Low-grade epilepsy-associated tumors: Epilepsy outcome and antiseizure medication discontinuation after lesionectomies as first-line surgical approach in pediatric population.

OBJECTIVE: This study aimed to evaluate epilepsy outcome and antiseizure medication (ASM) discontinuation after lesionectomies as first surgical approach in pediatric population diagnosed with low-grade epilepsy-associated neuroepithelial tumors (LEATs). METHODS: We conducted a retrospective study. Thirty-six consecutive patients with histological diagnoses of LEATs who underwent surgery between 2018 and 2021 at our institution were included. The clinical and surgical data were retrospectively analyzed. RESULTS: Thirty (83.3%) of 36 patients are free of disabling seizures (Engel class I) and 19 (63,4%) of them are classified as Engel Ia. In 17 (47.2%) patients, ASM could be discontinued. The mean age at surgery was 8.6 years (±4.04) and the mean age at onset of epilepsy was 7.2 years (±3.8), whereas the mean duration of epilepsy in months at the time of surgery was 21.3 months (±23.7). The epileptogenic tumor was in the temporal lobe in 20 (55.5%) patients. Because of seizure persistence, a second or a third surgery was necessary for six patients (16.7%) and four of them had residual lesions (three in temporal and one in extratemporal site). No perioperative complications were recorded, including acute seizures, with a median hospitalization time of 7 days. Shorter epilepsy duration at time of surgery as long as a single ASM was significantly correlated with an Engel class I outcome (p-value = .01 and p-value = .016, respectively). Focal seizure semeiology was associated with an increased probability of antiseizure medication discontinuation (p-value = .042). SIGNIFICANCE: Our findings confirm that shorter epilepsy disease duration, monotherapy before surgery, and seizure semeiology are determinant factors for a positive seizure outcome and medication discontinuation, also with less invasive surgical approaches such as lesionectomies. However, considering the intrinsic multifactorial epileptogenic nature of LEATs, a tailored surgical approach should be considered to optimize clinical and seizure outcome, especially for lesions located in the temporal lobe.

X-Linked Epilepsies: A Narrative Review.

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype-phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

Immediate and progressive neurological damage after electrical injury: A pediatric case report.

BACKGROUND: An electrical injury can cause multiple consequences, especially to the nervous system, both peripheral and central. Such consequences may present immediately as well as later on. AIMS OF THE STUDY: To report on a case of a 5-year-old boy with focal refractory status epilepticus after an electrical injury. METHODS: Clinical history, electroencephalography, neuroimaging, and laboratory data of a patient admitted to our emergency department. RESULTS: A 5-year-old male received an electrical shock by contact with an alternating current source after coming out of the pool. When reaching our emergency department, focal seizures was observed in the same site affected by the electrical insult, with progressive structural changes in the related brain area. In the days after, his neurological conditions dramatically evolved leading to brain death. CONCLUSIONS: Based on our knowledge, this is the first report on refractory status epilepticus in a child after electrical injury. The possible underlying pathogenetic mechanisms are not yet clear.

Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review.

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118-4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

The Relation of Callous-Unemotional Traits and Bullying in Early Adolescence Is Independent from Sex and Age and Moderated by Conduct Problems.

In youths, callous-unemotional (CU) traits and conduct problems (CP) are independently associated with bullying perpetration and these effects are also observed when controlling for sex. Moreover, research indicates that the co-existence of high levels of both CU and CP further increase the risk. Although several studies have examined the relationship between CU traits and traditional bullying, few have also included a measure of cyberbullying and very few of them have focused the early adolescence. The aim of this study was to replicate and extend these findings in a large sample of Italian early adolescents considering both traditional and cyberbullying behaviors. Data were extracted from the Bullying and Youth Mental Health Naples study (BYMHNS) which included 2959 students of 10-15 years of age. CP, CU traits, traditional bullying behaviors, and cyberbullying behaviors were assessed by multi-item self-report scales. As expected, we replicated the significant and specific association between CU traits and traditional bullying, extending the findings to cyberbullying. In addition, in the latter case the effect was moderated by CP. The theoretical and clinical implications of these results were discussed.

Neuroendoscopic treatment of symptomatic cyst of the septum pellucidum in children: A case series.

BACKGROUND: Symptomatic cysts of the septum pellucidum (CSP) are extremely rare in children and surgical indications are not well defined. A very careful clinical and neuroradiologic evaluation is necessary to consider a patient for surgical indication. METHODS: We present a surgical series of 7 pediatric patients. Clinical and radiological features of the patients, including clinical presentation, previous treatment, pre, and post-operative MRI, immediate postoperative, neuropsychiatric assessment, and outcomes were reviewed. RESULTS: There were 5 males and 2 females (mean age 8 yrs). Five patients presented a history of severe intermittent headaches, two of them were admitted with acute symptoms of raised intracranial pressure. One patient presented Epilepsy and ADHD and one patient had severe psychosis. Overall, psychiatric disorders were diagnosed in six patients, three patients had Intellectual Disability (ID). In all cases, the cyst presented a ballooning feature, with a mean volume of 18,36 cm3 (range 10,62-28,5) and significant lateral bulging of both layers. All were operated on endoscopically without complications. After surgery, a very significant decrease in cyst volume was observed (mean volume 5,68 cm3; range 3,18-10,1) with complete disappearance of the ballooning aspect. Headaches resolved in all patients. In two patients operated in emergency papilloedema and vision improved in the first week after surgery. No recurrence of the cysts was noted during follow-up in all patients. CONCLUSIONS: CSP may be associated with behavioral or psychiatric problems also in children. Neuroendoscopic surgery is a safe and effective therapeutic modality to treat CSP presenting with symptoms and signs of intracranial hypertension with good clinical results.

Temporal lobe malformations, focal epilepsy, and FGFR3 mutations: a non-causal association?

Temporal lobe abnormalities and focal epilepsy have been documented in FGFR3-related clinical condition, including hypochondroplasia and Muenke syndrome. FGFR3 is expressed in the brain during development and could play a role in nervous system development and hippocampal formation. These observations suggest a non-casual association between temporal malformation, epilepsy, and FGFR3 mutations. Herein, we report clinical, electroclinical, and neuroimaging findings of three additional cases of focal epilepsy and temporal lobe malformations occurring in children with FGFR3 gene mutations.

Aripiprazole-Induced Oculogyric Crisis: A Pediatric Case Series and A Brief Narrative Review.

Oculogyric crisis (OGC) represent an unusual type of dystonic movement disorder, usually reported as an adverse event of antipsychotic drugs, with acute or tardive onset, likely due to a functional disruption of dopaminergic neurotransmission. It is seldom reported in children with aripiprazole, an atypical antipsychotic commonly used in youths. In this manuscript, we report on a case series of three pediatric patients and provide a brief narrative review of the literature, in order to increase the awareness of clinicians and to foster future research in this area.

Vitamin D deficiency is not related to eating habits in children with Autistic Spectrum Disorder.

BACKGROUND AND AIMS: Autism Spectrum Disorder (ASD) is characterized by the impairment of communication and social interaction and by repetitive, restricted and stereotyped interests. ASD is often accompanied by comorbidities; eating disorders are frequent and imply important nutritional deficits (i.e. deficiencies of vitamins, minerals and fatty acids). Vitamin D has a critical role in neurodevelopment and serum levels in ASD are reported inadequate. A useful reference for setting up a correct diet in childhood is the food pyramid, which is inspired by the Mediterranean Diet (MD). The MD guarantees an intake of nutrients, considered optimal to maintain an adequate nutritional status. The aim of this study is to explore serum levels of Vitamin D and food habits (through MD adherence) in a sample of children with ASD and evaluate a possible correlation between these factors. METHODS: study participants include 91 children 47 presenting ASD and 44 healthy typically-developing (TD) subjects, as control group. We evaluated serum level of Vitamin D in both group; anthropometric parameters (weight, height, body mass index-BMI-and growth percentile) and MD adherence have been explored, in order to investigate the correlation among those data and level of Vitamin D in children with ASD. Lastly, the association between Vitamin D levels and severity of ASD symptoms has been analysed. RESULTS AND CONCLUSION: 74% of ASD group presented blood levels of Vitamin D under 30 ng/ml (normal range 30-100 ng/ml). The analysis performed showed that the two groups were significant different regards Vitamin D levels (t = 2.24, p < 0.05), according to literature. 31.9% of children with ASD presented a condition of overweight and 12.6% a condition of obesity. Adherence to the MD was low in 25.5% of cases. No significant statistical correlation has been found between Vitamin D serum levels, anthropometric parameters and the adherence to MD in the ASD group.

Neuronal Avalanches to Study the Coordination of Large-Scale Brain Activity: Application to Rett Syndrome.

Many complex systems, such as the brain, display large-scale coordinated interactions that create ordered patterns. Classically, such patterns have been studied using the framework of criticality, i.e., at a transition point between two qualitatively distinct patterns. This kind of system is generally characterized by a scale-invariant organization, in space and time, optimally described by a power-law distribution whose slope is quantified by an exponent α. The dynamics of these systems is characterized by alternating periods of activations, called avalanches, with quiescent periods. To maximize its efficiency, the system must find a trade-off between its stability and ease of propagation of activation, which is achieved by a branching process. It is quantified by a branching parameter σ defined as the average ratio between the number of activations in consecutive time bins. The brain is itself a complex system and its activity can be described as a series of neuronal avalanches. It is known that critical aspects of brain dynamics are modeled with a branching parameter σ = , and the neuronal avalanches distribution fits well with a power law distribution exponent α = -3/2. The aim of our work was to study a self-organized criticality system in which there was a change in neuronal circuits due to genetic causes. To this end, we have compared the characteristics of neuronal avalanches in a group of 10 patients affected by Rett syndrome, during an open-eye resting-state condition estimated using magnetoencephalography, with respect to 10 healthy subjects. The analysis was performed both in broadband and in the five canonical frequency bands. We found, for both groups, a branching parameter close to 1. In this critical condition, Rett patients show a lower distribution parameter α in the delta and broadband. These results suggest that the large-scale coordination of activity occurs to a lesser extent in RTT patients.

A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report.

BACKGROUND: Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson's disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype. CASE PRESENTATION: Here we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features but not the severe ID, behavioral problems, and aggressiveness. Family history suggested an X-linked condition and massively parallel sequencing of X-exome identified a novel RAB39B mutation (NM_171998.2:c.436_447del) in proband, his mother, and affected maternal uncle, subsequently validated by Sanger sequencing in these and other family members. CONCLUSIONS: The case presented here highlights how concurrent genetic defects should be considered in NF1 patients when NF1 mutations cannot reasonably explain all the observed clinical features.

Intrafamilial variability in SPTAN1-related disorder: From benign convulsions with mild gastroenteritis to developmental encephalopathy.

Mutations in SPTAN1 gene are responsible for a wide spectrum of neurodevelopmental disorders including early-onset epileptic encephalopathy with progressive brain atrophy, severe intellectual disability with cerebellar malformations, and relatively milder phenotypes with or without epilepsy. Herein, we report three affected individuals including two siblings of 13 and 8 years and their 39-year-old mother, carrying a novel pathogenic variant in SPTAN1 gene. The phenotype of the index cases and their mother was remarkable for the variable expressivity, including benign convulsions with mild gastroenteritis, intellectual disability and developmental encephalopathy with epilepsy. Our clinical observation suggests for the first time that variants in SPTAN1 gene might be involved in the aetiology of benign convulsions correlated with mild gastroenteritis.

Epilepsy in NF1: a systematic review of the literature.

Epilepsy is one of the possible neurological manifestations of the neurofibromatosis type 1 (NF1) that represents the most common neurocutaneous disorder. We performed a systematic review of the literature on epilepsy associated with NF1 since 1995 in order to better define prevalence and describe type and causes of seizures. Data on type, nature of studies, number of patients, gender, and inheritance of NF1 were recorded as well as data on causes, type, EEGs, brain imaging, intellectual disability (ID), surgical treatment, and outcome of epilepsy. We identified a total of 141 references through the literature search of Pubmed and Embase. After screening, 42 records were identified, including 11617 individuals with NF1 (53% of males). Overall prevalence was estimated at 5.4% lifelong with values that seemed to be slightly lower in children, 3.7% (p 0.0016). Neither gender differences nor correlation with NF1 inheritance was found. Focal with or without bilateral tonic-clonic seizures were the most common seizure type encountered (60.9%). Structural causes were identified in half of cases (114/226). Low-grade gliomas were the most frequent associated lesions followed by mesial temporal sclerosis, malformation of cortical development, dysembryoplastic neuroepithelial tumor, and cerebrovascular lesions. In these cases, the surgical approach improved the epileptic outcome. Prevalence of epilepsy is higher in subjects with NF1 respect of the general population, with values apparently significantly lower in pediatric age. Brain tumors and cytoarchitectural abnormalities are the most frequent causes of epilepsy in this population, although many other brain complications should be taken in account.

Neurophysiological Signatures of Motor Impairment in Patients with Rett Syndrome.

OBJECTIVE: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder due to pathogenic mutations in the MECP2 gene. Motor impairment constitutes the core diagnostic feature of RTT. Preclinical studies have consistently demonstrated alteration of excitation/inhibition (E/I) balance and aberrant synaptic plasticity at the cortical level. We aimed to understand neurobiological mechanisms underlying motor deficit by assessing in vivo synaptic plasticity and E/I balance in the primary motor cortex (M1). METHODS: In 14 patients with typical RTT, 9 epilepsy control patients, and 11 healthy controls, we applied paired-pulse transcranial magnetic stimulation (TMS) protocols to evaluate the excitation index, a biomarker reflecting the contribution of inhibitory and facilitatory circuits in M1. Intermittent TMS-theta burst stimulation was used to probe long-term potentiation (LTP)-like plasticity in M1. Motor impairment, assessed by ad hoc clinical scales, was correlated with neurophysiological metrics. RESULTS: RTT patients displayed a significant increase of the excitation index (p = 0.003), as demonstrated by the reduction of short-interval intracortical inhibition and increase of intracortical facilitation, suggesting a shift toward cortical excitation likely due to GABAergic dysfunction. Impairment of inhibitory circuits was also confirmed by the reduction of long-interval intracortical inhibition (p = 0.002). LTP-like plasticity in M1 was abolished (p = 0.008) and scaled with motor disability (all p = 0.003). INTERPRETATION: TMS is a method that can be used to assess cortical motor function in RTT patients. Our findings support the introduction of TMS measures in clinical and research settings to monitor the progression of motor deficit and response to treatment. ANN NEUROL 2020;87:763-773.

Sphingolipid Metabolism Perturbations in Rett Syndrome.

Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying MECP2 mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers.