Ashura Williams Buckley

An Open Label Trial of Donepezil for Enhancement of Rapid Eye Movement Sleep in Young Children with Autism Spectrum Disorders

BACKGROUND Rapid eye movement (REM) sleep is greatest in the developing brain, is driven by acetylcholine, and may represent a protected time for neuroplasticity. Recently published data from our lab observed that children with autism spent significantly less time in this state during a single night recording than did typically developing children and those with developmental delay without autism. The objective of this study was to determine whether or not donepezil can increase the REM % in children with diagnosed autism spectrum disorder (ASD) found to have REM % values of at least two standard deviations below expected for age. METHODS Five subjects found to have an ASD (ages 2.5-6.9 years) and demonstrated deficits in REM sleep compared with within-lab controls were enrolled in a dose finding study of donepezil. Each subject was examined by polysomnography for REM sleep augmentation after drug administration. RESULTS REM sleep as a percentage of Total Sleep Time was increased significantly and REM latency was decreased significantly after drug administration in all subjects. No other observed sleep parameter was changed significantly. CONCLUSIONS Donepezil can increase the amount of time that children with an ASD spend in the REM sleep state. A double-blind, placebo-controlled trial is needed to assess the association between REM sleep augmentation and learning, cognition, and behavior in such children.

Epilepsy and Autism

Epilepsy and autistic spectrum disorder frequently coexist in the same individual. Electroencephalogram (EEG) epileptiform activity is also present at a substantially higher rate in children with autism than normally developing children. As with epilepsy, there are a multitude of genetic and environmental factors that can result in autistic spectrum disorder. There is growing consensus from both animal and clinical studies that autism is a disorder of aberrant connectivity. As measured with functional magnetic resonance imaging (MRI) and EEG, the brain in autistic spectrum disorder may be under- or overconnected or have a mixture of over- and underconnectivity. In the case of comorbid epilepsy and autism, an imbalance of the excitatory/inhibitory (E/I) ratio in selected regions of the brain may drive overconnectivity. Understanding the mechanism by which altered connectivity in individuals with comorbid epilepsy and autistic spectrum disorder results in the behaviors specific to the autistic spectrum disorder remains a challenge.

State-Dependent Differences in Functional Connectivity in Young Children With Autism Spectrum Disorder

Background While there is increasing evidence of altered brain connectivity in autism, the degree and direction of these alterations in connectivity and their uniqueness to autism has not been established. The aim of the present study was to compare connectivity in children with autism to that of typically developing controls and children with developmental delay without autism. Methods We assessed EEG spectral power, coherence, phase lag, Pearson and partial correlations, and epileptiform activity during the awake, slow wave sleep, and REM sleep states in 137 children aged 2 to 6 years with autism (n = 87), developmental delay without autism (n = 21), or typical development (n = 29). Findings We found that brain connectivity, as measured by coherence, phase lag, and Pearson and partial correlations distinguished children with autism from both neurotypical and developmentally delayed children. In general, children with autism had increased coherence which was most prominent during slow wave sleep. Interpretation Functional connectivity is distinctly different in children with autism compared to samples with typical development and developmental delay without autism. Differences in connectivity in autism are state and region related. In this study, children with autism were characterized by a dynamically evolving pattern of altered connectivity.

Evaluation of Periodic Limb Movements in Sleep and Iron Status in Children With Autism.

OBJECTIVE Recent data suggest that both disordered sleep and low serum iron occur more frequently in children with autism compared with children with typical development. Iron deficiency has been linked to specific sleep disorders. The goal of the current study was to evaluate periodic limb movements in sleep and iron status in a group of children with autism compared with typically developing children and children with nonautism developmental delay to determine if iron status correlated with polysomnographic measures of latency and continuity and periodic limb movements in sleep. METHODS A total of 102 children (68 with autism, 18 typically developing, 16 with developmental delay) aged 2 to 7 years underwent a one-night modified polysomnography study and phlebotomy at the National Institutes of Health to measure serum markers of iron status (ferritin, iron, transferrin, percent transferrin saturation). RESULTS No serum iron marker was associated with periodic limb movements of sleep or any other sleep parameter; this did not differ among the diagnostic groups. No significant differences among groups were observed on serum iron markers or most polysomnogram parameters: periodic limb movements in sleep, periodic limb movements index, wake after sleep onset, or sleep efficiency. Children in the autism group had significantly less total sleep time. Serum ferritin was uniformly low across groups. CONCLUSIONS This study found no evidence that serum ferritin is associated with polysomnogram measures of latency or sleep continuity or that young children with autism are at increased risk for higher periodic limb movements index compared with typically developing and developmental delay peers.

First night effect analysis in a cohort of young children with autism spectrum disorder.

STUDY OBJECTIVES To evaluate for the first night effect (FNE) in a group of young children with autism. DESIGN Analysis of polysomnographic data from a 2-night sleep laboratory study. SETTING Clinical Center of the National Institutes of Health. PATIENTS OR PARTICIPANTS 15 children (aged 2-10 years) with a diagnosis of an ASD. INTERVENTIONS None. MEASUREMENTS AND RESULTS Polysomnographic analysis showed the presence of a FNE for wake after sleep onset minutes, stage 2, and sleep efficiency, but not for REM sleep parameters or TST. CONCLUSIONS In this 2-night polysomnographic analysis of sleep stages in young children with autism, we did not find the expected second night increase in total sleep time or REM sleep percentage or a decrease in REM sleep latency. This lack of an FNE for TST and REM parameters suggests that a single-night polysomnogram may be sufficient to evaluate children with an ASD for TST or REM parameters.

Rapid Eye Movement Sleep Abnormalities in Children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).

STUDY OBJECTIVES Polysomnographic investigation of sleep architecture in children presenting with pediatric acute-onset neuropsychiatric syndrome (PANS). METHODS Fifteen consecutive subjects meeting criteria for PANS (mean age = 7.2 y; range 3-10 y) underwent single-night full polysomnography (PSG) read by a pediatric neurologist. RESULTS Thirteen of 15 subjects (87%) had abnormalities detected with PSG. Twelve of 15 had evidence of rapid eye movement (REM) sleep motor disinhibition, as characterized by excessive movement, laughing, hand stereotypies, moaning, or the continuation of periodic limb movements during sleep (PLMS) into REM sleep. CONCLUSIONS This study shows various forms of REM sleep motor disinhibition present in a population of children with PANS.

Spindle activity in young children with autism, developmental delay, or typical development

Objective To determine whether spindle activity differs in young children with and without autism. Methods We investigated differences in spindle density, duration, and oscillatory features in 135 young children with autism, developmental delay without autism (DD), or typical development (TD) and secondarily assessed the dimensional relationship between spindle density and both cognitive ability and social functioning. Results Compared to TD, both spindle density (Cohen d 0.93, 95% confidence interval [CI] 0.49–1.37) and duration (Cohen d 0.58, 95% CI 0.15–1.01) were significantly decreased in autism. Spindle density was also significantly reduced in autism compared to DD (Cohen d 0.61, 95% CI 0.13–1.09). Decreased spindle frequency in autism compared to both TD (Cohen d 0.47, 95% CI 0.04–0.90) and DD (Cohen d 0.58, 95% CI 0.10–1.06) did not survive correction. The DD group did not differ significantly from the TD group on any spindle parameter. These results, suggesting a relationship between spindle density and autism but not DD, were further illustrated in exploratory analyses, wherein nonverbal ratio IQ (RIQ) and the Vineland Socialization domain standard score were strongly correlated with spindle density in the full sample (r = 0.33, p ≤ 001 and r = 0.41, p ≤ 001, respectively) but not within group. After nonverbal RIQ was accounted for, the relationship between spindle density and Vineland Socialization remained statistically significant (r = 0.23, p < 0.01). However, Vineland Socialization scores accounted for the relationship between spindle density and nonverbal RIQ (r = 0.04, p = 0.67). Conclusion In a large cohort of young children with autism, spindle density was reduced compared to groups of age-matched children with DD or TD. Alterations in the maturational trajectory of spindles may provide valuable insight into the neurophysiologic differences related to behavior in disorders of neurodevelopment.

Prospective longitudinal overnight video-EEG evaluation in Phelan–McDermid Syndrome

OBJECTIVE Phelan-McDermid Syndrome (PMS) is a rare genetic condition associated with loss of function mutations, including deletions, in the chromosome 22q13 region. This PMS phenotype includes intellectual disability, often minimal to absent verbal skills, and other neurologic features including autism spectrum disorder and seizures. Reports indicate seizures and abnormal electroencephalograms (EEGs) in this population, but previous studies do not describe EEG findings during sleep or prognostic value of abnormal EEG over any time period. METHODS During a natural history study, 16 consecutively enrolled participants (mean age 10years) with PMS underwent both routine (approximately 25min) and overnight (average 9.65h) video-EEG, in addition to genetic testing, neurodevelopmental assessment, neurological examination, and epilepsy phenotyping. Over 240h of EEG, data was recorded. Comparison of findings from the routine EEG was made with prolonged EEG acquired during awake and sleep the same night. In a subset of nine participants, the overnight EEG was repeated one or more years later to observe the natural evolution and prognostic value of any abnormalities noted at baseline. RESULTS A history of epilepsy, with multiple seizure types, was confirmed in seven of the 16 participants, giving a prevalence of 43.8% in this cohort. All but one EEG was abnormal (15 of 16), and 75% (12 of 16) showed epileptiform activity. Of these, only 25% of participants (3 of 12) showed definitive epileptiform discharges during the routine study. Overnight EEGs (sleep included) did not show any clinical events consistent with seizures or electrophic seizures, however, overnight EEG showed either more frequent and/or more definitive epileptiform activity in 68.75% (11 of 16) participants. All seven of the 16 participants who had previously been diagnosed with epilepsy showed epileptiform abnormalities. In addition to a wide range of epileptiform activity observed, generalized slowing with poor background organization was frequently noted. Follow-up EEG confirmed persistence of abnormal discharges, but none of the abnormal EEGs showed evolution to electrographic seizures. Clinically, there was no emergence of epilepsy or significant developmental regression noted in the time frame observed. CONCLUSIONS This is the first and most abundant prolonged awake and sleep video-EEG data recorded in a PMS cohort to date. The importance of overnight prolonged EEGs is highlighted by findings from this study, as they can be used to document the varied topographies of EEG abnormalities in conditions such as PMS, which are often missed during routine EEG studies. While the long-term significance of the EEG abnormalities found (beyond 1year) remains uncertain despite their persistence over time, these findings do underscore the current clinical recommendation that overnight prolonged EEG studies (with sleep) should be conducted in individuals with PMS.