Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Reliability of parental reporting of child snoring in children referred for obstructive sleep apnea.

Despite the high number of studies based on subjective reports of snoring, self-reported snoring has hardly been validated at all. As there is no "gold-standard" for objective snoring measurements, studies must evaluate whether the presence of snoring based on parental judgement is linked to objective measurements of nasal and/or pharyngeal obstruction in children referred for obstructive sleep apnea. A total of 146 children (median age 11 years) underwent polysomnography (with snoring recording using nasal cannula signal), acoustic rhinometry and pharyngometry, while their parents filled out the Spruyt-Gozal questionnaire assessing both frequency and loudness of subjective snoring. Three categories were further differentiated (null, low and high) for both frequency and loudness. The apnea-hypopnea index was significantly different in the three groups for both frequency (p = 0.04) and loudness (p = 0.01) of subjective snoring. Children in the low or high groups (frequency or loudness), compared with those in the null group, experienced a decline in both pharyngeal (sitting and supine positions) and nasopharyngeal (supine position) volumes (frequency, pharynx sitting: p = 0.03; supine: 0.005 and nasopharynx: p = 0.002; loudness, p = 0.03; p = 0.007 and p = 0.03; three group comparisons). Objective snoring frequency during the night obtained with cannula was weakly related to loudness of subjective snoring but not to subjective snoring frequency during the week, and was biased by nasal obstruction. In conclusion, our study showed that parental assessment of snoring is related to a reduction in both pharyngeal and nasopharyngeal volumes in snorers, arguing for the adequacy of their evaluation of both snoring frequency and loudness.

Developing a serious game for gaze stability rehabilitation in children with vestibular hypofunction.

BACKGROUND: Children with vestibular hypofunction (VH) may have gaze instability, balance disorders, and delayed postural-motor development. Gaze stabilization exercises (GSE) are designed to improve dynamic visual acuity (DVA). We aimed to assess the acceptability of a serious game prototype called Kid Gaze Rehab (KGR) designed to implement GSE training in children with VH, combined with traditional vestibular rehabilitation. Effects on DVA and motor performance were also analyzed. METHODS: Twelve children (6 to 9 years old) were included. Sessions were held at the hospital twice a week, for 5 weeks. An adapted French version of The Child Simulator Sickness Questionnaire (SSQ) and the Face Scale Pain-Revised (FPS-R) were used to assess pain in the cervical region and undesirable side effects after each session. Vestibular and motor function parameters (active and passive DVA and Movement Assessment Battery for Children-Second Edition, MABC-2) were assessed before and after the training. RESULTS: All children included completed the 10 sessions. The FPS-R visual analog scale and SSQ showed good cervical tolerance and no oculomotor or vegetative adverse effects nor spatial disorientation. After training, active DVA scores were significantly improved for the right, left, and up directions (p < 0.05). Passive DVA scores were significantly improved for the left and down directions (p < 0.01 and p < 0.05, respectively). MABC-2 scores were improved in the balance and ball skill sections (p < 0.05). CONCLUSION: An innovative pediatric training method, the use of a dedicated serious game for gaze stabilization was well-tolerated as a complement to conventional vestibular rehabilitation in children with VH. Moreover, both DVA and motor performance were found to improve in the study sample. Although replication studies are still needed, serious game-based training in children with VH could represent a promising rehabilitation approach for years to come. TRIAL REGISTRATION: The study was conducted in accordance with the Declaration of Helsinki and approved by an Institutional Review Board (local ethics committee, CPP Sud-Est IV, ID 2013-799). The study protocol was registered on ClinicalTrials.gov (NCT04353115).

Morphological and Age-Related Changes in the Narcolepsy Brain.

Morphological changes in the cortex of narcolepsy patients were investigated by surface-based morphometry analysis in this study. Fifty-one type 1 narcolepsy patients and 60 demographically group-matched healthy controls provided resting-state functional and high-resolution 3T anatomical magnetic resonance imaging scans. Vertex-level cortical thickness (CT), gyrification, and voxel-wise functional connectivity were calculated. Adolescent narcolepsy patients showed decreased CT in bilateral frontal cortex and left precuneus. Adolescent narcolepsy demonstrated increased gyrification in left occipital lobe, left precuneus, and right fusiform but decreased gyrification in left postcentral gyrus, whereas adult narcolepsy exhibited increased gyrification in left temporal lobe and right frontal cortex. Furthermore, sleepiness severity was associated with altered CT and gyrification. Increased gyrification was associated with reduced long-range functional connectivity. In adolescent patients, those with more severe sleepiness showed increased right postcentral gyrification. Decreased frontal and occipital gyrification was found in cases with hallucination. In adult patients, a wide range of regions showed reduced gyrification in those with adolescence-onset compared adult-onset narcolepsy patients. Particularly the frontal lobes showed altered brain morphology, being a thinner cortex and more gyri. The impact of narcolepsy on age-related brain morphological changes may remain from adolescence to young adulthood, and it was especially exacerbated in adolescence.

Sleep problems in Rett syndrome animal models: A systematic review.

Due to the discovery of Rett Syndrome (RTT) genetic mutations, animal models have been developed. Sleep research in RTT animal models may unravel novel neural mechanisms for this severe neurodevelopmental heritable rare disease. In this systematic literature review we summarize the findings on sleep research of 13 studies in animal models of RTT. We found disturbed efficacy and continuity of sleep in all genetically mutated models of mice, cynomolgus monkeys, and Drosophila. Models presented highly fragmented sleep with distinct differences in 24-hr sleep/wake cyclicity and circadian arrhythmicity. Overall, animal models mimic sleep complaints reported in individuals with RTT. However, contrary to human studies, in mutant mice, attenuated sleep delta waves, and sleep apneas in non-rapid eye movement sleep were reported. Future studies may focus on sleep structure and EEG alterations, potential central mechanisms involved in sleep fragmentation and the occurrence of sleep apnea across different sleep stages. Given that locomotor dysfunction is characteristic of individuals with RTT, studies may consider to integrate its potential impact on the behavioral analysis of sleep.

Combined effects of weight change trajectories and eating behaviors on childhood adiposity status: A birth cohort study.

Previous studies have suggested that infant rapid weight change can be associated with an increased weight later in life. However, the weight change trajectory in early life over time and which childhood lifestyle behaviors may modify the risk of rapid weight change have not been characterized. Using our ongoing birth cohort study, we have addressed these issues. Nine follow-up time points (birth, 3, 6, 9, 12, 18, 24, 36, and 48 months) were used to calculate the change between two adjacent weight-for-age z-scores (WAZ-change), and then WAZ-change trajectories were defined via group-based trajectory modeling. The solitary, independent and combined effects of WAZ-change trajectories and each lifestyle factor (eating behaviors, physical activity, media exposure time and total sleep duration) on childhood adiposity measures at age 4 years were determined using multivariate regression analysis. Overall, 84 (38%) children had a steady growth trajectory from birth to 4 years, while the other 137 (62%) children had an early infancy rapid growth trajectory, particularly in the first three months. Compared to children with steady growth, children with early infancy rapid growth had a significantly higher body mass index, waist circumference, and subcutaneous fat. Moreover, weight change trajectory and three eating behaviors (i.e. food responsiveness, satiety responsiveness and food fussiness), not only had independent effects, but also combined (synergistic) effects on the majority of adiposity measures. Our results extend the current literature and provide a potentially valuable model to aid clinicians and health professionals in designing early-life interventions targeting specific populations, specific ages and specific lifestyle behaviors to prevent childhood overweight/obesity.

Non-pharmacological management of problematic sleeping in children with developmental disabilities.

AIM: Sleep is important for underlying neural plasticity, and children with developmental disabilities suffer behavioural, emotional, cognitive, and sensory-motor issues that affect their wake and sleep states. Problematic sleeping can be hypothesized to have adverse effects on both of these areas in children with developmental disabilities. With this review, we aim to provide a benchmark in managing problematic sleeping in children with developmental disabilities. METHOD: A literature search was conducted and data on the study descriptives, patient characteristics, study design, study-related factors, criteria applied to operationalize sleep and developmental disability, and sleep 'management' were collected. Each management strategy was tabulated and analysed. RESULTS: We identified 90 studies involving 1460 children with developmental disabilities, of whom 61.6% were male. The highest proportion of studies, almost half, were in children with syndromes (44.4%), followed by studies in children with intellectual disabilities (18.9%). Non-pharmacological sleep management was primarily aimed at improving sleep quality (86.7%), followed by sleep-wake schedules and, to a certain extent, sleep regularity (42.2%). About 56.7% of the studies reported more than one approach. Studies mostly focused on disorders of initiating and maintaining sleep through a diversity of strategies and relied heavily on subjective measures to identify and monitor problematic sleeping. Sleep management approaches were primarily delivered at the level of the individual in the home setting. The number of management approaches per study was unrelated to the number of sleep problems discussed. INTERPRETATION: Modifying sleep management strategies to meet the specific needs of children with developmental disabilities is encouraged, and studies that look beyond sleep quality or sleep quantity are required. It is also advocated that modifications to sleep hygiene, sleep regularity, and sleep ecology in a population with developmental disabilities are rigorously investigated. Finally, daytime somnolence should not be overlooked when aiming to optimize sleep in children with developmental disabilities across the ages and stages of their lives. There were several limitations in the research findings of problematic sleep in children with developmental disabilities. In general, the sleep problems and the developmental disabilities investigated were multicomponent in nature. It is likely that management approaches impacted those problems on multiple levels or through diverse 'therapeutic' pathways. There is a need for randomized controlled trials and more objective measures that quantify improved sleep or wake states.

The relation among sleep duration, homework burden, and sleep hygiene in chinese school-aged children.

Insufficient sleep in school-aged children is common in modern society, with homework burden being a potential risk factor. The aim of this article is to explore the effect of sleep hygiene on the association between homework and sleep duration. Children filled out the Chinese version of the Adolescent Sleep Hygiene Scale, and parents filled out a sociodemographic questionnaire. The final sample included 363 boys and 371 girls with a mean age of 10.82 ± 0.38 years. Children with more homework went to bed later and slept less. Better sleep hygiene was associated with earlier bedtimes and longer sleep duration. Findings suggest that homework burden had a larger effect on sleep duration than sleep hygiene. Fifth-grade children in Shanghai have an excessive homework burden, which overwrites the benefit of sleep hygiene on sleep duration.

Neurocognitive Effects of Sleep Disruption in Children and Adolescents.

A main childhood task is learning. In this task, the role of sleep is increasingly demonstrated. Although most literature examining this role focuses on preadolescence and middle adolescence, some studies apply napping designs in preschoolers. Studies overall conclude that without proper sleep a child's cognitive abilities suffer, but questions on how and to what extent linger. Observational studies show the hazards of potential confounders such as an individual's resilience to poor sleep as well as developmental risk factors (eg, disorders, stressors). A better understanding of cognitive sleep neuroscience may have a big impact on pediatric sleep research and clinical applications.

Sleep and the Social Profiles of Individuals With Rett Syndrome.

BACKGROUND: This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye gaze communication, gait abnormalities, and sleep issues. The research aims to identify social profiles in RTT and explore their correlation with sleep, sleep-disordered breathing (SDB), and daytime sleepiness. METHODS: Standard overnight sleep macrostructure and respiratory parameters were assessed. Extracting 25 social-related items and one for daytime sleepiness from the Rett Syndrome Behavioral Questionnaire, factor analysis was applied to establish latent social profiles. These profiles were then correlated with sleep parameters. The nonparametric Mann-Whitney U test compared social profiles based on the presence of SDB (defined by an apnea-hypopnea index greater than one per hour) and daytime sleepiness. RESULTS: The study involved 12 female subjects with confirmed RTT diagnoses and MECP2 mutations, aged 8.54 ± 5.30 years. The Rett Syndrome Behavioral Questionnaire revealed a total average score of 25.83 ± 12.34, indicating varying degrees of social impairments. Comprising 25 social-related items, factor analysis yielded four social profiles: "interactive motricity," "mood change," "anxiety/agitation," and "gazing." Longer sleep onset latency correlated with increased socio-behavioral impairments, particularly in interactive motricity reduction. Conversely, higher rapid eye movement sleep was associated with fewer interactive socio-motor behaviors. No significant differences in social profiles were found concerning the presence of SDB or daytime sleepiness. CONCLUSIONS: The findings suggest four distinct social profiles in RTT individuals, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. Despite the absence of differences in SDB or daytime sleepiness, the study highlights the relationship between sleep parameters, such as sleep onset latency and rapid eye movement sleep, and socio-behavioral outcomes in RTT with MECP2 mutations.

A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep.

In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit. Highlights: Benzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.

Individualized approaches to pediatric chronic insomnia: Advancing precision medicine in sleep disorders.

The manifestations of chronic insomnia undergo age-related changes. In younger infants and children, behavioral insomnia emerges as the most prevalent form and typically responds to behavioral interventions. However, distinct clusters of clinical presentations suggest the presence of various phenotypes, potentially implicating the primary involvement of specific neurotransmitters. These conceptualizations, coupled with genetic studies on pleiotropy and polygenicity, may aid in identifying individuals at risk of persistent insomnia into adulthood and shed light on novel treatment options. In school-age children, the predominant presentation is sleep-onset insomnia, often linked with nighttime fears, anxiety symptoms, poor sleep hygiene, limit-setting issues, and inadequate sleep duration. The manifestations of insomnia in adolescence correlate with the profound changes occurring in sleep architecture, circadian rhythms, and homeostatic processes. The primary symptoms during adolescence include delayed sleep onset, sleep misperception, persistent negative thoughts about sleep, and physiological hyperarousal-paralleling features observed in adult insomnia. An approach centered on distinct presentations may provide a framework for precision-based treatment options. Enhanced comprehension of insomnia's manifestations across diverse developmental stages can facilitate accurate assessment. Efforts to subtype insomnia in childhood align with this objective, potentially guiding the selection of appropriate treatments tailored to individual neurobiological, clinical, and familial features.

Assessing psychometric properties and measurement invariance of the Sleep Quality Questionnaire among healthcare students.

OBJECTIVE: The sleep of healthcare students is worth discovering. Mental health and self-rated health are thought to be associated with sleep quality. As such, valid instruments to assess sleep quality in healthcare students are crucial and irreplaceable. This study aimed to investigate the measurement properties of the Sleep Quality Questionnaire (SQQ) for Chinese healthcare students. METHODS: Two longitudinal assessments were undertaken among healthcare students, with a total of 595, between December 2020 and January 2021. Measures include the Chinese version of the SQQ, Patient Health Questionnaire-4 (PHQ-4), Self-Rated Health Questionnaire (SRHQ), and sociodemographic questionnaire. Structural validity through confirmatory factor analysis (CFA) was conducted to examine factor structure of the SQQ. T-tests and ANOVAs were used to examine sociodemographic differences in sleep quality scores. Multi Group CFA and longitudinal CFA were respectively used to assess cross-sectional invariance and longitudinal invariance across two-time interval, i.e., cross-cultural validity. Construct validity, internal consistency, and test-retest reliability were correspondingly examined via Spearman correlation, Cronbach's alpha and McDonald's omega, and intraclass correlation coefficient. Multiple linear regression analysis was performed to examine incremental validity of the SQQ based on the PHQ-4 and SRHQ as indicators of the criterion variables. RESULTS: CFA results suggested that the two-factor model of the SQQ-9 (item 2 excluded) had the best fit. The SQQ-9 scores differed significantly by age, grade, academic stage, hobby, stress coping strategy, anxiety, depression, and self-rated health subgroups. Measurement invariance was supported in terms of aforesaid subgroups and across two time intervals. In correlation and regression analyses, anxiety, depression, and self-rated health were moderately strong predictors of sleep quality. The SQQ-9 had good internal consistency and test-retest reliability. CONCLUSION: Good measurement properties suggest that the SQQ is a promising and practical measurement instrument for assessing sleep quality of Chinese healthcare students.

Periodic limb movement disorder in children: A systematic review.

This systematic review evaluates the scientific literature on pediatric periodic limb movement disorder (PLMD), adhering to PRISMA guidelines and utilizing PICOS criteria. The search across PubMed, EMBASE, and Scopus yielded 331 articles, with 17 meeting inclusion criteria. Diagnostic criteria evolved, with polysomnography and PLMS index ≥5 required since 2003. Also, PLMD diagnosis mandates clinical consequences like insomnia, hypersomnia, and fatigue, excluding comorbidities causing sleep disruption. Prevalence in children is low (0.3%), emphasizing the need for meticulous investigation. Comorbidities, particularly the bidirectional relationship with ADHD, were explored. Challenges in diagnosis and understanding arise from overlapping conditions such as sleep disordered breathing, psychotropic medication, and criteria non-adherence. Despite generally good study quality, weaknesses include sample size justification and biases. The periodic leg movement index shows high sensitivity but low specificity, underscoring strict diagnostic criteria adherence. Diverse metrics for symptoms necessitate standardized approaches. Family history of RLS in children with PLMD suggests unexplored aspects. Treatment, mainly iron supplementation, lacks standardized assessment metrics. The review emphasizes diagnostic and treatment challenges, recommending unbiased studies with precise techniques. Comprehensive research, quantifying PLMS and objectively assessing sleep parameters, is crucial for advancing understanding in pediatric PLMD. PROSPERO REGISTRATION NUMBER: CRD42021251406.

Melatonin use in managing insomnia in children with autism and other neurogenetic disorders - An assessment by the international pediatric sleep association (IPSA).

Though it is widely prescribed for improving sleep of children with autism and other neurogenetic disorders, there is a need for practical guidance to clinicians on the use of melatonin for managing insomnia in this population. Because data were either lacking or inconclusive, a task force was established by the International Pediatric Sleep Association (IPSA) to examine the literature based on clinical trials from 2012 onwards. A summary of evidence pertaining to melatonin's utility and potential side effects, practice-related caveats, and insights for use are published herewith.

A mediation model linking body weight, cognition, and sleep-disordered breathing.

RATIONALE: Academic success involves the ability to use cognitive skills in a school environment. Poor academic performance has been linked to disrupted sleep associated with sleep-disordered breathing (SDB). In parallel, poor sleep is associated with increased risk for obesity, and weight management problems have been linked to executive dysfunction, suggesting that interactions may be operational between SDB and obesity to adversely affect neurocognitive outcomes. OBJECTIVES: To test whether mediator relationships exist between body weight, SDB, and cognition. METHODS: Structural equation modeling was conducted on data from 351 children in a community-based cohort assessed with the core subtests of the Differential Abilities Scales after an overnight polysomnogram. Body mass index, apnea-hypopnea index, and cognitive abilities were modeled as latent constructs. MEASUREMENTS AND MAIN RESULTS: In a sample of predominantly white children 6 to 10 years of age, SDB amplified the adverse cognitive and weight outcomes by 0.55- to 0.46-fold, respectively. Weight amplified the risk by 0.39- to 0.40-fold for SDB and cognitive outcomes, respectively. Poor ability to perform complex mental processing functions increased the risk of adverse weight and SDB outcomes by 2.9- and 7.9-fold, respectively. CONCLUSIONS: Cognitive functioning in children is adversely affected by frequent health-related problems, such as obesity and SDB. Furthermore, poorer integrative mental processing may place a child at a bigger risk for adverse health outcomes.

The interaction between stress and sleep disorders among foreign medical students in Georgia.

OBJECTIVES: This study aimed to: a. Investigate daytime sleepiness, stress, and pre-sleep arousal prevalence among foreign medical students in Georgia. b. Explore gender-based associations between sleep and stress parameters. METHODS: Mental health was assessed in 207 foreign medical students in Georgia using the Epworth Sleepiness Scale (ESS), Pre-Sleep Arousal Scale (PSAS), and Student-Life Stress Inventory (SLSI). RESULTS: Most participants reported elevated stress levels and excessive daytime sleepiness (EDS). EDS affected 25.1% of students, with slightly higher prevalence in males. PSAS was prevalent in 97.1% of students. Stress was widely reported, with 78% experiencing it, with a higher prevalence in females. Significant correlations were observed between sleepiness and arousal, including somatic (r = 0.41) and total scores (r = 0.28). Sleepiness was also linked to stressors like pressure, changes, self-imposed stress, and overall self-evaluation stress (r = 0.45). Strong correlations existed between ESS, Total PSAS, and overall self-evaluation SLSI scores for both genders. Gender differences were observed in the associations with Cohen's d within the small to moderate size. Men showed significant associations between ESS and stressors: conflict, pressure, chances, all stress reaction categories, and total SLSI scores (p < 0.001). In women, ESS correlated significantly only with overall self-evaluation (p < 0.001). Excessive daytime sleepiness, especially with somatic and total PSAS, predicted total SLSI scores for the entire sample and both genders, with stronger predictive values for total PSAS. CONCLUSION: The study reveals a high prevalence of clinical sleepiness and its significant correlation with pre-sleep arousal and stress among foreign medical students, with females experiencing more difficulties than males.

An investigation of the sleep macrostructure of girls with Rett syndrome.

OBJECTIVE/BACKGROUND: Methyl-CpG-binding protein 2 (MeCP2) is of utmost importance in neuronal function. We aim to characterize phenotypic traits in the sleep of individuals with Rett Syndrome (RTT, OMIM # 312750), a rare disorder predominantly caused by mutations of the MECP2 gene. PATIENTS/METHODS: An overnight polysomnographic recording was performed. Outcomes investigated were parameters of nocturnal sleep macrostructure, and sample stratification per genetic and clinical characteristics, and six key features of clinical severity was applied. RESULTS: The sleep of our 21 RTT female subjects with a mutant MECP2 gene, aged 8.8 ± 5.4 years, showed no significant differences within strata. However, compared to a normative dataset, we found longer duration of wake time after sleep onset and total sleep time (TST) but shorter sleep onset latency, in RTT. Regarding the proportion of sleep stages per TST, higher stage N3 (%) with lower stage N2 (%) and REM (%) were generally seen. Such abnormalities became more uniformly expressed at the severe level of clinical features, particularly for hand functioning and walking. CONCLUSIONS: RTT girls with MECP2 mutations in our study demonstrated an increased deep sleep and reduced rapid eye movement sleep proportion, which is mostly allied with their hand dysfunction severity. Poor sleep-on/off switching in RTT since embryogenesis is possibly linked to (psycho)motor impairment in the cases with MECP2 mutations.

A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use.

Background: There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review. Methods: We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents. Results: Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties. Discussion: Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication.

Development and validation of moderate to severe obstructive sleep apnea screening test (ColTon) in a pediatric population.

OBJECTIVE: Development and validation of a machine learning algorithm to predict moderate to severe obstructive sleep apnea syndrome (OSAS) in otherwise healthy children. DESIGN: Multivariable logistic regression and cforest algorithm of a large cross-sectional data set of children with sleep-disordered breathing. SETTING: An university pediatric sleep centre. PARTICIPANTS: Children underwent clinical examination, acoustic rhinometry and pharyngometry, and surveying through parental sleep questionnaires, allowing the recording of 14 predictors that have been associated with OSAS. The dataset was nonrandomly split into a training (development) versus test (external validation) set (2:1 ratio) based on the time of the polysomnography. We followed the TRIPOD checklist. RESULTS: We included 336 children in the analysis: 220 in the training set (median age [25th-75th percentile]: 10.6 years [7.4; 13.5], z-score of BMI: 1.96 [0.73; 2.50], 89 girls) and 116 in the test set (10.3 years [7.8; 13.0], z-score of BMI: 1.89 [0.61; 2.46], 51 girls). The prevalence of moderate to severe OSAS was 106/336 (32%). A machine learning algorithm using the cforest with pharyngeal collapsibility (pharyngeal volume reduction from sitting to supine position measured by pharyngometry) and tonsillar hypertrophy (Brodsky scale), constituting the ColTon index, as predictors yielded an area under the curve of 0.89, 95% confidence interval [0.85-0.93]. The ColTon index had an accuracy of 76%, sensitivity of 63%, specificity of 81%, negative predictive value of 84%, and positive predictive value of 59% on the validation set. CONCLUSION: A cforest classifier allows valid predictions for moderate to severe OSAS in mostly obese, otherwise healthy children.