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Abstract Attention-Deficit/Hyperactivity Disorder is not a single pathophysiological entity and appears to have a complex etiology. There are multiple genetic and environmental risk factors with small individual effect that act in concert to create a spectrum of neurobiological liability. Structural imaging studies show that brains of children with Attention-Deficit/Hyperactivity Disorder are significantly smaller than unaffected controls. The prefrontal cortex, basal ganglia and cerebellum are differentially affected and evidence indicating reduced connectivity in white matter tracts in key brain areas is emerging. Genetic, pharmacological, imaging, and animal models highlight the important role of dopamine dysregulation in the neurobiology of Attention-Deficit/Hyperactivity Disorder. To date, stimulants are the most effective psychopharmacological treatments available for Attention-Deficit/Hyperactivity Disorder. Currently only immediate release methylphenidate and atomoxetine are approved for the treatment of ADHD in Italy. Drug treatment should always be part of a comprehensive plan that includes psychosocial, behavioural and educational advice and interventions.

Study Objectives: Sleep disorders are a frequent comorbidity among children with autism spectrum disorder (ASD). Among sleep-related issues of ASD, restless sleep is a common complaint. In recent years, restless sleep disorder (RSD) has been proposed as a new clinical entity, characterized by agitated sleep as its predominant manifestation. Despite the high prevalence of sleep disorders and data reporting restless sleep among ASD patients, to date no study has yet characterized RSD within patients with ASD. Therefore, the aim of our study was to assess the occurrence of RSD in a sample of children and adolescents with ASD through clinical and polysomnographic assessment., Methods: Children and adolescents with ASD ages 6-18 years were recruited for the study. Through parental interviews, patients with a suspected RSD were selected and offered diagnostic investigation by video-polysomnography and blood tests to assess martial balance., Results: Among the 129 participants included, 16 patients (12.4%) were found to have a suspected RSD. Only 6 (4.7%) underwent video-polysomnography due to lack of compliance or family refusal. In 6/6 participants examined, the disorder was confirmed by video-polysomnography movement analysis (total movement index ≥ 5 events/h) and ferritin values were found in the normal range., Conclusions: RSD does not appear to be particularly frequent among patients with ASD and that of iron metabolism may not be the main factor implicated in the pathogenesis of RSD within this population. Additional evaluation is needed to confirm the result and further investigate the etiological mechanisms underlying the disorder., Citation: Voci A, Mazzone L, De Stefano D, Valeriani M, Bruni O, Moavero R. Restless sleep disorder in a sample of children and adolescents with autism spectrum disorder: preliminary results from a case series. J Clin Sleep Med . 2024;20(3):427-432., (© 2024 American Academy of Sleep Medicine.)

Background: Sotos syndrome (SoS) is a rare overgrowth genetic disease caused by intragenic mutations or microdeletions of the NSD1 gene located on chromosome 5q35. SoS population might present cognitive impairment and a spectrum of behavioral characteristics, with a worse profile in patients with microdeletion. Although patients with SoS are known to have impaired sleep habits, very little data are available. The present study aimed to assess the prevalence of sleep disorders (SDs) in a pediatric cohort of patients with SoS and their correlation with neuropsychiatric profiles., Methods: We included patients with a SoS diagnosis and age < 18 years; all patients underwent a comprehensive neuropsychological assessment, including evaluation of cognition, adaptive functions through the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and behavioral problems using the Achenbach Child Behavior Checklist (CBCL) and Conners' Parent Rating Scale-Revised (CPRS-R:L) questionnaire. To investigate the presence of SD parents, the Sleep Disturbance Scale for Children (SDSC) was completed., Results: Thirty-eight patients (M 61%, F 39%, mean age 11.1 ± 4.65 years) were included in the study. Although only two had a prior SD diagnosis, 71.1% (N = 27) exhibited pathological scores on SDSC. No statistically significant associations were found between positive SDSC results and genetic microdeletion, intellectual disability (ID), or other medical conditions/treatments. However, a positive correlation emerged between SDSC scores and Conners' Global Index ( p  = 0.048) and Restless/Impulsive ( p  = 0.01) scores, CBCL externalizing ( p  = 0.02), internalizing (p = 0.01), and total scores ( p  = 0.05). Conversely, a negative linear relationship was observed between the SDSC score and the ABAS GAC and ABAS CAD scores ( p  = 0.025)., Conclusion: We detected an SD in 71.1% of our sample, with a positive relation between SD and internalizing and externalizing symptom levels, especially hyperactivity and impulsivity. Our study demonstrated a high prevalence of SD in pediatric patients with SoS, highlighting that all patients should be screened for this problem, which has a great impact on the quality of life of patients and their families., Competing Interests: The 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., (Copyright © 2024 Frattale, Sarnataro, Siracusano, Riccioni, Galasso, Valeriani, Conteduca, Coviello, Mazzone and Moavero.)

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC., (© 2023. The Author(s).)

Background: COVID-19 pandemic has drastically increased the exposure to electronic devices in children, influencing their lifestyle and their sleep. This study was conducted to explore the relationship between the augmented screen exposure and sleep habits in children during and after the pandemic., Methods: Using the "Google Forms" tool, we created an online questionnaire addressed to parents of children and adolescents aged 2-18 years. We explored the use of screens before and during/after the lockdown and assessed the presence of sleep disturbances through the Sleep Disturbance Scale for Children (SDSC), referring to the period before and during/after COVID-19 pandemic., Results: We collected 1084 valid questionnaires (median age 8.5 ± 4.1 years). We observed a significant increase in screens exposure for school (72%) and for leisure (49.7%) during the pandemic. We reported an increased sleep disturbances prevalence from 22.1% before the pandemic to 33.9% during the outbreak (p < 0.001). Even before the pandemic, the highest risks for sleep disorders were related to daily screen time for school reasons (OR 1.65, p < 0.001) and total screen time after 6 p.m. (OR 1.59, p < 0.001). The augmented exposure to screens for any reasons during the pandemic was significantly related to an increase of sleep disorders, especially regarding the increased exposure after 6 p.m. (OR 1.67, p < 0.001)., Conclusions: The augmented use of electronic devices was recognized to be a significant predisposing factor in increasing the rate of sleep disorders during and after the pandemic, thus sleep hygiene recommendations should be highlighted to improve sleep habits., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Literature data report that the first COVID-19 pandemic had an impact on the progression of migraine both in adults and children. The present study aimed to verify how the migraine course and psychological aspects varied in adolescent patients in relation to some of the different phases of the COVID-19 pandemic and compared with the months before COVID-19. In addition, the relationship between the characteristics of headache episodes and psychological and school-related aspects were analyzed., Methods: The study included 418 adolescents. Based on the timing of the evaluation, they were categorized into patients observed before the COVID-19 pandemic (pre COVID) or during the first (COVID 1) or second (COVID 2) wave of the pandemic. Subjects were also categorized into three further groups: those who had high or low frequency of migraine attacks during the month, those who had mild or severe pain during the attack, and those who were taking prophylactic drugs. The Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) scales were utilized to assess depression and anxiety., Results: We observed a significant increase in the frequency of attacks and the use of prophylactic drugs during the COVID 2 period compared to the COVID 1 and pre-COVID periods ( p < 0.05). Patients showed higher levels of anxiety and depression during each of the two COVID periods compared with the pre-COVID months ( p < 0.05), especially during the COVID 2 period ( p < 0.05)., Conclusion: Our results show long-term negative impacts of the COVID-19 pandemic on clinical parameters and psychological symptoms in adolescents with migraine.

Introduction: Concern of a correlation between disease relapse in patients with acquired demyelinating disorders of central nervous system (CNS) and SARS-CoV2 vaccines has been raised. In this single center study, we retrospectively evaluated safety of SARS-CoV2 vaccination and COVID-19 short-term outcome in pediatric acquired demyelinating disorders of CNS., Materials and Methods: Patients with multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) with disease onset before 18 years of age were included. Demographic and clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected., Results: We included nine patients with MOGAD. Six patients received SARS-CoV2 vaccination and complained pain at injection site while only one had fever and fatigue. Median follow-up was 28 weeks (range 20-48). Seven patients had COVID-19 occurring with mild flu-like symptoms and median follow-up was 28 weeks (range 24-34). Nobody had disease relapse. Five patients with NMOSD were included. All patients received SARS-CoV2 vaccination (BNT162b2-Pfizer-BioNTech). The median follow-up was 20 weeks (range 14-24) and only two patients complained pain at injection site, fever and fatigue. Three patients had also COVID-19 with mild flu-like symptoms, despite two of them being under immunosuppressive treatment. Lastly, forty-three patients with MS were included. 35 out of 43 received SARS-CoV2 vaccination with a median follow-up of 24 weeks (range 8-36). Fourteen patients had no side effects, while 21 complained mild side effects (mainly pain at injection site) and one experienced a disease relapse with complete recovery after steroid therapy. At vaccination, all but one were under treatment. Sixteen patients had COVID-19 occurring with mild symptoms., Discussion: COVID-19 outcome was good although many patients were under immunosuppressive treatment. Vaccine-related side effects were frequent but were mild and self-limited. Only one MS patient had a post-vaccination relapse with complete recovery after steroid therapy. In conclusion, our data support the safety of SARS-CoV-2 vaccines in pediatric MS, MOGAD and NMOSD., Competing Interests: The 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 handling editor DL declared a shared parent affiliation with some of the authors RM, PP at the time of review., (Copyright © 2023 Monte, Papetti, Ferilli, Ursitti, Moavero, Sforza, Panella, Tarantino, Checchi, Vigevano, Palma and Valeriani.)

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

In 2018, the Food and Drug Administration (FDA) approval of anti-calcitonin gene-related peptide (CGRP) therapies for the treatment of migraine represented a milestone for the management of the disease in adults. On the contrary, the novelties in the field of pediatric migraine are inserted in a different scenario and still concern: (1) diagnostic criteria of the international classification of headache disorders-3 (ICHD-3) that show numerous limits of applicability in the developmental age; (2) the release of the results of the Childhood and Adolescent Migraine Prevention (CHAMP) study that raised doubts about the usefulness of traditional drugs for the treatment of pediatric migraine; (3) the Coronavirus disease 2019 (COVID-19) pandemic has put the spotlight on the importance of managing the psychological factors associated with the disease. In this mini review we discuss the most relevant news in pediatric migraine over the last 5 years., Competing Interests: The 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., (Copyright © 2022 Papetti, Tarantino, Ursitti, Moavero, Proietti, Sforza, Monte, Ferilli, Balestri, Vigevano and Valeriani.)

Primary headache is a very common and disabling disease. The burden of pain and recurrent attacks may lead to a poor quality of life, anxiety and depression. An increased risk of low functioning and curricular performances in young patients with primary headache has been described. The mechanisms underlying the relationship between migraine and poor school achievement may be various and could be a reflection of weak cognitive skills. Data concerning the cognitive functioning in the free pain interval in pediatric age are under-investigated and results are far from conclusive. The present review article suggests that, though considered a benign disease, pediatric migraine may be associated to altered neuropsychological functioning in the interictal phase. Although children and adolescents with migraine generally have a normal intelligence, they may show a not homogeneous cognitive profile, characterized by possible difficulties in verbal skills, in particular comprehension abilities. Pediatric primary headache may present altered neuropsychological functioning involving attentional resources, processing speed and memory, particularly verbal memory. Given the impact that this disease can have on school performance and the tendency to persist from childhood to adulthood, a cognitive screening in young patients affected by primary headache is pivotal. Additional neuropsychological research using more homogenous methods is needed., Competing Interests: The 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., (Copyright © 2022 Tarantino, Proietti Checchi, Papetti, Ursitti, Sforza, Ferilli, Moavero, Monte, Capitello, Vigevano and Valeriani.)

Tuberous sclerosis complex (TSC) is a genetic multisystem disease due to the mutation in one of the two genes TSC1 and TSC2, affecting several organs and systems and carrying a significant risk of early onset and refractory seizures. The pathogenesis of this complex disorder is now well known, with most of TSC-related manifestations being a consequence of the overactivation of the mammalian Target of Rapamycin (mTOR) complex. The discovery of this underlying mechanism paved the way for the use of a class of drugs called mTOR inhibitors including rapamycin and everolimus and specifically targeting this pathway. Rapamycin has been widely used in different animal models of TSC-related epilepsy and proved to be able not only to suppress seizures but also to prevent the development of epilepsy, thus demonstrating an antiepileptogenic potential. In some models, it also showed some benefit on neuropsychiatric manifestations associated with TSC. Everolimus has recently been approved by the US Food and Drug Administration and the European Medical Agency for the treatment of refractory seizures associated with TSC starting from the age of 2 years. It demonstrated a clear benefit when compared to placebo on reducing the frequency of different seizure types and exerting a higher effect in younger children. In conclusion, mTOR cascade can be a potentially major cause of TSC-associated epilepsy and neurodevelopmental disability, and additional research should investigate if early suppression of abnormal mTOR signal with mTOR inhibitors before seizure onset can be a more efficient approach and an effective antiepileptogenic and disease-modifying strategy in infants with TSC., 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 © 2020. Published by Elsevier Inc.)

Background and Objective: Tuberous Sclerosis Complex (TSC) is a rare systemic disease with a high prevalence of sleep disorders (SD), although they are still largely under-recognized. The objective of this study was to assess the prevalence of SD in adult patients with TSC, and to evaluate the relationship between sleep, epilepsy, and TSC associated neuropsychiatric disorders (TAND)., Materials and Methods: We administered Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) to 114 adult patients referring to different Italian centers. We also collected information on epilepsy and TAND., Results: PSQI, ISI, and ESS revealed a positive score, respectively, in 52 (46.0%), 30 (26.5%), and 16 (14.1%) patients. PSQI was positive in 26.7% of seizure free patients versus 61.9% with active epilepsy (p = 0.003), and the association remained significative applying a multivariate logistic model considering age, antiseizure medications, TAND and nocturnal epileptic seizures (p = 0.02). ISI was positive in 3.3% of seizure free patients versus 41.3% with active epilepsy (p = 0.0004). Applying a multivariate logistic model with the independent variables listed above, the association remained significant (p = 0.007). On the other hand, multivariate logistic model considering active epilepsy as an independent variable, revealed that TAND didn't appear a significant risk factor for positive PSQI (p = 0.43) nor ISI (p = 0.09)., Conclusions: Our results confirmed that SD are highly prevalent in adults with TSC, with active epilepsy acting as a significant risk factor. A careful assessment of sleep, above all in epileptic patients, is of crucial importance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The objective of this study is to present the rare case of a young girl with idiopathic intracranial hypertension secondary to hypoparathyroidism. Background: Idiopathic intracranial hypertension is a neurological syndrome characterized by elevated intracranial pressure (> 25 cmH 2 O) in the absence of intracerebral abnormalities or hydrocephalus. The pathophysiology of idiopathic intracranial hypertension is unknown, and rare cases of idiopathic intracranial hypertension secondary to hypoparathyroidism have been described. It is supposed that hypocalcemia causes decrease in the absorption of cerebrospinal fluid in arachnoidal granulations. Methods: The workup of the girl with idiopathic intracranial hypertension and hypoparathyroidism included physical examination, blood tests, diagnostic imaging, and lumbar puncture. Results: We present a 9-year-old female patient who was hospitalized for headache associated with nausea and vomiting for 3 weeks. She underwent an ophthalmologic examination that revealed papilledema. Lumbar puncture revealed an opening pressure of 65 cm H 2 O; cerebrospinal fluid analysis and brain computed tomography scan were normal. The patient started taking acetazolamide. Blood tests revealed hypocalcemia associated with high phosphorus level and undetectable PTH hormone, which led us to suspect hypoparathyroidism. She had never had cramps, paraesthesias, or tetany. Chvostek's and Trousseau's signs were positive. In the neck ultrasonography, parathyroids were not visible. Oral supplementation with calcitriol and calcium was started. Headache, nausea, and vomiting immediately disappeared after the lumbar puncture, and the papilledema improved gradually. Conclusions: Several anecdotal cases of idiopathic intracranial hypertension secondary to hypoparathyroidism have been described. However, our case report is of particular interest, since the child did not present with typical neurological hypoparathyroidism symptoms. Therefore, we recommend that hypoparathyroidism should be included in diagnostic investigations on children with clinical findings of idiopathic intracranial hypertension, because clinical manifestations of hypoparathyroidism are variable and may involve almost all organ systems., Competing Interests: The 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., (Copyright © 2022 Sforza, Deodati, Moavero, Papetti, Frattale, Vigevano, Cianfarani and Valeriani.)

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system (CNS) inflammatory demyelinating disease characterized by recurrent inflammatory events that primarily involve optic nerves and the spinal cord, but also affect other regions of the CNS, including hypothalamus, area postrema and periaqueductal gray matter. The aquaporin-4 antibody (AQP4-IgG) is specific for NMOSD. Recently, myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been found in a group of AQP4-IgG negative patients. NMOSD is rare among children and adolescents, but early diagnosis is important to start adequate therapy. In this report, we present cases of seven pediatric patients with NMOSD and we review the clinical and neuroimaging characteristics, diagnosis, and treatment of NMOSD in children.

Sleep disorders and primary headaches are frequent health problems in childhood, and they are often comorbid in an individual, linked by a mutual and complex relationship. This comorbidity is frequent and well-documented, but the available literature is usually biased in favor of one aspect or another, mainly depending on the expertise of the authors. The aim of this paper is to review existing literature on the diagnostic assessment of comorbid primary headaches and sleep disorders, so as to propose practical suggestions to accurately investigate the presence of comorbid conditions in children evaluated for primary headaches or for sleep disorders.

Migraine is the first in order of frequency of the neurological disorders, affecting both adult and paediatric populations. It is also the first cause of primary headaches in children. Migraine equivalents are periodic disorders that can be associated with migraine or considered as prognostic features of a future migraine manifestation. Despite the mechanisms underlying migraine and its equivalents are not entirely clear, several elements support the hypothesis of common pathophysiological patterns shared by these conditions. The aim of this review is thus to analyze the literature in order to highlight which currently known mechanisms may be common between migraine and its equivalents.

High Intellectual Potential (HIP) and High Functioning Autism (HFA) are two different conditions sharing some clinical and neurobiological features. The aim of the present study was to characterize a sample of HIP children (n: 16; M/F: 14/2; median age: 10 years) in comparison to those with HFA (n: 17; M/F: 16/1; median age: 13 years) and to neurotypically developed (NTD) children (n: 10; M/F: 4/6; median age: 11 years) from a clinical and neurophysiological perspective. Specifically, a standardized clinical assessment of cognitive and adaptive skills, autistic symptoms, executive functions and behavioral features was performed. Moreover, event-related potentials (ERPs) were recorded, referring specifically to the mismatch negativity (MMN) and P300 paradigm. Our data highlighted the presence of similarities between the intellectually gifted individuals and the ones with autism (i.e., a nonhomogeneous intellective profile, an adaptive skills impairment, subthreshold autistic symptoms and increased perfectionism). Interestingly, a distinct neurophysiological characterization between groups came out, with evidence of a reduced MMN amplitude only in the HFA group. Furthermore, no differences within groups in the P300 component emerged. Therefore, our results start to provide a more informative characterization of the HIP phenotype in comparison to those of HFA and NTD, highlighting the potential role of the MMN amplitude index in helping clinicians and researchers to distinguish between HIP and HFA. Nevertheless, further research on the topic is strongly needed.