Developmental outcome of electroencephalographic findings in SYNGAP1 encephalopathy.

SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials.

Documento internacional de consenso sobre apnea obstructiva del sueño / International Consensus Document on Obstructive Sleep Apnea

El objetivo principal de este documento internacional de consenso sobre apnea obstructiva del sueño es proporcionar unas directrices que permitan a los profesionales sanitarios tomar las mejores decisiones en la asistencia de los pacientes adultos con esta enfermedad según un resumen crítico de la literatura más actualizada. El grupo de trabajo de expertos se ha constituido principalmente por 17 sociedades científicas y 56 especialistas con amplia representación geográfica (con la participación de 4 sociedades internacionales), además de un metodólogo experto y un documentalista del Centro Cochrane Iberoamericano. El documento consta de un manuscrito principal, con las novedades más relevantes, y una serie de manuscritos online que recogen las búsquedas bibliográficas sistemáticas de cada uno de los apartados del documento internacional de consenso. Este documento no cubre la edad pediátrica ni el manejo del paciente en ventilación mecánica crónica no invasiva (que se publicarán en sendos documentos de consenso aparte). Palabras clave: Apnea obstructiva del sueño Diagnóstico Tratamiento

The main aim of this international consensus document on obstructive sleep apnea is to provide guidelines based on a critical analysis of the latest literature to help health professionals make the best decisions in the care of adult patients with this disease. The expert working group was formed primarily of 17 scientific societies and 56 specialists from a wide geographical area (including the participation of 4 international societies), an expert in methodology, and a documentalist from the Iberoamerican Cochrane Center. The document consists of a main section containing the most significant innovations and a series of online manuscripts that report the systematic literature searches performed for each section of the international consensus document. This document does not discuss pediatric patients or the management of patients receiving chronic non-invasive mechanical ventilation (these topics will be addressed in separate consensus documents). Keywords: Obstructive sleep apnea Diagnosis Treatment

International Consensus Document on Obstructive Sleep Apnea. / Documento internacional de consenso sobre apnea obstructiva del sueño.

The main aim of this international consensus document on obstructive sleep apnea is to provide guidelines based on a critical analysis of the latest literature to help health professionals make the best decisions in the care of adult patients with this disease. The expert working group was formed primarily of 17 scientific societies and 56 specialists from a wide geographical area (including the participation of 4 international societies), an expert in methodology, and a documentalist from the Iberoamerican Cochrane Center. The document consists of a main section containing the most significant innovations and a series of online manuscripts that report the systematic literature searches performed for each section of the international consensus document. This document does not discuss pediatric patients or the management of patients receiving chronic non-invasive mechanical ventilation (these topics will be addressed in separate consensus documents).

Sleep breathing disorders in pediatric patients with spinal muscular atrophy 2.

OBJECTIVES: The study is aimed to analyze both sleep architecture and prevalence of sleep-disordered breathing (SDB), in a group of patients with type 2 spinal muscular atrophy (SMA), considering motor dysfunction, and compare them with age-matched controls. METHODS: Eighteen SMA type 2 patients (nine males median age 9.5 (4-17) years) and eighteen controls (fourteen males, median age 8,5 (1-16) years) underwent nocturnal polysomnography. SMA type 2 patients were evaluated with motor scales; Hammersmith Functional Motor Scale Expanded (HFMSE), Revised upper limb model (ULMR) and Egen Klassification Scale Version 2 (EK2). Parents/tutors completed two pediatric sleep questionnaires (respiratory subscale from Chervin Pediatric Sleep Questionnaire and Bruni's Sleep Disturbance Scale for Children). RESULTS: When compared with controls, SMA type 2 patients showed no significant differences in age (9.72 ± 4.2 vs 8.22 ± 3.9 (p = 0.28), gender 9 (9 men (50%) vs 14 (77,8%) (p = 0.083) and nutritional status; Body Mass Index (BMI) (16.4 (12.2-34.8) vs 17.6 (4.4-24.2) (p = 0.83). Apnea Hypopnea Index (AHI) was statistically higher in SMA type 2 patients (6.7 ± 6.2 vs 0.4 ± 0.3) (p < 0.001). The SpO2 mean values in cases were (96% ± 1.4) vs (97.5% ± 1.2) (p = 0.007). TcPCO2 median value (41,5 mmHg; (range 34-47.2) in the SMA type-2 patients within normal reference values. Only one motor scale; Hammersmith Functional Motor Scale Expanded (HFMSE) showed a negative correlation with AHI (r = -0.132). CONCLUSIONS: Patients affected by SMA type 2 presented significantly higher apnea-hypopnea indices than controls; differences in sleep architecture identified include: decreased total sleep time, increased percentage of stage N1 of NREM sleep as well as increased sleep fragmentation seen in the SMA type 2 group, due to respiratory related arousals. We would like to point out that validated pediatric sleep questionnaires in general population, may not be useful tools when screening for SDB in these patients. This should be taken into consideration in clinical practice and in the elaboration of future clinical guidelines for these patients.

Trastornos del movimiento y de la conducta durante el sueño en el adulto / Sleep-related movement and behavioural disorders in adults

Los trastornos del movimiento y de la conducta durante el sueño pueden tener un impacto en la calidad del sueño del paciente y dar lugar a síntomas diurnos. En estos grupos de enfermedades se incluyen entidades como el síndrome de piernas inquietas, los movimientos periódicos de las piernas y las parasomnias del sueño de movimientos oculares rápidos (REM) y no REM. El conocimiento de sus características clínicas y nociones sobre su manejo es de gran importancia para el neurólogo y especialista en sueño por su frecuencia e impacto en la calidad del sujeto. Con frecuencia, estos pacientes son referidos a dichos especialistas, y es relevante conocer que ciertos trastornos del sueño pueden asociarse a otras enfermedades neurológicas

Sleep-related movement and behaviour disorders may have an impact on sleep quality and lead to daytime symptoms. These groups of conditions include diseases such as restless legs syndrome, periodic leg movements, and REM and NREM parasomnias. The knowledge of their clinical features and management is of utmost importance for the neurologist and sleep specialist. Frequently, these patients are referred to such specialists and it is relevant to know that certain sleep disorders may be associated with other neurological conditions

Prevalence of sleep-related breathing disorders in children with malocclusion.

BACKGROUND: The paediatric population has a high incidence of sleep-related breathing disorders (SRBD). A notable risk factor is the presence of craniofacial abnormalities. The objective of the study was therefore to survey the prevalence of SRBD in patients presenting for interceptive treatment. MATERIAL AND METHODS: Prospective study with a sample of 249 healthy patients. The "Paediatric Sleep Questionnaire" and "Sleep Disturbance Scale for Children" were completed by the children's parents and the results were evaluated. All patients had their medical records reviewed and underwent orthodontic diagnosis by oral examination, as well as dental cast and cephalometric analysis. Finally, we compared the results of the pre- and post-treatment questionnaires of 50 patients in the sample. RESULTS: Based on the results of the questionnaires, 22.8% of the study sample had SRBD. No statistically significant correlation was found between SRBD and the anthropometric characteristics and occlusal variables assessed. According to the cast analysis, patients with SRBD had a smaller maxillary width (p<0.003), and according to the cephalometric study, less overbite (p<0.003). Furthermore, the prevalence of SRBD was higher among patients with a history of adenotonsillectomy (p<0.02). Comparison of the results of pre- and post-treatment questionnaires revealed significant differences after orthodontic treatment (p<0.0005). CONCLUSIONS: It is necessary to identify the presence of SRBD in orthodontic patients given its high prevalence. Patients with SRBD have a smaller maxillary width and less overbite. Key words:Sleep-related breathing disorders, paediatric sleep questionnaire, cephalometry.

Nocturnal Oximetry-based Evaluation of Habitually Snoring Children.

RATIONALE: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea-hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA. METHODS: Deidentified nSpO2 recordings from a total of 4,191 children originating from 13 pediatric sleep laboratories around the world were prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single-channel nSpO2 recordings from 589 patients referred for suspected OSA. MEASUREMENTS AND MAIN RESULTS: The automatically estimated apnea-hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively). CONCLUSIONS: Neural network-based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.

Carbamacepina como tratamiento sintomático de las mioclonías en la panencefalitis esclerosante subaguda / Carbamazepine as treatment for the symptoms of myoclonias in subacute sclerosing panencephalitis

No disponible

Documento de consenso del síndrome de apneas-hipopneas durante el sueño en niños (versión completa) / Consensus document on sleep apnea-hypopnea syndrome in children (full version)

No disponible

Comorbilidades de los trastornos respiratorios del sueño en los niños / Comorbidities of sleep-disordered breathing in children

Los trastornos respiratorios del sueño en los niños, y especialmente el síndrome de apnea-hipopnea infantil, se asocian a un ramillete de comorbilidades de entre las que destacan las cognitivoconductuales, las metabólicas y de crecimiento, así como las cardiovasculares. Los 2 factores más importantes que contribuyen a su fisiopatología son la hipoxia intermitente y la fragmentación del sueño, que parecen ser las responsables de la respuesta inflamatoria sistémica que acabará produciendo el daño multistémico mencionado(AU)

Sleep-related respiratory disorders in children, especially childhood sleep apnea-hypopnea syndrome, are associated with a wide range of comorbidities affecting the central nervous system, cardiovascular and metabolic systems, and growth. The two most important factors contributing to the physiopathology of this disorder are intermittent hypoxia and sleep fragmentation, which seem to cause the systemic inflammatory response resulting in these end-organ consequences(AU)

Dietary and physical activity patterns in children with obstructive sleep apnea.

OBJECTIVE: To assess dietary and physical activity patterns and morning circulating blood levels of the orexigenic hormones ghrelin and visfatin in children with either obesity, obstructive sleep apnea (OSA), or both conditions. STUDY DESIGN: In this cross-sectional design, 5- to 9-year-old participants (n = 245) from the community were identified. After overnight polysomnography, caregivers filled out a food and physical activity questionnaire, and the child underwent a fasting blood draw for ghrelin and visfatin plasma levels. RESULTS: Compared with control subjects, obese children with OSA ate 2.2-times more fast food, ate less healthy food such as fruits and vegetables, and were 4.2-times less frequently involved in organized sports. OSA was positively correlated with plasma ghrelin levels (R(2), 0.73; P < .0001), but not visfatin levels, particularly when obesity was present. CONCLUSION: OSA and obesity in children may adversely impact dietary preferences and may be particularly detrimental to daily physical activity patterns. Furthermore, increased ghrelin levels support the presence of increased appetite and caloric intake in obese patients with OSA, which in turn may further promote the severity of the underlying conditions.

Insulin sensitivity, serum lipids, and systemic inflammatory markers in school-aged obese and nonobese children.

The impact of obesity as a systemic low-grade inflammatory process has only partially been explored. To this effect, 704 community-based school-aged children (354 obese children and 350 age-, gender-, and ethnicity-matched controls) were recruited and underwent assessment of plasma levels of fasting insulin and glucose, lipids, and a variety of proinflammatory mediators that are associated with cardiometabolic dysfunction. Obese children were at higher risk for abnormal HOMA and cholesterol levels. Furthermore, BMI z score, HOMA, and LDL/HDL ratio strongly correlated with levels of certain inflammatory mediators. Taken together, obesity in children is not only associated with insulin resistance and hyperlipidemia, but is accompanied by increased, yet variable, expression of markers of systemic inflammation. Future community-based intervention and phenotype correlational studies on childhood obesity will require inclusion of expanded panels of inflammatory biomarkers to provide a comprehensive assessment of risk on specific obesity-related morbidities.

[Comorbidities of sleep-disordered breathing in children]. / Comorbilidades de los trastornos respiratorios del sueño en los niños.

Sleep-related respiratory disorders in children, especially childhood sleep apnea-hypopnea syndrome, are associated with a wide range of comorbidities affecting the central nervous system, cardiovascular and metabolic systems, and growth. The two most important factors contributing to the physiopathology of this disorder are intermittent hypoxia and sleep fragmentation, which seem to cause the systemic inflammatory response resulting in these end-organ consequences.

Nocturnal polysomnographic characteristics of habitually snoring children initially referred to pediatric ENT or sleep clinics.

OBJECTIVES: To determine clinical and polysomnographic characteristics of children initially referred by primary care physicians (PCP) to either otolaryngology or sleep clinics for a history of habitual snoring. METHODS: Retrospective review of clinical characteristics and nocturnal polysomnograms (PSG) of snoring children referred initially to otolaryngologists by PCP (i.e., ENT) compared to a cross matched population of snoring children initially referred to a pediatric sleep center (i.e., SLEEP). RESULTS: Sixty-eight ENT referred children were cross-matched to 68 SLEEP children. ENT referred children were found to have significantly larger tonsillar size compared to SLEEP children (tonsil size score 3.1 vs. 2.5, p value <0.01). Despite larger tonsillar size, there were no differences observed in the number of children with clinically significant obstructive sleep apnea syndrome (OSAS) with an obstructive apnea hypopnea index (OAHI)5/h TST (40 ENT vs. 38 SLEEP children). Furthermore, SLEEP children with OSAS exhibited more severe sleep related breathing disturbances compared to ENT children (obstructive apnea index: 5.0 vs. 1.5 /h TST, p value <0.01; mean oxygen saturation nadir [76.3% vs. 87.0%, p<0.01]). Finally, in 28 ENT referred children vs. 30 SLEEP the OAHI was <5/h TST. CONCLUSIONS: Children referred by ENT are not more likely to be diagnosed with OSAS than snoring children directly referred to a pediatric sleep clinic by their pediatricians. The only difference in the referral decision between ENT and SLEEP seems to be tonsil size. Furthermore, PSG revealed a large percentage of children in whom surgical indication for AT is not obvious, thus suggesting that PSG is useful in determining the management of snoring children initially referred to ENT. Finally, SLEEP referred children diagnosed with OSAS exhibited increased indices among selected parameters indicative of sleep-disordered breathing.

Obstructive sleep apnea in children: relative contributions of body mass index and adenotonsillar hypertrophy.

BACKGROUND: The obesity epidemic has prompted remarkable changes in the proportion of obese children who are referred for habitual snoring. However, the contribution of obesity to adenotonsillar hypertrophy remains undefined. METHODS: In our study, 206 nonobese habitually snoring children with polysomnographically diagnosed obstructive sleep apnea (OSA) were matched for age, gender, ethnicity, and obstructive apnea-hypopnea index (OAHI) to 206 obese children. Size estimates of tonsils and adenoids, and Mallampati class scores were obtained, and allowed for the assessment of potential relationships between anatomic factors and obesity in pediatric OSA. RESULTS: The mean OAHI for the two groups was approximately 10.0 episodes/h total sleep time. There was a modest association between adenotonsillar size and OAHI in nonobese children (r = 0.22; p < 0.001) but not in obese children. The mean (+/- SEM) adenotonsillar size was larger in nonobese children (3.85 +/- 0.16 vs 3.01 +/- 0.14, respectively; p < 0.0001), and conversely Mallampati class scores were significantly higher in obese children (p < 0.0001). CONCLUSION: The magnitude of adenotonsillar hypertrophy required for any given magnitude of OAHI is more likely to be smaller in obese children compared to nonobese children. Increased Mallampati scores in obese children suggest that soft-tissue changes and potentially fat deposition in the upper airway may play a significant role in the global differences in tonsillar and adenoidal size among obese and nonobese children with OSA.

Plasma IGF-1 levels and cognitive dysfunction in children with obstructive sleep apnea.

BACKGROUND: Pediatric OSA is associated with substantial morbidity in cognitive function. However, for any given OSA severity level, altered cognitive performance may or may not be present. Since IGF-1 is neuroprotective, we hypothesized that higher systemic IGF-1 levels may identify children at lower susceptibility for cognitive morbidity. METHODS: Consecutive habitually snoring and non-snoring children ages 5-7 years were recruited from the community, and underwent overnight polysomnography, and neurocognitive testing and a blood draw the next morning. Snoring children were divided into OSA or no OSA, and OSA children were further subdivided into those with >=2 abnormal cognitive subtests and into those with normal cognitive scores. Plasma levels of IGF-1 were also measured using ELISA. RESULTS: Among snoring children without OSA, circulating IGF-1 was 910 +/- 110 pg/mL compared with 1070 +/- 240 pg/mL in those with OSA (p<0.01). However, IGF-1 was 540 +/- 70 pg/mL in children with OSA and cognitive deficits, compared to 1370 +/- 170 microg/L in children with OSA and normal cognitive scores (p<0.001). CONCLUSIONS: IGF-1 levels are higher in children with OSA, particularly in those who do not manifest neurocognitive deficits, suggesting that the magnitude of the IGF-1 response elicited by OSA may play a significant protective role against the neurocognitive dysfunction associated with OSA.

Increased morning brain natriuretic peptide levels in children with nocturnal enuresis and sleep-disordered breathing: a community-based study.

INTRODUCTION: Habitual snoring and obstructive sleep apnea have been associated with bed-wetting in children, and effective obstructive sleep apnea treatment may improve enuresis. OBJECTIVES: The purpose of this work was to assess whether habitual snoring is associated with increased incidence of enuresis and whether severity of obstructive sleep apnea correlates with enuretic frequency and to evaluate brain natriuretic peptide levels. METHODS: Parental surveys of 5- to 7-year-old children were reviewed for habitual snoring and enuresis. Enuresis was also assessed in a cohort of 378 children with habitual snoring undergoing overnight polysomnographic evaluation, and brain natriuretic peptide plasma levels were determined in 20 children with obstructive sleep apnea, 20 with habitual snoring without obstructive sleep apnea, and 20 nonsnoring children, matched for enuresis. RESULTS: There were 17,646 surveys completed (50.6% boys; 18.3% black). A total of 1976 (11.2%) of these children were habitual snoring (53% boys; 25.2% black). A total of 531 habitual snoring children also had enuresis (26.9%), with a predominant representation of boys (472 boys [87.5%]). Among the 15670 nonsnoring children, enuresis was reported in 1821 children (11.6%), of whom 88.8% were boys. However, enuresis among 378 children with habitual snoring did not correlate with the magnitude of sleep respiratory disturbances. Indeed, enuresis was reported in 33 of 149 children with obstructive sleep apnea (obstructive apnea hypopnea index: >2 per hour of total sleep time; 53% boys) as compared with 36 habitual snoring children with enuresis (62% boys) and obstructive apnea hypopnea index <2 per hour of total sleep time. Brain natriuretic peptide levels were elevated among children with enuresis and were marginally increased among children with obstructive sleep apnea. CONCLUSIONS: Habitual snoring is associated with increased prevalence of enuresis, and brain natriuretic peptide levels are increased in enuretic children with further increases with obstructive sleep apnea. However, the prevalence of enuresis is not modified by severity of sleep disturbance. Even mild increases in sleep pressure because of habitual snoring may raise the arousal threshold and promote enuresis, particularly among prone children, that is, those with elevated brain natriuretic peptide levels.

Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea.

BACKGROUND: Fatty liver disease (FLD) is a highly prevalent condition in obese (Ob) children, who are at increased risk for obstructive sleep apnea (OSA). However, the contribution of OSA to FLD remains unknown. DESIGN: Prospective study. SETTING: Polysomnographic evaluation and assessment of plasma levels of insulin, glucose, and lipids, and liver function tests. PARTICIPANTS: A total of 518 consecutive snoring children 4 to 17 years of age who were being evaluated for habitual snoring and suspected OSA. RESULTS: A total of 376 children had body mass index z score of < 1.20 (non-Ob children), 3 children (<1%) had elevated serum aminotransferase (LFT) levels, and 248 had OSA (65.9%). Among the 142 overweight/Ob children, 46 had elevated LFT levels (32.4%); of these children, 42 had OSA (91.3%). In contrast, OSA was present in only 71.8% of Ob children without elevated LFT level (p < 0.01). Insulin resistance and hyperlipidemia were more likely to occur in children with FLD. Furthermore, FLD was improved after treatment of OSA in 32 of 42 Ob children (p < 0.0001). CONCLUSION: Increased liver enzyme levels are frequently found in Ob snoring children, particularly among those with OSA and/or metabolic dysfunction. Effective treatment of OSA results in improved liver function test results in the vast majority of these patients.