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To evaluate the effects of bupropion on periodic limb movements during sleep (PLMS) and chin electromyography tone in children taking it for their mood disorder, compared to the effects of selective serotonin reuptake inhibitors (SSRIs) and of bupropion combined with SSRIs.Six adolescents (aged 16.0 ± 0.63 years) taking bupropion alone and 6 adolescents (aged 15.9 ± 1.36 years) taking bupropion in combination with an SSRI antidepressant were recruited, along with 10 adolescents (aged 16.2 ± 0.2 years) taking different SSRIs, and they were also enrolled together with 17 age- and sex-matched control patients (aged 15.5 ± 1.26 years). Polysomnographic studies were obtained, and participants' leg movement activity during sleep and muscle tone were assessed quantitatively (atonia index) during all sleep stages.Participants taking SSRIs showed PLMS indices significantly higher than those of control patients, whereas adolescents taking bupropion showed only slightly increased indexes of nonperiodic leg movements during sleep. No differences in PLMS were observed between adolescents taking bupropion alone or in association with SSRIs. The atonia index showed, within each sleep stage, the lowest values in the 2 groups taking SSRIs and the highest in the control patients; adolescents taking bupropion alone tended to show values slightly smaller than those of the control patients.We found that similar to adults, in adolescents SSRIs but not bupropion are associated with increased PLMS. Bupropion also seems to counteract the SSRI-induced increase of PLMS, when administered in combination; thus, the dopaminergic effect of bupropion seems to outmatch the antidopaminergic action of SSRIs. Conversely, bupropion does not counteract the effects of SSRIs on chin electromyography tone.DelRosso LM, Mogavero MP, Fickensher A, Bruni O, Schenck CH, Ferri R. Effects of bupropion and SSRI antidepressants on leg movement activity and chin muscle tone during sleep in adolescents.

Introduction Children with Down Syndrome (DS) are at high risk of sleep disordered breathing (SDB). We aimed to examine the burden of SDB in infants with DS referred to tertiary sleep center. Methods Infants (≤12 months old) with DS who underwent consecutive polysomnography (PSG) at a single academic sleep center over a 6-year period were included. OSA (obstructive apnea hypopnea index [oAHI]>1/hr), central sleep apnea (central apnea index>5/hr) and the presence of hypoventilation (% time spent with CO2 > 50 mmHg either by end-tidal or transcutaneous> 25% of total sleep time) and hypoxemia (time spent with O2 saturation 5 min) were ascertained. For infants who underwent adenotonsillectomy (AT), we compared the SDB metrics before and after the AT. Results A total of 40 infants were included (Mean age 6.6 months, male 66%). PSGs consisted of diagnostic (n=13) and split night (n=27, 68%) studies. All met criteria for OSA with mean oAHI 34.6 (32.3). Central sleep apnea was present in 11 (27.5%) of infants. A total of 11 (27.5%) had hypoxemia. Hypoventilation was present in 10 (25%) infants. There was a trend of association between hypothyroidism and hypoventilation (OR: 5.5 [0.96-34.4], p=0.056). Among 13 infants who underwent AT and had a follow up PSG, severity of OSA markedly reduced after AT (oAHI difference: 34/hr [29], p=0.0002). Conclusion This study highlights the high prevalence of SDB in infants with DS and supports early PSG assessment in this patient population.

After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.

To test the hypothesis that children taking trazodone have less leg movements during sleep (LMS) and higher rapid eye movement (REM) sleep atonia than children taking selective serotonin reuptake inhibitors (SSRIs) but more than normal controls.Fifteen children (9 girls and 6 boys, mean age 11.7 years, standard deviation [SD] 3.42) taking trazodone (median dosage 50 mg/d, range 25-200 mg) for insomnia and 19 children (11 girls and 8 boys, mean age 13.7 years, SD 3.07) taking SSRIs for depression, anxiety, or both were consecutively recruited, as well as an age- and sex-matched group of 25 control children (17 girls and 8 boys, mean age 13.7 years, SD 3.11). LMS were scored and a series of parameters was calculated, along with the analysis of their time structure. The Atonia Index was then computed for each non-REM sleep stage and for REM sleep.Children taking trazodone exhibited slightly higher leg movement indices than controls but lower than those found in children taking SSRIs and their time structure was different. Chin electromyogram atonia in all sleep stages was not significantly altered in children taking trazodone but was decreased in children taking SSRIs, especially during non-REM sleep.In children, SSRIs but not trazodone are associated with a significantly increased number of LMS, including periodic LMS, and increased chin tone in all sleep stages. The assessment of periodic limb movement disorder and REM sleep without atonia might not be accurate when children are taking SSRIs because of their significant impact.DelRosso LM, Mogavero MP, Bruni O, Schenck CH, Fickenscher A, Ferri R. Trazodone affects periodic leg movements and chin muscle tone during sleep less than selective serotonin reuptake inhibitor antidepressants in children.

The vagal nerve stimulator (VNS) is a nonpharmacological treatment for refractory epilepsy. A side effect of the VNS is sleep-disordered breathing. The purpose of this study was to demonstrate how a surface electrode placed over the VNS lead can help distinguish whether sleep-disordered breathing is due to VNS discharge.Seven pediatric patients (aged 7.7 ± 2.2 years) with a VNS underwent a polysomnogram with an additional surface electrode on the left anterolateral neck to detect VNS discharge. The VNS-associated apnea-hypopnea index was calculated by determining the number of hypopneas and apneas occurring during VNS discharge. We evaluated the veracity of the VNS electrode by comparing signal duration and total number to those expected by programmed settings. We compared these findings to chin electromyogram signal change.Three patients had an obstructive pattern with VNS discharge, and 3 had an increase in respiratory rate without gas exchange abnormalities, including 1 with both patterns; 1 patient experienced no respiratory abnormalities. The mean obstructive apnea-hypopnea index was 8.2 ± 8.3 events/h. The mean VNS-associated apnea-hypopnea index was 4.8 ± 6.2 events/h and accounted for 46.9 ± 30.2% of the total obstructive apnea-hypopnea index. The additional electrode captured a statistically high percentage of expected discharges (94.7 ± 6.5%) compared to chin electromyogram (36.1 ± 35.8%;We demonstrated that a surface electrode on the VNS lead can temporally coregister VNS discharges and enabled us to attribute sleep-disordered breathing to VNS stimulation in 4 patients. We propose that this sensor be standard procedure in patients with VNS undergoing polysomnogram.Chan JHM, DelRosso LM, Ruth C, Wrede JE. A surface electrode adjacent to vagal nerve stimulator lead can aid in characterizing vagal nerve stimulator-mediated pediatric sleep-disordered breathing: a case series of 7 patients.

Sleep problems are common and often increase when initiating pharmacotherapy for ADHD. Stimulants are commonly associated with delayed sleep onset/insomnia although nonstimulants can be associated with daytime sleepiness. There is a wide variability in severity and duration of sleep effects, but most effects are mild and improve over time. Although sleep problems occur in all age groups, preschoolers and adolescents appear to be more vulnerable to adverse effects on sleep than adults and children. Interventions to improve sleep include behavioral therapy, changing dose schedules or formulations, and adding a sleep-promoting agent such as melatonin.

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.

Restless sleep is a common complaint in children with sleep and other disorders, when it occurs as an isolated symptom it can depict a separate condition called restless sleep disorder (RSD). A key diagnostic feature of RSD is the polysomnographic (PSG) scoring of five or more large muscle movements (LMM) per hour of sleep. Initial publications on RSD used video-PSG (vPSG) analysis to count LMM. However, recently, scoring criteria for LMM on PSG signals alone have been published, but their correlation with vPSG scoring has not been done. In this study we compare vPSG to PSG scoring of LMM in a group of children with restless sleep.Video-PSG studies from 20 children (14 boys and six girls, mean age 11.3 years, SD 4.17) were reviewed by a blinded scorer. First, scorer used a video analysis (video-LMM), then on a different day the scorer used PSG criteria for LMM without video (PSG-LMM).PSG-LMM were found to be significantly more numerous than video-LMM (mean LMM index 8.6 ± 2.95 SD vs. 6.9 ± 2.40 SD, respectively) while their duration was not statistically different (mean LMM duration 11.6 ± 2.33 s vs. 11.6 ± 2.99 s, respectively). 95.4% of video-LMM were also detected by PSG. Both LMM indexes and durations obtained by the two methods correlated significantly between them. A cut off of 6.24 LMM/hour by PSG-LMM was calculated to be equivalent to 5 LMM by video-LMM.PSG-LMM scoring criteria detects95% of LLM scored by video-PSG. PSG-LMM lead to the detection of a higher number of movements, indicating their higher sensitivity in picking up LMM in PSG recording. This further supports that these criteria need adequate consideration for their eventual inclusion into the current sleep scoring manual. A higher index may be needed to diagnose RSD.

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.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.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.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 legs syndrome (RLS) may be underdiagnosed in children with autism spectrum disorder (ASD) due to difficulty expressing the symptoms in their own words. In addition, administration of oral iron may be particularly difficult in children with ASD.This was a retrospective, open-label case series of children with ASD, restless legs (RL) symptoms, and serum ferritin30 μg/L, who either had failed or did not tolerate oral iron, and were subsequently treated with intravenous (IV) ferric carboxymaltose (FCM). Patients received a single dose of IV FCM, 15 mg/kg up to a maximum dose of 750 mg. Data collected pre- and eight weeks post-infusion included presenting symptoms, serum ferritin, iron profile, and Clinical Global Impression Scale (CGI-Severity pre- and CGI-Improvement post-infusion). Adverse effects were assessed.Nineteen children, 4-11 years old (12 male, median age 6, interquartile range (IQR 4-11) were included. A definite RLS diagnosis was identified in 6 verbal children (31.6%). RL symptoms (designated probable RLS) in the 13 other children met all RLS diagnostic criteria except "improvement of symptoms with movement," which was not definitively determined. Baseline median values were: ferritin 10 μg/L (IQR 10-16), iron 66.5 μg/dL (IQR 57-96), TIBC 382 μg/dL (IQR 360-411) and transferrin saturation 19% (IQR 14-28). Median CGI-S was 4 (moderate symptoms) (IQR 3-4). At eight weeks after IV FCM, all measures were improved. Median ferritin was 68 μg/L (IQR 62.5-109, p 0.00045). Median CGI-I was 1 (very much improved) (IQR 1-2). All children meeting definite RLS criteria improved. Three children in the probable RLS group did not improve. Children meeting the full RLS criteria had lower baseline ferritin levels than those with a probable diagnosis (9 μg/L, IQR 9-10 vs. 13 μg/L, IQR 10-16, Mann-Whitney test p 0.045). Adverse effects included lightheadedness, gastrointestinal discomfort, fever, and headache among others.The majority of children (84.2%) with ASD, restless legs symptoms, and serum ferritin30 μg/L had clinical improvement and significantly better serum iron parameters after a single IV FCM infusion. Although larger, randomized trials are needed, IV FCM appears to be a promising treatment for this subset of children with ASD.

This paper aims to review the limitations of the current classification of insomnia of early childhood and propose a new conceptual model allowing a better understanding of its pathophysiology. Our hypothesis is that chronic insomnia of childhood has different phenotypical expressions, associated to different pathophysiological mechanisms. Based on a long-lasting experience in evaluating a very large number of children with specific insomnia symptoms (nocturnal awakenings, difficulty in falling asleep, nocturnal restlessness, early morning awakenings) and on published data, we hypothesize that different phenotypes of insomnia might exist with different therapeutic implications. We describe three phenotypes of insomnia in early childhood: a) insomnia with motor restlessness; b) insomnia characterized without difficulties in falling asleep but with long-lasting early morning awakenings; c) insomnia with multiple night awakenings and falling asleep difficulty. This type of categorization might have important implications for treatment, based on the different hypothetical neurotransmitter dysfunctions. The early identification of a phenotype of insomnia might guide to specific behavioral and/or pharmacological interventions with the aim to prevent chronic insomnia.