Randomized, Placebo-Controlled Trial of Ferrous Sulfate to Treat Insomnia in Children With Autism Spectrum Disorders.

BACKGROUND: Insomnia and low iron stores are common in children with autism spectrum disorders, and low iron stores have been associated with sleep disturbance. METHODS: We performed a randomized placebo-controlled trial of oral ferrous sulfate to treat insomnia in children with autism spectrum disorders and low normal ferritin levels. Twenty participants who met inclusion criteria and whose insomnia did not respond to sleep education were randomized to 3 mg/kg/day of ferrous sulfate (n = 9) or placebo (n = 11) for three months. RESULTS: Iron supplementation was well tolerated, and no serious adverse events were reported. Iron supplementation improved iron status (+18.4 ng/mL active versus -1.6 ng/mL placebo, P = 0.044) but did not significantly improve the primary outcome measures of sleep onset latency (-11.0 minutes versus placebo, 95% confidence interval -28.4 to 6.4 minutes, P = 0.22) and wake time after sleep onset (-7.7 minutes versus placebo, 95% confidence interval -22.1 to 6.6 min, P = 0.29) as measured by actigraphy. Iron supplementation was associated with improvement in the overall severity score from the Sleep Clinical Global Impression Scale (-1.5 points versus placebo, P = 0.047). Changes in measures of daytime behavior did not differ between groups. CONCLUSION: This trial demonstrated no improvement in primary outcome measures of insomnia in subjects treated with ferrous sulfate compared with placebo. Interpretation was limited by low enrollment.

Heart rate variability during sleep in children with autism spectrum disorder.

PURPOSE: Autonomic dysfunction has been reported in autism spectrum disorders (ASD). Less is known about autonomic function during sleep in ASD. The objective of this study is to provide insight into the autonomic cardiovascular control during different sleep stages in ASD. We hypothesized that patients with ASD have lower vagal and higher sympathetic modulation with elevated heart rate, as compared to typical developing children (TD). METHODS: We studied 21 children with ASD and 23 TD children during overnight polysomnography. Heart rate and spectral parameters were calculated for each vigilance stage during sleep. Data from the first four sleep cycles were used to avoid possible effects of different individual sleep lengths and sleep cycle structures. Linear regression models were applied to study the effects of age and diagnosis (ASD and TD). RESULTS: In both groups, HR decreased during non-REM sleep and increased during REM sleep. However, HR was significantly higher in stages N2, N3 and REM sleep in the ASD group. Children with ASD showed less high frequency (HF) modulation during N3 and REM sleep. LF/HF ratio was higher during REM. Heart rate decreases with age at the same level in ASD and in TD. We found an age effect in LF in REM different in ASD and TD. CONCLUSION: Our findings suggest possible deficits in vagal influence to the heart during sleep, especially during REM sleep. Children with ASD may have higher sympathetic dominance during sleep but rather due to decreased vagal influence.

Melatonin in Children with Autism Spectrum Disorders: How Does the Evidence Fit Together?

Autism spectrum disorders (ASD) are prevalent neurodevelopmental conditions, affecting 1 in 68 children in the United States alone. Sleep disturbance, particularly insomnia, is very common in children diagnosed with ASD, with evidence supporting overlapping neurobiological and genetic underpinnings. One of the most well studied mechanisms related to ASD and insomnia is dysregulation of the melatonin pathway, which has been observed in many individuals with ASD compared to typically developing controls. Furthermore, variation in genes whose products regulate endogenous melatonin modify sleep patterns in humans and have also been implicated in some cases of ASD. However, the relationship between comorbid insomnia, melatonin processing, and genes that regulate endogenous melatonin levels in ASD is complex and requires further study to fully elucidate. The aim of this review is to provide an overview of the current findings related to the effects of genetic variation in the melatonergic pathway on risk for expression of sleep disorders in children with ASD. In addition, functional findings related to endogenous levels of melatonin and pharmacokinetic profiles in this patient population are evaluated.

Association between sleep duration and mortality is mediated by markers of inflammation and health in older adults: the Health, Aging and Body Composition Study.

STUDY OBJECTIVES: Inflammation may represent a common physiological pathway linking both short and long sleep duration to mortality. We evaluated inflammatory markers as mediators of the relationship between sleep duration and mortality in community-dwelling older adults. DESIGN: Prospective cohort with longitudinal follow-up for mortality outcomes. SETTING: Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Participants in the Health, Aging and Body Composition (Health ABC) Study (mean age 73.6 ± 2.9 years at baseline) were sampled and recruited from Medicare listings. MEASUREMENTS AND RESULTS: Baseline measures of subjective sleep duration, markers of inflammation (serum interleukin-6, tumor necrosis factor-α, and C-reactive protein) and health status were evaluated as predictors of all-cause mortality (average follow-up = 8.2 ± 2.3 years). Sleep duration was related to mortality, and age-, sex-, and race-adjusted hazard ratios (HR) were highest for those with the shortest (< 6 h HR: 1.30, CI: 1.05-1.61) and longest (> 8 h HR: 1.49, CI: 1.15-1.93) sleep durations. Adjustment for inflammatory markers and health status attenuated the HR for short (< 6 h) sleepers (HR = 1.06, 95% CI = 0.83-1.34). Age-, sex-, and race-adjusted HRs for the > 8-h sleeper group were less strongly attenuated by adjustment for inflammatory markers than by other health factors associated with poor sleep with adjusted HR = 1.23, 95% CI = 0.93-1.63. Inflammatory markers remained significantly associated with mortality. CONCLUSION: Inflammatory markers, lifestyle, and health status explained mortality risk associated with short sleep, while the mortality risk associated with long sleep was explained predominantly by lifestyle and health status.

Conducting actigraphy research in children with neurodevelopmental disorders--a practical approach.

The literature has been highly informative for when to use actigraphy and its validity in pediatric research. However, minimal literature exists on how to perform actigraphy, especially in special populations. We determined whether providing actigraphy training to parents and coordinators increased the nights of actigraphy data that could be scored. We compared two studies in children with autism spectrum disorders, one of which provided a basic level of training in a single-site trial and the other of which provided more detailed training to parents and coordinators in a multisite trial. There was an increase in scorable nights in the multisite trial containing a one-hour structured parent training session. Our results support the use of educational tools in clinical trials that use actigraphy.

Concordance of Mother/Child Sleep Patterns Using Actigraphy: Preliminary Findings.

Sleep problems are common in children with autism spectrum disorder (ASD) and are often associated with problem behaviors. Problematic sleep in the child may impact maternal sleep. We examined the association of sleep in mother-child dyads to child daytime behavior and maternal insomnia and daytime sleepiness in 11 children with ASD and 6 children of typical development (TD) using wrist actigraphs over 14 consecutive nights. Early morning wakenings were significantly associated with poorer daytime behavior as measured by the Child Behavior Checklist in both ASD and TD children. Additionally, associations were found between mother and child sleep and between the child's sleep and maternal daytime sleepiness. These results highlight the need to consider the potential interaction of maternal-child sleep in future studies.

Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep.

Supplemental melatonin has been used to treat sleep onset insomnia in children with autism spectrum disorders (ASD), although the mechanism of action is uncertain. We assessed endogenous and supplemental melatonin profiles in relation to sleep in nine children with ASD. In endogenous samples, maximal melatonin concentration (C(max)) and time to peak concentration (T(max)) were comparable to those previously published in the literature for typically developing children, and dim light melatonin onsets were captured in the majority of children. In treatment samples (supplemental melatonin), melatonin parameters were also comparable to those previously published for typically developing children. Our findings support that children with ASD and insomnia responsive to low dose melatonin treatment have relatively normal profiles of endogenous and supplemental melatonin.

Parent-based sleep education for children with autism spectrum disorders.

This study provided sleep education to parents of children with autism spectrum disorder (ASD) to determine whether an individual or group format was more effective in improving sleep and aspects of daytime behavior and family functioning. Eighty children, ages 2-10 years, with ASD and sleep onset delay completed the study. Actigraphy and parent questionnaires were collected at baseline and 1 month after treatment. Mode of education did not affect outcomes. Sleep latency, insomnia subscales on the Children's Sleep Habits Questionnaire, and other outcomes related to child and family functioning improved with treatment. Parent-based sleep education, delivered in relatively few sessions, was associated with improved sleep onset delay in children with ASD. Group versus individualized education did not affect outcome.

A practice pathway for the identification, evaluation, and management of insomnia in children and adolescents with autism spectrum disorders.

OBJECTIVE: This report describes the development of a practice pathway for the identification, evaluation, and management of insomnia in children and adolescents who have autism spectrum disorders (ASDs). METHODS: The Sleep Committee of the Autism Treatment Network (ATN) developed a practice pathway, based on expert consensus, to capture best practices for an overarching approach to insomnia by a general pediatrician, primary care provider, or autism medical specialist, including identification, evaluation, and management. A field test at 4 ATN sites was used to evaluate the pathway. In addition, a systematic literature review and grading of evidence provided data regarding treatments of insomnia in children who have neurodevelopmental disabilities. RESULTS: The literature review revealed that current treatments for insomnia in children who have ASD show promise for behavioral/educational interventions and melatonin trials. However, there is a paucity of evidence, supporting the need for additional research. Consensus among the ATN sleep medicine committee experts included: (1) all children who have ASD should be screened for insomnia; (2) screening should be done for potential contributing factors, including other medical problems; (3) the need for therapeutic intervention should be determined; (4) therapeutic interventions should begin with parent education in the use of behavioral approaches as a first-line approach; (5) pharmacologic therapy may be indicated in certain situations; and (6) there should be follow-up after any intervention to evaluate effectiveness and tolerance of the therapy. Field testing of the practice pathway by autism medical specialists allowed for refinement of the practice pathway. CONCLUSIONS: The insomnia practice pathway may help health care providers to identify and manage insomnia symptoms in children and adolescents who have ASD. It may also provide a framework to evaluate the impact of contributing factors on insomnia and to test the effectiveness of nonpharmacologic and pharmacologic treatment strategies for the nighttime symptoms and daytime functioning and quality of life in ASD.

Effects of a standardized pamphlet on insomnia in children with autism spectrum disorders.

OBJECTIVE: Sleep difficulties are common reasons why parents seek medical intervention in children with autism spectrum disorders (ASDs). We determined whether a pamphlet alone could be used by parents to help their child's insomnia. METHODS: Thirty-six children with ASD, ages 2 to 10 years, were enrolled. All had prolonged sleep latency confirmed by actigraphy showing a mean sleep latency of 30 minutes or more. Parents were randomly assigned to receive the sleep education pamphlet or no intervention. Children wore an actigraphy device to record baseline sleep parameters, with the primary outcome variable being change in sleep latency. Actigraphy data were collected a second time 2 weeks after the parent received the randomization assignment and analyzed by using Student's t test. Parents were also asked a series of questions to gather information about the pamphlet and its usefulness. RESULTS: Although participants randomized to the 2 arms did not differ statistically in age, gender, socioeconomic status, total Children's Sleep Habits Questionnaire score, or actigraphy parameters, some differences may be large enough to affect results. Mean change in sleep-onset latency did not differ between the randomized groups (pamphlet versus no pamphlet). Parents commented that the pamphlet contained good information, but indicated that it would have been more useful to be given specific examples of how to take the information and put it into practice. CONCLUSIONS: A sleep education pamphlet did not appear to improve sleep latency in children with ASDs.

A pilot study of shoulder placement for actigraphy in children.

Children with neurodevelopmental disorders may have difficulty tolerating devices that monitor sleep, presenting challenges in measuring sleep disturbances in this population. Although wrist actigraphy has advantages over polysomnography, some children remain unable to tolerate wrist placement. This study piloted an alternative site for actigraphy in 8 children with autism, ages 6-10 years. Results are presented from the 2 locations (custom pocket shoulder location and wrist location) using Bland-Altman limits of agreement and other statistical measures to compare sleep onset latency, total sleep time, sleep efficiency, and wake after sleep onset. The use of an alternative actigraphy site for children with autism, who have difficulty tolerating actigraphy placement, appears promising and worthy of further study.

Parental sleep concerns in autism spectrum disorders: variations from childhood to adolescence.

Sleep problems of adolescents and older children with Autism Spectrum Disorder (ASD) were compared to toddlers and young children in 1,859 children. Sleep was measured with the Children's Sleep Habits Questionnaire. Total sleep problems were significant across all age groups, however the factors contributing to these problems differed. Adolescents and older children had more problems with delayed sleep onset, shorter sleep duration, and daytime sleepiness; while younger children had more bedtime resistance, sleep anxiety, parasomnias, and night wakings. The results suggest that sleep problems persist through adolescence in ASD with differences in types of problems experienced and emphasize the need for clinicians to address sleep behaviors not only in young children with ASD but throughout the age span.

Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes.

Supplemental melatonin has shown promise in treating sleep onset insomnia in children with autism spectrum disorders (ASD). Twenty-four children, free of psychotropic medications, completed an open-label dose-escalation study to assess dose-response, tolerability, safety, feasibility of collecting actigraphy data, and ability of outcome measures to detect change during a 14-week intervention. Supplemental melatonin improved sleep latency, as measured by actigraphy, in most children at 1 or 3 mg dosages. It was effective in week 1 of treatment, maintained effects over several months, was well tolerated and safe, and showed improvement in sleep, behavior, and parenting stress. Our findings contribute to the growing literature on supplemental melatonin for insomnia in ASD and inform planning for a large randomized trial in this population.

Parent-based sleep education workshops in autism.

To determine if parents can successfully teach their children with autism spectrum disorders to become better sleepers, we piloted small group parent education workshops focused on behavioral sleep strategies. Workshops consisted of three 2-hour sessions conducted over consecutive weeks by 2 physicians. Curricula included establishing effective daytime and nighttime habits, initiating a bedtime routine, and optimizing parental interactions at bedtime and during night wakings. Baseline and treatment questionnaires and actigraphy were analyzed in 20 children, ages 3 to 10 years. Improvements after treatment were seen in the total scale and several insomnia-related subscales of the Children's Sleep Habits Questionnaire. Actigraphy documented reduced sleep latency in children presenting with sleep onset delay. Improvements were also noted in measures of sleep habits and daytime behavior. Brief parent-based behavioral sleep workshops in children with autism spectrum disorders appear effective in improving subjective and objective measures of sleep, sleep habits, and daytime behavior.

Defining the sleep phenotype in children with autism.

Sleep concerns are common in children with autism spectrum disorders (ASD). We identified objective sleep measures that differentiated ASD children with and without parental sleep concerns, and related parental concerns and objective measures to aspects of daytime behavior. ASD poor sleepers differed from ASD good sleepers on actigraphic (sleep latency, sleep efficiency, fragmentation) and polysomnographic (sleep latency) measures, and were reported to have more inattention, hyperactivity, and restricted/repetitive behaviors. Fragmentation was correlated with more restricted/repetitive behaviors. This work provides the foundation for focused studies of pathophysiology and targeted interventions to improve sleep in this population.

Sleep problems and associated daytime fatigue in community-dwelling older individuals.

BACKGROUND: Reported fatigue has been identified as a component of frailty. The contribution of nighttime sleep quality (duration and complaints) to fatigue symptoms in community-dwelling older adults has not been evaluated. METHODS: We studied 2264 men and women, aged 75-84 years (mean 77.5 years; standard deviation [SD] 2.9), participating in the Year 5 (2001--2002) clinic visit of the Health, Aging, and Body Composition (Health ABC) study. Fatigue was determined using a subscale of the Modified Piper Fatigue Scale (0-50; higher score indicating higher fatigue). Hours of sleep per night, trouble falling asleep, waking up during the night, and waking up too early in the morning were assessed using interviewer-administered questionnaires. RESULTS: The average fatigue score was 17.7 (SD 8.4). In multivariate models, women had a 3.8% higher fatigue score than men did. Individuals who slept < or = 6 hours/night had a 4.3% higher fatigue score than did those who slept 7 hours/night. Individuals with complaints of awakening too early in the morning had a 5.5% higher fatigue score than did those without these complaints. These associations remained significant after multivariate adjustment for multiple medical conditions. CONCLUSION: The association between self-reported short sleep duration (< or = 6 hours), and waking up too early and fatigue symptoms suggests that better and more effective management of sleep behaviors may help reduce fatigue in older adults.

Cognition in older women: the importance of daytime movement.

OBJECTIVES: To determine whether an objective measure of daytime movement is associated with better cognitive function in women in their 80s. DESIGN: Cross-sectional. SETTING: A study of health and aging. PARTICIPANTS: Two thousand seven hundred thirty-six older women without evidence of dementia. MEASUREMENTS: Daytime movement was assessed using actigraphy, which involved wearing a watch-like device that objectively quantified accelerometer motion over a mean of 3.0+/-0.8 days. Cognitive function was measured using the Trail-Making Test, Part B (Trails B) and the Mini-Mental State Examination (MMSE). Cognitive impairment was defined as performing 1.5 standard deviations (SDs) worse than the mean on a given test. RESULTS: Participants had a mean age of 83+/-4; 10% were African American. After adjustment for age, race, and education, women in the highest movement quartiles had better mean cognitive test scores (20+/-0.3 seconds faster on Trails B and 0.3+/-0.2 points higher on MMSE, both P<.001) than those in the lowest quartile and were less likely to be cognitively impaired (odds ratio (OR)=0.61, 95% confidence interval (CI)=0.41-0.92 for Trails B; OR=0.68, 95% CI=0.44-1.07 for MMSE). Associations were similar in different subgroups and were independent of self-reported walking, medical comorbidities, physical function, and other health-related behaviors. CONCLUSION: Daytime movement as measured objectively using actigraphy was associated with better cognitive function and lower odds of cognitive impairment in women in their 80s. Additional studies are needed to clarify the direction of the association and to explore potential mechanisms.

Self-reported napping and duration and quality of sleep in the lifestyle interventions and independence for elders pilot study.

OBJECTIVES: To determine the prevalence of self-reported napping and its association with subjective nighttime sleep duration and quality, as measured according to sleep-onset latency and sleep efficiency. DESIGN: Cross-sectional study. SETTING: Lifestyle Interventions and Independence for Elders Pilot Study. PARTICIPANTS: Community-dwelling older adults (N=414) aged 70 to 89. MEASUREMENTS: Self-report questionnaire on napping and sleep derived from the Pittsburgh Sleep Quality Index (PSQI) scale. RESULTS: Fifty-four percent of participants reported napping, with mean nap duration of 55.0+/-41.2 minutes. Nappers were more likely to be male (37.3% vs 23.8%, P=.003) and African American (20.4% vs 14.4%, P=.06) and to have diabetes mellitus (28% vs 14.3%, P=.007) than non-nappers. Nappers and non-nappers had similar nighttime sleep duration and quality, but nappers spent approximately 10% of their 24-hour sleep occupied in napping. In a multivariate model, the odds of napping were higher for subjects with diabetes mellitus (odds ratio (OR)=1.9, 95% confidence interval (CI)=1.2-3.0) and men (OR=1.9, 95% CI=1.2-3.0). In nappers, diabetes mellitus (beta=12.3 minutes, P=.005), male sex (beta=9.0 minutes, P=.04), higher body mass index (beta=0.8 minutes, P=.02), and lower Mini-Mental State Examination score (beta=2.2 minutes, P=.03) were independently associated with longer nap duration. CONCLUSION: Napping was a common practice in community-dwelling older adults and did not detract from nighttime sleep duration or quality. Given its high prevalence and association with diabetes mellitus, napping behavior should be assessed as part of sleep behavior in future research and in clinical practice.

Association between nighttime sleep and napping in older adults.

STUDY OBJECTIVES: Napping might indicate deficiencies in nighttime sleep, but the relationship is not well defined. We assessed the association of nighttime sleep duration and fragmentation with subsequent daytime sleep. DESIGN: Cross-sectional study. PARTICIPANTS: 235 individuals (47.5% men, 29.7% black), age 80.1 (2.9) years. MEASUREMENTS AND RESULTS: Nighttime and daytime sleep were measured with wrist actigraphy and sleep diaries for an average of 6.8 (SD 0.7) nights. Sleep parameters included total nighttime sleep (h), movement and fragmentation index (fragmentation), and total daytime sleep (h). The relationship of total nighttime sleep and fragmentation to napping (yes/no) was assessed using logistic regression. In individuals who napped, mixed random effects models were used to determine the association between the previous night sleep duration and fragmentation and nap duration, and nap duration and subsequent night sleep duration. All models were adjusted for age, race, gender, BMI, cognitive status, depression, cardiovascular disease, respiratory symptoms, diabetes, pain, fatigue, and sleep medication use. Naps were recorded in sleep diaries by 178 (75.7%) participants. The odds ratios (95% CI) for napping were higher for individuals with higher levels of nighttime fragmentation (2.1 [0.8, 5.7]), respiratory symptoms (2.4 [1.1, 5.4]), diabetes (6.1 [1.2, 30.7]), and pain (2.2 [1.0, 4.7]). Among nappers, neither sleep duration nor fragmentation the preceding night was associated with nap duration the next day. CONCLUSION: More sleep fragmentation was associated with higher odds of napping although not with nap duration. Further research is needed to determine the causal association between sleep fragmentation and daytime napping.

Poor sleep is associated with poorer physical performance and greater functional limitations in older women.

STUDY OBJECTIVES: This study examined the association between disturbed sleep and poorer daytime function in older women. DESIGN: Observational study. PARTICIPANTS: 2,889 women, mean age 83.5 years, participating in the 2002-2004 examination of the Study of Osteoporotic Fractures. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants wore actigraphs for an average +/- SD of 4.1 +/- 0.83 24-hour periods. Actigraphy measured sleep variables were total sleep time and hours awake after sleep onset during the night and daytime napping behavior. Neuromuscular performance measurements included gait speed, chair stands, and grip strength. Functional limitations were assessed as self-reported difficulty with one or more of 6 instrumental activities of daily living (IADL). In fully adjusted, multivariable models, women who slept <6 hours per night walked 3.5% slower than those who slept 6.0-6.8 hours. Those who slept > or =7.5 hours took 4.1% longer to complete 5 chair stands than those who slept 6.8-7.5 hours. With higher wake after sleep onset (> or =1.6 hours compared to <0.7 hours) gait speed was 9.1% slower; it took 7.6% longer to complete 5 chair stands, and odds of functional limitation were 1.8 (95% CI: 1.4, 2.4) higher. Women with 1.0-1.8 hours of daytime sleep had higher odds (1.4 [95% CI: 1.1, 1.8]) of a functional limitation than those with <0.5 hours. Sleep variables did not appear to be associated with grip strength. CONCLUSIONS: Objectively measured poorer sleep was associated with worse physical function. Future research is needed to identify the underlying mechanisms for the association between poor sleep and functional decline.