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.

Unveiling the pathophysiology of restless legs syndrome through transcriptome analysis.

The aim of this study was to analyze signaling pathways associated with differentially expressed messenger RNAs in people with restless legs syndrome (RLS). Seventeen RLS patients and 18 controls were enrolled. Coding RNA expression profiling of 12,857 gene transcripts by next-generation sequencing was performed. Enrichment analysis by pathfindR tool was carried-out, with p-adjusted ≤0.001 and fold-change ≥2.5. Nine main different network groups were significantly dysregulated in RLS: infections, inflammation, immunology, neurodegeneration, cancer, neurotransmission and biological, blood and metabolic mechanisms. Genetic predisposition plays a key role in RLS and evidence indicates its inflammatory nature; the high involvement of mainly neurotropic viruses and the TORCH complex might trigger inflammatory/immune reactions in genetically predisposed subjects and activate a series of biological pathways-especially IL-17, receptor potential channels, nuclear factor kappa-light-chain-enhancer of activated B cells, NOD-like receptor, mitogen-activated protein kinase, p53, mitophagy, and ferroptosis-involved in neurotransmitter mechanisms, synaptic plasticity, axon guidance, neurodegeneration, carcinogenesis, and metabolism.

European expert guidance on management of sleep onset insomnia and melatonin use in typically developing children.

Sleeping problems are prevalent among children and adolescents, often leading to frequent consultations with pediatricians. While cognitive-behavioral therapy has shown effectiveness, especially in the short term, there is a lack of globally endorsed guidelines for the use of pharmaceuticals or over-the-counter remedies in managing sleep onset insomnia. An expert panel of pediatric sleep specialists and chronobiologists met in October 2023 to develop practical recommendations for pediatricians on the management of sleep onset insomnia in typically developing children. When sleep onset insomnia is present in otherwise healthy children, the management should follow a stepwise approach. Practical sleep hygiene indications and adaptive bedtime routine, followed by behavioral therapies, must be the first step. When these measures are not effective, low-dose melatonin, administered 30-60 min before bedtime, might be helpful in children over 2 years old. Melatonin use should be monitored by pediatricians to evaluate the efficacy as well as the presence of adverse effects.    Conclusion: Low-dose melatonin is a useful strategy for managing sleep onset insomnia in healthy children who have not improved or have responded insufficiently to sleep hygiene and behavioral interventions.

The impact of COVID-19 on menstrual cycle's alterations, in relation to depression and sleep disturbances: a prospective observational study in a population of medical students.

BACKGROUND: The sars-Cov-2 pandemic has determined psychological stress, particularly in the young population of medical students. We studied the impact of the pandemic on menstrual cycle alteration in relation to psychological stress, presence of depression, sleep disturbances and post-traumatic stress, on a population of medical students. METHODS: 293 female students at the Faculty of Medicine and Psychology of the Sapienza University of Rome (23.08 years old ± 3.8) were enrolled. In March 2021, one year after quarantine, a personal data sheet on menstrual cycle, examining the quality of the menstrual cycle during the pandemic, compared to the previous period. Concomitantly, the Beck Depression Inventory and the Impact of Event Scale have been administered. A Pearson chi-square test was assessed to evaluate the difference between the characteristics of the menstrual cycle and the scores obtained with the questionnaires. RESULTS: A statistically significant association between menstrual alterations and stress during pandemic had been found. The onset of depressive symptoms and sleep disturbances was observed in 57.1% and in 58.1% of young women with cycle's alterations, respectively. Amenorrhea was three times more common in female students with depressive symptoms, premenstrual syndrome had a significant correlation with both depression and sleep disturbances. The pandemic has been related to menstrual alterations, with depressive symptoms and sleep disorders. Amenorrhea is connected to depression, as observed on the functional hypothalamic amenorrhea. CONCLUSIONS: The pandemic affected the menstrual cycle as well as the depressive symptoms and sleep. Practical implications of the study lead to the development of strategies for psychological intervention during the pandemic experience, in order to help medical trainees, with specific attention to women's needs. Future studies should analyze the impact of other types of social stress events, on sleep, depression and the menstrual cycle beside the pandemic.

Changes in time structure of periodic leg movements during sleep in restless legs syndrome: Effects of sex and age.

BACKGROUND: The objective of this study was to check the hypothesis that in women with restless legs syndrome (RLS) different changes occur in periodic leg movements during sleep (PLMS) during the post-menopausal period (using >50 years as a proxy) than in men of the same age. METHODS: We recruited 36 untreated patients aged 18-50 years (19 men, median age 40 years, and 17 women, median age 37 years) while the remaining 67 were >50 years old (24 men, median age 66.6 years, and 43 women, median age 60.0 years). Leg movement activity during sleep was analyzed by means of an approach utilizing indexes especially suitable to assess leg movement periodicity. RESULTS: No significant difference was seen between men in the two age groups; conversely, in women, a clear and significant increase in Periodicity Index was observed in the older group, along with a decrease in isolated leg movements. In women, a clear age-related enhancement of PLMS was found in the intermovement interval graphs, especially in the 16-22 s range, which was more evident than that observed in men. The results remained unchanged also when they were replicated by selecting only subjects aged 18-45 years vs. those aged >55 years. CONCLUSIONS: Our findings indicate that assessing PLMS in women after menopause is clinically relevant because they are probably connected with the hormonal fluctuations of this period of life. Translationally, identifying and addressing PLMS in post-menopausal women is crucial for optimizing their sleep health and addressing potential health risks associated with sleep disturbances.

The Parasomnias.

Parasomnias usually present in childhood and resolve spontaneously. The diagnosis of non-rapid eye movement-related parasomnias is mainly based on clinical descriptors and can be challenging. Rapid eye movement-related parasomnias may index an underlying psychiatric disorder. Even if benign, parasomnias can affect quality of life. Pediatricians and child psychiatrists should be familiarized with these sleep disorders and suggest adequate sleep hygiene, avoidance of sleep deprivation, and regular bedtimes even on weekends as the first step in management of these disorders. Clinicians should pursue the opportunity for tailoring treatments and consider referral to a sleep expert when indicated.

Restless Legs Syndrome in Children and Adolescents.

Children with psychiatric comorbidities frequently are referred for evaluation of sleep complaints. Common sleep symptoms can include difficulty falling asleep, frequent nocturnal awakening, restless sleep, and symptoms of restless legs syndrome (RLS). The understanding of the sleep condition in relation to the psychiatric comorbidity often is a challenge to the physician and often sleep disorders remain undiagnosed, untreated, or undertreated. Restless legs syndrome has been associated with psychiatric comorbidities and with certain medications, such as antidepressants, antihistamines, and antipsychotics. This article reviews the presentation of RLS and restless sleep, the association with psychiatric comorbidities, and treatment options.

Role of Daytime Continuous Polysomnography in the Diagnosis of Pediatric Narcolepsy Type 1.

BACKGROUND AND OBJECTIVES: Narcolepsy type 1 (NT1) is still largely underdiagnosed or diagnosed too late in children. Difficulties in obtaining rapid and reliable diagnostic evaluations of the condition in clinical practice partially explain this problem. Predictors of NT1 include cataplexy and sleep-onset REM periods (SOREMPs), documented during nocturnal polysomnography (N-PSG) or through the multiple sleep latency test (MSLT), although low CSF hypocretin-1 (CSF hcrt-1) is the definitive biological disease marker. Obtaining reliable MSLT results is not always feasible in children; therefore, this study aimed to validate daytime continuous polysomnography (D-PSG) as an alternative diagnostic tool. METHODS: Two hundred consecutive patients aged younger than 18 years (112 with NT1; 25 with other hypersomnias, including narcolepsy type 2 and idiopathic hypersomnia; and 63 with subjective excessive daytime sleepiness) were randomly split into 2 groups: group 1 (n = 133) for the identification of diagnostic markers and group 2 (n = 67) for the validation of the detected markers. The D-PSG data collected included the number of spontaneous naps, total sleep time, and the number of daytime SOREMPs (d-SOREMP). D-PSG data were tested against CSF hcrt-1 deficiency (NT1 diagnosis) as the gold standard using receiver operating characteristic (ROC) curve analysis in group 1. ROC diagnostic performances of single and combined D-PSG parameters were tested in group 1 and validated in group 2. RESULTS: In group 1, the areas under the ROC curve (AUCs) were 0.91 (95% CI 0.86-0.96) for d-SOREMPs, 0.81 (95% CI 0.74-0.89) for the number of spontaneous naps, and 0.70 (95% CI 0.60-0.79) for total sleep time. A d-SOREMP count ≥1 (sensitivity of 95% and specificity of 72%), coupled with a diurnal total sleep time above 60 minutes (sensitivity of 89% and specificity of 91%), identified NT1 in group 1 with high reliability (area under the ROC curve of 0.93, 95% CI 0.88-0.97). These results were confirmed in the validation group with an AUC of 0.88 (95% CI 0.79-0.97). DISCUSSION: D-PSG recording is an easily performed, cost-effective, and reliable tool for identifying NT1 in children. Further studies should confirm its validity with home D-PSG monitoring. These alternative procedures could be used to confirm NT1 diagnosis and curtail diagnostic delay.

Restless sleep disorder in a sample of children and adolescents with autism spectrum disorder: preliminary results from a case series.

STUDY OBJECTIVES: Sleep disorders are a frequent comorbidity among children with autism spectrum disorder (ASD). Among sleep-related issues of ASD, restless sleep is a common complaint. In recent years, restless sleep disorder (RSD) has been proposed as a new clinical entity, characterized by agitated sleep as its predominant manifestation. Despite the high prevalence of sleep disorders and data reporting restless sleep among ASD patients, to date no study has yet characterized RSD within patients with ASD. Therefore, the aim of our study was to assess the occurrence of RSD in a sample of children and adolescents with ASD through clinical and polysomnographic assessment. METHODS: Children and adolescents with ASD ages 6-18 years were recruited for the study. Through parental interviews, patients with a suspected RSD were selected and offered diagnostic investigation by video-polysomnography and blood tests to assess martial balance. RESULTS: Among the 129 participants included, 16 patients (12.4%) were found to have a suspected RSD. Only 6 (4.7%) underwent video-polysomnography due to lack of compliance or family refusal. In 6/6 participants examined, the disorder was confirmed by video-polysomnography movement analysis (total movement index ≥ 5 events/h) and ferritin values were found in the normal range. CONCLUSIONS: RSD does not appear to be particularly frequent among patients with ASD and that of iron metabolism may not be the main factor implicated in the pathogenesis of RSD within this population. Additional evaluation is needed to confirm the result and further investigate the etiological mechanisms underlying the disorder. CITATION: Voci A, Mazzone L, De Stefano D, Valeriani M, Bruni O, Moavero R. Restless sleep disorder in a sample of children and adolescents with autism spectrum disorder: preliminary results from a case series. J Clin Sleep Med. 2024;20(3):427-432.

An online survey among general pediatricians on melatonin use in children with chronic insomnia.

OBJECTIVES: Although melatonin (MLT) is the molecule most used by pediatricians for sleep problems, scarce evidence exists on its use in healthy pediatric population. The objective of this study was to describe MLT use by Italian pediatricians in healthy children with chronic insomnia. STUDY DESIGN: A cross-sectional open survey was administered to Italian pediatricians, between June and November 2022, collecting information about their use of MLT in healthy children: age range of patients, dosages used, time of administration, duration of treatment, association with other treatments, perceived efficacy, and side effects. Data were reported as frequencies with their respective 95% confidence intervals. Chi-square statistics assessed significant differences between pediatricians who had training in pediatric sleep and those who did not. RESULTS: Among 428 respondents, 97.4% of pediatricians used MLT; 87.3% of them prescribed MLT in children aged 1-2 years, 62.1% in 2-5 years and 42.5% in 10-18 years. 84.9% of them suggested to take MLT 30 min before bedtime. 37.9% indicated to continue treatment for one month, 30.2% for 2-3 months. 74.1% of pediatricians usually prescribed MLT 1 mg/day. The most frequent treatment associated with MLT was sleep hygiene (85.4%). Almost all pediatricians found MLT effective in reducing difficulties falling asleep. Only 3.2% of them reported mild side effects. CONCLUSIONS: MLT is widely prescribed by Italian pediatricians, but no consensus exists about its use in typically developing children. There is a need for clear guidelines to optimize the use of MLT in healthy children.

Using pharmacotherapy to address sleep disturbances in autism spectrum disorders.

INTRODUCTION: Sleep disorders are the second most common medical comorbidity in autism spectrum disorder (ASD), with effects on daytime behavior and functioning, mood and anxiety, and autism core features. In children with ASD, insomnia also has a negative impact on the whole family's quality of life. Therefore, treatment of sleep disturbances should be considered as a primary goal in the management of ASD patients, and it is important to clarify the scientific evidence to inappropriate treatments. AREAS COVERED: The authors review the current literature concerning the pharmacological treatment options for the management of sleep-related disorders in patients with ASD (aged 0-18 years) using the PubMed and Cochrane Library databases with the search terms: autism, autistic, autism spectrum disorder, ASD, drug, drug therapy, drug intervention, drug treatment, pharmacotherapy, pharmacological treatment, pharmacological therapy, pharmacological intervention, sleep, sleep disturbance, and sleep disorder. EXPERT OPINION: Currently, clinicians tend to select medications for the treatment of sleep disorders in ASD based on the first-hand experience of psychiatrists and pediatricians as well as expert opinion. Nevertheless, at the present time, the only compound for which there is sufficient evidence is melatonin, although antihistamines, trazodone, clonidine, ramelteon, gabapentin, or suvorexant can also be considered for selection.

Sleep architecture and Nusinersen therapy in children with Spinal Muscular Atrophy type 1.

BACKGROUND: Spinal muscular atrophy (SMA) is a severe neuromuscular disorder, the phenotype of the disease is caused by the mutation of the SMN1 (survival motor neuron 1) gene which encodes for the SMN protein. Innovative treatments for SMA have become available and the first molecule approved is Nusinersen, an antisense oligonucleotide that increases the production of SMN protein. Nusinersen has been shown to be associated with a significant motor improvement and an increase of the event-free survival. For these reasons the aim of the present study is to assess if Nusinersen is able modify sleep architecture and microstructure and to improve sleep structure in these patients. METHODS: Sixteen patients affected by SMA1 were enrolled in the study (4 boys, 12 girls; median age 72.5 months, intelligence quotient range 24-84). All patients underwent complete nocturnal PSG before the start of the treatment trough intrathecal injections with Nusinersen (T0) and after the fifth infusion (day 180, T180). PSG recordings were visually scored and interpreted according to the indications of the American Academy of Sleep Medicine (AASM) and and microstructure by means of the Cyclic Alternating Pattern (CAP). RESULTS: After 6 months therapy we found a significantly reduced sleep latency and a significantly increased sleep efficiency. Regarding sleep microstructure parameters (CAP), we did not find any significant change after therapy however, it is worth mentioning that a moderate effect size was observed for the increase in CAP A3 index. CONCLUSIONS: We observed short-term effects of Nusinersen on sleep with an improvement in sleep efficiency and reduction in sleep onset latency; regarding sleep microstructure, a moderate effect size was found for the number of CAP A3 subtypes that slightly increased, possibly indicating a slightly higher arousability. This finding points at a probably overall better sleep pattern organization associated with the treatment, but they need to be confirmed by larger studies with patients treated earlier in life and for a longer period.

Sleep disturbances in subjects with autism spectrum disorder: A parental perspective.

OBJECTIVE: To investigate the prevalence of sleep disturbances (SDs), their related comorbidities, interventions and the impact on the family for individuals with current SDs and those who had SDs in the past. METHODS: Members of the Italian national association of parents of persons with autism (ANGSA) completed an anonymous online survey collecting demographic data, the presence of comorbidities and specific information on sleep arrangement and sleep disorders using a modified version of the of the Sleep Disturbance Scale for Children (SDSC). RESULTS: The final sample consisted of 143 participants, 90 patients presented current SDs (C_SDs) and 53 reported previous SDs (P_SDs). In the C_SDs group, the most prevalent sleep disorders were related to insomnia and, especially, difficulty falling asleep; a high number of individuals presented with restless sleep. Also, the parents in the P_SDs group retrospectively reported a high prevalence of insomnia with difficulty falling asleep, night awakenings and restless sleep. Parents reported that sleep hygiene practice were effective in less than one third of cases in both groups and the most used compound was immediate-release melatonin, followed by antihistamines and then benzodiazepines, antipsychotics, and antidepressants, with approximately 60-70% reported efficacy. Parents of both groups reported that insomnia negatively affected their children behavior and caused stress, mood changes or physical fatigue in their daily life. CONCLUSION: Our study shows that insomnia is most prevalent in individuals with autism with several consequences on children and family behavior and quality of life. As reported by parents, melatonin might be helpful for sleep disturbances in these children and the causes of restless sleep need further investigations.

The Role of Supplements and Over-the-Counter Products to Improve Sleep in Children: A Systematic Review.

The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin and GABA, that can be, in turn, regulated by different nutrients involved in their metabolic pathways. Although good sleep quality in children has been proven to be a key factor for optimal cognitive, physical and psychological development, a significant and ever-increasing percentage of the pediatric population suffers from sleep disorders. In children, behavioral interventions along with supplements are recommended as the first line treatment. This systematic review was conducted, according to the PRISMA guidelines, with the purpose of assessing the principal nutrients involved in the pathways of sleep-regulating neurotransmitters in children and adolescents. Our focus was the utilization of over the counter (OTC) products, specifically iron, hydroxytryptophan, theanine and antihistamines in the management of different pediatric sleep disorders with the intention of providing a practical guide for the clinician.

Screen exposure and sleep: How the COVID-19 pandemic influenced children and adolescents - A questionnaire-based study.

BACKGROUND: COVID-19 pandemic has drastically increased the exposure to electronic devices in children, influencing their lifestyle and their sleep. This study was conducted to explore the relationship between the augmented screen exposure and sleep habits in children during and after the pandemic. METHODS: Using the "Google Forms" tool, we created an online questionnaire addressed to parents of children and adolescents aged 2-18 years. We explored the use of screens before and during/after the lockdown and assessed the presence of sleep disturbances through the Sleep Disturbance Scale for Children (SDSC), referring to the period before and during/after COVID-19 pandemic. RESULTS: We collected 1084 valid questionnaires (median age 8.5 ± 4.1 years). We observed a significant increase in screens exposure for school (72%) and for leisure (49.7%) during the pandemic. We reported an increased sleep disturbances prevalence from 22.1% before the pandemic to 33.9% during the outbreak (p < 0.001). Even before the pandemic, the highest risks for sleep disorders were related to daily screen time for school reasons (OR 1.65, p < 0.001) and total screen time after 6 p.m. (OR 1.59, p < 0.001). The augmented exposure to screens for any reasons during the pandemic was significantly related to an increase of sleep disorders, especially regarding the increased exposure after 6 p.m. (OR 1.67, p < 0.001). CONCLUSIONS: The augmented use of electronic devices was recognized to be a significant predisposing factor in increasing the rate of sleep disorders during and after the pandemic, thus sleep hygiene recommendations should be highlighted to improve sleep habits.

Frequency of antidepressant use and clinical characteristics of children and adolescents undergoing polysomnography: an observational study.

BACKGROUND: Antidepressants are increasingly used in children for various psychiatric disorders but also for sleep disorders such as insomnia; however, it is currently unknown how many children undergoing polysomnography (PSG) are taking anti-depressants. The aims were: to determine the frequency of use of antidepressants in paediatric patients referred for PSG, to identify the most common antidepressants used, to investigate the reasons for their use, and to analyse the PSG parameters found in children taking antidepressants. METHOD: An observational cross-sectional retrospective chart review of all children undergoing PSG at Seattle Children's Hospital from 6/14/2020 to 12/8/2022 was carried out. Clinical features (such as diagnosis, especially psychiatric), sleep disorders (such as insomnia and restless sleep), and class of antidepressant used [selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCA), or atypical antidepressants], and PSG parameters were collected for further analysis. RESULTS: Among 3,371 patients who underwent PSG during the study, 367 children were selected who were taking one antidepressant only (154 boys and 213 girls, mean age was 13.7 ± years 3.69). A significantly decreased sleep stage N3 was found in girls, who were older than boys. Children with insomnia had longer sleep latency than children without, but more N3. There was a prolonged rapid eye movement (REM) sleep latency in children with attention-deficit/hyperactivity disorder and children with autism. REM latency was longer and REM percentage smaller in children taking SNRIs. Periodic leg movement index ≥ 5/hour was found in a higher number of children taking SSRIs or SNRIs (24.9%) than in subjects taking TCA or atypical antidepressants (13.3%) (chi-square 5.29, p = 0.013). CONCLUSIONS: Child and adolescent psychiatrists should question about the effects on sleep (both positive and negative) after initiating therapy with antidepressant medications.

Restless Legs Syndrome and Restless Sleep Disorder in Children.

Restless legs syndrome (RLS) affects 2% of children presenting with symptoms of insomnia, restless sleep, decreased quality of life, and effects on cognition and behavior. The International RLS Study Group and the American Academy of Sleep Medicine have published guidelines for the diagnosis and treatment of RLS in children. Restless sleep disorder has been recently identified in children and presents with frequent movements during sleep and daytime symptoms with polysomnography findings of at least 5 large muscle movements at night. Treatment options for both disorders include iron supplementation, either oral or intravenous with improvement in nighttime and daytime symptoms.

Sleep counts! Role and impact of sleep in the multimodal management of multiple sclerosis.

BACKGROUND: In the last years, research on pharmacotherapy and non-pharmacological approaches to Multiple Sclerosis (MS) has significantly increased, along with a greater attention to sleep as a clinical outcome measure. This review aims to update the state of the art on the effects of MS treatments on sleep, but above all to evaluate the role of sleep and its management within the current and future therapeutic perspectives for MS patients. METHOD: A comprehensive MEDLINE (PubMed)-based bibliographic search was conducted. This review includes the 34 papers that met the selection criteria. RESULTS: First-line disease modifying therapies (especially the interferon-beta) seem to have a negative impact on sleep, assessed subjectively or objectively, while second-line treatments (in particular, natalizumab) do not seem to lead to the onset of daytime sleepiness (also evaluated objectively) and, in some cases, an improvement in sleep quality has been observed as well. Management of sleep is considered a major factor in modifying disease progression in pediatric MS; however, probably because only fingolimod has recently been approved in children, information is still scarce in this group of patients. CONCLUSIONS: Studies on the effect of drugs and non-pharmacological treatments for MS on sleep are still insufficient and there is a lack of investigations on the most recent therapies. However, there is preliminary evidence that melatonin, chronotherapy, cognitive-behavioral therapy, and non-invasive brain stimulation techniques might be further assessed as adjuvant therapies, thus representing a promising field of research.

Periodic leg movements during sleep associated with antidepressants: A meta-analysis.

Studies explicitly reporting data concerning the evaluation of the effect of antidepressants on the periodic leg movements during sleep (PLMS) index obtained by polysomnography were reviewed and selected. A random-effects model meta-analysis was carried out. The level of evidence was also assessed for each paper. Twelve studies were included in the final meta-analysis, seven interventional and five observational. Most studies were characterized by Level III evidence (non-randomized controlled trials), with the exception of four studies, which were classified as Level IV (case series, case-control, or historically controlled studies). Selective serotonin reuptake inhibitors (SSRIs) were used in seven studies. The analysis of the assessments involving SSRIs or venlafaxine showed an overall large effect size, clearly much larger than that obtained with studies using other antidepressants. Heterogeneity was substantial. This meta-analysis confirms the previous reports on the increase in PLMS often associated with the use of SSRIs (and venlafaxine); however, the absent or smaller effect of the other categories of antidepressants needs to be confirmed by more numerous and better controlled studies.