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Information gathered with built-in software (BIS) on new ventilators allow clinicians to access long-term noninvasive ventilation (LTNIV) data. Nevertheless, few evidence are available in literature that highlight potential strengths and disadvantages of using BIS in pediatrics. We aim to evaluate the use of BIS in a cohort of 90 children on LTNIV in our unit, focusing mainly on adherence, air leaks, and residual sleep events. We found that caregivers' perception of ventilator use is independent from objective adherence (P = .137). Furthermore, we failed to find any predictors of adherence. As regards air leaks, we found that pre-scholars' (0-6 years old) total air leaks are lower than teenagers' (more than 12 years old) (P < .05). Multiple regressive analysis showed that age at the beginning of therapy is a predictor of total air leaks: prescholars are associated with lower values (P < .05), while scholars (6-12 years old) are associated with higher values (P < .05). Finally, we explored the validity of BIS automatic scoring of sleep events (AHIBIS ) as compared with the manual scoring of polygraphy (AHIPG ). AHIBIS is within a range of 3.98 from AHIPG in 95% of cases, with a 64% of sensitivity and a 67% of specificity in identifying a pathological state. The disagreement between the two methods seems to increase for high AHI values. In conclusion, data gathered by BIS are a useful support tool for the clinician in assessing the course of LTNIV. However, clinicians must be aware of the several limitations of built-in software, especially in pediatrics.

Objective Changes of sleep architecture have been reported in children with Spinal Muscular Atrophy type 2 (SMA2), mainly represented by a decrease of arousability. No studies have evaluated the effect of long-term ventilation on sleep parameters in these children. The aim of this study was to evaluate the effects of long-term non-invasive positive pressure ventilation (LTNPPV) on sleep architecture and to assess the residual differences from normal controls. Methods Nine consecutive children with SMA2 underwent two distinct polysomnographic (PSG) studies, one in spontaneous breathing, and subsequently after LTNPPV. The results were then compared to 15 age-matched controls. Results SMA2 patients showed only slightly modified sleep architecture on LTNPPV: increased stage N2% and decreased number of awakenings, while several significant differences persisted between SMA2 patients on LTNPPV and controls (decreased total sleep time, number of awakenings, sleep efficiency, and percentage of REM sleep). Sleep microstructure, evaluated by means of the Cyclic alternating pattern (CAP) showed only marginal changes on LTNPPV (small shortening of CAP A1 subtype duration and small increase in CAP A3 index). Conversely, CAP parameters on LTNPPV showed significant differences between SMA2 patients vs. controls, with increased A1 subtype percentage and decreased percentage of A2 and A3 subtypes. Conclusions This is the first study in children affected by SMA2 reporting data on sleep microstructure and their changes after LTNPPV. We found persisting, small but important changes in sleep microstructure during LTNPPV in these children, suggesting that this treatment only partially improves their arousability.

Background: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a very rare and complex pediatric syndrome characterized by altered hypothalamic thermal regulation, pain threshold, and respiratory control, hyperphagia with rapid weight gain and, often, hypothalamic-pituitary dysfunction. Its etiopathogenesis remains undetermined. We investigated the presence of alterations to target genes and hypothalamic-pituitary autoimmunity in a patient with ­ROHHAD syndrome. Methods: A 3-year-old girl presenting with obesity after rapid weight gain was diagnosed with ROHHAD syndrome based on clinical features and abnormal biochemical and functional testing results. Because of worsening of rapid symptoms and demonstration of oligoclonal bands on cerebrospinal fluid (CSF) analysis, she was treated with plasmapheresis, methylprednisolone, anti-CD20 monoclonal antibodies, and azathioprine. Despite initial partial clinical improvement, the patient soon died of cardiorespiratory arrest. Post-mortem, whole exome sequencing, high-resolution comparative genomic hybridization array, and optimized indirect immunofluorescence (IIF) analysis were performed on blood and CSF. Results: No putative causative genomic variants compatible with dominant or recessive inheritance nor clinically significant structural rearrangement were detected. IIF on serum and CSF demonstrated the presence of anti-pituitary and anti-hypothalamus autoantibodies. Conclusions: These findings support the involvement of autoimmunity in ROHHAD syndrome. However, response to immunosuppressive treatment was only transient and the patient died. Further cases are required to define the complex disease pathogenesis.

Children with medical complexity (CMC) are patients with one or more complex chronic conditions dependent on medical technologies. In our unit (Pediatric Pulmonology and Respiratory Intermediate Care Unit, Department of Pediatrics, “Bambino Gesù” Children's Hospital and Research Institute), we regularly follow‐up CMC patients, particularly children on long‐term, invasive (IMV) or noninvasive (NIV), ventilation. Children suffering from chronic diseases and with medical complexity have lost the possibility to go to the hospital during the COVID‐19 pandemic. The aim of this article is to describe our experience with telemedicine (teleconsultation [TC] and telemonitoring of ventilator [TM]) in CMC on ventilation. We presented 21 children on long‐term ventilation (NIV or IMV) whose planned hospital admission was postponed due to lockdown. A total of 12 healthcare problems were detected during scheduled TCs. Only one problem was not solved by our remote intervention. Specifically, TM has allowed us to change the ventilator parameters and to monitor patients on ventilation remotely. In conclusion, the use of telemedicine in CMC ventilated patients resulted in a feasible tool to avoid in‐person visits during the pandemic.

Non-invasive ventilation is increasingly used in children for acute and chronic respiratory failure. Ventilators available for clinical use have different levels of complexity, and clinicians need to know in detail their characteristics, setting variables, and performances. A wide range of ventilators are currently used in non-invasive ventilation including bi-level ventilators, intermediate ventilators, and critical care ventilators. Simple or advanced continuous positive airway pressure devices are also available. Differences between ventilators may have implications on the development of asynchronies and air leaks and may be associated with discomfort and poor patient tolerance. Although pressure-targeted (controlled) mode is preferable in children because of barotrauma concerns, volume-targeted (controlled) ventilators are also available. Pressure support ventilation represents the most used non-invasive ventilation mode, as it is more physiological. The newest ventilators allow the clinicians to use the hybrid modes that combine the advantages of volume- and pressure-targeted (controlled) ventilation while limiting their drawbacks. The use of in-built software may help clinicians to optimize the ventilator setting as well as to objectively monitor patient adherence to the treatment. The present review aims to help the clinician with the choice of the ventilator and its ventilation modalities to ensure a successful non-invasive ventilation program.

Background Children with chronic respiratory failure and/or sleep disordered breathing due to a broad range of diseases may require long-term ventilation to be managed at home. Advances in the use of long-term non-invasive ventilation has progressively leaded to a reduction of the need for invasive mechanical ventilation through tracheostomy. In this study, we sought to characterize a cohort of children using long-term NIV and IMV and to perform an analysis of those children who showed significant changes in ventilatory support management. Methods We performed a retrospective cohort study of pediatric (within 18 years old) patients using long-term, NIV and IMV, hospitalized in our center between January 1, 2000 and December 31, 2017. A total of 432 children were included in the study. Long Term Ventilation (LTV) was defined as IMV or NIV, performed on a daily basis, at least 6 h/day, for a period of at least 3 months. Results 315 (72.9%) received non-invasive ventilation (NIV); 117 (27.1%) received invasive mechanical ventilation (IMV). Children suffered mainly from neuromuscular (30.6%), upper airway (24.8%) and central nervous system diseases (22.7%). Children on IMV were significantly younger when they start LTV [NIV: 6.4 (1.2–12.8) years vs IMV 2.1 (0.8–7.8) years] (p p = 0.0220), and being a child with home health care (aOR 11.4; p Conclusions Children on LTV suffered mainly from neuromuscular, upper airways, and central nervous system diseases. Children invasively ventilated usually started support younger and were more severely ills.

BACKGROUND Tracheobronchomalacia, defined as variable collapse of the airways, has been recognized as an important cause of respiratory morbidity but still widely underdiagnosed. Bronchoscopy is still considered as the gold standard, but numerous limitations are known, especially for fragile sick children. Moreover, information on parenchymal lung disease cannot be described. There is a real need for a reliable, non-invasive test to help detection of airway and parenchymal malformations in children, specifically when bronchoscopy cannot be performed. METHODS AND RESULTS 34 paediatric patients underwent cine multidector CT for ongoing respiratory symptoms and were included. All CT images were of good quality and sedation was never needed. Airway disease such as trachea-broncomalacia with/without stenosis was described in 53% with the first being more frequent. Bronchomalacia alone was described in 10 patients and in 4 patients was associated with tracheomalacia. Moreover, CT allowed identification of parenchymal disease in 10 patients. Airways stenosis alone was detected in seven patients. The majority of patients (85%) underwent also bronchoscopy for clinical decision. The agreement between CT and bronchoscopy was explored. The two examinations did not agree only in two cases. CT dynamic showed an excellent sensitivity of 100% (81.47-100 %), a great specificity of 82% (48.22-97.72 %), NPV 100%, and PPV 90% (72-96.9 %). CONCLUSION Dynamic CT results an effective and highly sensitive diagnostic exam for children with tracheo-bronchomalacia. CT is especially indicated for those small and fragile patients that cannot undergo an invasive investigation. Moreover, CT allows a detailed evaluation both of the airways and the lungs which is useful for the clinical management.

Neuromuscular diseases are a heterogeneous group of diseases affecting the nerves, muscles, anterior horn cells, or the neuromuscular junctions. They cause muscular weakness and, in most cases, involve the respiratory system, with a variable course that can lead to respiratory failure. Sleep disorders are often present in these patients, and their evaluation is necessary to assess the requirements for correct management. Hypoventilation, obstructive sleep apnea, and central apneas must be assessed and eventually treated with mechanical ventilatory support. Polysomnography with capnography is the gold standard in assessing sleep-disordered breathing. This review aims to provide an overview of the literature on the most common neuromuscular diseases with related sleep breathing disorders in children, highlighting the main features of sleep in these patients and the role of noninvasive ventilation in treating these conditions.

Rationale Long-life ventilatory assistance is necessary for survival in pediatric patients with congenital central hypoventilation syndrome (CCHS). Invasive mechanical ventilation (IMV) through tracheostomy is the most used method, especially in the first years of life when the central nervous system is maturing. Nevertheless, IMV via tracheostomy is not ideal because tracheostomy in children is associated with impaired speech and language development, also frequent infections of the lower airway tract occur. Objective Only few reports describe the transition from IMV to the noninvasive method, ending with decannulation in CCHS affected patients. We aim to provide our experience regarding decannulation program in CCHS affected children and to describe a proposal of an algorithm concerning transition from invasive to noninvasive ventilation (NIV) in CCHS patients. Methods The study has been conducted retrospectively. Four children from two European centers underwent tracheostomy removal and decannulation, upon request of patients and their families. Results All children were trained to carry out tracheostomy capping before decannulation and underwent endoscopic assessment of upper and lower airway. Subsequently they started training to NIV at mean age of 106.25 months (±40.7 SD). Decannulation occurred 12 months after and no patients needed the reintroduction of tracheal cannula in either short or long term follow up. Conclusions our study shows that effective liberation from IMV, the transition to NIV and decannulation are possible in CCHS affected children and offers a proposal of an algorithm which can be applied in selected centers.

Objective There have been few published reports on the sleep patterns of patients with spinal muscular atrophy (SMA) type 2, and none on sleep microstructure. The aim of this study was to analyze sleep architecture and microstructure in a group of children with SMA type 2, compared with age-matched and sex-matched controls. Methods Seventeen SMA type 2 children (seven males, mean age 4.2 years) and 12 controls (five males, mean age 5.0 years) underwent full polysomnography to evaluate sleep architecture and microstructure by means of the Cyclic Alternating Pattern (CAP). Results Compared with the control children, the SMA type 2 patients showed a mild increase in the apnea/hypopnea index. Sleep was characterized by a decrease in the number of sleep stage shifts per hour, of percentage of stage N3, of stage R, and of sleep efficiency. On the contrary, significant increases of awakenings per hour, wake after sleep onset, and percentage of stage N1 were found. The CAP analysis revealed a significant increase in the percentage of A1 CAP subtypes, a reduction of that of A3 subtypes, and of A2 and A3 indexes. Conclusions The results indicated an abnormality of sleep macrostructure and microstructure in SMA type 2 patients, which was characterized by a reduction of A2 and A3 subtypes (low and high power arousals), supporting the concept of a decreased arousability in SMA type 2 patients. Similar to a previous report on SMA type 1, the findings might be additional proof of central nervous system involvement, although these alterations are less severe than those observed in infants with SMA type 1.

Objective Narcolepsy is a lifelong disease, manifesting with excessive daytime sleepiness and cataplexy, arising between childhood and young adulthood. The diagnosis is typically made after a long delay that burdens the disease severity. The aim of the project, promoted by the “Associazione Italiana Narcolettici e Ipersonni” is to develop Red Flags to detect symptoms for early referral, targeting non-sleep medicine specialists, general practitioners, and pediatricians. Materials and methods A multidisciplinary panel, including patients, public institutions, and representatives of national scientific societies of specialties possibly involved in the diagnostic process of suspected narcolepsy, was convened. The project was accomplished in three phases. Phase 1: Sleep experts shaped clinical pictures of narcolepsy in pediatric and adult patients. On the basis of these pictures, Red Flags were drafted. Phase 2: Representatives of the scientific societies and patients filled in a form to identify barriers to the diagnosis of narcolepsy. Phase 3: The panel produced suggestions for the implementation of Red Flags. Results Red Flags were produced representing three clinical pictures of narcolepsy in pediatric patients ((1) usual sleep symptoms, (2) unusual sleep symptoms, (3) endocrinological signs) and two in adult patients ((1) usual sleep symptoms, (2) unusual sleep symptoms). Inadequate knowledge of symptoms at onset by medical doctors turned out to be the main reported barrier to diagnosis. Conclusions This report will hopefully enhance knowledge and awareness of narcolepsy among non-specialists in sleep medicine in order to reduce the diagnostic delay that burdens patients in Italy. Similar initiatives could be promoted across Europe. Electronic supplementary material The online version of this article (10.1007/s10072-018-3666-x) contains supplementary material, which is available to authorized users.

Background and objectives Infants with congenital myasthenic syndrome (CMS) are at risk of brief resolved unexplained event (BRUE) and sleep-disordered breathing. The aim of the study was to explore sleep in infants with CMS with a particular focus on heart rate (HR) variability. Methods Overnight polygraphy was performed and HR variations associated with respiratory events were analysed. Bradycardia and tachycardia were defined as a variation of HR of ±10 bpm from baseline and analysed as events/hour. Results The data of 5 infants with CMS were analysed. Two patients had known mutations (COLQ and RAPSN). One patient had a tracheostomy. The apnoea-hypopnoea index (AHI) was abnormal in all the patients (range 2.8–47.7 events/h), with the highest AHI being observed in the 3 youngest infants. Nocturnal transcutaneous gas exchange was normal in all patients except the tracheostomised patient. Mean HR was 114 ± 23 bpm with a mean HR index of 4.5 ± 4.3 events/h. The amplitudes of HR variations (bradycardia or tachycardia) were around 15–20 bpm, regardless of the type of respiratory event, and comparable between patients. No correlations were found between HR indexes or variations and the type and mean duration of respiratory events. Ventilatory support was initiated in 3 infants immediately after the sleep study because of a high AHI and/or nocturnal hypoventilation. Conclusions All 5 infants had an abnormal AHI with younger infants having the highest AHI. Three infants required ventilatory support after the polygraphy, underlining its clinical usefulness. No significant abnormalities of HR were observed during the sleep studies.

Non-invasive positive pressure ventilation is increasingly used in children both in acute and in chronic setting. Clinical data supporting safety, efficacy and limitations in children are growing. Technical problems related to the ventilators performance and interfaces selection have not been fully resolved, especially for younger children. Non-invasive ventilation can be applied at home. Its use at home requires appropriate diagnostic procedures, accurate titration of the ventilators, cooperative and educated families and careful, well-organized follow-up programs.

Nocturnal pulse oximetry has a high positive predictive value for polysomnographically diagnosed obstructive sleep apnoea (OSA) in children. When significant adenotonsillar hypertrophy is diagnosed, adenotonsillectomy (TA) represents a common treatment for OSA in children. We investigated the role of pulse oximetry in predicting those patients, referred for suspected OSA, who subsequently needed TA. At-home nocturnal pulse oximetry was performed on 380 children (65.7% males), median age 4.1(IRQ 3.0-5.6) years, referred for suspected OSA, and data were retrospectively analysed. For each recording McGill Oximetry Score (MOS) was categorized. Mean pulse rate (PR) z-score and pulse rate variability (PRV)-corrected (PRSD/meanPR) were significantly higher in children with abnormal MOS. Both parameters were significantly higher in subjects who underwent TA compared with those not surgically treated. Both DIIn our study, children with OSA who subsequently needed TA showed higher PRV compared to those without surgical indication. Children with abnormal MOS were nearly 20 times more likely to undergo TA. What is Known: • Nocturnal pulse oximetry has a high positive predictive value for polysomnographically diagnosed obstructive sleep apnoea in children. • When significant adenotonsillar hypertrophy is diagnosed, adenotonsillectomy represents a common treatment for OSA in children. What is New: • An abnormal pulse oximetry highly predict the indication for adenotonsillectomy. • We suggest the use of at-home pulse oximetry as method to predict prescription of adenotonsillectomy, and this may be useful in contexts where polysomnography is not readily available.

Objectives Only few studies are available in the literature on sleep in children with Prader–Willi syndrome (PWS) and one single study analyzed the cyclic alternating pattern (CAP) in young adults with PWS, showing that patients with a higher proportion of A1 subtypes presented less severe GH deficiency. The aims of our study were to evaluate CAP in children with PWS compared to an age-matched control group and to evaluate the differences between PWS children with (GH+) and without (GH−) GH therapy. Methods Laboratory polysomnographic sleep recordings were obtained from 30 children with PWS (17 GH− and 13 GH+ patients) and 15 age-matched normal controls. Results Compared to controls, PWS children had a reduction of sleep efficiency, of sleep stage 2 and of REM sleep. GH− PWS patients showed a global decrease in total CAP rate during S1 and S2 but not in SWS. In GH+ PWS patients, SWS CAP rate and A1 index were increased vs. GH− children. Discussion The decrease in total CAP rate and all A subtypes might suggest the presence of a decreased NREM sleep instability in our PWS children and can be considered to be in agreement with the reported generalized hypoarousal state of PWS subjects. GH therapy is likely to increase CAP rate and A1 index during SWS in PWS patients.

Sleep disturbances are frequent in Angelman syndrome (AS); however, beside the few studies which have investigated sleep disorders in AS by means of questionnaires, to our knowledge, no systematic polysomnographic recordings have been carried out in AS patients. The present study represents the first attempt to study sleep patterns of AS by polysomnography, to evaluate the influences of sleep on the paroxysmal electroencephalogram (EEG) patterns of AS and to assess the eventual age-related changes of sleep architecture and of sleep EEG abnormalities in children and adolescents with AS.Fifteen children with AS (7 males and 8 females, mean age 7.2 years, range 3-16 years), attending the Sleep Center of the Department of Child Neurology and Psychiatry of the University of Rome 'La Sapienza' and the Sleep Research Centre of the Oasi Institute (IRCCS) of Troina were included and subdivided into two subgroups by age: subgroup 1, aged 3-5 years, and subgroup 2, aged 9-17 years. Two control groups of age-matched normal subjects were also included: one aged less than 8 years and another aged more than 8 years; additionally, two other groups of age-matched children with epilepsy and mental retardation of different origin, one aged less and one aged more than 9 years were taken into consideration. The statistical comparison between the sleep parameters obtained from the patients and those from the other groups was carried out by means of the non-parametric Kruskal-Wallis ANOVA and the Mann-Whitney U test.The most frequent EEG abnormality found in AS patients appeared to be the 2-3 c/s poorly defined spike/waves complexes. This pattern was influenced by sleep stages; the duration of the runs showed an increasing length with sleep deepening from sleep stage 1 to slow-wave sleep (SWS). Moreover, the 2-3 c/s bursts activity present in sleep stage 2 showed a slowing to 1-2 c/s during SWS. Regarding sleep architecture, in subjects with AS aged8 year there was a significant reduction in sleep efficiency as compared to normal controls, while the percentage and duration of REM sleep was significantly lower and the percentage of SWS was significantly higher. REM sleep time was reduced in AS subjects aged8 years than in normal controls. The comparison between AS groups and mental retardation with epilepsy groups did not show significant differences.Similarly to other types of genetically determined mental retardation syndromes, also subjects with AS seems to show important abnormalities of their sleep polysomnographic patterns.This is the first study which reports, in detail, these abnormalities and opens a new path for further insight into the knowledge of additional sleep-related disturbances which are reported in sleep questionnaires by the caregivers of AS subjects.

In our previous study we found a high prevalence of disordered sleep breathing in migraine children vs. controls. Since no quantitative studies about sleep respiratory disorders have been carried out in migraine children, we performed a polysomnographic (PSG) study in 10 migraine patients (7 boys, 3 girls; mean age 8.11 years, range, 5.8–14.5) attending the Headache Center of our department, to evaluate the presence of sleep apnea. Mothers completed a headache diary and a sleep diary for at least 1 month and filled out a sleep questionnaire. PSG data showed a normal sleep architecture in 3 cases, an insomnia pattern in 2, a reduction of slow wave sleep in 3 and a reduction of REM sleep in 2. Respiratory analysis revealed that 2 of 10 patients had obstructive sleep apnea. These 2 patients presented habitual snoring and associated sleep disturbances such as restless sleep and hypnic jerks. Sleep apnea may be a subtle and often undiagnosed symptom in several migraine patients. The report of habitual snoring associated with other sleep disturbances such as restless sleep and other parasomnias may be a sign of sleep apnea in migraine children.

We investigated in children with spinal muscular atrophy type 2 the consistency of 4 different equations for predicting resting energy expenditure (REE) compared with measured REE by using indirect calorimetry. In patients with spinal muscular atrophy type 2, measured REE was lower than predicted. We also found a correlation between energy consumption and motor skills.

Rationale At-home nocturnal pulse oximetry has a high positive predictive value (PPV) for polysomnographically-diagnosed obstructive sleep apnea (OSA) but no studies have been published testing the night-to-night consistency of at-home nocturnal pulse oximetry for the evaluation of suspected OSA in children. We therefore determined the night-to-night consistency of nocturnal pulse oximetry as a diagnostic test for OSA in children. Methods We prospectively studied 148 children (96 male) aged 4.9 ± 2.4 (1.2–11.8) years, referred for suspected OSA. To evaluate night-to-night consistency, we compared an oximetry analysis method, the McGill Oximetry Score (MOS), from two consecutive at-home nocturnal pulse oximetry recordings. Results Pulse oximetry metrics were similar on the two nights. The MOS on the two nights showed excellent night-to-night consistency when analyzed as positive for OSA versus inconclusive, 143/148 (Spearman's correlation coefficient = 0.90). A more detailed analysis using four categories (MOS 1, 2, 3, and 4) of OSA severity showed very good night-to-night agreement, 133/148 (Spearman's correlation coefficient = 0.91). Variability was increased in children younger than 4 years of age compared to older children. Conclusions Night-to-night consistency of nocturnal pulse oximetry as a diagnostic test for OSA showed excellent agreement. Night-to-night consistency of pulse oximetry, as analyzed by the MOS, for diagnosis and severity evaluation further validates this abbreviated testing method for pediatric OSA. Polysomnography (PSG) is required to rule in or rule out OSA in children if a single night oximetry testing is inconclusive. Pediatr Pulmonol. 2013; 48:754–760. © 2012 Wiley Periodicals, Inc.

Objective Children with GH deficiency (GHD) show a general decrease in electroencephalographic (EEG) arousability represented by a significant global decrease in Cyclic Alternating Pattern (CAP). The aim of the present study was to evaluate if sleep structure is influenced by GH substitutive therapy by analyzing the classical sleep architecture parameters and sleep microstructure by means of CAP. Subjects and methods Laboratory polysomnographic sleep recordings were obtained from five children affected by GHD (two girls and three boys; mean age: 4.6 ± 3.1 years), at baseline and after GH therapy, and from 10 normal healthy children (four girls and six boys, mean age: 5.6 ± 2.2 years). Results Compared to controls, GHD subjects showed a reduced total sleep time with increased wakefulness and a consequent decrease in sleep efficiency; GH therapy was associated with an increase of the awakenings/hour and a large effect size was evident for sleep latency, sleep efficiency, and stage N3, which were decreased, and for stage W, which was increased. CAP appeared to be globally reduced and all phase A subtypes and CAP cycle showed a longer duration in GHD children vs. controls. GH substitutive treatment was followed by an increase in CAP rate (total, in N2, and in N3); additionally, A1 index was also significantly increased, especially during stage N3, with a very large effect size. On the other hand, A2 and A3 index and CAP cycle mean duration were reduced. Conclusion Sleep stage architecture seems to be influenced by the GH status, but the analysis of sleep microstructure by means of CAP reveals an enhancement of EEG slow oscillations in GHD patients (demonstrated by an increase in CAP rate and A1 index during N3) after the start of GH replacement therapy. These findings deserve to be verified in a larger trial.

Purpose of review Although several studies in the last years have evaluated obesity, obstructive sleep apnea (OSAS), and excessive daytime sleepiness (EDS) in patients with Prader-Willi syndrome (PWS), their pathophysiologies and interactions and the role of treatment with growth hormone are not completely understood. The present review analyzes the contributing role of obesity, OSAS, and sleep structure abnormalities in determining the EDS and the role of specific treatment in improving the clinical outcome. Recent findings The studies on sleep structure of PWS patients show abnormalities of rapid eye movement (REM) sleep and a decrease in non-REM sleep instability, corroborating the hypothesis of the presence of a primary disorder of vigilance and the similarities with narcolepsy. These sleep alterations might also be linked to the action of mediators of inflammation (i.e. adiponectin or cytokines) determined by obesity. Obesity and hypothalamic dysfunction could be responsible for the primary abnormalities of ventilation during sleep that, in turn, might contribute to EDS. Although EDS seems to resemble narcolepsy, PWS patients do not present the other typical symptoms of narcolepsy. Summary The most consistent hypothesis for linking the three different symptoms of PWS is a primary central hypothalamic dysfunction. Further research is needed to evaluate the contribution of the upper airway resistance syndrome in the pathogenesis of EDS, the role of the alterations of sleep microstructure, the relationships between PWS and narcoleptic phenotype, the involvement of orexin/hypocretin, and the effects of drugs acting on REM sleep and/or wakefulness.

Background: Laron syndrome (LS), known as growth hormone (GH) receptor deficiency, is a rare form of inherited GH resistance. Sleep disorders were described as a common feature of adult LS patients, while no data are available in children. Bi-directional interactions between human sleep and the somatotropic system were previously described, mainly between slow wave sleep and the nocturnal GH surge. Aims: To analyze the sleep macro- and microstructure in LS and to evaluate the influence of substitutive insulin-like growth factor 1 (IGF-1) therapy on it. Methods: Two young LS females underwent polysomnography; the first study was performed during IGF-1 therapy, the second one after a 3-month wash-out period. Results: In both patients, the sleep macrostructure showed that time in bed, sleep period time, total sleep time, sleep efficiency and rapid eye movement (REM) percentage were all increased during wash-out. The sleep microstructure (cyclic alternating pattern: CAP) showed significantly higher EEG slow oscillations (A1%) in NREM sleep, both during IGF-1 therapy and wash-out. Conclusions: Sleep macrostructure in LS children is slightly affected by substitutive IGF-1 therapy. Sleep microstructure shows an increase of A1%, probably related to abnormally high hypothalamic GHRH secretion, due to GH insensitivity.

Objective To analyze sleep architecture and NREM sleep alterations by means of the Cyclic Alternating Pattern (CAP) in children with Down syndrome (DS) and Fragile-X syndrome (fraX), the two most common causes of inherited mental retardation, in order to find out eventual alterations of their sleep microstructure related to their mental retardation phenotypes. Methods Fourteen patients affected by fraX (mean age 13.1 years) and 9 affected by Down syndrome (mean age 13.8 years) and 26 age-matched normal controls were included. All subjects underwent overnight polysomnography in the sleep laboratory, after one adaptation night and their sleep architecture and CAP were visually scored. Results FraX subjects showed a reduced time in bed compared to DS subjects, whereas DS subjects showed a lower sleep efficiency, a higher percentage of wakefulness after sleep onset, and a reduced percentage of stage 2 NREM compared to the other groups. Furthermore, DS and fraX subjects, compared to normal controls, showed a higher percentage of stage 1 NREM and a lower percentage of REM sleep. FraX subjects showed the most disrupted sleep microstructure with low total CAP rate and CAP rate in S2 NREM. Both patient groups showed a lower percentage of A1 and higher percentage of A2 and A3 compared to normal controls. Conclusions The analysis of CAP might be able to disclose new important findings in the sleep architecture of children with mental retardation and might characterize sleep microstructural patterns of the different phenotypes of intellectual disability. Significance The NREM sleep microstructure alterations found in our subjects, associated with the reduction in REM sleep percentage, seem to be distinctive features of intellectual disability.

Objective To evaluate sleep in children with autistic spectrum disorder (ASD) by means of sleep questionnaires and polysomnography; moreover, to analyze their cyclic alternating pattern (CAP). Methods Thirty-one patients with ASD (28 males, 3 females, aged 3.7–19 years) and age-matched normal controls were included. ASD children were evaluated by a standard sleep questionnaire that consisted of 45 items in a Likert-type scale covering several areas of sleep disorders and by overnight polysomnography in the sleep laboratory after one adaptation night. Results The questionnaire results showed that parents of ASD children reported a high prevalence of disorders of initiating and maintaining sleep, enuresis, repetitive behavior when falling asleep, and daytime sleepiness. Polysomnographically, ASD children showed reduced time in bed, total sleep time, sleep period time and rapid eye movement (REM) latency. ASD subjects had a CAP rate during slow-wave sleep (SWS) lower than normal controls, together with a lower percentage of A1 subtypes. Conclusions ASD children questionnaires showed a higher percentage of disorders of initiating and maintaining sleep than normal controls; this was not completely confirmed by sleep staging. CAP measures showed subtle alterations of NREM sleep which could be detected with an appropriate methodology of analysis. The reduction of A1 subtypes during SWS might play a role in the impairment of cognitive functioning in these subjects.

Objective The aim of this study was to evaluate the sleep breathing patterns and to detect the eventual presence of periodic leg movements (PLMs) in patients affected by Angelman syndrome (AS). Methods Ten children with AS were recruited to participate in the study; the clinical diagnosis was confirmed by the genetic analysis (maternal 15q deletion, uniparental paternal disomy, or mutation of the UBE3A gene). All patients but two had presented epileptic seizures. Two age-matched groups of patients with mental retardation (MR) associated (MRE+) or not (MRE−) to epilepsy were used as control groups. All subjects underwent one polysomnographic recording, after one adaptation night. Sleep stages were scored according to standard criteria slightly modified in order to take into account the specific EEG patterns of AS, also the apnea/hypopnea index (AHI) was quantified; PLMs were identified and the PLM index (PLMI) was computed. The statistical analysis was carried out by means of the one-way ANOVA, followed by the Fisher LSD post-hoc test, when appropriate, and by means of the linear correlation coefficient between AHI and PLMI. Results Sleep macrostructure showed only few significant differences between children with AS and the other two groups of subjects: AS patients showed higher percentage of wakefulness after sleep onset and sleep onset latency; moreover, the percentage of REM sleep was reduced in AS and in MRE+ subjects. A tendency for AS subjects to present a higher PLMI than the other two groups was also found. AHI >5 was found in 30% of AS subjects, in 30.8% of MRE+, and only in 20% of MRE− patients ( χ 2 =2.359, NS); 70% of AS patients, 38.5% of MRE+, and 46.7% of MRE− subjects had PLMI >5 ( χ 2 =3.088, NS). Conclusions These results confirm our previous questionnaire-based findings of a high prevalence of sleep breathing disorder and important PLMs in AS and allow us to hypothesize that epilepsy, rather than mental retardation, might exacerbate these sleep disorders. Significance Sleep breathing disorder and PLMs might contribute to the cognitive impairment and to the worsening of life quality of subjects with AS and with MR (mostly those with epilepsy). Therefore, our findings suggest the need to explore these sleep disorders in children affected by MR and to set up a correct treatment.

To test the hypothesis that the administration of l -5-hydroxytryptophan ( l -5-HTP) might exert beneficial effects on sleep terrors, we carried out an open pharmacological trial in a group of children with sleep terrors compared to a group of children with the same disorder but without l -5-HTP treatment. Participants in the trial were 45 children (34 males and 11 females; age range 3.2–10.6 years), referred to the Sleep Centre of the Department of Developmental Neurology and Psychiatry of the University of Rome “La Sapienza”, affected by sleep terrors. All subjects underwent: (1) complete medical and sleep history; (2) complete neurological examination and EEG recording whilst awake and sleeping, (3) a structured sleep diary for 2 months, (4) after 1 month, all subjects were examined again from the clinical and EEG points of view and (5) after 6 months, a structured interview in order to evaluate the clinical outcome. After the first visit, l -5-HTP was administered (2 mg/kg per day) at bedtime to 31 randomly selected patients for a single period of 20 consecutive days. After 1 month of treatment, 29/31 (93.5%) of patients showed a positive response. In the comparison group without drug therapy, after 1 month, the episodes disappeared only in four children (28.6%) while ten children (71.4%) showed the persistence of episodes with the same frequency as before. After 6 months, 26/31 (83.9%) of children treated with l -5HTP were sleep terror-free, while in five children (16.1%) sleep terror episodes persisted. Of the children in the comparison group, ten (71.4%) continued to show sleep terrors at 6-month follow-up. Conclusion:to our knowledge, this is the first study demonstrating the efficacy of a new drug treatment for sleep terrors. These results confirm our initial hypothesis and represent evidence that treatment with l -5-hydroxytryptophan is able to modulate the arousal level in children and to induce a long-term improvement of sleep terrors.

Objectives : To evaluate cyclic alternating pattern (CAP) in sleep of school-age children in order to obtain a standardized database for CAP parameters in this age range. Methods : CAP parameters were quantified in 10 normal healthy subjects (6 males and 4 females, mean age 8.3 years; range 6–10 years). All subjects underwent polysomnography recordings for two consecutive nights in a standard laboratory setting. Sleep data were stored on computer using a 16-channel polysomnography digital system. Sleep macrostructure was visually scored according to the criteria by Rechtschaffen and Kales (Brain Information Service/Brain Research Institute, University of California, Los Angeles, 1968); CAP was visually scored following the criteria by Terzano et al. (Sleep Med 2 (2001) 537). Results : CAP rate showed a progressive increase with the deepness of sleep, with high values during slow wave sleep (SWS). CAP time showed its longest duration during non-REM (NREM) sleep stage 2 (S2), followed by SWS and sleep stage 1 (S1). No differences across NREM sleep stages were found for CAP cycle and phase B mean duration; on the contrary, phase A showed longer duration during SWS than in S1 and S2. Phases A1 were the most numerous (84.45%) followed by A3 (9.14%) and by A2 (6.44%). The distribution of phases A subtypes across NREM stages showed significant differences for the A1 subtypes that occurred more frequently during SWS than in S2 and S1 (and during S2 than in S1). Subtypes A3 were more frequent during S1 than SWS while no differences were found for subtype A2. The analysis of A1 interval distribution showed a log-normal-like distribution with a peak around 25 s for the A1 phases and no clear peak for A2–A3 phases. Conclusions : The analysis of CAP in school-age children is characterized by an increase of CAP rate during SWS and a high percentage of A1 phases. The distribution of interval between consecutive A1 phases showed a peak around 25 s.

Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown.To assess the relationship of OSAS with liver injury in pediatric NAFLD.Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h.Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2)90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis.In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.

Study objectives To evaluate the characteristics of the cyclic alternating pattern (CAP) in the sleep of preschool-aged children in order to obtain normative parameters in this age range. Design Prospective study. Settings University sleep laboratory. Participants Ten normal healthy subjects (6 girls and 4 boys, mean age 4.6 years; range 3-6 years) underwent polysomnography recordings for 2 consecutive nights in a standard laboratory setting. Sleep data were stored on a computer using a polysomnography digital system (Embla N7000, Medcare, Iceland). Sleep structure was visually scored according to the Rechtschaffen and Kales criteria. The cyclic alternating pattern was visually scored following the criteria by Terzano et al. These criteria were modified for the purposes of this study because it was noticed that, at the age of the group under analysis, most electroencephalogram arousals, often accompanied by electromyogram activation, are expressed at the level of the electroencephalogram by theta frequencies and not alpha or higher frequencies. Measurements and results The CAP rate in preschool-aged children (25.93%) showed a progressive increase with the deepness of sleep, with highest values during non-rapid eye movement (NREM) stage 3 (44.0%) and 4 sleep (46.08%) and lowest values in NREM stage 2 (17.26%). The CAP time showed its longest duration during stage 2 sleep, followed by stage 4, stage 3, and NREM stage 1. The CAP cycle duration showed no differences across NREM stages. The cyclic alternating pattern phase A was longer and phase B was shorter during stage 1 than during stages 2, 3, and 4. A1 phases were the most numerous (63.2%), followed by A2 (21.5%) and by A3 (15.3%). The distribution of A-phase subtypes across NREM sleep stages (A index) showed significant differences for the A1 subtypes that occurred more frequently during stage 3 and 4 sleep than during stages 1 and 2. The A2 index showed no significant differences across NREM sleep stages, while the A3 index was significantly higher during stage 1 sleep than during stages 2, 3, and 4. The analysis of the A1 interval distribution showed a log-normal-like distribution with a peak around 25 seconds for the A1 phases and no clear peak for A2-A3 phases. Conclusions The analysis of CAP in preschool-aged children is characterized by an increase of CAP rate during slow-wave sleep and a high percentage of A1 phases and A2 phases. However, the lower percentage of A1 paralleled by an increase of A2 could represent a signal of higher sleep instability in this age group as compared with prepubertal school-aged children.