Clinical manifestations

Presentation and course

Neuropsychological associations with obstructive sleep apnea are inconsistent across studies. Some studies suggest decreased executive function, specific memory issues, and increased behavioral issues.

Pediatric obstructive sleep apnea is now recognized to be part of a spectrum of disorders characterized by repeated events of partial or complete upper airway obstruction during sleep. The phenotype of sleep-disordered breathing in children is variable, but the most prominent symptom is snoring (41). Although primary snoring is not usually associated with apnea, it is usually an indication of obstructive sleep apnea when it is accompanied by gasps, pauses in breathing, or arousals from sleep. Obstructive sleep apnea is caused by upper airway resistance or obstruction during sleep, typically associated with enlarged adenoids or tonsils. Though adenoids and tonsils have a typical developmental trajectory with decreasing size over time, children with obstructive sleep apnea have disproportionately larger adenoids and tonsils than their typically developing peers (27). Other factors can also contribute to obstructive sleep apnea in children such as abnormalities in craniofacial features, including retrognathia, and micrognathia, as well as the presence of underlying genetic syndromes such as Down syndrome, Prader-Willi syndrome, or Marfan syndrome. The International Classification of Sleep Disorders, 3rd edition, classifies sleep disorders into seven major categories: insomnia, sleep-related breathing disorder, hypersomnia of central origin, circadian rhythm sleep-wake disorders, parasomnias, sleep-related movement disorders, and “other” sleep disorders. Within this system, obstructive sleep apnea falls in the sleep-related breathing disorders category, and it applies to both adults and child populations (02).

Neuropsychological correlates of obstructive sleep apnea. Results of investigations examining neuropsychological correlates of obstructive sleep apnea in children have been quite variable, most likely related to differences in study design. For example, studies have differed in their definition and quantification of the sleep disorder, with some depending on parents’ report of sleep disturbance, whereas others employed objective assessment of obstructive sleep apnea through polysomnography (04; 30). Outcome measures have also differed, with some reports relying primarily on parental report of behavior or cognitive performance. Within cognitive domains, as well, some studies have emphasized general intellectual functioning, whereas others have included more specific areas of cognitive performance.

Intellectual functioning has a long history of study in the psychological sciences and was originally hypothesized as a construct using a single overall score from intelligence tests. The concept of intelligence has evolved over time to include several skill areas, most notably verbal and nonverbal domains (03). Some investigations of obstructive sleep apnea in children included measures of intellectual functioning and reported that children with obstructive sleep apnea tend to have lower scores than healthy, normal control children; however, the obtained scores of those with obstructive sleep apnea fall within normal limits (07; 43; 19). Kohler and colleagues found a range of deficits in children with documented sleep-disordered breathing, including poorer performance on measures of intellectual functioning as well as language and executive functioning, in comparison to controls (36). Hunter and colleagues found that children who snore performed less efficiently and with less capability across verbal and nonverbal cognitive demands (32). Lee and colleagues found that children with Down syndrome and obstructive sleep apnea, defined as greater than 1 on the apnea-hypopnea index, were associated with lower subtest scores of language domain and lower scores of expressive communications (39). In a cohort of 27 children with a mean age of 7.6 years, Wechsler test scores of full-scale intelligence quotient and verbal intelligence quotient were compared. The OSA group, defined as having an average AHI of 9.7, demonstrated much lower test scores (31). However, other studies have failed to find this association. For example, Giordani and colleagues examined baseline neuropsychological performance in children (aged 5 to 12 years) referred for adenotonsillectomy versus surgical controls and did not find differences in intellectual functioning (19). The discrepancy across studies may be due to differences in the tests that were used, as those that found an association used comprehensive batteries of intellectual functioning (07; 43; 19), whereas those that did not used abbreviated batteries that estimate general intellect (23; 11; 37; 36).

Executive functioning is a complex concept but is generally thought to comprise skills such as planning ability, behavioral inhibition, and concept formation and is hypothesized to be a key domain affected by obstructive sleep apnea (04). Several studies have been published examining the impact of obstructive sleep apnea on executive functioning, though again, with variable results. For example, Beebe and colleagues found an association between executive functioning and obstructive sleep apnea (05). Specifically, they compared the neuropsychological performances of children referred to a sleep center due to concerns related to obstructive sleep apnea versus community controls. The groups were characterized as “primary snorers,” “mild obstructive sleep apnea,” “moderate obstructive sleep apnea,” and “controls.” He reported that obstructive sleep apnea was related to behavioral regulation and executive functioning, though no other differences were observed on other cognitive domains. However, Giordani and colleagues did not find significant differences on measures of executive functioning, although working memory differences were observed (19). The Pre-School OSA Tonsillectomy Adenoidectomy Study (POSTA) assessed executive functioning between children with primary snoring (AHI < 1) and obstructive sleep apnea (AHI > 1) (09). No statistical difference was observed between the two groups, but high median subscores were noted. This suggests that there is a high proportion of behavioral problems in preschool children with primary snoring or obstructive sleep apnea. Seventy-eight children with sleep-disordered breathing, 61 of whom were diagnosed with OSA and 17 with primary snoring, used parent-report scales to measure daytime behavior (13). Children with sleep-disordered breathing demonstrated a higher level of inattentiveness and hyperactive behavior, including aggressive and rule-breaking behavior, compared to controls. This suggests that snoring and OSA are risks for developing behavioral and emotional dysfunction. The Tucson Children’s Assessment of Sleep Apnea study identified a negative correlation between the apnea-hypopnea index (AHI) and immediate recall, full scale intelligence quotient, performance IQ, and math achievement (34). Five-year follow-up results demonstrated that youth with untreated obstructive sleep apnea demonstrated hyperactivity, attention problems, aggressive behaviors, lower social competencies, poorer communication, or diminished adaptive skills (45). The discrepancies between these findings could be due to differences in the executive functioning measures used, or it is also possible that when executive measures include working memory, the associations with obstructive sleep apnea may account for the significant impairment in executive-related functioning.

Memory refers to the ability to take in and retain information over an extended period of time. Explicit memory includes both episodic (conscious memory for events) and semantic memory (fact knowledge) (03). The research evidence linking obstructive sleep apnea and memory has been mixed. For example, Blunden and colleagues found that children with obstructive sleep apnea showed poorer performance on memory screen (07), and Kaemingk found a similar association on a verbal learning task (34). However, O’Brien and colleagues failed to find an association between memory performance and obstructive sleep apnea in their group (43). Giordani and colleagues found delayed visual memory differences between children referred for adenotonsillectomy and control groups, although the difference between the adenotonsillectomy group with obstructive sleep apnea and the adenotonsillectomy group without obstructive sleep apnea was not significant, suggesting that obstructive sleep apnea was not necessarily the key contributing factor (19).

Visual perception and visuoconstruction refers to the ability to accurately perceive visual stimuli, copy a complex figure, or construct block designs under timed conditions. Researchers have failed to find any differences between children with obstructive sleep apnea and controls on these measures, except for one study that involved copying a complex figure (03; 05).

In summary, the neuropsychological associations with obstructive sleep apnea are inconsistent across studies. The reasons for this lack of consistency are puzzling and suggest that some perhaps more subtle, yet clinically significant disorder, other than obstructive sleep apnea underlies most cognitive deficits that have been tied to sleep disturbance in children. It is also possible that the alterations in brain functioning due to obstructive sleep apnea occur earlier in child development, and by the time children with obstructive sleep apnea reach school age, the issues resolve or are fixed and no longer variable with respect to severity of obstructive sleep apnea. It is also important to note that most studies do show that parent ratings appear to be sensitive to behavioral aspects associated with obstructive sleep apnea, as most studies that include parent ratings show that children with obstructive sleep apnea are generally more symptomatic than control groups included (04). It is possible that parents are detecting symptoms that objective neuropsychological measures do not. It also is possible that the generally more robust relationship between parental behavior ratings and polysomnography findings as compared to objective neuropsychological test results may be related to parents’ expectations of these behavioral problems and parents’ obvious awareness of sleep symptoms. Finally, other symptoms associated with obstructive sleep apnea may be the primary factors leading to disruption in cognitive functioning, such as elevated body mass index, presence of allergic rhinitis or repeated throat infections, and use of steroid inhalers.

Biological basis

Etiology and pathogenesis

Although not clearly identified, several hypotheses exist as to the underlying drivers of neuropsychological deficits in children with obstructive sleep apnea, including hypoxemia, sleep fragmentation, chronic inflammation, and obesity-related issues.

The etiology of neuropsychological deficits in children with obstructive sleep apnea is unknown, though possible associated factors include the cumulative effect of hypoxemia over time, cumulative effects of sleep fragmentation, underlying inflammation, or obesity-related issues (04; 21; 40).

The underlying mechanisms that contribute to the neuropsychological difficulties in obstructive sleep apnea are likely variable and multifactorial, involving multiple brain regions, neurotransmitter substances, and other factors. For example, the chronic and cumulative effect of hypoxemia over time or repeated episodes of sleep fragmentation may cause disruption in the normal development of the prefrontal cortex and related structures (04; 19). Although the prefrontal cortex has been shown to be particularly susceptible to disruption associated with hypoxemia in adults and animals, a clearly established link has not been documented in children (05). Yu and colleagues analyzed the gray matter volume of the right middle frontal gyrus in children aged 8 to 13 years with and without OSA (48). The Das-Naglieri cognitive assessment system was used to assess subjects’ cognition. Analysis demonstrated that children with OSA had large gray matter volume in the right middle frontal gyrus and lower word scores in the word series in the Das-Naglieri assessment. This suggests that development of gray matter volume in the frontal cortex associated with attention may be sensitive to the effects of OSA independent of the degree of obstructive apnea hypopnea index. In addition, other structures such as the hippocampus have also been implicated. For example, mouse models have shown associations between obstructive sleep apnea and oxidative stress that contribute to cell death within the hippocampus. Intermittent hypoxia in young children may be attributed to changes in the hippocampus, the mammalian center for early learning and memory. These structural alternations further cause a reduction in hippocampal long-term potentiation as well as functional deficits in spatial learning. Oxidative stress and reactive oxygen species may be central to neurocognitive change (08). Although these specific pathophysiological findings have not been documented in children, Giordani’s findings related to delayed visual memory suggest that such associations are possible. Research has also begun to establish the association of elevations in proinflammatory markers in children with obstructive sleep apnea as well as symptoms of daytime sleepiness and difficulties in school (21). Although some may argue that proinflammatory markers may be a consequence of obesity, which is known to be associated with obstructive sleep apnea, Gozal and colleagues reported on a group of non-obese children who exhibited elevated proinflammatory markers in the presence of obstructive sleep apnea (21). A study focusing on carotid changes and inflammatory markers found that children aged 5 to 13 years with obstructive sleep apnea demonstrated upregulation of proinflammatory cytokines, including sCD40-L, IL6, and IL-8 (47). Brain-derived neurotrophic factor, tyrosine kinase receptor B, interleukin-1beta, and tumor necrosis factor-alpha were analyzed in children with OSA and primary snoring and control groups. Serum brain-derived neurotrophic factor as well as tyrosine kinase receptor B levels were lower in children with OSA and primary snoring. Serum interleukin-1 beta as well as tumor necrosis factor-alpha levels were higher compared to controls (17).

Epidemiology

The percentage of children with obstructive sleep apnea and neuropsychological impairment is unknown. An estimated 15% to 25% of patients who present with the more common neuropsychological symptoms associated with obstructive sleep apnea, including inattention, hyperactivity, or learning problems, may also suffer from sleep-disordered breathing.

Patients who present with the more common neuropsychological symptoms associated with obstructive sleep apnea, including inattention, hyperactivity, or learning problems, should also be screened for symptoms of obstructive sleep apnea as the percentage of children with attention-deficit/hyperactivity disorder who may also suffer from sleep-disordered breathing has been estimated in the range of 15% to 25% (43; 11). Large-scale epidemiologic studies of obstructive sleep apnea and neuropsychological deficits in children with obstructive sleep apnea have not been completed. However, given that lab-based studies of obstructive sleep apnea report prevalence estimates of 1% to 4%, the percentage of children within this group who also demonstrate deficient neuropsychological functioning is probably less than the estimates of prevalence of obstructive sleep apnea (40). Smaller studies assessing neurocognitive impairment associated with obstructive sleep apnea and specific disease processes have been conducted. Among 30 children with congenital heart disease, the incidence of obstructive sleep apnea was 57% (12). In this sample, children with obstructive sleep apnea and congenital heart disease were found to have 12 fewer IQ points than children with congenital heart disease only. Obstructive sleep apnea was also associated with memory impairment in this sample. Among children with sickle cell disease, the prevalence of obstructive sleep apnea is estimated to be as high as 41% (35). When comparing neurocognitive function in children with both sickle cell disease and obstructive sleep apnea, children with sickle cell disease only, and children without a chronic health condition, there was no evidence that sickle cell disease and obstructive sleep apnea contributed to decreased cognitive functioning compared to sickle cell disease alone (06). The prevalence of obstructive sleep apnea among children with Down syndrome has been estimated to be between 45% and 76% (38). Obstructive sleep apnea has been associated with lower language subscores in children with Down syndrome (39).

Diagnostic workup

In laboratory overnight polysomnography with carbon dioxide monitoring is the gold standard for evaluating sleep-related breathing disorders in children.

Evaluation of the symptoms of sleep-disordered breathing using parent rating scales may be helpful as an initial screen of possible sleep-disordered breathing symptoms. The Pediatric Sleep Questionnaire (PSQ) (10) and the Obstructive Sleep Apnea Quality of Life Survery-18 (OSA-18) (18) are examples. Overnight polysomnography with carbon dioxide monitoring continues to be the gold standard in evaluation of obstructive sleep apnea in children. This method measures and quantifies ventilatory symptoms and sleep abnormalities associated with sleep-disordered breathing but involves overnight stays in sleep laboratories so that respiratory functions, sleep-wake cycles, cardiac function, oxygen saturation, and carbon dioxide tension and behavior can be monitored.

Management

Therapies to treat obstructive sleep apnea in children promote airway patency through several modalities, including surgical intervention, orthodontia, positive airway pressure therapy, and other medical interventions. Tonsillectomy and adenoidectomy are typically first-line therapy but may not effectively relieve the airway obstruction in sleep, especially in obese patients.

Treatment of obstructive sleep apnea in children can involve several modalities ranging from additional surgical intervention, high-flow air via nasal cannula, positive airway pressure therapy, oral appliance therapy, positional therapy, and medication management. The most common treatment of obstructive sleep apnea in children remains adenotonsillectomy. However, adenotonsillectomy may not provide complete remission of obstructive sleep apnea–related neuropsychological inefficiencies. If surgical or orthodontic therapy is performed, reassessment of residual sleep apnea is important. Parents and physicians should consider additional therapies to treat any residual sleep apnea. Although it is unknown whether treatment for obstructive sleep apnea provides relief or remission of neurobehavioral problems in children with obstructive sleep apnea, accumulating evidence suggests that parents and physicians need to consider this possibility, along with medication or other alternative approaches used to control these conditions (29).

Outcomes

In cases where adenotonsillectomy is performed, rates of remission from obstructive sleep apnea have been reported as high as 85% (46). However, in cases where surgery cannot be performed or in cases where surgery has not provided remission, the use of continuous positive airway pressure (CPAP) and bilevel positive airway pressure BiPAP can be considered postoperatively in order to improve the airway. It is important to note that compliance with these devices can be quite poor, and they are not typically recommended for children with adenotonsillar hypertrophy. In addition, studies examining the impact of adenotonsillectomy on obstructive sleep apnea outcomes have not been supportive (29). For example, in a longitudinal study of children with obstructive sleep apnea referred for adenotonsillectomy, Giordani and colleagues found that children exhibited declines in learning and memory measures, as well as verbal abstraction, suggesting the need for ongoing monitoring following surgery (20). Recognizing that baseline levels of inflammatory cytokines (IL-6, IL-8, Il-17, CRP, TNF-alpha) increase proportionately to severity of OSA in children from previous studies, Eldin and colleagues found adenotonsillectomy improved cognitive function attributed to decreased serum levels of inflammatory cytokines (15).

CHAT was the first large randomized controlled trial to evaluate the efficacy of early adenotonsillectomy versus watchful waiting with supportive care in children with obstructive sleep apnea (42). Neurobehavioral measure of attention and executive function was the primary outcome, and secondary outcomes included caregiver and teacher ratings of behavior, symptoms of obstructive sleep apnea, sleepiness, disease-specific quality of life, and global quality of life. Children 5 to 9 years of age with obstructive sleep apnea were randomly assigned to early adenotonsillectomy or watchful waiting. Results demonstrated no correlation between severity of obstructive sleep apnea and treatment when assessed attention and executive function. Early adenotonsillectomy was found to reduce obstructive sleep apnea symptoms and improve secondary outcomes such as behavior, quality of life, selective attention, and visual scanning. The PSGs of children who underwent watchful waiting with supportive care had normalized by seven months in almost half of this treatment arm, suggesting that children with nonsevere obstructive sleep apnea may recover over time without surgical intervention (42).

The CHAT study did not include children younger than 5 years old, but the Karolinska Adenotonsillectomy (KATE) randomized controlled trial examined whether adenotonsillectomy was more effective than watchful waiting for treating mild to moderate obstructive sleep apnea in healthy children 2 to 4 years of age (16). Both groups had a reduction in mean obstructive AHI score, with the adenotonsillectomy group reporting a decrease of 2.9 and the watchful waiting group reporting a decrease of 1.9. There was not a significant difference in decrease in obstructive AHI between the two groups. Completed questionnaires demonstrated that there was a larger difference in reported measures of quality following adenotonsillectomy. The KATE study suggests that children 2 to 4 years of age with mild obstructive sleep apnea may benefit from watchful waiting whereas children 2 to 4 years of age with moderate obstructive sleep apnea may be considered for early adenotonsillectomy.

High flow air via nasal cannula (HFNC) as treatment for obstructive sleep apnea in children has gained ground, particularly in children who have difficulty complying with continuous positive airway pressure (CPAP). In a small study of 10 school-age subjects, high-flow nasal cannula reduced respiratory events and heart rate, and it improved oxygenation in CPAP intolerant children with moderate to severe obstructive sleep apnea (28). In a study of a small sample of eight patients who were not compliant with CPAP therapy (less than 2 hours/night) who were started on HFNC demonstrated that after 1 month, five out eight patients were able to increase compliance to greater than 4 hours/night with resolution of obstructive sleep apnea (01).

In several small sample studies, medical management with oral montelukast has been shown to improve symptoms, including snoring and mouth breathing. Oral montelukast was also shown to reduce tonsil morphology measured by grading. Comparing polysomnography monitoring parameters and high-flow air via nasal cannula, oral montelukast also demonstrated a decrease on the apnea-hypopnea index ranging from 0.46 to 1.62 (33).