Mona F. Philby

Effect of Sleep-disordered Breathing Severity on Cognitive Performance Measures in a Large Community Cohort of Young School-aged Children

RATIONALE Sleep-disordered breathing (SDB) in children is associated with cognitive challenges. However, potential associations between SDB severity and neurocognitive function, as well as the presence of an SDB cutoff, have not been fully explored. OBJECTIVES To determine whether SDB-associated adverse changes in neurocognitive functioning are severity dependent. METHODS A total of 1,010 snoring and nonsnoring children ages 5-7 years were prospectively recruited from public schools and underwent polysomnography and neurocognitive assessments of intellectual, attention, memory, language, and executive function development. The children were subdivided into four severity groups on the basis of apnea-hypopnea index (AHI), followed by comparisons of cognitive function, with a particular focus on standardized subtests of intellectual, language, attention, memory, and executive function. MEASUREMENT AND MAIN RESULTS Differential Ability Scales Verbal (P < 0.001) and Nonverbal (P = 0.002) performance, as well as global conceptual ability (IQ) (P < 0.001) scores, differed significantly across the groups, with individuals with higher AHI showing worse performance. Additionally, specific NEPSY (a Developmental Neuropsychological Assessment) subscores focused on attention and executive skills differed across the groups, indicating differences in levels of engagement and problem solving. Children with higher AHI (>5 per hour of total sleep time) were significantly more impaired than all three lower AHI groups, indicating a dose-response impact of SDB. CONCLUSIONS This large community-based sample of children highlights the significant deleterious impact of SDB, particularly in children with moderate to severe obstructive sleep apnea, and also that even snoring alone affects neurocognitive function. By affecting developing capabilities, as illustrated by cognitive measures in a severity-graded manner, SDB could adversely impact childrens capacity to attain academic and adaptive goals, ultimately hampering their ability to reach independence. Our findings support the need for increased awareness of SDB, with particular emphasis on children with more severe obstructive sleep apnea.

Impact of obstructive sleep apnoea on insulin resistance in nonobese and obese children.

Obstructive sleep apnoea (OSA) has been inconsistently associated with insulin resistance and adverse metabolic states. We aimed to assess independent contributions of OSA to insulin resistance and dyslipidaemia in a large paediatric cohort. Habitually snoring children underwent overnight polysomnography, anthropometric measurements and fasting laboratory evaluations. Primary outcome measures included insulin, glucose, homeostasis model of insulin resistance, lipoproteins and sleep disturbance measures. Among 459 children aged 5–12 years, obesity was the primary driver of most associations between OSA and metabolic measures, but sleep duration was inversely associated with glucose levels, with N3 and rapid eye movement (REM) sleep being negatively associated and sleep fragmentation positively associated with insulin resistance measures. In children with mild OSA, the presence of obesity increased the odds for insulin resistance, while higher apnoea/hypopnoea index values emerged among obese children who were more insulin-resistant. The exclusive presence of interactions between OSA and obesity in the degree of insulin resistance is coupled with synergistic contributions by sleep fragmentation to insulin resistance in the context of obesity. Insufficient N3 or REM sleep may also contribute to higher glycaemia independently of obesity. Studies are needed to better delineate the roles of puberty and sleep fragmentation in insulin resistance and the metabolic syndrome. OSA and obesity jointly affect insulin resistance, but insulin resistance is absent in nonobese children with OSA http://ow.ly/W4BmY

Impact of Adenotonsillectomy on Insulin Resistance and Lipoprotein Profile in Nonobese and Obese Children

BACKGROUND OSA associates with insulin resistance (IR), hyperglycemia, and dyslipidemia consistently in adults, but inconsistently in children. We set out to quantify the impact of OSA treatment upon obesity and metabolic outcomes and thus assess causality. METHODS Sixty-nine children with OSA; mean age, 5.9 years (range, 3-12.6); 55% boys; and 68% nonobese (NOB) underwent baseline overnight polysomnography, anthropometric and metabolic measurements, adenotonsillectomy (T&A), and follow-up testing a mean 7.9 months (range, 2-20) later. RESULTS Fifty-three children (77% of study cohort; 91% of obese children) had residual OSA (apnea-hypopnea index > 1 event/h) post-T&A. Fasting plasma insulin (FPI, 14.4 ± 9.4 → 12.6 ± 9.7 μIU/mL, P = .008), homeostasis model assessment-IR (3.05 ± 2.13 → 2.62 ± 2.22, P = .005), and high-density lipoprotein (HDL) (51.0 ± 12.9 → 56.5 ± 14.4 mg/dL, P = .007) improved despite increased BMI z score (1.43 ± 0.78 → 1.52 ± 0.62, P = .001); changes did not differ significantly between sexes or NOB and obese participants; however, post-T&A BMI z score rather than apnea-hypopnea index was the main predictor of levels of follow-up FPI, HDL, and other metabolic parameters. Higher baseline FPI and BMI-z predicted likelihood of residual OSA; conversely, on regression analysis, follow-up IR, HDL, and triglycerides were predicted by BMI z score, not residual OSA. CONCLUSIONS T&A improved IR and HDL, and residual OSA is predicted by baseline FPI and BMI z score, indicating a causal relationship; however, following T&A, residual metabolic dysfunction related to underlying adiposity rather than remaining sleep-disordered breathing. Finally, T&A cured OSA in < 25% of all children and only 10% of obese children; post-T&A polysomnography is indicated to assess which children still require treatment.

Reduced Regional Grey Matter Volumes in Pediatric Obstructive Sleep Apnea

Pediatric OSA is associated with cognitive risk. Since adult OSA manifests MRI evidence of brain injury, and animal models lead to regional neuronal losses, pediatric OSA patients may also be affected. We assessed the presence of neuronal injury, measured as regional grey matter volume, in 16 OSA children (8 male, 8.1 ± 2.2 years, AHI:11.1 ± 5.9 events/hr), and 200 control subjects (84 male, 8.2 ± 2.0 years), 191 of whom were from the NIH-Pediatric MRI database. High resolution T1-weighted whole-brain images were assessed between groups with voxel-based morphometry, using ANCOVA (covariates, age and gender; family-wise error correction, P < 0.01). Significant grey matter volume reductions appeared in OSA throughout areas of the superior frontal and prefrontal, and superior and lateral parietal cortices. Other affected sites included the brainstem, ventral medial prefrontal cortex, and superior temporal lobe, mostly on the left side. Thus, pediatric OSA subjects show extensive regionally-demarcated grey matter volume reductions in areas that control cognition and mood functions, even if such losses are apparently independent of cognitive deficits. Since OSA disease duration in our subjects is unknown, these findings may result from either delayed neuronal development, neuronal damaging processes, or a combination thereof, and could either reflect neuronal atrophy or reductions in cellular volume (neurons and glia).

Impact of sleep disordered breathing on behaviour among elementary school-aged children: a cross-sectional analysis of a large community-based sample

Sleep disordered breathing (SDB) in children has been associated with inattention, impulsivity and hyperactivity, but the associations between SDB severity and the type and severity of behavioural disruption are unclear. 1022 children aged 5–7 years old prospectively underwent sleep studies and behavioural assessments through completion of standardised instruments. Participants were subdivided into four categorical groups based on the apnoea–hypopnoea index (AHI; measured per hour of total sleep time (hTST)), i.e. Group 1: nonsnoring and AHI <1 hTST–1; Group 2: habitual snoring and AHI <1 hTST–1; Group 3: habitual snoring and AHI 1–5 hTST–1; and Group 4: habitual snoring and AHI >5 hTST–1, followed by comparisons of behavioural functioning across the groups. All 10 behavioural variables differed significantly between Group 1 and all other groups. Post hoc comparisons indicated that Group 2 was the most impaired for most behavioural measures. Furthermore, differences between Group 2 and more severe sleep pathology conditions were rarely significant. This large community-based paediatric cohort confirms earlier findings highlighting a significant impact of SDB on behavioural regulation, with the greatest impact being already apparent among habitually snoring children. Thus, a likely low asymptote exists regarding SDB behavioural impact, such that further increases in severity do not measurably increase parent-rated difficulties with behavioural regulation relative to controls. Our findings do support the need for considering early intervention, particularly among those children manifesting a behavioural impact of SDB. Snoring in school-aged children, even without sleep/respiratory disturbances, is linked to behavioural disturbances http://ow.ly/G4xJ302JlLF

Nocturnal Oximetry–based Evaluation of Habitually Snoring Children

Rationale: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea‐hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA. Methods: Deidentified nSpO2 recordings from a total of 4,191 children originating from 13 pediatric sleep laboratories around the world were prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single‐channel nSpO2 recordings from 589 patients referred for suspected OSA. Measurements and Main Results: The automatically estimated apnea‐hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively). Conclusions: Neural network‐based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.

Biomarkers of Alzheimer Disease in Children with Obstructive Sleep Apnea: Effect of Adenotonsillectomy.

STUDY OBJECTIVE Obese children are at increased risk for developing obstructive sleep apnea (OSA), and both of these conditions are associated with an increased risk for end-organ morbidities. Both OSA and obesity (OB) have been associated with increased risk for Alzheimer disease (AD). This study aimed to assess whether OSA and OB lead to increased plasma levels of 2 AD markers amyloid β protein 42 (Aβ42) and pre-senilin 1 (PS1). METHODS Fasting morning plasma samples from otherwise healthy children with a diagnosis of OB, OSA, or both (OSA+OB), and controls, and in a subset of children with OSA after adenotonsillectomy (T&A) were assayed for Aβ42 and PS1 levels using commercial enzyme-linked immunosorbent assay kits. RESULTS 286 children (mean age of 7.2 ± 2.7 y) were evaluated. Compared to control subjects, OB children had similar Aβ42 (108.3 ± 31.7 pg/mL versus 83.6 ± 14.6 pg/mL) and PS1 levels (0.89 ± 0.44 ng/mL versus 0.80 ± 0.29 pg/mL). However, OSA children (Aβ42: 186.2 ± 66.7 pg/mL; P < 0.001; PS1: 3.42 ± 1.46 ng/mL; P < 0.001), and particularly OSA+OB children had significant elevations in both Aβ42 (349.4 ± 112.9 pg/mL; P < 0.001) and PS1 (PS1: 4.54 ± 1.16 ng/mL; P < 0.001) circulating concentrations. In a subset of 24 children, T&A resulted in significant reductions of Aβ42 (352.0 ± 145.2 versus 151.9 ± 81.4 pg/mL; P < 0.0001) and PS1 (4.82 ± 1.09 versus 2.02 ± 1.18 ng/mL; P < 0.0001). CONCLUSIONS Thus, OSA, and particularly OSA+OB, are associated with increased plasma levels of AD biomarkers, which decline upon treatment of OSA in a representative, yet not all- encompassing subset of patients, suggesting that OSA may accelerate AD-related processes even in early childhood. However, the cognitive and overall health-related implications of these findings remain to be defined.

Analysis and classification of oximetry recordings to predict obstructive sleep apnea severity in children.

Current study is focused around the potential use of oximetry to determine the obstructive sleep apnea-hypopnea syndrome (OSAHS) severity in children. Single-channel SpO2 recordings from 176 children were divided into three severity groups according to the apnea-hypopnea index (AHI): AHI<;1 events per hour (e/h), 1≤AHI<;5 e/h, and AHI ≥5 e/h. Spectral analysis was conducted to define and characterize a frequency band of interest in SpO2. Then we combined the spectral data with the 3% oxygen desaturation index (ODI3) by means of a multi-layer perceptron (MLP) neural network, in order to classify children into one of the three OSAHS severity groups. Following our MLP multiclass approach, a diagnostic protocol with capability to reduce the need of polysomnography tests by 46% could be derived. Moreover, our proposal can be also evaluated, in a binary classification task for two common AHI diagnostic cutoffs (AHI = 1 e/h and AHI= 5 e/h). High diagnostic ability was reached in both cases (84.7% and 85.8% accuracy, respectively) outperforming the clinical variable ODI3 as well as other measures reported in recent studies. These results suggest that the information contained in SpO2 could be helpful in pediatric OSAHS severity detection.

Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Elevated Lipoprotein‐Associated Phospholipase A2 Plasma Activity Levels

Background Obstructive sleep apnea (OSA) is a highly prevalent condition, especially in obese children, and has been associated with increased risk for endothelial dysfunction and dislipidemia, which are precursors of atherosclerosis. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) is recognized as an independent risk factor for cardiovascular risk and atheromatous plaque activity. We hypothesized that Lp‐PLA2 levels would be elevated in children with OSA, particularly among obese children who also manifest evidence of endothelial dysfunction. Methods and Results One hundred sixty children (mean age 7.1±2.3 years), either nonobese with (n=40) and without OSA (n=40) or obese with (n=40) and without OSA (n=40) underwent overnight polysomnographic and postocclusive reperfusion evaluation and a fasting blood draw the morning after the sleep study. In addition to lipid profile, Lp‐PLA2 plasma activity was assessed using a commercial kit. Obese children and OSA children had significantly elevated plasma Lp‐PLA2 activity levels compared to controls. Furthermore, when both obesity and OSA were concurrently present or when endothelial function was present, Lp‐PLA2 activity was higher. Treatment of OSA by adenotonsillectomy resulted in reductions of Lp‐PLA2 activity (n=37; P<0.001). Conclusions Lp‐PLA2 plasma activity is increased in pediatric OSA and obesity, particularly when endothelial dysfunction is present, and exhibits decreases on OSA treatment. The short‐term and long‐term significance of these findings in relation to cardiovascular risk remain undefined.

Automated analysis of nocturnal oximetry as screening tool for childhood obstructive sleep apnea-hypopnea syndrome.

Childhood obstructive sleep apnea-hypopnea syndrome (OSAHS) is a highly prevalent condition that negatively affects health, performance and quality of life of infants and young children. Early detection and treatment improves neuropsychological and cognitive deficits linked with the disease. The aim of this study was to assess the performance of automated analysis of blood oxygen saturation (SpO2) recordings as a screening tool for OSAHS. As an initial step, statistical, spectral and nonlinear features were estimated to compose an initial feature set. Then, fast correlation-based filter (FCBF) was applied to search for the optimum subset. Finally, the discrimination power (OSAHS negative vs. OSAHS positive) of three pattern recognition algorithms was assessed: linear discriminant analysis (LDA), quadratic discriminant analysis (QDA) and logistic regression (LR). Three clinical cutoff points commonly used in the literature for positive diagnosis of the disease were applied: apnea-hypopnea index (AHI) of 1, 3 and 5 events per hour (e/h). Our methodology reached 88.6% accuracy (71.4% sensitivity and 100.0% specificity, 100.0% positive predictive value, and 84.0% negative predictive value) in an independent test set using QDA for a clinical cut-off point of 5 e/h. These results suggest that SpO2 nocturnal recordings may be used to develop a reliable and efficient screening tool for childhood OSAHS.