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Transition from the paediatric holistic approach to the adult more individual care of epilepsy is a process that carries a high level of complexity and involves many actors. It is a mandatory step so to provide a gold-standard quality of care in young people with epilepsy. Its failure is strongly associated with a poor epilepsy, cognitive, and behavioural outcome. Although the interest of the scientific community on transition has increased, in the clinical practice it is still considered a sensitive issue, in particular for adult neurologists. In this study we aimed at exploring pitfalls and unmet needs of transition from the adult neurologists' perspective. A short survey, aimed to adult neurologists, was designed to explore i) whether transition is considered a problematic issue for the adult neurologist, ii) how transition impact his/her clinical practice, iii) which are the major problems related to the process, and iv) how transition may be improved. The results of the survey showed that transition is felt as a complex process that needs a shared action plan between child and adult neurologists, possibly with multidisciplinary team meetings as well as a higher training on childhood epilepsies for the adult neurologist., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Subclinical rhythmic electrographic discharge of adults (SREDA) is one of the rarest and most challenging non-epileptic electroencephalographic variants. Although the pathogenesis of this activity is unclear, an association with vascular insufficiency and cerebral hypoxia has been proposed. SREDA usually occurs in adulthood, but there are few reports in the pediatric population. We performed a systematic review of the literature, confirming the rarity of this condition in children, and added 5 more subjects. We report on a total of 16 children with SREDA. Sufficient data are available for 15 patients. The mean age at first detection of SREDA was 11.5 years. We observed that 67% (10/15) of the subjects had previous seizures: 80% (8/10) of them had an epilepsy diagnosis and 38% (3/8) had generalized epilepsy. Moreover, 8 of 13 subjects whose medical history was available (61%) had a neurodevelopmental disorder. From an electroencephalographic point of view, we noted a prevalence of bilateral SREDA with atypical localization and abrupt onset and end. Since SREDA can be incorrectly interpreted as an epileptic discharge, with possible therapeutic implications, it is important to consider its possible occurrence also in pediatric patients, perhaps more frequently in those with neurodevelopmental disorders., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Sleep problems are common in neurological conditions for which ketogenic dietary therapies (KDTs) are recognised as an effective intervention (drug-resistant epilepsy, autism spectrum disorder, and migraine). Given the composite framework of action of ketogenic dietary therapies, the prevalence of sleep disturbance, and the importance of sleep regulation, the present scoping review aimed at identifying and mapping available evidence of the effects of ketogenic dietary therapies on sleep. A comprehensive web-based literature search was performed retrieving publications published to June 2023 using PubMed and Scopus, yielding to 277 records. Twenty papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study design and sleep outcome evaluation among the selected studies. Several changes in sleep quality and sleep structure under ketogenic dietary therapies were found, namely an improvement of overall sleep quality, improvement in the difficulty falling asleep and nighttime awakenings, improvement in daytime sleepiness and an increase of REM sleep. The relevance and possible physiological explanations of these changes, clinical recommendations, and future directions in the field are discussed., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

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 13 014 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.

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., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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., Competing Interests: Declaration of competing interest Oliviero Bruni is consultant for Neurim and FIDIA. Other authors certify that there is no actual or potential conflict of interest in regards to the present article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024. The Author(s).)

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 χ 2 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., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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 [P H2O (pt)] and carbon dioxide [P CO2 (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., Competing Interests: The co-author AmB is an advisor of Accyourate Group SpA, a sponsor of the research. PM was employed by Croce Rossa Italiana. AlB was employed by Italian Color Solutions I.C.S. S.r.l. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Leoncini, Boasiako, Di Lucia, Beker, Scandurra, Vignoli, Canevini, Prato, Nobili, Nicotera, Di Rosa, Chiarini, Cutrera, Grosso, Lazzeri, Tongiorgi, Morano, Botteghi, Barducci and De Felice.)

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., (© 2024 European Sleep Research Society.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Insomnia is the most reported sleep disorder in industrialized countries, affecting, in the chronic form, around 10% of the European population. In Italy, such a percentage seems to be even higher. Although insomnia can be an independent disorder, it is frequently described as comorbid condition and may precipitate, exacerbate, or prolong a broad range of physical and mental disorders. Evaluating and targeting insomnia in the Italian clinical practice should be a priority., Methods: The present expert opinions and recommendations represent an update from 2020 and insights from Insomnia Expert Consensus Group, based on systematic reviews according to PRISMA on available options in Italy from January 2020 to March 2023., Results: We evaluated 28 papers among international guidelines, expert opinions, systematic reviews, and meta-analysis produced during the last 26 months., Conclusions: Our findings suggest that symptoms of insomnia must be assessed in the Italian clinical practice by evaluating nocturnal and daytime symptoms, comorbid conditions, and lifestyle. Cognitive behavioral therapy for insomnia should be the first option according to availability. The choice of the drug should be based on different factors including type of insomnia, age, comorbidities, and potential side effects. If the choice would be a Z-drug or a short-acting benzodiazepine (in subjects < 65 years old), the use should be in the short term (≤ 4 weeks). Indeed, eszopiclone, as a new option in Italy, may present a different profile and may be used for up to 6 months, also in the elderly. If the choice is melatonin, it should be used melatonin 2 mg prolonged release in adults ≥ 55 years for up to 13 weeks. A new dual orexin antagonist, daridorexant, is available in Italy; it has been shown to be effective in adults and elderly and it can be used for at least 3 months and up to 1 year., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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 ˂ 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.

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., (© 2024. The Author(s).)

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.

Background: During the last decades, severe brain lesions affecting very low birth weight (<1500 gr, VLBW) infants were gradually substituted by milder lesions with debatable prognoses., Objective: The objective of this study is to define type, frequency and 3 years of neurodevelopmental outcome of prematurity-related brain lesions in a modern cohort of VLBW infants., Methods: VLBW infants admitted to our NICU in 5 years period with brain MRI at term-equivalent age were included. MRI scans were reviewed to identify and grade white matter lesions (WML), intraventricular hemorrhage (IVH), and cerebellar hemorrhage (CBH). Linear measurements of brain size, biparietal width (BPW) and trans-cerebellar diameter (TCD) were carried out. Total maturation score (TMS) was calculated. Developmental Coefficients (DQ) on Griffiths Scale at 3 years of age were compared between patients with different types and grades of lesions and patients without lesions; possible correlations between linear brain measurements, brain maturation and outcome were explored., Results: Study included 407 patients. Of them, 187 (46%) had at least one brain lesion on MRI, while 37 (9%) had severe lesions. The most frequent lesion was IVH (28%), followed by WML (21%) and CBH (17%). Mild and severe IVH, moderate and severe WML and all grades of CBH were related to worst outcome at 3 years. In patients without lesions, small BPW and small TCD were associated with worse outcomes. No correlations were observed between TMS and outcome., Conclusion: We have observed that even mild brain lesions have a negative influence on neurological outcome at 3 years of age., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene ( EHMT1 , *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking. The purpose of this study is to investigate epilepsy features in a cohort of epileptic patients with KS., Methods: This multicenter study investigated eight patients with KS and epilepsy. Our findings were compared with literature data., Results: We included five patients with 9q or 9q34.33 deletions, a subject with a complex translocation involving EHMT1 , and two with pathogenic EHMT1 variants. All patients presented with moderate to severe developmental delay, language impairment, microcephaly, and infantile hypotonia. Although the epileptic manifestations were heterogeneous, most patients experienced focal seizures. The seizure frequency differs according to the age of epilepsy onset, with patients with early-onset epilepsy (before 36 months of age) presenting more frequent seizures. An overtime reduction in seizure frequency, as well as in antiseizure drug number, was observed in all patients. Developmental delay degree did not correlate with seizure onset and frequency or drug resistance., Conclusion: Epilepsy is a frequent finding in KS, but the underlying pathogenetic mechanism and specific features remain elusive., Competing Interests: None declared., (Thieme. All rights reserved.)

The MYT1L gene plays a critical role in brain development, promoting the differentiation and proliferation of cells, important for the formation of brain connections. MYT1L is also involved in regulating the development of the hypothalamus, which is a crucial actor in weight regulation. Genetic variants in the MYT1L are associated with a range of developmental disorders, including intellectual disability, autism spectrum disorder, facial dysmorphisms, and epilepsy. The specific role of MYT1L in epilepsy remains elusive and no patients with developmental and epileptic encephalopathy (DEE) have been described so far. In this study, we report a patient with DEE presenting with severe refractory epilepsy, obesity, and behavioral abnormalities. Exome sequencing led to the identification of the heterozygous variant NM&#95;001303052.2: c.1717G>A, p.(Gly573Arg) (chr2-1910340-C-T; GRCh38.p14) in the MYT1L gene. This variant was found to be inherited by the father, who was a mosaic and did not suffer from any neuropsychiatric disorders. Our observations expand the molecular and phenotype spectrum of MYT1L-related disorders, suggesting that affected individuals may present with severe epileptic phenotype leading to neurocognitive deterioration. Furthermore, we show that mosaic parents may not display the disease phenotype, with relevant implications for genetic counseling., (© 2023 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The occurrence of combined central and peripheral demyelination (CCPD) is rare, data are limited to small case and cohort studies, mainly concerning adults. In few patients positivity to anti MOG antibody is reported, thus widening the spectrum of anti-MOG associated disorders (MOGAD). We describe a 7-year-old girl with optic neuritis followed 8 years later by peripheral demyelination, with fluctuating anti-MOG antibody positivity at cell-based assay. From the review of the literature, MOGAD-CCPD appear very rare in childhood, especially with asynchronous course. Clinicians should keep this possibility in mind to better define diagnosis in atypical demyelination syndromes, with therapeutical implications., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 Elsevier B.V. All rights reserved.)