKG, electrocardiography EMG, electromyogram EOG, electrooculogram ETCO 2, end-tidal CO 2 GER, gastroesophageal reflux ICSA, idiopathic central sleep apnea MRI, magnetic resonance imaging N/A, not applicable NREM, non-rapid eye movement NS, nonsignificant PSG, polysomnography REM, rapid eye movement REFERENCES 1. Eckert D, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: Pathophysiology and treatment. Chest. 2007;131(2): Journal of Clinical Sleep Medicine, Vol. 13, No. 6,

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