Genetics and epigenetics of rare hypersomnia.

Herein we focus on connections between genetics and some central disorders of hypersomnolence - narcolepsy types 1 and 2 (NT1, NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS) - for a better understanding of their etiopathogenetic mechanisms and a better diagnostic and therapeutic definition. Gene pleiotropism influences neurological and sleep disorders such as hypersomnia; therefore, genetics allows us to uncover common pathways to different pathologies, with potential new therapeutic perspectives. An important body of evidence has accumulated on NT1 and IH, allowing a better understanding of etiopathogenesis, disease biomarkers, and possible new therapeutic approaches. Further studies are needed in the field of epigenetics, which has a potential role in the modulation of biological specific hypersomnia pathways.

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.

The dynamics of cyclic-periodic phenomena during non-rapid and rapid eye movement sleep.

Sleep is a complex physiological state characterized by distinct stages, each exhibiting unique electroencephalographic patterns and physiological phenomena. Sleep research has unveiled the presence of intricate cyclic-periodic phenomena during both non-rapid eye movement and rapid eye movement sleep stages. These phenomena encompass a spectrum of rhythmic oscillations and periodic events, including cyclic alternating pattern, periodic leg movements during sleep, respiratory-related events such as apneas, and heart rate variability. This narrative review synthesizes empirical findings and theoretical frameworks to elucidate the dynamics, interplay and implications of cyclic-periodic phenomena within the context of sleep physiology. Furthermore, it invokes the clinical relevance of these phenomena in the diagnosis and management of sleep disorders.

Sex-based disparities in dopamine agonist response in patients with restless legs syndrome.

This study aimed to investigate sex-related differences in the response to ropinirole and pramipexole in patients with restless legs syndrome (RLS). By analysing clinical parameters and polysomnographic (PSG) findings, we sought to elucidate the potential factors related to sex disparities modulating treatment responses and sleep quality in RLS. A total of 41 drug-free patients with RLS, aged ≥18 years, underwent two consecutive nocturnal PSG recordings, without medication at baseline; before the second night, 26 patients received an oral dose of 0.25 mg pramipexole whereas 15 received 0.5 mg ropinirole. After each PSG recording, patients self-evaluated the severity of their previous night symptoms by means of an ad hoc visual analogue scale (VAS). At baseline, sleep efficiency and percentage of Stage N2 tended to be higher in females while wakefulness after sleep onset was significantly higher in males. After treatment, total leg movements during sleep (LMS), periodic LMS (PLMS), and periodicity indexes were significantly lower in females than in males. The VAS score was lower after treatment in all patients, without differences between the two sexes. This study demonstrates a higher acute responsiveness of PLMS to dopamine agonists (pramipexole and ropinirole) in females than in males with RLS. These findings might be explained by differential sex-related expression of dopamine receptors, especially D3, within the central nervous system. In addition, our findings provide translational hints toward a better tailored and sex-specific approach to the treatment of RLS associated with PLMS, with dopamine agonist possibly associated with a better outcome in females than in males.

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.

Periodic leg movements during sleep and iron status in infants with prematurity, Down syndrome and Prader-Willi syndrome.

Sleep disturbances including bedtime problems and night awakenings are common during infancy. Polysomnography during the first years of life is performed mainly to rule out sleep-disordered breathing; however, sleep-related movement disorders can constitute a significant contributor to sleep disruption in this age group. Almost no studies have investigated the presence of periodic limb movements during sleep and underlying iron deficiency in infants, especially in those born preterm or with an underlying genetic syndrome. In this retrospective study we included infants 3-24 months referred for polysomnography for snoring or frequent nocturnal awakenings. All children had bloodwork (ferritin and haemoglobin) conducted within 3 months of the overnight sleep study. We studied 79 infants, including 31 (39.2%) full-term without diagnosis, 10 (12.7%) born premature, 16 (20.3%) with Down syndrome, 15 (19.0%) with Prader-Willi syndrome, and the remaining seven (8.9%) had various disorders. Compared with those with Down syndrome, Prader-Willi syndrome and full-term infants, those with prematurity showed a statistically significant elevated periodic limb movement index and lower ferritin levels than the other groups. Both ferritin (r = -0.18) and haemoglobin (r = -0.30) were negatively correlated with periodic limb movement index; however, this correlation reached statistical significance only for haemoglobin. Iron deficiency is associated with increased periodic leg movements during sleep in infants. Infants with prematurity had higher periodic limb movement index and lower ferritin levels than infants with Down syndrome, Prader-Willi syndrome or without diagnosis.

Clonazepam for the management of sleep disorders.

BACKGROUND: The objectives of this review and meta-analysis of polysomnographic data are those to focus on the clinical use of clonazepam for the management of sleep disorders by re-analyzing clinical trials and randomized clinical trials which have been published in peer-reviewed journals. METHODS: A review of the literature including clinical trials and randomized controlled trials was performed in PubMed®, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. A random effects model meta-analysis was then carried out for the four more frequently reported polysomnographic measures: total sleep time, sleep latency, sleep efficiency, and periodic leg movement during sleep (PLMS) index. RESULTS: A total of 33 articles were retrieved and screened in full text, of which 18 met the criteria for review; among the latter, nine met the criteria for meta-analysis. The studies included in the review involved patients with insomnia, REM sleep behavior disorder, sleep bruxism, and restless leg syndrome or PLMS which reported, most often, an increase in total sleep time with clonazepam. A clear sleep-promoting effect of clonazepam was found also by meta-analysis. DISCUSSION AND CONCLUSIONS: Our results indicate that the pharmacological treatment of sleep disorders with clonazepam must always be personalized according to the type of patient, the risk of addiction and the concomitant presence of respiratory disorders are key factors to take into account. However, in light of the clinical evidence of the few studies in the literature on the different types of disorders, more studies on the use of clonazepam (also in association with first choice treatments) are definitely needed.

Restless Sleep Disorder (RSD): a New Sleep Disorder in Children. A Rapid Review.

PURPOSE OF REVIEW: Restless sleep disorder (RSD) is a recently identified pediatric sleep disorder characterized by frequent movements during sleep associated with daytime symptoms. In this review we summarize the expanding evidence of the clinical presentation of RSD, potential pathophysiology, associated comorbidities, and current treatment options that will help the pediatrician identify children with RSD in a timely manner. RECENT FINDINGS: RSD is diagnosed in 7.7% of children referred evaluated in a pediatric sleep center. Children with RSD present with frequent nightly movements during sleep for at least 3 months, and have daytime symptoms related to poor sleep quality including excessive sleepiness, hyperactivity, irritability among other symptoms. Current evidence shows an increased sympathetic predominance, increased NREM sleep instability, and iron deficiency, as well as increased prevalence in parasomnias and attention deficit hyperactivity disorder. Consensus diagnostic criteria were recently published to diagnose RSD and emergent evidence suggests that iron supplementation improves its nighttime and daytime symptoms.

Ambulatory blood pressure monitoring in children undergoing polysomnography.

Ambulatory blood pressure monitoring (ABPM) is recommended for the diagnosis of hypertension in children at high risk, such as children with obesity or obstructive sleep apnea (OSA). Nocturnal hypertension is highly predictive of cardiovascular outcomes. ABPM allows for early detection of nocturnal hypertension in children. Although OSA is the most common sleep disorder associated with hypertension, studies have also shown an increase in cardiovascular risk in adult patients with other sleep disorders; therefore, there is an imperative need to provide early diagnosis in children at high risk. In the present study, we evaluated the feasibility of using ABPM during polysomnography (PSG) in children referred for sleep disordered breathing to the Seattle Children's Hospital Sleep Disorders Center. A total of 41 children aged 7-18 years were included in this study. The ABPM monitor was worn for a mean (SD) of 10.2 (1.5) hr. No significant changes were seen in PSG parameters when ABPM was co-performed with PSG, including sleep efficiency and arousals. In total, 12 of the 41 patients were identified as having nocturnal hypertension. Our study is important in that it shows that concomitant use of ABPM during PSG can aid in the early identification of nocturnal hypertension in this population.

Heart rate changes associated with the different types of leg movements during sleep in children, adolescents and adults with restless legs syndrome.

The objective of this study was to describe in detail the heart rate changes accompanying short-interval leg movements during sleep, periodic leg movements during sleep, and isolated leg movements during sleep in children and adolescents with restless legs syndrome, and to compare them with the same findings in adults with restless legs syndrome. We analysed time series of R-R intervals synchronized to the onset of short-interval leg movements during sleep, periodic leg movements during sleep or isolated leg movements during sleep that entailed an arousal during non-rapid-eye-movement sleep. We assessed cardiac activation based on the heart rate changes with respect to baseline during non-rapid-eye-movement sleep without leg movements. All types of leg movements recorded during sleep were accompanied by important heart rate changes also in children, with an overall impact similar to that observed in adults. In all age groups, heart rate changes accompanying short-interval leg movements during sleep were constituted by a tachycardia, without a subsequent relative bradycardia, that was instead evident for periodic leg movements during sleep and isolated leg movements during sleep. Moreover, an age-related decline of the relative bradycardia following the heart rate increase, in association with periodic leg movements during sleep and isolated leg movements during sleep, was observed. Our findings show that important heart rate changes accompany all leg movements during sleep at all ages in restless legs syndrome, with significant age-related differences. This information represents an important contribution to the ongoing scientific debate on the possibility and opportunity to treat periodic leg movements during sleep.

Peculiar lifespan changes of periodic leg movements during sleep in restless legs syndrome.

The objective of this observational cohort study was to analyse the age-related changes of periodic leg movements during sleep using the newest international scoring rules, to expand past analyses, including patients in the paediatric age range, and also to analyse the changes of short-interval and isolated leg movements during sleep throughout the lifespan. One hundred and sixty-five patients (84 women) with restless legs syndrome were recruited in the following age groups: 16 preschoolers (≤5 years of age), 29 school-age children (6-12 years), 19 adolescents (13-17 years), 17 young adults (19-40 years), 47 adults (41-60 years) and 37 seniors (>60 years). Total, periodic, short-interval and isolated leg movements during sleep and periodicity indexes were obtained by polysomnography. The total index showed (quartic polynomial interpolation) a decrease before 10 years, followed by a steady increase up to 30 years, a relatively stable period until 60 years, and a final increase up to 80 years. This course was almost entirely due to changes in periodic movements. Isolated movements did not change significantly and short-interval movements showed only an increase in seniors. Our study indicates that, in restless legs syndrome, the total index shows a peculiar and unique course throughout the lifespan, mainly due to periodic movements. These age-related changes may mirror developmental changes in network complexity known to occur in dopaminergic circuits. These data further confirm the need to better assess the periodicity of leg movements in sleep during the human development period, in order to obtain clinically useful information.

Effect of Sleep Disorders on Blood Pressure and Hypertension in Children.

PURPOSE OF REVIEW: In this review, we aim to discuss the pathophysiologic basis of hypertension in sleep disorders and the current evidence in the medical literature linking sleep disorders and hypertension in children. RECENT FINDINGS: The medical literature in adults is clear about the contribution of sleep disorders, poor sleep quality, and sleep deprivation to hypertension and increased cardiovascular risk. The literature on cardiovascular consequences of sleep disorders in children is not as robust, but there is some evidence of early cardiovascular changes in children with sleep deprivation and obstructive sleep apnea. Children with obstructive sleep apnea have increased sympathetic activation during sleep, blunted dipping, or elevated systolic or diastolic pressures. Although the literature on other sleep disorders such as narcolepsy and restless legs syndrome is scarce, there is evidence in adults and some recent supportive data in children.

The prevalence of restless sleep disorder among a clinical sample of children and adolescents referred to a sleep centre.

Restless sleep disorder (RSD) is a newly described sleep disorder in children characterized by large body movements and repositioning that lasts all night with at least five body movements per hour and a significant impact on daytime behaviours. The authors have previously identified and described the syndrome and compared the sleep parameters and sleep-related movements to those in children with restless legs syndrome, normal controls and snorers. The current study is a retrospective review of the sleep diagnosis in 300 consecutive children seen and evaluated in a single sleep disorders centre; 252 children underwent polysomnography, as clinically indicated, to identify the proper diagnosis. The current research estimates the prevalence of RSD in a sleep clinical setting to be 7.7% and compares it to the prevalence of other common sleep disorders in the same setting. Another important addition to the literature is the fact that RSD can coexist with other sleep disorders, such as habitual snoring and parasomnia, without confounding the diagnosis.

Systolic Blood Pressure Elevation in Children with Obstructive Sleep Apnea Is Improved with Positive Airway Pressure Use.

INTRODUCTION: To evaluate the effect of continuous positive airway pressure (CPAP) treatment on blood pressure (BP) in children with obstructive sleep apnea (OSA). STUDY DESIGN: Retrospective chart review of children aged 7-17 referred to Benioff Children's Hospital Oakland for the evaluation of snoring. Data collected included age, body mass index (BMI), BP, heart rate, apnea-hypopnea index, and oxygen saturation nadir. Children were divided into 3 groups: snorers, untreated OSA, and OSA treated with CPAP. Seventy-five children were identified, 25 in each group. RESULTS: There was no difference in age or apnea-hypopnea index among the groups. The CPAP group had higher BMI than the snorers and untreated OSA groups. Systolic BP was higher in the 2 OSA groups compared with the snorers. After CPAP treatment, systolic BP decreased. The BP decrease was significantly greater in patients with higher BMI at baseline. There was no significant change in diastolic BP in the 3 groups. CONCLUSION: Children with OSA have higher systolic BP than habitual snorers. Treatment with CPAP in children with OSA for 6 months reduced their systolic BP despite a small increase in their BMI.

Photographic art in exam rooms may reduce white coat hypertension.

INTRODUCTION: Blood pressure (BP) elevation in medical office settings in patients who are normotensive in nonmedical settings is an effect known as 'white coat hypertension'. This phenomenon is thought to be due to situational anxiety caused by the experience of visiting a doctor and the anxiety-inducing nature of the medical office. Our study was designed to determine if carefully selected photographic art could counter the anxiety that causes white coat hypertension and lead to lower BP recordings in some patients. METHODS: 117 adults, non-pregnant patients from the Louisiana State University Health Sciences Center Family Medicine Resident Clinic participated in this study. After the triage nurse measured the BP, the patients were randomly placed in either an exam room with standard medical posters (control room) or in an exam room with photographic art (photo room). The BP was measured in the exam room. After the medical visit, the patients switched rooms and the BP was measured a third time. The patients were asked to fill out a questionnaire to identify room preference. RESULTS: On average, the BP obtained in the control rooms was higher than that obtained in the photo rooms. There was a statistically significant difference between the mean arterial pressure, systolic BP and diastolic BP between the control room and the photo room. CONCLUSIONS: Landscape photographic art may have the beneficial effect of reducing BP in medical office examination rooms.

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 positive airway pressure (PAP) adherence. The Patient Health Questionnaire (PHQ-9) is a validated depression screening and severity scoring tool recommended by the Diagnostic and Statistical Manual of Mental Disorders (fifth edition). In this retrospective observational study, we evaluate the interrelationship between age at OSA diagnosis, depression severity, and 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 to 5 scale (1 = none, 2 = mild, 3 = moderate, 4 moderately severe, 5 = severe). The PHQ-9 was administered at the time of OSA diagnosis and follow-up. Average daily PAP usage hours were obtained from PAP devices between 1 to 3 months after 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 apnea-hypopnea index was 34.5 (standard deviation 31.8), with a PHQ-9 mean of 8.3 with standard deviation ± 5.9. A Mann-Whitney comparison between the group with normal PHQ-9 scores and the group with PHQ-9 scores consistent with depression (score of 5 or greater) showed no statistically significant differences in apnea-hypopnea index (P = .470) or average night hour use (P = .195). There was a statistically significant difference in age between both groups (P = .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. CITATION: Niraula R, Singh A, DelRosso LM, Meghpara S, Keenan L. Age matters: association between age and depression severity at the time of OSA diagnosis and PAP adherence in adult patients. J Clin Sleep Med. 2024;20(6):859-862.

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.

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.