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PURPOSE: We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. METHODS: We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. RESULTS: Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. CONCLUSION: Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.
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Anomalías Múltiples , Anomalías Craneofaciales , Anomalías Musculoesqueléticas , Trastornos del Neurodesarrollo , Animales , Humanos , Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética , Anomalías Musculoesqueléticas/genética , Trastornos del Neurodesarrollo/genética , Fenotipo , Síndrome , Pez Cebra/genéticaRESUMEN
OBJECTIVE: Postsurgical seizure freedom in drug-resistant epilepsy (DRE) patients varies from 30% to 80%, implying that in many cases the current approaches fail to fully map the epileptogenic zone (EZ). We aimed to advance a novel approach to better characterize epileptogenicity and investigate whether the EZ encompasses a broader epileptogenic network (EpiNet) beyond the seizure zone (SZ) that exhibits seizure activity. METHODS: We first used computational modeling to test putative complex systems-driven and systems neuroscience-driven mechanistic biomarkers for epileptogenicity. We then used these biomarkers to extract features from resting-state stereoelectroencephalograms recorded from DRE patients and trained supervised classifiers to localize the SZ against gold standard clinical localization. To further explore the prevalence of pathological features in an extended brain network outside of the clinically identified SZ, we also used unsupervised classification. RESULTS: Supervised SZ classification trained on individual features achieved accuracies of .6-.7 area under the receiver operating characteristic curve (AUC). Combining all criticality and synchrony features further improved the AUC to .85. Unsupervised classification discovered an EpiNet-like cluster of brain regions, in which 51% of brain regions were outside of the SZ. Brain regions in the EpiNet-like cluster engaged in interareal hypersynchrony and locally exhibited high-amplitude bistability and excessive inhibition, which was strikingly similar to the high seizure risk regime revealed by our computational modeling. SIGNIFICANCE: The finding that combining biomarkers improves SZ localization accuracy indicates that the novel mechanistic biomarkers for epileptogenicity employed here yield synergistic information. On the other hand, the discovery of SZ-like brain dynamics outside of the clinically defined SZ provides empirical evidence of an extended pathophysiological EpiNet.
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Epilepsia Refractaria , Electroencefalografía , Humanos , Electroencefalografía/métodos , Epilepsia Refractaria/fisiopatología , Masculino , Femenino , Biomarcadores , Adulto , Red Nerviosa/fisiopatología , Encéfalo/fisiopatología , Adolescente , Adulto Joven , Niño , Simulación por Computador , Mapeo Encefálico/métodosRESUMEN
While research interest in the relationship between sleep and epilepsy is growing, it primarily centres on the effects of non-rapid eye movement (NREM) sleep in favouring seizures. Nonetheless, a noteworthy aspect is the observation that, in the lives of patients with epilepsy, REM sleep represents the moment with the least epileptic activity and the lowest probability of having a seizure. Studies demonstrate a suppressive effect of phasic REM sleep on interictal epileptiform discharges, potentially offering insights into epilepsy localisation and management. Furthermore, epilepsy impacts REM sleep, with successful treatment correlating with improved REM sleep quality. Novel therapeutic strategies aim to harness REM's anti-epileptic effects, including pharmacological approaches targeting orexinergic systems and neuromodulation techniques promoting cortical desynchronisation. These findings underscore the intricate relationship between REM sleep and epilepsy, highlighting avenues for further research and therapeutic innovation in epilepsy management.
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BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. METHODS: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. RESULTS: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). CONCLUSIONS: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.
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Encéfalo , Imagen por Resonancia Magnética , Trastornos del Neurodesarrollo , Columna Vertebral , Anomalías Urogenitales , Humanos , Masculino , Femenino , Niño , Preescolar , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/etiología , Trastornos del Neurodesarrollo/diagnóstico , Columna Vertebral/anomalías , Columna Vertebral/diagnóstico por imagen , Anomalías Urogenitales/epidemiología , Anomalías Urogenitales/complicaciones , Anomalías Urogenitales/diagnóstico , Encéfalo/diagnóstico por imagen , Encéfalo/anomalías , Encéfalo/patología , Estudios Retrospectivos , Lactante , Adolescente , Reflujo VesicoureteralRESUMEN
Sleeping problems are prevalent among children and adolescents, often leading to frequent consultations with pediatricians. While cognitive-behavioral therapy has shown effectiveness, especially in the short term, there is a lack of globally endorsed guidelines for the use of pharmaceuticals or over-the-counter remedies in managing sleep onset insomnia. An expert panel of pediatric sleep specialists and chronobiologists met in October 2023 to develop practical recommendations for pediatricians on the management of sleep onset insomnia in typically developing children. When sleep onset insomnia is present in otherwise healthy children, the management should follow a stepwise approach. Practical sleep hygiene indications and adaptive bedtime routine, followed by behavioral therapies, must be the first step. When these measures are not effective, low-dose melatonin, administered 30-60 min before bedtime, might be helpful in children over 2 years old. Melatonin use should be monitored by pediatricians to evaluate the efficacy as well as the presence of adverse effects. Conclusion: Low-dose melatonin is a useful strategy for managing sleep onset insomnia in healthy children who have not improved or have responded insufficiently to sleep hygiene and behavioral interventions.
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Melatonina , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Melatonina/uso terapéutico , Melatonina/administración & dosificación , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Niño , Adolescente , Depresores del Sistema Nervioso Central/uso terapéutico , Depresores del Sistema Nervioso Central/administración & dosificación , Preescolar , Europa (Continente) , Higiene del SueñoRESUMEN
OBJECTIVE: Cerebral cavernous malformations (CCMs) are cerebral vascular lesions that occasionally occur with seizures. We present a retrospective case series from IRCCS Gaslini Children's Hospital, a systematic review, and meta-analysis of the literature with the goal of elucidating the post-surgery seizure outcome in children with CCMs. METHODS: a retrospective review of children with cavernous malformation related epilepsy who underwent surgery at Gaslini Children's Hospital from 2005 to 2022 was conducted. We also conducted a comprehensive search on PubMed/MEDLINE and Scopus databases from January 1989 to August 2022. Inclusion criteria were: presence of CCMs-related epilepsy, in under 18 years old subjects with a clear lesion site. Presence of post-surgery seizure outcome and follow-up ≥ 12 months. RESULTS: we identified 30 manuscripts and 223 patients with CCMs-related epilepsy, including 17 patients reported in our series. We identified 85.7% Engel class I subjects. The risk of expected neurological deficits was 3.7%; that of unexpected neurological deficits 2.8%. We found no statistically significant correlations between Engel class and the following factors: site of lesion, type of seizure, drug resistance, duration of disease, type of surgery, presence of multiple CCMs. However, we found some interesting trends: longer disease duration and drug resistance seem to be more frequent in subjects in Engel class II, III and IV; multiple cavernomas would not seem to influence seizure outcome. CONCLUSIONS: epilepsy surgery in children with CCMs is a safe and successful treatment option. Further studies are necessary to define the impact of clinical features on seizure prognosis.
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Epilepsia , Hemangioma Cavernoso del Sistema Nervioso Central , Procedimientos Neuroquirúrgicos , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Epilepsia/cirugía , Hemangioma Cavernoso del Sistema Nervioso Central/cirugía , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Procedimientos Neuroquirúrgicos/métodos , Estudios Retrospectivos , Convulsiones/cirugía , Convulsiones/etiología , Resultado del Tratamiento , LactanteRESUMEN
The present article explores the connection between insomnia and Autism Spectrum Disorder (ASD), focusing on the efficacy and safety of melatonin treatments as supported by existing research and current guidelines. In this narrative review a group of Italian experts provide an analysis of the various aspects of managing insomnia in children with ASD, highlighting key points that could enhance the quality of life for both patients and their caregivers. This includes the significance of comprehensively understanding the root causes of a child's sleep difficulties for more effective, long-term management. Insomnia, a condition frequently documented in neurodevelopmental disorders such as ASD, greatly affects the lives of patients and caregivers. Recent data show that melatonin-based formulations are effective and safe for treating ASD-related insomnia both short and long term. In particular, prolonged-release melatonin is poised to be the optimal choice for this patient population. This formulation is approved for the treatment of insomnia in children and adolescents aged 2-18 years suffering from ASD and/or Smith-Magenis syndrome, where sleep hygiene measures and behavioral treatments have not been sufficient. In support, emerging research in pediatric settings indicates long-term efficacy and safety, although further research efforts are still needed. Current guidelines recommend managing insomnia and sleep disturbances in ASD using a combination of behavioral and pharmacological methods, primarily melatonin. Recent concerns about accidental melatonin ingestion highlight the need for high purity standards, such as pharmaceutical-grade prolonged-release formulations. The article also summarizes emerging molecular mechanisms from preclinical research, suggesting future therapeutic approaches.
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Trastorno del Espectro Autista , Melatonina , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Melatonina/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/complicaciones , Niño , Adolescente , Calidad de VidaRESUMEN
Somnambulism, also called sleepwalking, classified as a non-rapid eye movement sleep parasomnia, encompasses a range of abnormal paroxysmal behaviors, leading to sleepwalking in dissociated sleep in an altered state of consciousness with impaired judgment and configuring a kind of hierarchical continuum with confusional arousal and night terror. Despite being generally regarded as a benign condition, its potential severity entails social, personal, and even forensic consequences. This comprehensive review provides an overview on the current state of knowledge, elucidating the phenomenon of somnambulism and encompassing its clinical manifestations and diagnostic approaches.
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Terrores Nocturnos , Parasomnias , Trastornos del Despertar del Sueño , Sonambulismo , Humanos , Sonambulismo/diagnóstico , Sonambulismo/terapia , Terrores Nocturnos/diagnóstico , Parasomnias/diagnóstico , Trastornos del Despertar del Sueño/diagnóstico , SueñoRESUMEN
Narcolepsy type 1 is a central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy and other rapid eye movement sleep-related manifestations. Neurophysiological studies suggest that narcolepsy type 1 patients may experience impairment in emotional processing due to structural and functional changes in limbic structures and associated areas. However, the only study exploring narcolepsy behavioural responses found no impairment in the ability to recognize emotions, possibly due to compensatory mechanisms. The present study was designed to fill this gap in the literature by investigating the behavioural impairment related to emotional processing focusing on an advanced socio-cognitive skill, namely Theory of Mind, in paediatric narcolepsy type 1 patients. Twenty-two narcolepsy type 1 children and adolescents (six female; age range: 8.0-13.5) and 22 healthy controls matched for age and sex (six female; age range: 8.9-13.0) underwent a neuropsychological evaluation to assess socio-economic status, verbal abilities, working memory, social anxiety and Theory of Mind via a verbal task (i.e. Strange Stories task) and a visual task (i.e. Silent Films). Narcolepsy type 1 patients were also evaluated for disease severity. Patients exhibited impairment in Theory of Mind skills, as assessed both through both verbal (controls median = 8; patients median = 5; P = 0.009) and visual tasks (controls median = 8; patients median = 6; P = 0.003), compared to healthy controls. Correlation analyses showed that verbal and visual Theory of Mind was negatively related to narcolepsy severity (ρ = -0.45, P = 0.035 and ρ = -0.52, P = 0.012), and daytime sleepiness (ρ = -0.48, P = 0.025 and ρ = -0.45, P = 0.038). Our study shows a selective impairment in the Theory of Mind domain in children and adolescents with narcolepsy type 1. In addition, our results highlight a link between symptom severity and Theory of Mind, suggesting that lower Theory of Mind levels are associated with higher symptom severity. Further, longitudinal studies are needed to disentangle the direction of this relation and to disambiguate if narcolepsy severity impaired children's Theory of Mind or if Theory of Mind skills modulate the severity of narcolepsy symptoms by providing a greater ability to avoid cataplexy.
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BACKGROUND: Rett syndrome (RTT) is a rare neurological disorder primarily associated with mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The syndrome is characterized by cognitive, social, and physical impairments, as well as sleep disorders and epilepsy. Notably, dysfunction of the autonomic nervous system is a key feature of the syndrome. Although Heart Rate Variability (HRV) has been used to investigate autonomic nervous system dysfunction in RTT during wakefulness, there is still a significant lack of information regarding the same during sleep. Therefore, our aim was to investigate cardiovascular autonomic modulation during sleep in subjects with RTT compared to an age-matched healthy control group (HC). METHOD: A complete overnight polysomnographic (PSG) recording was obtained from 11 patients with Rett syndrome (all females, 10 ± 4 years old) and 11 HC (all females, 11 ± 4 years old; p = 0.48). Electrocardiogram and breathing data were extracted from PSG and divided into wake, non-REM, and REM sleep stages. Cardiac autonomic control was assessed using symbolic non-linear heart rate variability analysis. The symbolic analysis identified three patterns: 0 V% (sympathetic), 2UV%, and 2LV% (vagal). RESULTS: The 0 V% was higher in the RTT group than in the HC group during wake, non-REM, and REM stages (p < 0.01), while the 2LV and 2UV% were lower during wake and sleep stages (p < 0.01). However, the 0 V% increased similarly from the wake to the REM stage in both RTT and HC groups. CONCLUSIONS: Therefore, the sympatho-vagal balance shifted towards sympathetic predominance and vagal withdrawal during wake and sleep in RTT, although cardiac autonomic dynamics were preserved during sleep.
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Frecuencia Cardíaca , Polisomnografía , Síndrome de Rett , Vigilia , Humanos , Síndrome de Rett/fisiopatología , Síndrome de Rett/complicaciones , Femenino , Frecuencia Cardíaca/fisiología , Niño , Vigilia/fisiología , Adolescente , Sistema Nervioso Simpático/fisiopatología , Electrocardiografía , Sueño/fisiología , Fases del Sueño/fisiología , Corazón/fisiopatología , Corazón/inervaciónRESUMEN
Epilepsy surgery is an option for people with focal onset drug-resistant (DR) seizures but a delayed or incorrect diagnosis of epileptogenic zone (EZ) location limits its efficacy. Seizure semiological manifestations and their chronological appearance contain valuable information on the putative EZ location but their interpretation relies on extensive experience. The aim of our work is to support the localization of EZ in DR patients automatically analyzing the semiological description of seizures contained in video-EEG reports. Our sample is composed of 536 descriptions of seizures extracted from Electronic Medical Records of 122 patients. We devised numerical representations of anamnestic records and seizures descriptions, exploiting Natural Language Processing (NLP) techniques, and used them to feed Machine Learning (ML) models. We performed three binary classification tasks: localizing the EZ in the right or left hemisphere, temporal or extra-temporal, and frontal or posterior regions. Our computational pipeline reached performances above 70% in all tasks. These results show that NLP-based numerical representation combined with ML-based classification models may help in localizing the origin of the seizures relying only on seizures-related semiological text data alone. Accurate early recognition of EZ could enable a more appropriate patient management and a faster access to epilepsy surgery to potential candidates.
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Epilepsia Refractaria , Epilepsias Parciales , Epilepsia , Humanos , Procesamiento de Lenguaje Natural , Convulsiones , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/cirugía , Electroencefalografía , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/cirugíaRESUMEN
Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioral alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioral alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioral tests. Pharmacological enhancement of GABAergic tonic inhibition by the U.S. Food and Drug Administration-approved drug ganaxolone rescued functional/behavioral alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviors and identifies a readily translatable therapeutic strategy for preterm brain disorders.
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Encefalopatías , Factor I del Crecimiento Similar a la Insulina , Estados Unidos , Niño , Humanos , Recién Nacido , Embarazo , Femenino , Animales , Ratones , Receptor IGF Tipo 1 , Placenta , Recien Nacido Prematuro , Encefalopatías/tratamiento farmacológicoRESUMEN
Extra-uterine growth restriction (EUGR) is a common complication and a known risk factor for impaired development in very-low-birth-weight (VLBW) neonates. We report a population of 288 patients with no or with low-grade MRI lesions scanned at a term equivalent age (TEA) born between 2012 and 2018. Griffiths Mental Development Scale II (GMDS II) at 2 and 3 years, preterm complications and weight growth were retrospectively analyzed. EUGR was defined for weight z-score Ë 10 percentile at TEA, 6 and 12 months of correct age or as z-score decreased by 1-point standard deviation (SDS) from birth to TEA and from TEA to 6 months. Multivariate analysis showed that a higher weight z-score at 6 months is protective for the global developmental quotient (DQ) at 2 years (OR 0.74; CI 95% 0.59-0.93; p = 0.01). EUGR at 6 months was associated with worse locomotor, personal/social, language and performance DQ at 2 years and worse language and practical reasoning DQ at 3 years. In conclusion, a worse weight z-score at 6 months of age seems to be an independent risk factor for significantly reduced GMDS in many areas. These results suggest that we should invest more into post-discharge nutrition, optimizing family nutritional education.
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Cuidados Posteriores , Recien Nacido Prematuro , Recién Nacido , Humanos , Lactante , Estudios Retrospectivos , Alta del Paciente , Recién Nacido de muy Bajo Peso , Peso al Nacer , Encéfalo/diagnóstico por imagenRESUMEN
BACKGROUND AND OBJECTIVES: Narcolepsy type 1 (NT1) is still largely underdiagnosed or diagnosed too late in children. Difficulties in obtaining rapid and reliable diagnostic evaluations of the condition in clinical practice partially explain this problem. Predictors of NT1 include cataplexy and sleep-onset REM periods (SOREMPs), documented during nocturnal polysomnography (N-PSG) or through the multiple sleep latency test (MSLT), although low CSF hypocretin-1 (CSF hcrt-1) is the definitive biological disease marker. Obtaining reliable MSLT results is not always feasible in children; therefore, this study aimed to validate daytime continuous polysomnography (D-PSG) as an alternative diagnostic tool. METHODS: Two hundred consecutive patients aged younger than 18 years (112 with NT1; 25 with other hypersomnias, including narcolepsy type 2 and idiopathic hypersomnia; and 63 with subjective excessive daytime sleepiness) were randomly split into 2 groups: group 1 (n = 133) for the identification of diagnostic markers and group 2 (n = 67) for the validation of the detected markers. The D-PSG data collected included the number of spontaneous naps, total sleep time, and the number of daytime SOREMPs (d-SOREMP). D-PSG data were tested against CSF hcrt-1 deficiency (NT1 diagnosis) as the gold standard using receiver operating characteristic (ROC) curve analysis in group 1. ROC diagnostic performances of single and combined D-PSG parameters were tested in group 1 and validated in group 2. RESULTS: In group 1, the areas under the ROC curve (AUCs) were 0.91 (95% CI 0.86-0.96) for d-SOREMPs, 0.81 (95% CI 0.74-0.89) for the number of spontaneous naps, and 0.70 (95% CI 0.60-0.79) for total sleep time. A d-SOREMP count ≥1 (sensitivity of 95% and specificity of 72%), coupled with a diurnal total sleep time above 60 minutes (sensitivity of 89% and specificity of 91%), identified NT1 in group 1 with high reliability (area under the ROC curve of 0.93, 95% CI 0.88-0.97). These results were confirmed in the validation group with an AUC of 0.88 (95% CI 0.79-0.97). DISCUSSION: D-PSG recording is an easily performed, cost-effective, and reliable tool for identifying NT1 in children. Further studies should confirm its validity with home D-PSG monitoring. These alternative procedures could be used to confirm NT1 diagnosis and curtail diagnostic delay.
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Trastornos de Somnolencia Excesiva , Narcolepsia , Humanos , Niño , Anciano , Diagnóstico Tardío , Polisomnografía , Reproducibilidad de los Resultados , Narcolepsia/diagnósticoRESUMEN
Background: Sleep is disturbed in Rett syndrome (RTT), a rare and progressive neurodevelopmental disorder primarily affecting female patients (prevalence 7.1/100,000 female patients) linked to pathogenic variations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Autonomic nervous system dysfunction with a predominance of the sympathetic nervous system (SNS) over the parasympathetic nervous system (PSNS) is reported in RTT, along with exercise fatigue and increased sudden death risk. The aim of the present study was to test the feasibility of a continuous 24 h non-invasive home monitoring of the biological vitals (biovitals) by an innovative wearable sensor device in pediatric and adolescent/adult RTT patients. Methods: A total of 10 female patients (mean age 18.3 ± 9.4 years, range 4.7-35.5 years) with typical RTT and MECP2 pathogenic variations were enrolled. Clinical severity was assessed by validated scales. Heart rate (HR), respiratory rate (RR), and skin temperature (SkT) were monitored by the YouCare Wearable Medical Device (Accyourate Group SpA, L'Aquila, Italy). The average percentage of maximum HR (HRmax%) was calculated. Heart rate variability (HRV) was expressed by consolidated time-domain and frequency-domain parameters. The HR/LF (low frequency) ratio, indicating SNS activation under dynamic exercise, was calculated. Simultaneous continuous measurement of indoor air quality variables was performed and the patients' contributions to the surrounding water vapor partial pressure [PH2O (pt)] and carbon dioxide [PCO2 (pt)] were indirectly estimated. Results: Of the 6,559.79 h of biovital recordings, 5051.03 h (77%) were valid for data interpretation. Sleep and wake hours were 9.0 ± 1.1 h and 14.9 ± 1.1 h, respectively. HRmax % [median: 71.86% (interquartile range 61.03-82%)] and HR/LF [median: 3.75 (interquartile range 3.19-5.05)] were elevated, independent from the wake-sleep cycle. The majority of HRV time- and frequency-domain parameters were significantly higher in the pediatric patients (p ≤ 0.031). The HRV HR/LF ratio was associated with phenotype severity, disease progression, clinical sleep disorder, subclinical hypoxia, and electroencephalographic observations of multifocal epileptic activity and general background slowing. Conclusion: Our findings indicate the feasibility of a continuous 24-h non-invasive home monitoring of biovital parameters in RTT. Moreover, for the first time, HRmax% and the HR/LF ratio were identified as potential objective markers of fatigue, illness severity, and disease progression.
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OBJECTIVE: To assess seizure and developmental outcomes, their predictors, and complications in 160 children who, between 1998 and 2022, underwent surgery for lesional epilepsy with curative intent before the age of 3 years. To compare trends in epilepsy surgery in this age group before and after the year 2014. METHODS: Retrospective multicenter study. Descriptive and univariate analyses, and multivariable models for all outcomes. RESULTS: These 160 patients (76 F; 47.5%) underwent 169 surgeries (age at surgery 20.4 ± 9.4 months). At the last follow-up (77 ± 57.4 months), 121 patients (75.6%) were in Engel class I, 106 (66.2%) of whom were in Engel class Ia. Antiseizure medications were stopped in 84 patients (52.5%). Complications requiring reoperations were observed in 16 patients (10%; 9.5% of surgeries) and unexpected permanent deficits in 12 (7.5%; 7.1% of surgeries). Postoperative cognitive functions remained unchanged in 56 patients (44.4%), improved in 51 (40.5%), and worsened in 19 (15.1%). Multivariable analyses showed that the probability of achieving Engel class Ia was lower when the duration of epilepsy was longer, patients underwent preoperative video-EEG, and unexpected postoperative permanent deficits occurred. Cognitive improvement after surgery was associated with lower preoperative seizure frequency, better preoperative developmental level, and a longer postoperative follow-up. FCDII and tumors were the histopathologies carrying a higher probability of achieving seizure freedom, while polymicrogyria was associated with a lower probability of cognitive improvement. The number of patients operated on after 2014 was higher than before (61.3% vs. 38.7%), with stable outcomes. SIGNIFICANCE: Epilepsy surgery is effective and safe in infants and toddlers, although the complication rate is higher than seen in older patients. Shorter duration of epilepsy, lower seizure frequency, no need for video-EEG, tumors, and some malformations of cortical development are robust predictors of seizure and cognitive outcome that may be exploited to increase earlier referral. PLAIN LANGUAGE SUMMARY: This study analyzed the results of epilepsy surgery in 160 children who had been operated on before the age of 3 years at four Italian centers between 1998 and 2022. At the last follow-up (77 ± 57.4 months), 121 patients (75.6%) were free from disabling seizures, of which 106 (66.2%) were completely seizure-free since surgery. Major surgical complications occurred in 28 patients (17.5%), which is higher than observed with epilepsy surgery in general, but similar to hemispheric/multilobar surgery. Postoperative cognitive function remained unchanged in 56 patients (44.4%), improved in 51 (40.5%), and worsened in 19 (15.1%). Epilepsy surgery is effective and safe in infants and toddlers.
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Epilepsia , Procedimientos Neuroquirúrgicos , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Lactante , Estudios Retrospectivos , Preescolar , Epilepsia/cirugía , Complicaciones Posoperatorias/epidemiología , Resultado del Tratamiento , Procedimientos Neuroquirúrgicos/efectos adversosRESUMEN
Importance: There are suggestions that school pressure may be stressful and a factor in child and adolescent mental health disturbances, but data about this association are scarce and inconclusive. Objective: To assess whether varying degrees of school interruption were associated with changes in emergency department (ED) psychiatric visits of children and adolescents before and after the COVID-19 outbreak. Design, Setting, and Participants: A cross-sectional observational study was conducted at 9 urban university hospitals in Italy. All ED visits from January 1, 2018, to December 31, 2021, for psychiatric reasons of patients younger than 18 years were examined for demographic characteristics and type of psychopathologic factors. Data analysis was conducted from July 1 to August 31, 2023. Exposure: The disruption in the usual succession of school and holiday periods brought on by the COVID-19 pandemic at different times and with various degrees of intensity. Main Outcomes and Measures: Total number of pediatric ED visits, psychiatric ED visits, and psychiatric ED visits categorized by specific reasons (eg, psychomotor agitation, suicide ideation [SI] or suicide attempt [SA], and eating disorders) on a weekly basis. Results: A total of 13â¯014 psychiatric ED visits (1.3% of all pediatric ED visits) were recorded (63.2% females; mean [SD] age, 13.8 [3.8] years). The number of ED psychiatric visits increased over time (incidence rate ratio [IRR], 1.19; 95% CI, 1.16-1.22 for each year). Significant increases in ED visits were observed for eating disorders (294.8%), SI (297.8%), and SA (249.1%). School opening, but not social lockdown restriction, was associated with an increase in the number of ED psychiatric visits (IRR, 1.29; 95% CI, 1.23-1.34), which was evident for females and for SI with SA. Socioeconomic status was associated with an increase in psychiatric visits for males (IRR, 1.12; 95% CI, 1.04-1.20) but not females (IRR, 1.04; 95% CI, 0.98-1.10). Conclusions and Relevance: In this study, school opening was associated with an increased incidence of acute psychiatric emergencies among children and adolescents, suggesting that school can be a substantial source of stress with acute mental health implications.
Asunto(s)
COVID-19 , Servicio de Urgencia en Hospital , Instituciones Académicas , Humanos , COVID-19/epidemiología , COVID-19/psicología , Femenino , Masculino , Niño , Adolescente , Estudios Transversales , Italia/epidemiología , Servicio de Urgencia en Hospital/estadística & datos numéricos , Salud Mental/estadística & datos numéricos , Trastornos Mentales/epidemiología , SARS-CoV-2 , Pandemias , Ideación SuicidaRESUMEN
OBJECTIVE: To investigate the Italian experience on the surgical and radiosurgical treatment of drug-resistant epilepsy due to hypothalamic hamartoma (HH) in the period 2011-2021 in six Italian epilepsy surgery centers, and to compare safety and efficacy profiles of the different techniques. METHODS: We collected pseudo-anonymized patient's data with at least 12 months of follow-up. Surgical outcome was defined according to Engel classification of seizure outcome. Univariate analysis was performed to assess the risk of post-operative seizures, categorized in dichotomous variable as favorable and unfavorable; explanatory variables were considered. Mann-Whitney or Chi-squared test were used to assess the presence of an association between variables (p < 0.05). RESULTS: Full presurgical and postoperative data about 42 patients from 6 epilepsy surgery centers were gathered. Engel class I was reached in the 65.8% and 66.6% of patients with gelastic and non-gelastic seizures, respectively. Other than daily non-gelastic seizures were associated with seizure freedom (p = 0.01), and the radiological type presented a trend toward significance (p = 0.12). SIGNIFICANCE: Endoscopic disconnection and laser interstitial thermal therapy are effective in the treatment of HH-related epilepsy, with a tolerable safety profile. Both gelastic and non-gelastic seizures can be treated, also in patients with a long history of seizures. PLAIN LANGUAGE SUMMARY: This study collected data about 42 patients with HH-related epilepsies. Endoscopic disconnection and laser therapy are both effective and safe in the treatment of hypothalamic hamartoma-related epilepsies.