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1.  Childhood Obstructive Sleep Apnea Associates with Neuropsychological Deficits and Neuronal Brain Injury 
PLoS Medicine  2006;3(8):e301.
Background
Childhood obstructive sleep apnea (OSA) is associated with neuropsychological deficits of memory, learning, and executive function. There is no evidence of neuronal brain injury in children with OSA. We hypothesized that childhood OSA is associated with neuropsychological performance dysfunction, and with neuronal metabolite alterations in the brain, indicative of neuronal injury in areas corresponding to neuropsychological function.
Methods and Findings
We conducted a cross-sectional study of 31 children (19 with OSA and 12 healthy controls, aged 6–16 y) group-matched by age, ethnicity, gender, and socioeconomic status. Participants underwent polysomnography and neuropsychological assessments. Proton magnetic resonance spectroscopic imaging was performed on a subset of children with OSA and on matched controls. Neuropsychological test scores and mean neuronal metabolite ratios of target brain areas were compared.
Relative to controls, children with severe OSA had significant deficits in IQ and executive functions (verbal working memory and verbal fluency). Children with OSA demonstrated decreases of the mean neuronal metabolite ratio N-acetyl aspartate/choline in the left hippocampus (controls: 1.29, standard deviation [SD] 0.21; OSA: 0.91, SD 0.05; p = 0.001) and right frontal cortex (controls: 2.2, SD 0.4; OSA: 1.6, SD 0.4; p = 0.03).
Conclusions
Childhood OSA is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex. We speculate that untreated childhood OSA could permanently alter a developing child's cognitive potential.
Childhood obstructive sleep apnea is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex.
Editors' Summary
Background.
Sleep is essential for health, and in children it is crucial to normal development. Symptomatic childhood sleep-disordered breathing (SDB) is the name for a range of conditions in which children have difficulties with breathing when they are asleep. The conditions range from simple snoring to the most severe condition, known as obstructive sleep apnea (OSA). Apnea means a temporary absence of breathing, and in OSA this is caused by a temporary but repeated blockage of the flow of air to the lungs. In children, OSA occurs for a number of reasons including enlarged tonsils, long-term allergy, and obesity. About two in every hundred children have OSA. The symptoms of OSA are loud snoring at night, disrupted, restless sleep, undue tiredness, and difficulties in concentration. The main test for it is a sleep study (polysomnography). If untreated, researchers believe that it may lead to a number of long-term problems with health and learning; children with disorders of sleep have been shown to have memory problems, lower general intelligence, and worse executive function (the ability to adapt to new situations), and may have behavioral problems similar to those of attention deficit hyperactivity disorder (ADHD).
Why Was This Study Done?
Adults with sleep apnea have been shown to have abnormalities of parts of their brain, specifically the frontal cortex, cerebellum, and hippocampus, but so far there are no data on whether there are similar changes in children. Children with sleep apnea may have cognitive deficits, but the research on this topic is limited.
What Did the Researchers Do and Find?
The researchers wanted to investigate the brains of children with OSA to see if there was any evidence of changes in the brain and if these changes were associated with any learning problems. They studied 31 children (19 with OSA and 12 healthy controls, aged 6–16 y). Participants underwent polysomnography and neuropsychological assessments, such as IQ tests and tests of their ability to perform tasks involving decision making. Some of the children also had specialized scans of their brains (known as proton magnetic resonance spectroscopic imaging) that can measure the levels of certain metabolites—substances that are produced as a result of brain activity. The researchers then compared the neuropsychological test scores with the levels of the metabolites. They found that relative to controls, children with severe OSA had lower IQ and ability to perform tasks involving decision making. Children with OSA also had changes in metabolites in the brain similar to those seen in diseases in which there is damage to brain cells.
What Do These Findings Mean?
It seems clear that OSA in children is associated with learning problems, and that these learning problems may in turn be associated with changes in brain metabolites. The changes in metabolites are not necessarily permanent—in other diseases where changes have been found they can be reversed with treatment. If these results are confirmed in other children with OSA, it will highlight the importance of treating children for OSA as soon as possible. In addition, the measurement of metabolites may be a way of measuring how well children are responding to treatment.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030301.
MedlinePlus's encyclopedia has an entry on sleep apnea
The American Sleep Apnea Association has information about having a child investigated for sleep apnea
The National Sleep Foundation also provides information about sleep disorders
doi:10.1371/journal.pmed.0030301
PMCID: PMC1551912  PMID: 16933960
2.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Objective
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Design
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Results
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Conclusions
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
doi:10.1542/peds.2006-0092
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
3.  Sleep disorders in children 
Clinical Evidence  2010;2010:2304.
Introduction
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for dyssomnias in children? What are the effects of treatments for parasomnias in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 28 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihistamines; behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives; benzodiazepines alone; exercise; extinction and graduated extinction; 5-hydroxytryptophan; light therapy; melatonin; safety/protective interventions for parasomnias; scheduled waking (for parasomnias); sleep hygiene; and sleep restriction.
Key Points
Sleep disorders may affect between 20% and 30% of young children, and include problems getting to sleep (dyssomnias) or undesirable phenomena during sleep (parasomnias), such as sleep terrors and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders. Other risk factors include the child being the first born, having a difficult temperament or having had colic, and increased maternal responsiveness.
There is a paucity of evidence about effective treatments for sleep disorders in children, especially parasomnias, but behavioural interventions may be the best first-line approach.
Extinction and graduated extinction in otherwise healthy children with dyssomnia may improve sleep quality and settling, and reduce the number of tantrums and wakenings compared with no treatment. Extinction and graduated extinction in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder with dyssomnia may be more effective at improving settling, reducing the frequency and duration of night wakings, and improving parental sleep compared with no treatment; however, we don't know whether it is more effective in improving sleep duration.Graduated extinction may be less distressing for parents, and therefore may have better compliance.
Sleep hygiene for dyssomnia in otherwise healthy children may be more effective in reducing the number and duration of bedtime tantrums compared with placebo, but we don’t know if it is more effective at reducing night wakenings, improving sleep latency, improving total sleep duration, or improving maternal mood. Sleep hygiene and graduated extinction seem to be equally effective at reducing bedtime tantrums in otherwise healthy children with dyssomnia.We don't know whether sleep hygiene for dyssomnia in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder is effective.
Melatonin for dyssomnia in otherwise healthy children may be more effective at improving sleep-onset time, total sleep time, and general health compared with placebo. Evidence of improvements in dyssomnia with melatonin is slightly stronger in children with physical disabilities, learning disabilities, epilepsy, or attention-deficit disorder.
Little is known about the long-term effects of melatonin, and the quality of the product purchased could be variable as melatonin is classified as a food supplement.
Antihistamines for dyssomnia may be more effective than placebo at reducing night wakenings and decreasing sleep latency, but we don’t know if they are more effective at increasing sleep duration. The evidence for antihistamines in dyssomnia comes from only one small, short-term study.
We don’t know whether behavioural therapy plus antihistamines, plus benzodiazepines, or plus chloral and derivatives, exercise, light therapy, or sleep restriction are effective in children with dyssomnia.
We don’t know whether antihistamines, behavioural therapy plus benzodiazepines or plus chloral and derivatives, benzodiazepines, 5-hydroxytryptophan, melatonin, safety/protective interventions, scheduled waking, sleep hygiene, or sleep restriction are effective in children with parasomnia.
PMCID: PMC3217667  PMID: 21418676
4.  Sleep disorders in children 
Clinical Evidence  2007;2007:2304.
Introduction
Sleep disorders may affect 20-30% of young children, and include excessive daytime sleepiness, problems getting to sleep (dysomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors, and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for dysomnias in children? What are the effects of treatments for parasomnias in children? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihistamines, behavioural therapy plus benzodiazepines, or plus chloral and derivates, exercise, extinction and graduated extinction, light therapy, melatonin, safety/protective interventions for parasomnias, scheduled waking (for parasomnias), sleep hygiene, and sleep restriction.
Key Points
Sleep disorders may affect 20-30% of young children, and include excessive daytime sleepiness, problems getting to sleep (dysomnias), or undesirable phenomena during sleep (parasomnias), such as sleep terrors, and sleepwalking. Children with physical or learning disabilities are at increased risk of sleep disorders. Other risk factors include the child being the first born, having a difficult temperament or having had colic, and increased maternal responsiveness.
There is a paucity of evidence about effective treatments for sleep disorders in children, especially parasomnias, but behavioural interventions may be the best first-line approach.
Extinction and graduated extinction interventions improve settling and reduce night wakes compared with placebo in healthy children, and in children with learning disabilities. Graduated extinction may be less distressing for parents, and therefore may have better compliance.Sleep hygiene interventions may reduce bedtime tantrums in healthy children compared with placebo, with similar effectiveness to graduated extinction.Sleep hygiene plus graduated extinction may reduce bedtime tantrums in children with physical or learning disabilities.We don't know whether combining behavioural therapy with benzodiazepines or with chloral improves sleep or parasomnias.
Melatonin may improve sleep onset and sleep time compared with placebo in healthy children, but we don't know if it is beneficial in children with disabilities, if it improves parasomnias, or what its long-term effects might be. We don't know whether antihistamines, exercise, light therapy, or sleep restriction improve dysomnias or parasomnias in children.We don't know whether safety or protective interventions, scheduled waking, extinction, or sleep hygiene are effective in children with parasomnias.
PMCID: PMC2943792  PMID: 19450298
5.  Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 
PLoS Medicine  2009;6(8):e1000132.
In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.
Background
Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
Methods and Findings
We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
Conclusions
Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.
Why Was This Study Done?
Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.
What Did the Researchers Do and Find?
At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.
What Do These Findings Mean?
These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000132.
The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)
The UK National Heath Service also provides information for patients about sleep apnea
MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)
More information on the Sleep Heart Health Study is available
doi:10.1371/journal.pmed.1000132
PMCID: PMC2722083  PMID: 19688045
6.  Primary nocturnal enuresis as a risk factor for sleep disorders: an observational questionnaire-based multicenter study 
Introduction
Primary nocturnal enuresis (PNE) is a common problem in developmental age with an estimated overall prevalence ranging from 1.6% to 15%, and possible persistence during adolescence. There is a growing interest in the sleep habits of children affected by PNE, which is derived from the contradictory data present in clinical literature. The aim of the present study was to evaluate the presence of sleep disturbances in a population of children affected by PNE, and to identify whether PNE could be considered as a risk factor for sleep disturbances among children.
Materials and methods
A total of 190 PNE children (97 males, 93 females) aged 7–15 years, (mean 9.64 ± 1.35 years), and 766 typically developing children matched for age (P = 0.131) and gender (P = 0.963) were enrolled. To evaluate the presence of sleep habits and disturbances, all of the subjects’ mothers filled out the Sleep Disturbances Scale for Children (SDSC), a questionnaire consisting of six subscales: Disorders in Initiating and Maintaining Sleep (DIMS), Sleep Breathing Disorders (SBD), Disorders of Arousal (DA), Sleep–Wake Transition Disorders (SWTD), Disorders of Excessive Somnolence (DOES), and Nocturnal Hyperhidrosis (SHY). The results were divided into “pathological” and “normal” scores using a cut-off value (pathological score = at least three episodes per week), according to the validation criteria of the test. Then, the Chi-square test was used to calculate the statistical difference and a univariate logistic regression analysis was applied to determine the role of PNE as a risk factor for the development of each category of sleep disorders and to calculate the odds ratio (OR).
Results
PNE children show a higher prevalence of all sleep disturbances (41.03% DIMS; 85.12% SBD; 63.29% DA; 67.53% SWTD; 31.28% DOES; 37.92% SHY; 25.33% SDSC total score), and according to OR results (SDSC total score OR = 8.293, 95% confidence interval [CI] = 5.079–13.540; DIMS OR = 7.639, 95% CI = 5.192–11.238; SBD OR = 35.633, 95% CI = 22.717–55.893; DA OR = 13.734, 95% CI = 9.476–19.906; SWTD OR = 14.238, 95% CI = 9.829–20.625; DOES OR = 5.602, 95% CI = 3.721–8.432; SHY OR = 6.808, 95% CI = 4.608–10.059), PNE could be considered as a risk factor for the development of sleep disorders.
Conclusion
Among PNE children, sleep could be strongly altered, thus helping to affirm the hypothesis that PNE tends to alter sleep architecture, or it could itself be the consequence of an abnormal sleep structure. The findings also point to the existence of a potential increase in the risk of developing sleep disorders in the presence of PNE.
doi:10.2147/NDT.S43673
PMCID: PMC3621720  PMID: 23579788
primary nocturnal enuresis; SDSC; sleep
7.  Polysomnography in Patients With Obstructive Sleep Apnea 
Executive Summary
Objective
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario.
Clinical Need: Target Population and Condition
Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies.
The Technology Being Reviewed
There is no ‘gold standard’ for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs.
In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as “The Sleep Book.” The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered.
Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective.
Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value.
At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments.
Methods
Review Strategy
There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature.
To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed.
Diffusion of Sleep Laboratories
To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases.
Summary of Findings
Literature Review
A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study.
Prevalence
Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men.
Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups.
Diagnostic Value of Polysomnography
It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined.
Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population.
Obstructive Sleep Apnea and Obesity
Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m2) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals.
Obstructive Sleep Apnea and Cardiovascular Diseases
Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values.
A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m2; range = 32.30–68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension.
Health Technology Assessments, Guidelines, and Recommendations
In April 2005, the Centers for Medicare and Medicaid Services (CMS) in the United States published its decision and review regarding in-home and in-lab sleep studies for the diagnosis and treatment of OSA with CPAP. In order to cover CPAP, CMS requires that a diagnosis of OSA be established using PSG in a sleep laboratory. After reviewing the literature, CMS concluded that the evidence was not adequate to determine that unattended portable sleep study was reasonable and necessary in the diagnosis of OSA.
In May 2005, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) published a review of guidelines for referral of patients to sleep laboratories. The review included 37 guidelines and associated reviews that covered 18 applications of sleep laboratory studies. The CCOHTA reported that the level of evidence for many applications was of limited quality, that some cited studies were not relevant to the recommendations made, that many recommendations reflect consensus positions only, and that there was a need for more good quality studies of many sleep laboratory applications.
Diffusion
As of the time of writing, there are 97 licensed sleep laboratories in Ontario. In 2000, the number of sleep studies performed in Ontario was 376/100,000 people. There was a steady rise in sleep studies in the following years such that in 2004, 769 sleep studies per 100,000 people were performed, for a total of 96,134 sleep studies. Based on prevalence estimates of the Wisconsin Sleep Cohort Study, it was estimated that 927,105 people aged 30 to 60 years have sleep-disordered breathing. Thus, there may be a 10-fold rise in the rate of sleep tests in the next few years.
Economic Analysis
In 2004, approximately 96,000 sleep studies were conducted in Ontario at a total cost of ~$47 million (Cdn). Since obesity is associated with sleep disordered breathing, MAS compared the costs of sleep studies to the cost of bariatric surgery. The cost of bariatric surgery is $17,350 per patient. In 2004, Ontario spent $4.7 million per year for 270 patients to undergo bariatric surgery in the province, and $8.2 million for 225 patients to seek out-of-country treatment. Using a Markov model, it was concluded that shifting costs from sleep studies to bariatric surgery would benefit more patients with OSA and may also prevent health consequences related to diabetes, hypertension, and hyperlipidemia. It is estimated that the annual cost of treating comorbid conditions in morbidly obese patients often exceeds $10,000 per patient. Thus, the downstream cost savings could be substantial.
Considerations for Policy Development
Weight loss is associated with a decrease in OSA severity. Treating and preventing obesity would also substantially reduce the economic burden associated with diabetes, hypertension, hyperlipidemia, and OSA. Promotion of healthy weights may be achieved by a multisectorial approach as recommended by the Chief Medical Officer of Health for Ontario. Bariatric surgery has the potential to help morbidly obese individuals (BMI > 35 kg/m2 with an accompanying comorbid condition, or BMI > 40 kg/m2) lose weight. In January 2005, MAS completed an assessment of bariatric surgery, based on which OHTAC recommended an improvement in access to these surgeries for morbidly obese patients in Ontario.
Habitual snorers with excessive daytime sleepiness have a high pretest probability of having OSA. These patients could be offered a therapeutic trial of CPAP to diagnose OSA, rather than a PSG. A majority of these patients are also obese and may benefit from weight loss. Individualized weight loss programs should, therefore, be offered and patients who are morbidly obese should be offered bariatric surgery.
That said, and in view of the still evolving understanding of the causes, consequences and optimal treatment of OSA, further research is warranted to identify which patients should be screened for OSA.
PMCID: PMC3379160  PMID: 23074483
8.  Are sleep problems under-recognised in general practice? 
Archives of Disease in Childhood  2004;89(8):708-712.
Aims: To evaluate the frequency of sleep problems in Australian children aged 4.5–16.5 years, and to determine whether the frequency of sleep problems on questionnaire predicts the reporting of sleep problems at consultation.
Methods: Parents of 361 children (aged 4.5–16.5 years) attending their general practitioner for "sick" visits were asked to assess their child's sleep over the previous six months using the Sleep Disturbance Scale for Children, from which six sleep "disorder" factors and a total sleep problem score were obtained.
Results: The percentage of children with a total sleep problem score indicative of clinical significance (T score >70 or >95th centile) was 24.6% (89/361). Despite this high frequency, parents only addressed sleep problems in 4.1% (13/317) of cases and reported that GPs discussed sleep problems in 7.9% (25/317) of cases. Of the 79 children who reported total sleep problem T scores in the clinical range, only 13.9% (11/79) discussed sleep with their general practitioner within the previous 12 months. Regression analyses revealed an age related decrease in problems with sleep-wake transition and sleep related obstructive breathing; sleep hyperhydrosis, initiating and maintaining sleep, and excessive daytime sleepiness did not significantly decrease with age. No significant gender differences were observed.
Conclusions: Results suggest that chronic sleep problems in Australian children are significantly under-reported by parents during general practice consultations despite a relatively high frequency across all age groups. Given the impact on children and families, there is a need for increased awareness of children's sleep problems in the community and for these to be more actively addressed at consultation.
doi:10.1136/adc.2003.027011
PMCID: PMC1720041  PMID: 15269066
9.  Prevalence of Diagnosed Sleep Disorders in Pediatric Primary Care Practices 
Pediatrics  2010;125(6):e1410-e1418.
OBJECTIVES
The primary aim was to determine the prevalence of International Classification of Diseases, Ninth Revision (ICD-9), sleep disorders diagnosed by pediatric providers in a large, primary care network. Secondary aims were to examine demographic variables related to these diagnoses and to examine the frequency of prescriptions for medications potentially used to treat sleep disorders.
METHODS
Electronic medical records were reviewed for 154 957 patients (0 –18 years) seen for a well-child visit in 2007. Information collected included ICD-9 sleep diagnoses, demographic variables, comorbid attention-deficit/hyperactivity disorder and autism spectrum disorders, provider type, and medications.
RESULTS
Across all ages, 3.7% of youths had an ICD-9 diagnosis for a sleep disorder. The most-common diagnoses were sleep disorder not otherwise specified, enuresis, and sleep-disordered breathing. Predictors of sleep disorders varied according to developmental age group and included growth parameters, comorbid attention-deficit/hyperactivity disorder or autism spectrum disorder, and provider type. Potential sleep-related medications were prescribed for 6.1% of the sample subjects.
CONCLUSIONS
This study is one of the first to examine comprehensively ICD-9 sleep diagnoses given by primary care providers in a large representative sample of children 0 to 18 years of age. The 3.7% of patients with ICD-9 sleep diagnoses is significantly lower than prevalence rates reported in epidemiological studies, which suggests that primary care providers may be underdiagnosing sleep disorders in children and adolescents. Because sleep disorders are treatable when recognized, the results from this study suggest a significant need for additional education and support for primary care providers in the diagnosis and treatment of pediatric sleep disorders.
doi:10.1542/peds.2009-2725
PMCID: PMC3089951  PMID: 20457689
sleep disorders; children; adolescents; primary care
10.  Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders 
PLoS ONE  2013;8(5):e63773.
Study Objectives
To investigate the efficacy of melatonin compared to placebo in improving sleep parameters in patients with primary sleep disorders.
Design
PubMed was searched for randomized, placebo-controlled trials examining the effects of melatonin for the treatment of primary sleep disorders. Primary outcomes examined were improvement in sleep latency, sleep quality and total sleep time. Meta-regression was performed to examine the influence of dose and duration of melatonin on reported efficacy.
Participants
Adults and children diagnosed with primary sleep disorders.
Interventions
Melatonin compared to placebo.
Results
Nineteen studies involving 1683 subjects were included in this meta-analysis. Melatonin demonstrated significant efficacy in reducing sleep latency (weighted mean difference (WMD) = 7.06 minutes [95% CI 4.37 to 9.75], Z = 5.15, p<0.001) and increasing total sleep time (WMD = 8.25 minutes [95% CI 1.74 to 14.75], Z = 2.48, p = 0.013). Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time. Overall sleep quality was significantly improved in subjects taking melatonin (standardized mean difference = 0.22 [95% CI: 0.12 to 0.32], Z = 4.52, p<0.001) compared to placebo. No significant effects of trial duration and melatonin dose were observed on sleep quality.
Conclusion
This meta-analysis demonstrates that melatonin decreases sleep onset latency, increases total sleep time and improves overall sleep quality. The effects of melatonin on sleep are modest but do not appear to dissipate with continued melatonin use. Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents.
doi:10.1371/journal.pone.0063773
PMCID: PMC3656905  PMID: 23691095
11.  The Underlying Interactome of Childhood Obesity: The Potential Role of Sleep 
Childhood Obesity  2012;8(1):38-42.
Abstract
Fine-tuning and integration between social rhythms and biological rhythms should be a priority for all, especially for children. As such, the opportunity to sleep should fit the evolving needs for sleep in a child. Unfortunately, children today are highly unlikely to obtain sufficient sleep or live under stable and regular schedules. Poor or dysregulated sleep affects the regulation of homeostatic and hormonal systems underlying somatic and intellectual growth, maturation, and bioenergetics. Therefore, in the prevention and management of childhood obesity, assessments of the “obesogenic” lifestyle, such as dietary and physical activity patterns, need to be coupled with accurate evaluation of the quality and quantity of sleep and with the potential co-existence of sleep-disordered breathing or other sleep disorders. Incorporation of sleep as an integral component of many childhood research studies on obesity should be done a priori rather than as an afterthought. Although parents and health professionals have meticulously delineated, observed, and quantified normal patterns of activities such as eating or playing, the absence of reliable sleep health data in children is all the more puzzling considering that young children engage in sleeping activities more than in any other activity during the 24-hour cycle. Therefore, the most forgotten, overlooked, or even actively ignored behavior of this century is undoubtedly childhood sleep. Trends aiming to reduce sleep in children have emerged, and regrettably continue to gain momentum. In parallel with such undesirable consequences, leading to the blatant disregard of sleep as a vital function rather than a commodity, a reciprocal increase in obesity rates has emerged. The mechanistic links between sleep and metabolism are now emerging, and should prompt incorporation of measures aiming to align sleep with any other antiobesity campaign. To paraphrase a well-known dictum “Somni sano in corpore sano” (healthy sleep in healthy bodies).
doi:10.1089/chi.2011.0105
PMCID: PMC3647589  PMID: 22799478
12.  Intrinsic connectivity network mapping in young children during natural sleep 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.05.020.
Structural and functional neuroimaging have substantively informed the pathophysiology of numerous adult neurological and psychiatric disorders. While structural neuroimaging is readily acquired in sedated young children, pediatric application of functional neuroimaging has been limited by the behavioral demands of in-scanner task performance. Here, we investigated whether functional magnetic resonance imaging (fMRI) acquired during natural sleep and without experimental stimulation offers a viable strategy for studying young children. We targeted the lengthy epoch of non-Rapid Eye Movement, stage 3 (NREM3) sleep typically observed at sleep onset in sleep-deprived children. Seven healthy, preschool-aged children (24-58 months) were studied, acquiring fMRI measurements of cerebral blood flow (CBF) and of intrinsic connectivity networks (ICNs), with concurrent sleep-stage monitoring. ICN data (T2* fMRI) were reliably obtained during NREM3 sleep; CBF data (arterial spin labeled fMRI) were not reliably obtained, as scanner noises disrupted sleep. Applying independent components analysis (ICA) to T2* data, distinct ICNs were observed which corresponded closely with those reported in the adult literature. Notably, a network associated with orthography in adults was not observed, suggesting that ICNs exhibit a developmental trajectory. We conclude that resting-state fMRI obtained in sleep is a promising paradigm for neurophysiological investigations of young children.
doi:10.1016/j.neuroimage.2013.05.020
PMCID: PMC3815484  PMID: 23727317
Magnetic Resonance Imaging; Intrinsic Connectivity Network; Sleep; pediatric; biomarker
13.  Sleep Items in the Child Behavior Checklist: A Comparison With Sleep Diaries, Actigraphy, and Polysomnography 
Objective
The Child Behavior Checklist is sometimes used to assess sleep disturbance despite not having been validated for this purpose. This study examined associations between the Child Behavior Checklist sleep items and other measures of sleep.
Method
Participants were 122 youth (61% female, aged 7 through 17 years) with anxiety disorders (19%), major depressive disorder (9%), both anxiety and depression (26%), or a negative history of any psychiatric disorder (46%). Parents completed the Child Behavior Checklist and children completed a sleep diary, wore actigraphs for multiple nights, and spent 2 nights in the sleep laboratory. Partial correlations ([pr], controlling for age, gender and diagnostic status) were used to examine associations.
Results
Child Behavior Checklist sleep items were associated with several other sleep variables. For example, “trouble sleeping” correlated significantly with sleep latency assessed by both diary (pr(113) = 0.25, p = .008) and actigraphy (pr(105) = 0.21, p = .029). Other expected associations were not found (e.g., “sleeps more than most kids” was not significantly correlated with EEG-assessed total sleep time: pr(84) = 0.12, p = .258).
Conclusions
Assessing sleep using the Child Behavior Checklist exclusively is not ideal. Nonetheless, certain Child Behavior Checklist items (e.g., “trouble sleeping”) may be valuable. Although the Child Behavior Checklist may provide a means of examining some aspects of sleep from existing datasets that do not include other measures of sleep, hypotheses generated from such analyses need to be tested using more rigorous measures of sleep.
doi:10.1016/j.jaac.2011.02.003
PMCID: PMC3581333  PMID: 21515199
actigraphy; CBCL; poly somnography; sleep diary
14.  Sleep Lab Adaptation in Children with Attention-Deficit/Hyperactivity Disorder and Typically Developing Children 
Sleep Disorders  2013;2013:698957.
Objectives. Research has shown inconsistencies across studies examining sleep problems in children with attention-deficit/hyperactivity disorder (ADHD). It is possible that these inconsistencies are due to sleep lab adaptation. The goal of the current study was to investigate the possibility that children with ADHD adapt differently to the sleep lab than do typically developing (TD) children. Patients and Methods. Actigraphy variables were compared between home and the sleep lab. Sleep lab adaptation reports from the parent and child were compared between children with ADHD (n = 25) and TD children (n = 25). Results. Based on actigraphy, both groups had reduced sleep duration and reduced wake after sleep onset in the sleep lab compared to home. The only interaction effect was that TD children had increased sleep efficiency in the sleep lab compared to home. Conclusions. The results of this study do not support the hypothesis that children with ADHD adjust to the sleep lab differently than their typically developing peers. However, both groups of children did sleep differently in the sleep lab compared to home, and this needs to be considered when generalizing research findings from a sleep lab environment to children's sleep in general.
doi:10.1155/2013/698957
PMCID: PMC3666280  PMID: 23766917
15.  Sleep habits and sleep disturbances in Dutch children: a population-based study 
European Journal of Pediatrics  2010;169(8):1009-1015.
Sleep disorders can lead to significant morbidity. Information on sleep in healthy children is necessary to evaluate sleep disorders in clinical practice, but data from different societies cannot be simply generalized. The aims of this study were to (1) assess the prevalence of sleep disturbances in Dutch healthy children, (2) describe sleep habits and problems in this population, (3) collect Dutch norm data for future reference, and (4) compare sleep in children from different cultural backgrounds. A population-based descriptive study was conducted using the Children’s sleep habits questionnaire and the sleep self-report. One thousand five hundred seven proxy-reports and 262 self-reports were analyzed. Mean age was 8.5 years (95% confidence interval, 8.4–8.6), 52% were boys. Sleep problems in Dutch children were present in 25%, i.e., comparable to other populations. Sleep habits were age-related. Problem sleepers scored significantly higher on all scales. Correlations between parental and self-assessments were low to moderate. Dutch children had significantly more sleep disturbances than children from the USA and less than Chinese children. Cognitions and attitudes towards what is considered normal sleep seem to affect the appraisal of sleep, this probably accounts partly for cultural differences. For a better understanding of cultural influences on sleep, more information on these determinants and the establishment of cultural norms are mandatory.
doi:10.1007/s00431-010-1169-8
PMCID: PMC2890079  PMID: 20191392
Sleep; Children’s sleep habits questionnaire (CSHQ); Sleep self-report (SSR); Cultural comparison; Dutch
16.  Behavioural sleep problems in children with attention-deficit/hyperactivity disorder (ADHD): protocol for a prospective cohort study 
BMJ Open  2014;4(2):e004070.
Introduction
Children with attention-deficit/hyperactivity disorder (ADHD) commonly experience behavioural sleep problems, yet these difficulties are not routinely assessed and managed in this group. Presenting with similar symptoms to ADHD itself, sleep problems are complex in children with ADHD and their aetiology is likely to be multifactorial. Common internalising and externalising comorbidities have been associated with sleep problems in children with ADHD; however, this relationship is yet to be fully elucidated. Furthermore, limited longitudinal data exist on sleep problems in children with ADHD, thus their persistence and impact remain unknown. In a diverse sample of children with ADHD, this study aims to: (1) quantify the relationship between sleep problems and internalising and externalising comorbidities; (2) examine sleep problem trajectories and risk factors; and (3) examine the longitudinal associations between sleep problems and child and family functioning over a 12-month period.
Methods and analysis
A prospective cohort study of 400 children with ADHD (150 with no/mild sleep problems, 250 with moderate/severe sleep problems) recruited from paediatric practices across Victoria, Australia. The children's parents and teacher provide data at baseline and 6-month and 12-month post enrolment.
Key measures
Parent report of child's sleep problem severity (no, mild, moderate, severe); specific sleep domain scores assessed using the Child Sleep Habits Questionnaire; internalising and externalising comorbidities assessed by the Anxiety Disorders Interview Schedule for Children IV/Parent version.
Analyses
Multiple variable logistic and linear regression models examining the associations between key measures, adjusted for confounders identified a priori.
Ethics and dissemination
Ethics approval has been granted. Findings will contribute to our understanding of behavioural sleep problems in children with ADHD. Clinically, they could improve the assessment and management of sleep problems in this group. We will seek to publish in leading paediatric journals, present at conferences and inform Australian paediatricians through the Australian Paediatric Research Network.
doi:10.1136/bmjopen-2013-004070
PMCID: PMC3927707  PMID: 24523423
Sleep Medicine
17.  Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial 
Objective To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders.
Design 12 week double masked randomised placebo controlled phase III trial.
Setting 19 hospitals across England and Wales.
Participants 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours’ continuous sleep.
Interventions Immediate release melatonin or matching placebo capsules administered 45 minutes before the child’s bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment.
Main outcome measures Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy.
Results Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups.
Conclusions Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required.
Trial registration ISRCT No 05534585.
doi:10.1136/bmj.e6664
PMCID: PMC3489506  PMID: 23129488
18.  Parasomnias and sleep disordered breathing in Caucasian and Hispanic children – the Tucson children's assessment of sleep apnea study 
BMC Medicine  2004;2:14.
Background
Recent studies in children have demonstrated that frequent occurrence of parasomnias is related to increased sleep disruption, mental disorders, physical harm, sleep disordered breathing, and parental duress. Although there have been several cross-sectional and clinical studies of parasomnias in children, there have been no large, population-based studies using full polysomnography to examine the association between parasomnias and sleep disordered breathing. The Tucson Children's Assessment of Sleep Apnea study is a community-based cohort study designed to investigate the prevalence and correlates of objectively measured sleep disordered breathing (SDB) in pre-adolescent children six to 11 years of age. This paper characterizes the relationships between parasomnias and SDB with its associated symptoms in these children.
Methods
Parents completed questionnaires pertaining to their child's sleep habits. Children had various physiological measurements completed and then were connected to the Compumedics PS-2 sleep recording system for full, unattended polysomnography in the home. A total of 480 unattended home polysomnograms were completed on a sample that was 50% female, 42.3% Hispanic, and 52.9% between the ages of six and eight years.
Results
Children with a Respiratory Disturbance Index of one or greater were more likely to have sleep walking (7.0% versus 2.5%, p < 0.02), sleep talking (18.3% versus 9.0%, p < 0.006), and enuresis (11.3% versus 6.3%, p < 0.08) than children with an Respiratory Disturbance Index of less than one. A higher prevalence of other sleep disturbances as well as learning problems was observed in children with parasomnia. Those with parasomnias associated with arousal were observed to have increased number of stage shifts. Small alterations in sleep architecture were found in those with enuresis.
Conclusions
In this population-based cohort study, pre-adolescent school-aged children with SDB experienced more parasomnias than those without SDB. Parasomnias were associated with a higher prevalence of other sleep disturbances and learning problems. Clinical evaluation of children with parasomnias should include consideration of SDB.
doi:10.1186/1741-7015-2-14
PMCID: PMC419382  PMID: 15115546
19.  Habitual snoring and atopic state: correlations with respiratory function and teeth occlusion 
BMC Pediatrics  2012;12:175.
Background
Allergy represents a risk factor at the base of sleep-disordered breathing in pediatric age. Among allergic diseases, the atopy is characterized by a tendency to be “hyperallergic.” Sleep-disordered breathing is also known in orthodontics as correlated with the morphology of craniofacial complex. The aim of this study was to investigate the relation between atopy and sleep-disordered breathing (oral breathers with habitual snoring), comparing atopic children with sleep-disordered breathing (test group) with nonatopic ones with sleep-disordered breathing (control group), in the prevalence of dento-skeletal alterations and other risk factors that trigger sleep-disordered breathing, such as adenotonsillar hypertrophy, turbinate hypertrophy, obesity, and alteration of oxygen arterial saturation.
Methods
In a group of 110 subjects with sleep-disordered breathing (6 to 12 years old), we grouped the subjects into atopic (test group, 60 subjects) and nonatopic (control group, 50 subjects) children and compared the data on the following: skin allergic tests, rhinoscopy, rhinomanometry, night home pulsoxymetry, body mass index, and dento-facial alterations.
Results
Even if our results suggest that atopy is not a direct risk factor for sleep-disordered breathing, the importance of a physiologic nasal respiration in the pathogenesis of sleep-disordered breathing seems to be demonstrated in our study by the higher prevalence of hypertrophy in the adenotonsillar lymphatic tissue, odontostomatological alterations, alterations of the oxygen saturation to pulsoxymetry, and higher prevalence of obesity observed in our children with sleep-disordered breathing, in percentages higher than that of the general pediatric population previously observed in the literature.
Conclusions
The importance of a physiologic nasal respiration in the pathogenesis of sleep-disordered breathing is demonstrated in our study.
doi:10.1186/1471-2431-12-175
PMCID: PMC3506469  PMID: 23134563
Sleep-disordered breathing (SDB); Atopy; Dento-facial morphology; Allergy; Oral breathing; Snoring
20.  The influence of emerging low mood symptoms on sleep in children: a pilot study 
Nature and Science of Sleep  2012;4:133-142.
Purpose
Sleep disturbances can lead to the onset and relapse of psychiatric disorders. However, the age at which this relationship begins and the role of sleep disturbances in the trajectory to the onset of a psychiatric disorder are still not fully understood. The purpose of this study was to explore, based on self- and parental-reports of mood symptoms, subjective and objective sleep in young children who are at risk of developing a psychiatric disorder but who have not yet met diagnostic criteria.
Patients and methods
Twenty-one children (eleven girls) between the ages of 8 and 11 (mean age = 9.7 years, standard deviation = 1.1 years) were dichotomized into low mood (LM) and not low mood (NLM) groups based on scoring below or above the median threshold score on at least two of the following questionnaires: the Child Depressive Rating Scale (CDRS), Weinberg Screening Affective Scale (WSAS), and Quick Inventory of Depressive Symptomatology (QIDS). The children completed sleep diaries and underwent two nights (for adaptation and baseline) of polysomnography. Sleep stages and sleep microarchitecture (alpha, sigma, beta, and delta) in the first half of the night, were analyzed.
Results
Self-reported sleep disturbance accounted for 72% of the variance (F[3, 20] = 15, P < 0.005) of the Weinberg Screening Affective Scale in LM children. LM children had fewer arousals at night, but awakened earlier than NLM children. Regardless of mood, girls had more sleep disturbance, as well as lower alpha, beta, and delta power in the first half of the night, compared to boys. Girls with LM had shorter sleep times and a lower percentage of rapid eye movement sleep.
Conclusions
Girls with and without LM, and without a clinical diagnosis of depression, showed more sleep disturbances than boys of the same age. Sleep disturbances evident early in life and in LM girls may reflect greater risk for future sleep or psychiatric disorders.
doi:10.2147/NSS.S36460
PMCID: PMC3630979  PMID: 23620686
depression; insomnia; EEG; pediatrics
21.  Sleep apnea in childhood migraine 
The Journal of Headache and Pain  2000;1(3):169-172.
In our previous study we found a high prevalence of disordered sleep breathing in migraine children vs. controls. Since no quantitative studies about sleep respiratory disorders have been carried out in migraine children, we performed a polysomnographic (PSG) study in 10 migraine patients (7 boys, 3 girls; mean age 8.11 years, range, 5.8–14.5) attending the Headache Center of our department, to evaluate the presence of sleep apnea. Mothers completed a headache diary and a sleep diary for at least 1 month and filled out a sleep questionnaire. PSG data showed a normal sleep architecture in 3 cases, an insomnia pattern in 2, a reduction of slow wave sleep in 3 and a reduction of REM sleep in 2. Respiratory analysis revealed that 2 of 10 patients had obstructive sleep apnea. These 2 patients presented habitual snoring and associated sleep disturbances such as restless sleep and hypnic jerks. Sleep apnea may be a subtle and often undiagnosed symptom in several migraine patients. The report of habitual snoring associated with other sleep disturbances such as restless sleep and other parasomnias may be a sign of sleep apnea in migraine children.
doi:10.1007/s101940070039
PMCID: PMC3611783
Key words Migraine; Sleep; Sleep apnea; Children
22.  Rapid Eye Movement Sleep in Relation to Overweight in Children and Adolescents 
Archives of general psychiatry  2008;65(8):924-932.
Context
Short sleep duration is associated with obesity, but few studies have examined the relationship between obesity and specific physiological stages of sleep.
Objective
To examine specific sleep stages, including rapid eye movement (REM) sleep and stages 1 through 4 of non-REM sleep, in relation to overweight in children and adolescents.
Design, Setting, and Participants
A total of 335 children and adolescents (55.2% male; aged 7-17 years) underwent 3 consecutive nights of standard polysomnography and weight and height assessments as part of a study on the development of internalizing disorders (depression and anxiety).
Main Outcome Measures
Body mass index (calculated as weight in kilograms divided by height in meters squared) z score and weight status (normal, at risk for overweight, overweight) according to the body mass index percentile for age and sex.
Results
The body mass index z score was significantly related to total sleep time (β=-0.174), sleep efficiency (β=-0.027), and REM density (β=-0.256). Compared with normal-weight children, overweight children slept about 22 minutes less and had lower sleep efficiency, shorter REM sleep, lower REM activity and density, and longer latency to the first REM period. After adjustment for demographics, pubertal status, and psychiatric diagnosis, 1 hour less of total sleep was associated with approximately 2-fold increased odds of overweight (odds ratio=1.85), 1 hour less of REM sleep was associated with about 3-fold increased odds (odds ratio=2.91), and REM density and activity below the median increased the odds of overweight by 2-fold (odds ratio=2.18) and 3-fold (odds ratio=3.32), respectively.
Conclusions
Our results confirm previous epidemiological observations that short sleep time is associated with overweight in children and adolescents. A core aspect of the association between short sleep duration and overweight may be attributed to reduced REM sleep. Further studies are needed to investigate possible mechanisms underpinning the association between diminished REM sleep and endocrine and metabolic changes that may contribute to obesity.
doi:10.1001/archpsyc.65.8.924
PMCID: PMC2729137  PMID: 18678797
23.  Determinants of Regional Cerebral Oxygenation in Children with Sleep-disordered Breathing 
Rationale: An association between neurocognitive deficits and pediatric sleep-disordered breathing has been suggested; however, weak correlations between disease severity and functional outcomes underscore the lack of knowledge regarding factors modulating cognitive morbidity of sleep-disordered breathing.
Objectives: To identify the parameters affected by sleep-disordered breathing that modulate cerebral oxygenation, an important determinant of cognition. A further objective was to use these parameters with demographic data to develop a predictive statistical model of pediatric cerebral oxygenation.
Methods: Ninety-two children (14 control subjects, 32 with primary snoring, and 46 with obstructive sleep apnea) underwent polysomnography with continuous monitoring of cerebral oxygenation and blood pressure. Analysis of covariance was used to relate the blood pressure, sleep diagnostic parameters, and demographic characteristics to regional cerebral oxygenation.
Measurements and Main Results: To account for anatomic variability, an index of cerebral oxygenation during sleep was derived by referencing the measurement obtained during sleep to that obtained during wakefulness. In a repeated measures model predicting the index of cerebral oxygenation, mean arterial pressure, rapid eye movement (REM) sleep, female sex, age, and oxygen saturation had a positive effect on cerebral oxygenation levels, whereas arousal index and non-REM (NREM) sleep had a negative effect.
Conclusions: Increasing mean arterial pressure, age, oxygen saturation, and REM sleep augment cerebral oxygenation, while sleep-disordered breathing, male sex, arousal index, and NREM sleep diminish it. The proposed model may explain the sources of variability in cognitive function of children with sleep-disordered breathing.
doi:10.1164/rccm.200802-321OC
PMCID: PMC2566795  PMID: 18658114
children; sleep-disordered breathing; cerebral oxygenation
24.  Sleep problems and functional disability in children with functional gastrointestinal disorders: An examination of the potential mediating effects of physical and emotional symptoms 
BMC Gastroenterology  2012;12:142.
Background
Sleep disturbances are increasingly recognized as a common problem for children and adolescents with chronic pain conditions, but little is known about the prevalence, type, and impact of sleep problems in pediatric functional gastrointestinal disorders (FGIDs). The objectives of the current study were two-fold: 1) to describe the pattern of sleep disturbances reported in a large sample of children and adolescents with FGIDs; and, 2) to explore the impact of sleep by examining the inter-relationships between sleep disturbance, physical symptoms, emotional problems, and functional disability in this population.
Methods
Over a 3-year period, 283 children aged 8–17 years who were diagnosed with an FGID and a primary caretaker independently completed questionnaires regarding sleep, emotional functioning, physical symptoms, and functional disability during an initial evaluation for chronic abdominal pain at a pediatric tertiary care center. A verbal review of systems also was collected at that time. Descriptive statistics were used to characterize the pattern of sleep disturbances reported, while structural equation modeling (SEM) was employed to test theorized meditational relationships between sleep and functional disability through physical and emotional symptoms.
Results
Clinically significant elevations in sleep problems were found in 45% of the sample, with difficulties related to sleep onset and maintenance being most common. No difference was seen by specific FGID or by sex, although adolescents were more likely to have sleep onset issues than younger children. Sleep problems were positively associated with functional disability and physical symptoms fully mediated this relationship. Emotional symptoms, while associated with sleep problems, evidenced no direct link to functional disability.
Conclusions
Sleep problems are common in pediatric FGIDs and are associated with functional disability through their impact on physical symptoms. Treatments targeting sleep are likely to be beneficial in improving physical symptoms and, ultimately, daily function in pediatric FGIDs.
doi:10.1186/1471-230X-12-142
PMCID: PMC3527282  PMID: 23067390
Sleep; Functional disability; Functional gastrointestinal disorders; Pediatrics
25.  Sleep and cognitive problems in patients with attention-deficit hyperactivity disorder 
Objectives
Attention-deficit hyperactivity disorder (ADHD) is characterized by inattentive and impulsive behavior. Many ADHD patients reportedly have cognitive dysfunction and sleep problems, including longer sleep latency, lower sleep efficiency, and shorter total sleep time. The purpose of this study was to examine neurocognitive functions and nocturnal sleep parameters in patients with ADHD, using a cognitive function test and actigraphy.
Methods
Subjects included 37 male patients with ADHD and 32 controls (7–12 years of age). For each participant, we determined intelligence quotient (IQ) and administered the Matching Familiar Figures Test (MFFT) and 72-hour actigraphy. The relationships between sleep parameters and cognitive functions were assessed.
Results
ADHD patients significantly differed from controls in several cognitive functions and sleep variables. In the MFFT, response error rate (P<0.001) and error counts (P=0.003) were significantly increased in ADHD patients compared with control children. MFFT response latency was significantly shorter in ADHD patients than in controls (P<0.001). In addition, sleep latency (P=0.01), wake after sleep onset (WASO) (P<0.001), and fragmentation index (P<0.001) were evaluated by actigraphy and found to be significantly increased in patients with ADHD compared with controls. However, no significant differences in total sleep time or sleep efficiency were observed. WASO and response error rates were positively correlated in patients with ADHD (rho =0.52, P=0.012). Furthermore, fragmentation index sleep variables were significantly positively correlated with response error (rho =0.44, P=0.008) and response latency rates (rho =0.4, P=0.018) in the MFFT. Reaction error rate was significantly associated with the fragmentation index (beta =0.94, P=0.024).
Conclusion
Patients with ADHD had more sleep problems, including significantly increased sleep latency, WASO, and fragmentation index, and poorer cognitive function, compared with controls. Some of these sleep problems, including WASO and the fragmentation index, were positively correlated with impulsivity, illustrated by the cognitive function tests in patients with ADHD. However, further studies with large sample sizes and the addition of polysomnography and determination of ADHD subtypes should be performed to confirm our results regarding sleep and cognitive problems in patients with ADHD.
doi:10.2147/NDT.S69562
PMCID: PMC4172104  PMID: 25258537
ADHD; sleep problems; actigraphy; MFFT

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