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.

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.

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.

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.

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.

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.

The Ponto-Geniculo-Occipital (PGO) Waves in Dreaming: An Overview.

Rapid eye movement (REM) sleep is the main sleep correlate of dreaming. Ponto-geniculo-occipital (PGO) waves are a signature of REM sleep. They represent the physiological mechanism of REM sleep that specifically limits the processing of external information. PGO waves look just like a message sent from the pons to the lateral geniculate nucleus of the visual thalamus, the occipital cortex, and other areas of the brain. The dedicated visual pathway of PGO waves can be interpreted by the brain as visual information, leading to the visual hallucinosis of dreams. PGO waves are considered to be both a reflection of REM sleep brain activity and causal to dreams due to their stimulation of the cortex. In this review, we summarize the role of PGO waves in potential neural circuits of two major theories, i.e., (1) dreams are generated by the activation of neural activity in the brainstem; (2) PGO waves signaling to the cortex. In addition, the potential physiological functions during REM sleep dreams, such as memory consolidation, unlearning, and brain development and plasticity and mood regulation, are discussed. It is hoped that our review will support and encourage research into the phenomenon of human PGO waves and their possible functions in dreaming.

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).

Hyperactivity in patients with narcolepsy and idiopathic hypersomnia: an exploratory study.

Introduction: Patients with either Idiopathic Hypersomnia or Narcolepsy demonstrate excessive daytime somnolence (EDS) with resultant inattention mimicking Attention Deficit Hyperactivity Disorder (ADHD). Patients with ADHD also often express sleep problems including EDS. Thus, patients with ADHD and patients with idiopathic hypersomnia or narcolepsy may share inattention and daytime drowsiness as common features. However, it is not known whether EDS patients with idiopathic hypersomnia or narcolepsy also have increased movement (hyperactivity) like ADHD patients, the determination of which is the purpose of this study. Methods: We studied 12 patients (7 Narcolepsy type 2 and 5 Idiopathic Hypersomnia) with EDS as shown by Multiple Sleep Latency Test which served as the gold standard for entry into the study. Twelve subjects without symptoms of EDS served as the control group. None of the participants had a previous history of ADHD. Each participant underwent a one-hour session laying at 45 degrees with surveys about the need to move and actigraphy as an objective measure of movement. Results: Sleep-disordered patients with EDS reported more symptoms of inattention and hyperactivity on the ADHD Self-Report Scale. At each of the time points patients with EDS had a clear trend to express the need to move more than controls on the Suggested Immobilization Test (SIT). For the total 60 minutes, a large effect size for the need to move during the SIT test was found between patients and controls (Cohen's d = 0.61, p=0.01). Patients with EDS did not express a need to move more to combat drowsiness than controls, nor did actigraphy show any difference in objective movement between patients and controls during the SIT. Conclusion: Patients with EDS express inattention and a need to move more than controls. However, hyperactivity was not verified by objective measurement, nor did the EDS patients express a need to move to combat drowsiness more than controls. Thus, a hypothesis to be further tested, is whether narcolepsy and idiopathic hypersomnia may be more a model of the inattentive form of ADHD rather than the combined or inattentive/hyperactive form of ADHD. Further studies are needed to explore the relationship between EDS and hyperactivity.

Polysomnographic study in pediatric neurofibromatosis type 1.

Background: Neurofibromatosis type 1 (NF1) is a genetic disease that alters neurodevelopment. We aimed to analyze the sleep macrostructure of a sample of children affected by NF1 without neurocognitive co-morbidities and MRI reports of unidentified bright objects (UBOs). Methods: A 100 pre-pubertal children participated in the cross-sectional study: 50 subjects were children diagnosed with NF1 and 50 subjects were typically developing healthy children (TDC). All participants underwent polysomnographic evaluation through which conventional sleep parameters were collected: Total sleep time (TST), Sleep latency (SOL), first REM latency (FRL), number of stage shifts/h (SS/h), number of awakenings/h (AWN/h), wake after sleep onset (WASO%), sleep efficiency percentage (SE%), percentage of sleep time spent in sleep stages 1 (N1%) and 2 (N2%), slow-wave sleep (N3%), and REM sleep (REM%). Additionally, nocturnal respiratory events such as apnea/hypopnea index (AHI), oxygen desaturation index (ODI), and periodic limb movement index (PLMI) were recorded. Results: Neurofibromatosis type 1 children showed a reduction in sleep duration parameters (TST; p < 0.001), sleep efficiency (SE%; p < 0.001), and stage N2% (p < 0.001). Moreover, the number of awakenings per hour (AWN/h), wake after sleep onset (WASO%), and respiratory events such as AHI, ODI, and PLMI resulted higher in NF1 vs. TDC children. Conclusion: The data showed that the sleep macrostructure differs between NF1 and TDC children. These findings suggest that the evaluation of sleep may provide useful support in corroborating the diagnosis and offers additional therapeutic management perspectives in NF1 and genetic neurodevelopmental disorders in general.

Validation of the Chinese version of the Perceived Stress Scale-10 integrating exploratory graph analysis and confirmatory factor analysis.

OBJECTIVE: The study aimed to initially assess the measurement properties of the 10-item simplified Chinese version of the Perceived Stress Scale (PSS-C-10) and as a first, assess a longitudinal measurement invariance (LMI). METHODS: A longitudinal survey was conducted with a convenient sample of healthcare students using the PSS-C-10. We assessed the PSS-C-10 mainly using composite analytical approaches, including exploratory graph analysis (EGA) and confirmatory factor analysis (CFA) to suggest the best-fit factor structure and assess measurement invariance. RESULTS: The EGA identified a two-factor structural solution with an accuracy of 98.6% at baseline and 100% at a 7-day follow-up. The CFA subsequently confirmed this structure, with a comparative fit index of 0.963 at baseline and 0.987 at follow-up, Tucker-Lewis index of 0.951 at baseline and 0.982 at follow-up, and root mean square error of approximation of 0.111 at baseline and 0.089 at follow-up. The LMI was supported by the goodness-of-fit indices, and their changes fell within the recommended cut-off range. Additionally, Cronbach's alpha (0.885 at baseline and 0.904 at follow-up), McDonald's omega (0.885 at baseline and 0.902 at follow-up), and an ICC value of 0.816 for 7 days demonstrated the robust reliability of the PSS-C-10. CONCLUSION: The PSS-C-10 exhibited a stable two-factor structure with promising LMI and measurement properties.

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.

The RU_SATED as a measure of sleep health: cross-cultural adaptation and validation in Chinese healthcare students.

BACKGROUND: The RU_SATED scale is a multidimensional instrument measuring sleep health, consisting of Regularity, Satisfaction, Alertness, Timing, Efficiency, Duration dimensions. We adapted and validated the Chinese RU_SATED (RU_SATED-C) scale. METHODS: The RU_SATED-C scale was developed through a formal linguistic validation process and was validated in an observational longitudinal survey design. Healthcare students completed the RU_SATED scale, Sleep Quality Questionnaire, and Patient Health Questionnaire-4 among two sites of Hangzhou and Ningbo, China. Psychometric assessments included structural validity, longitudinal measurement invariance, convergent and divergent validity, internal consistency, and test-retest reliability. RESULTS: A total of 911 healthcare students completed the RU_SATED-C scale at baseline (Time 1, T1) and follow-up (Time 2, T2) with an average time interval of 7 days + 5.37 h. Confirmatory factor analysis (CFA) confirmed a single-factor model and resulted in an acceptable model fit. The two-factor model previously found in the Japanese version fit better than the one-factor model, whereas the one-factor model fit had a better fit than the two-factor model found in the English version. Longitudinal CFA resulted in negligible changes in fit indices for four forms of increasingly restrictive models and supported that a single-factor model was equivalent over time. The data also endorsed longitudinal measurement invariance among the two-factor models found in the English and Japanese samples. The RU_SATED-C scale total score displayed a moderately strong negative correlation with sleep quality; however, negligible associations were observed with anxiety and depression. Ordinal Cronbach's alpha and Ordinal McDonald's omega at T1 and T2 ranged from suboptimal to acceptable. The RU_SATED-C scale and all items were significantly correlated across time intervals. CONCLUSION: The RU_SATED-C scale is an easy-to-use instrument with potentially valid data for the measurement of multidimensional sleep health. Use of the RU_SATED-C scale can help raise awareness of sleep health and could pave the way for important efforts to promote healthy sleep.

Development and validation of the narcolepsy severity scale in school aged children.

OBJECTIVE: To develop and psychometrically test the pediatric narcolepsy severity scale (P-NSS) for pediatric with narcolepsy type 1 (NT1). METHODS: Item pool was formed based on literature review, clinical judgement of the expert panel and input of the narcoleptic patients and their parents. Psychometric properties were evaluated after applying the P-NSS in a sample of 200 patients (8-18 years age) with narcolepsy. Analyses included item analysis, validity analysis and reliability analysis. RESULTS: P-NSS consisted four factors with a total of 17 items. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) revealed four distinct and theoretically coherent factors, explaining 63.4% of the total variance. The fitting results of the CFA model were χ2/dƒ = 2.235, GFI = 0.876, AGFI = 0.822, RMSEA = 0.079, TLI = 0.908, CFI = 0.927. P-NSS score is correlated with Pediatric Daytime Sleepiness Scale (r = 0.512, P < 0.01), Epworth Sleepiness Scale for Children and Adolescents (r = 0.355, P < 0.01) and Narcolepsy quality-of-life instrument with 21 questions (r = -0.512, P < 0.01). Cronbach's α coefficient for P-NSS and four dimensions were from 0.732 to 0.915. The split-half reliability was 0.882 (P < 0.01). CONCLUSION: P-NSS is proved to be a reliable and valid measure for Chinese children with NT1. It may serve in China as a valuable and easily accessible outcome measure for using in narcolepsy trials, the clinic with improved responsiveness and long term follow-up.