Sleep Measures and Morning Plasma TNF-α Levels in Children with Sleep-Disordered Breathing

OBSTRUCTIVE SLEEP APNEA (OSA) IS A RELATIVELY HIGHLY PREVALENT CONDITION IN CHILDREN AND HAS RECENTLY EMERGED AS MAJOR CAUSE OF neurobehavioral dysfunction and cardiovascular morbidity. In adults affected with OSA, excessive daytime sleepiness (EDS) is extremely frequent and accounts for one of the most important symptoms prompting medical referral for evaluation and treatment. However, the prevalence of EDS in children with OSA is somewhat unclear and probably depends on the perceptions of caretakers, since children are unlikely to verbalize such symptoms. In a 1995 study, parental reports in children being evaluated for suspected OSA initially indicated that only a small minority of these children (7%) present symptoms compatible with EDS.1 In contrast, more recent studies using questionnaires that included more specific questions on behaviors associated with EDS suggested that the frequency of EDS may revolve around the 20% to 50% of all children.2 When sleepiness was measured using the Multiple Sleep Latency Test (MSLT), approximately 13 to 20% of nonobese children fulfilling the criteria for OSA displayed EDS, whereas 40% to 60% of obese children with OSA fulfilled MSLT criteria of EDS.3–5 One of the major questions emanating from the aforementioned studies was whether polysomnographic measures could provide insights and identify increased risk for having EDS in children with OSA. To this effect, the magnitude of sleep fragmentation induced by OSA was quantified in both children and adults and allowed for development of a numerical algorithm, i.e., the sleep pressure score (SPS), that would theoretically indicate a putative threshold for disruption of sleep homeostasis such that further sleep disruption would then be theoretically met with increased EDS.6,7 Of note, the SPS derived from the arousal indices in each individual overnight sleep study seemed to confer improved prediction for the occurrence of both cognitive and behavior disturbances in snoring children.8 Notably, working under similar assumptions, Chervin and colleagues showed the presence of respiratory cycle-related electroencephalographic spectral changes in patients with OSA that seemed to correlate with EDS measures.9 Tumor necrosis factor (TNF)-α is one of the most important cytokines involved in sleep regulation.10 For example, injection of TNF-α induces physiologic sleep and increases the time spent in non-rapid eye movement phase. In addition, TNF-α levels follow a circadian variation and are increased after sleep deprivation; inhibition of TNF-α receptors in the brain is accompanied by the suppression of spontaneous non-rapid eye movement sleep. It is now well established that TNF-± levels are elevated in adults patients with OSA, and, in fact, circulating TNF-α levels have been proposed as a biologic marker of EDS. Indeed, Vgontzas and colleagues demonstrated that neutralizing TNF-α activity by administration of etanercept is associated with significant reductions in EDS in adult patients with OSA.11 We therefore conducted the present study to assess whether TNF-α levels are elevated in children with OSA and, if so, to determine whether specific demographic characteristics or polysomnographic measures would account for the variance in morning TNF-α plasma concentrations. We also examined whether the presence of EDS, as determined by MSLT, is associated with increased TNF-α levels in children with OSA and whether improved MSLT and TNF-α levels would emerge after surgical treatment of OSA.