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.

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.

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.

Elevated periodic limb movement index is associated with hypoxemia in children with early onset scoliosis.

PURPOSE: Patients with early onset scoliosis are at high risk of sleep disordered breathing, sleep disruption, and adverse consequences of poor sleep. In this study, we aim to assess the prevalence of periodic limb movements of sleep in a cohort of children with early onset scoliosis and identify factors that correlate with the presence of periodic limb movements. METHODS: This is a retrospective chart review of 40 patients with EOS (ages 1-17 years) who underwent a PSG from 2003 through 2019. Data collected included age, sex, and polysomnography parameters. Descriptive statistics were used: independent T test and Pearson correlation. RESULTS: The average age was 9.6 years (SD 5.2); 22 were female. Eleven patients (27.5%) had elevated periodic limb movement index (PLMI) (≥ 5). Those with PLMI ≥ 5 had arousal index of 15.4 (SD 7.2) and those with normal PLMI having an arousal index of 9.4 (SD 4.9); this reached statistical significance (p < 0.05). Those with elevated PLMI spent 4.9 (SD 8.3) minutes with saturations below 88%, while those with normal PLMI spent 1.0 (SD 1.8); this was statistically significant. There was a moderate positive correlation between arousal index, hypoxemia, and PLMI. CONCLUSION: The study suggests that children with early onset scoliosis have higher frequency of periodic limb movements during sleep, and these may be correlated with increased arousal and with hypoxemia.

Age related disparities in sleep apnea diagnosis using a wearable device: Implications of 4% vs. 3% hypopnea scoring criteria.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) diagnosis relies on the Apnea-Hypopnea Index (AHI), with discrepancies arising from the 3% and 4% desaturation criteria. This study investigates age-related variations in OSA severity classification, utilizing data from 1201 adult patients undergoing Home Sleep Apnea Testing (HSAT) with SleepImage Ring@. METHODS: The study employs Bland-Altman analysis to compare AHI values obtained with the 3% and 4% desaturation criteria. Age-stratified analysis explores discrepancies across different age groups. RESULTS: The analysis reveals a systematic bias favoring the 3% criterion, impacting the quantification of apnea events. Age-specific patterns demonstrate diminishing agreement between criteria with increasing age. CONCLUSION: This comprehensive study underscores the importance of standardized criteria in OSA diagnosis. The findings emphasize age-specific considerations and ethical concerns, providing crucial insights for optimizing patient care and advancing sleep medicine practices.

Sleep and follow-up characteristics of Hispanic patients: Insights from a comparative analysis with White patients in polysomnographic split-night studies.

BACKGROUND: Limited attention has been given to exploring the efficacy of titration in split-night polysomnography (PSG) and the factors influencing adherence to continuous positive airway pressure (CPAP) therapy. This study aims to evaluate the severity of OSA and PSG parameters in HP compared to WP. METHODS: Split-night PSG studies conducted on adults. Participants were categorized based on self-reported ethnicity as either HP or WP. RESULTS: The study enrolled 50 WP (15 women, 35 men, mean age 60.5 ± 13.60 years, mean BMI 34.2 ± 7.48) and 45 HP (24 women, 21 men, mean age 54.9 ± 13.06 years, mean BMI 37.3 ± 7.88). HP exhibited a mean apnea-hypopnea index (AHI) of 51.1 ± 33.67, saturation nadir of 77.8 ± 10.19, and time spent with saturation <90% of 21.0 ± 26.93 min. In WP, the mean AHI was 39.2 ± 24.49, saturation nadir 81.6 ± 9.04, and time spent <90% was 10.4 ± 17.17 min. All observed differences were statistically significant (p < 0.05). Auto CPAP was prescribed to all patients, with adherence at 3-4 months being 75% ± 30 for HP, with a usage of 5.5 ± 2.2 h, and a residual AHI of 3 ± 3.5. In WP, adherence was 79% ± 30, usage was 5.9 ± 2.1 h, and residual AHI was 3.6 ± 6.2. None of these differences reached statistical significance. Among HP, 37% missed follow-up appointments compared to 12% of WP. More HP used full-face masks, while more WP preferred nasal masks. CONCLUSIONS: HP exhibited significantly worse OSA parameters during the diagnostic phase of PSG compared to WP. HP had a significantly higher no-show percentage than WP. CPAP adherence and residual AHI were not statistically different, but more HP missed follow-up appointments than WP.

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.

Polysomnographic features associated with clonazepam and melatonin treatment in isolated REM sleep behavior disorder: Time for new therapeutic approaches?

AIMS: Although clonazepam (CLO) and melatonin (MLT) are the most frequently used treatments for REM sleep behavior disorder, the polysomnographic features associated with their use are little known. The aim of this study was to evaluate polysomnographic and clinical parameters of patients with idiopathic/isolated REM sleep behavior disorder (iRBD) treated chronically with CLO, sustained-release MLT, alone or in combination, and in a group of drug-free iRBD patients. METHODS: A total of 96 patients were enrolled: 43 drug-free, 21 with CLO (0.5-2 mg), 20 with sustained-release MLT (1-4 mg), and 12 taking a combination of them (same doses). Clinical variables and polysomnography were collected. RESULTS: Although clinical improvement was reported in all groups, MLT impacted sleep architecture more than the other treatments, with significant and large increase in N3 stage, moderate reduction in N2 and REM sleep, and moderate increase in REM latency. CLO moderately increased the percentage of both REM sleep and especially N2, while reducing N1 and wakefulness. Patients treated with both CLO and MLT did not show major changes in sleep architecture. CONCLUSION: These results suggest that the administration of MLT or CLO impacts (positively) on sleep parameters of iRBD patients. However, there is a need to better stratify patients, in order to treat them in a targeted manner, depending on the patient's individual sleep architecture and expected differential effects of these agents.

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.

Age matters: association between age and depression severity at the time of OSA diagnosis, and PAP adherence in adult patients.

STUDY OBJECTIVES: Numerous studies have shown an association and symptom overlaps between obstructive sleep apnea (OSA) and depression. However, data are limited on the association between age, sex, the severity of depression at the time of OSA diagnosis, and its impact on PAP adherence. Patient Health Questionnaire-9 (PHQ-9) is a validated depression screening and severity scoring tool recommended by DSM-5. In this retrospective observational study, we evaluate the interrelationship between age at OSA diagnosis, depression severity, and positive airway pressure (PAP) adherence. METHODS: Patients with new OSA diagnosis, seen at the University of California San Francisco-Fresno Sleep Center between February and October of 2022, were evaluated. PHQ-9 scores for depression severity uses a 1-5 scale (1 = none, 2 = mild, 3 = moderate, 4 moderately severe, 5 = severe). PHQ-9 was administered at the time of OSA diagnosis and follow-up. Average daily PAP usage hours were obtained from PAP devices between one to three months of therapy initiation. IBM SPSS version 29.0.0 was used to calculate descriptive statistics, Pearson correlation, and Mann-Whitney test. RESULTS: Seventy-seven patients fit the inclusion criteria, of which 28 were women (36.4%). The average baseline AHI was 34.5 (S.D. 31.8). PHQ-9 mean of 8.3 with SD +/- 5.9. Mann Whitney comparison between the group with normal PHQ-9 and the group with PHQ-9 scores consistent with depression (score of 5 or greater) showed no statistically significant differences in AHI (p=0.470), or average night hour use (p=0.195). There was a statistically significant difference in age between both groups (p=0.031). Spearman correlation confirmed a negative, statistically significant correlation between PHQ-9 scores and age in patients with OSA. CONCLUSIONS: This study showed that PHQ-9 scores at the time of OSA diagnosis are moderately correlated with younger age, with those patients younger than 50 years old having more moderate to severe depression scores than older patients. We did not find a correlation between age and PAP adherence or between PHQ-9 scores and PAP adherence. Our findings can help identify high-risk depression patients early in the diagnosis of OSA and bring awareness that the young adult population can be particularly vulnerable.

Restless sleep disorder in children with epileptic and non-epileptic nocturnal attacks.

Restless sleep disorder (RSD) is an important sleep disorder characterised by the presence of frequent large muscle movements (LMM) during sleep, which may be comorbid to other conditions/diseases. In this study, we investigated the frequency and the characteristics of RSD among children who were evaluated by polysomnography (PSG) due to epileptic and non-epileptic nocturnal attacks. We analysed consecutively children younger than 18 years who were referred for PSG recording due to abnormal motor activities during sleep. The diagnosis of nocturnal events as sleep-related epilepsy was made based on the current consensus. Patients who were referred with suspicion of sleep-related epilepsy, but who were diagnosed to have non-epileptic nocturnal events and children with a definitive diagnosis of NREM sleep parasomnias were also enrolled. Sixty-two children were analysed in this study (17 children with sleep-related epilepsy, 20 children with NREM parasomnia, and 25 children with nocturnal events not otherwise classified [neNOS]). The mean number of LMM, LMM index, LMM-associated with arousal and its index were all significantly higher in children with sleep-related epilepsy. Restless sleep disorder was present in 47.1% of patients with epilepsy, 25% of patients with parasomnia, and in 20% of patients with neNOS. The mean A3 duration and the A3 index were higher in children with sleep-related epilepsy and RSD compared with those with parasomnia and restless sleep disorder. Patients with RSD had lower ferritin levels than those without RSD in all subgroups. Our study demonstrates a high prevalence of restless sleep disorder in children with sleep-related epilepsy, associated with an increased cyclic alternating pattern.

"Count on Sleep": an OSA awareness project update.

Obstructive sleep apnea (OSA) is a common, chronic sleep-related breathing disorder that affects approximately 12% of the US adult population. Greater public awareness of OSA is necessary to decrease the number of people with undiagnosed or untreated OSA and reduce the negative health consequences of unrecognized OSA. In 2021, the American Academy of Sleep Medicine initiated the "Count on Sleep" project in partnership with key stakeholders with the objective of raising the awareness of OSA among the public, health care providers, and public health officials. Four workgroups implemented strategies and completed tasks focused on increasing OSA awareness in their targeted areas to address the objectives of the project including (1) Public Awareness and Communications, (2) Provider Education, (3) Tool Development and Surveillance, and (4) a Strategic Planning workgroup that coordinated efforts across the project. Over the first 2 years, workgroups made substantial progress toward project goals including holding "listening sessions" with representatives of communities disproportionately affected by OSA and its consequences, developing resources for primary care providers that can be easily accessed and used in practice, and developing a brief survey for use in estimating and tracking OSA risk across the population. Over the first 2 project years, workgroups made significant progress in advancing efforts to increase awareness of OSA in US communities. The third year of the project will focus on dissemination of campaign materials and resources for all targeted groups, including the public, health care professionals, and public health professionals. CITATION: Martin JL, Rowley J, Goel N, et al. "Count on Sleep": an OSA awareness project update. J Clin Sleep Med. 2024;20(2):303-307.

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.

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.

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.