Brain Tissue Integrity and Autonomic Function Alterations in Childhood Obstructive Sleep Apnea and Attention-deficit/Hyperactivity Disorder, and After Adenotonsillectomy.

Background To date, obstructive sleep apnea (OSA) is a chronic and serious disorder with an increasing prevalence in many developed countries. OSA is characterized by dynamic imbalance between airway patency and collapse during sleep leading recurrent airway obstruction (partial or complete) and repetitive apneas and hypopneas. OSA results in gas exchange abnormalities, cortical arousals, autonomic arousals, sleep fragmentation, and systemic fragmentation. Notably, OSA has a prevalence of up to 5% in children and 50% in obese children. OSA is associated with various co-morbidities which affect multiple organ systems, resulting in acute events or long-term sequelae, and consequently incurring considerable social, economic, and health costs. For example, pediatric OSA can induce hypertension, cardiovascular disorder, metabolic syndrome, growth retardation, learning problem, night enuresis, and attention-deficit/hyperactivity disorder (ADHD). Persistent OSA severity is associated with the decreased quality of life of patients' families and increased concern regarding financial burden.

In children, behavioral impairment, neurocognitive dysfunction, and reduced scholastic achievements are now well-characterized morbidities of OSA. In addition, parentally reported daytime sleepiness, hyperactivity, and aggressive behaviors can also develop, albeit to a lesser extent in children who habitually snore but in the absence of OSA. Degrees of discipline problems and poor attention span were significantly higher in OSA children compared with non-OSA controls. However, a recent meta-analysis found that there were few studies with low risk of bias (levels of evidence I and II) showed that OSA children's intellectual abilities may be impaired but remain within the normal range. Capdevila et al (2008) recognized that 'the major intriguing component of the association between OSA and cognitive functioning lies in the observation that not all children with OSA actually manifest cognitive morbidities.'. Nevertheless, which specific cognitive ability (language, memory, attention, executive function) drives poor academic performance is unclear. Therefore, we must test OSA patients using measures that allow for fractionated higher- and lower-order cognitive abilities based on accepted cognitive neuropsychology models and find other factors may be recreating a role of OSA-associated neurobehavioral consequences.

OSA severity is potentially associated with genetic and environmental determinants of susceptibility in children. Increased body mass index (BMI), having the potential to central obesity, is one of the most important risk factors for OSA and is more strongly associated with neurocognitive and behavioral problems in children than OSA alone. Inflammation is associated with increased risk for neurocognitive deficits in children with obesity and/or OSA. Although obesity could influence academic performance, there was insufficient evidence to support a direct link between obesity and poor academic performance in school age children and change in weight status was not associated with change in cognitive function in children with obesity. Therefore, current evidences support that obesity has the potential to be a marker rather than a cause of low academic performance. Furthermore, the ε4 allele of the APOE gene is associated with increased risk of OSA and poorer cognition in children. However, APOE ε4 status alone was associated with memory, not language/executive functioning, in later life in a longitudinal study. Pediatric OSA is associated with sympathetic outflow in terms of overnight increases in urinary concentrations of catecholamines whereas increased urinary levels of γ-aminobutyric acid and decreased urinary level of taurine could underlie mechanisms of neuronal excitotoxicity and dysfunction. Both pediatric OSA and cognitive deficits might be to be predicted by overnight changes in urinary concentrations of selected neurotransmitters. However, those findings could not generalize to other disease entity. Incorporation of environmental elements such as nutrition, recurrent exposure to respiratory viruses, passive or active exposure to cigarette smoking, intensity of intellectual activity, and socioeconomic status is important in children because all these can affect both the pathophysiological risk for OSA as well as modify the susceptibility to the consequences of OSA. Unfortunately, there is still no consensus if we should consider OSA as a single disease with different phenotypes with or without neurocognitive deficits, or if there are different diseases with different genetic determinants, pathogenic mechanisms, prognosis, and treatment. Most of this important information is not routinely collected during clinical assessment of children with habitual snoring in ENT clinics.

ADHD, characterized by symptoms of inattention and hyperactivity/ impulsivity, often emerges during the preschool years and remains impairing throughout the life span. ADHD is among the most commonly diagnosed neurodevelopmental disorders, affecting approximately 8%-12% of children worldwide. Prevalence of ADHD in preschoolers, recently estimated to be 2.1%, is lower than that of school-age children and adolescents. The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) identifies 3 types of ADHD: primarily hyperactive-impulsive, primarily inattentive, and combined type. There is a body of evidence emerging that indicates that hyperactivity-impulsivity declines in preschoolers with ADHD, and inattention increases or at least becomes more evident when children enter structured school settings. ADHD is a heterogeneous disorder, in terms of the multifactorial etiological risk factors, diverse expressions of the symptom domains, comorbid disorders, neuropsychological impairments, and long-term trajectories. Both sleep and behavior problems are common in preschool and school-aged children. Notably, lower quality of sleep in infancy significantly predicts compromised attention regulation and behavior problems at 3-4 years of age. In our previous studies, we identified that pediatric OSA is closely associated with ADHD. In pediatric OSA, 32% and 35% had concomitant ADHD in children aged 4 to 5 years and those aged 6 to 11 years, respectively. In contrast, a full sleep assessment in children with ADHD found 50% of them had OSA that caused chronic sleep deprivation and could be considered as a signature of ADHD.

Alterations in the genes encoding for molecules involved in catecholamine signaling that weaken nor epinephrine production may impair the prefrontal cortex (PFC) circuits mediating the regulation of attention and behavior. Inadequate catecholamine release is associated with fatigue and ADHD, and therapeutic doses of ADHD medications likely normalize catecholamine transmission in patients with inadequate norepinephrine and dopamine levels, or both, thus bringing PFC function to more optimal levels. Prescription stimulants such as methylphenidate and non-stimulants such as atomoxetine are labeled for the treatment of ADHD from age approximately 6 and above years. Although there was no evidence of increased serious cardiovascular risk in children with ADHD exposed to ADHD medications, ADHD medications have been shown to increase blood pressure, heart rate, and QT interval in children. Halperin and Marks (2019) concluded that acute treatments of ADHD have demonstrable efficacy, but do not appear to fundamentally alter underlying mechanism. For example, improvement of pediatric OSA after adenotonsillectomy results in improvement of behavior problems during short-term follow-up and long-term follow-up. Recently, a combination of atomoxetine (norepinephrine reuptake inhibitor) and oxybutynin (antimuscarinic agent) administered orally before bedtime on 1 night greatly reduced adulthood OSA severity, and these findings also open new possibilities for the pharmacologic treatment for pediatric OSA with ADHD.