Introduction Traumatic brain injury (TBI), caused by external force to the head, leads to anatomical or functional damage to cranial structures. It is a leading cause of morbidity and mortality in adults worldwide, with substantial economic burden. Post-traumatic epilepsy (PTE) is a significant complication of TBI, posing immense challenges to rehabilitation and exacerbating socioeconomic burdens. The incidence of PTE varies widely, underscoring the need for early detection and treatment. Objective Through prospective electroencephalography (EEG) evaluations over a two-year period, our study aims to identify electrographic patterns indicative of PTE development, offering crucial insights for timely intervention and improved patient outcomes. Methods Seventy-three adult participants with acute TBI, admitted to a reference hospital in Brazil between 2018 and 2020, were recruited based on eligibility criteria. EEG evaluations monitored seizure occurrence with follow-ups for up to 24 months post-TBI, though these were disrupted by the COVID-19 pandemic. Analyses included established EEG protocols, examining factors such as background activity and epileptiform paroxysms. Relative risk (RR), Multiple Correspondence Analysis (MCA), logistic regression, and Generalized Estimating Equations (GEE) were employed to predict variables associated with PTE development. Results Both PTE and NO-PTE (no post-traumatic epilepsy) patients showed improving background activity over 2 years. EEG recordings revealed that injuries in the temporal region, diffuse theta waves and abnormal bilateral sleep elements indicated a higher risk of PTE development. Additionally, multiple lesions were also associated with PTE. Conclusion This comprehensive approach provides valuable insights for clinical management and sheds light on the complex interplay of factors influencing TBI outcomes.

Case presentation: 12-year-old boy, unrelated parents, uncomplicated pregnancy, full term, no relevant family and neonatal history, no dysmorphic features. The first afebrile seizure was at 3 months (hypotonic, cyanotic, hypoventilation, less than a minute), neurological exam, cerebrospinal fluid, brain MRI and electroencephalogram (EEG) were normal. After a week he had recurred focal motor seizures. Carbamazepine was prescribed. Until 3 years old, the seizures remained every 6 months, and an episode of status epilepticus occurred. The patient stayed seizure-free for two years and antiseizure medication (ASM) was withdrawn. After one month seizures had recurred, and levetiracetam, pyridoxine, clobazam, and sodium valproate were administered unsuccessfully. EEG demonstrated normal background and sporadic centrotemporal, frontocentral, bifrontal, central epileptiform discharges. The genetic panel at this time (2017) had no pathogenic variants. In the following two years, although the patient had a normal neuropsychological test and no changes in neurodevelopment, the seizures remained bilateral, tonic-clonic, generalized, and pharmacoresistant. Exome revealed a pathogenic variant of the FGF12 gene, missense, resulting in a substitution of glycine-to-serine [(Chr3: 192.335.441 C>T, p(Gly112Ser ENST 00000454309)]. After this finding we prescribed phenytoin. The patient remains seizure-free to date. Discussion: Recent studies have identified mutations in the fibroblast growth factor 12 (FGF12) gene as a potential genetic cause of epilepsy and neurodevelopmental disorders. The gene encodes a cytosolic binding protein that enhances the voltage-dependent fast inactivation of neuronal sodium channels, modifying their excitability. Pathogenic variants in FGF12 have few published case reports, with most other cases with neuropsycomotor development disorder and refractory epilepsy (Developmental and Epileptic Encephalopathy 47). In our patient, neurodevelopment was normal and revealed an expansion of phenotype. Genetic panel had identified no pathogenic variants, at this time FGF12 gene had not yet been related to epilepsy. Due to the persistence of the seizures, an exome was requested and revealed a pathogenic variant of the FGF12 gene. Phenytoin was utilized in other published cases of refractory epilepsy with this gene mutation, owing to its molecular mechanism, which stabilizes neuronal membranes by blocking voltage-gated sodium channels, thereby inhibiting excessive neuronal firing. New generation sequencing is essential in refractory epilepsy guiding ASM strategies for better outcomes. Final comments: Genetic causes of epilepsy, particularly FGF12 gene mutations, highlight the relevance of precision medicine strategies for treatment selection.

Introduction:When vital functions are maintained, but the patient is unconscious, in a coma or in a vegetative state, it is important to predict the chance of regaining consciousness, that is, the ability to carry out simple orders or purposeful reproducible and sustained behavior.Studies suggest that the presence of reactivity on the electroencephalogram (EEG-R) predicts a greater chance of regaining consciousness.The aim of this study is to verify the prognostic value of electroencephalographic reactivity in comatose patients.Methods:The study included EEG of patients who were in a coma without sedation, from June 2016 to June 2017.The presence or absence of electroencephalographic reactivity was verified, and the outcome of each patient was based on the analysis of the medical records after the procedure.minimum of 2 months of follow-up.Data were descriptively analyzed using absolute and percentage frequencies, while Pearson's chi-square test was used to assess the significant association between electroencephalographic reactivity and the chance of regaining consciousness.Results: Of the total of 116 electroencephalographic recordings, traumatic brain injury and hemorrhagic stroke accounted for more than 50% of the causes of coma and death.The percentage that regained consciousness was 46.4% among the EEG-R and was null among the non-reactive ones (p < 0.01).Discussion and conclusion: Frequency, amplitude and reactivity of brain electrical activity have been demonstrated as predictors of improvement in coma.The presence of reactivity in the EEG, in this study, was not as favorable as the possibility of improvement in consciousness.However, non-reactive EEG was shown to be strongly related to a poor prognosis.Therefore, it is important to research electroencephalographic reactivity to external stimuli in comatose patients undergoing EEG, as this is a simple, useful and noninvasive method that can provide information regarding the prognosis in coma.

We highlight the unpredictable risk of recurrence caused by parental germline mosaicism in pathogenic variants in SCN3A. We would like to provide additional data on the family of patient 1 from our article “Neurological development disorder associated with new SCN3A pathogenic variants: two new cases and literature review” published in 2019 in Brain of Development [ [1] Inuzuka L.M. Macedo-Souza L.I. Della-Ripa B. Cabral K.S.S. Monteiro F. Kitajima J.P. de Souza Godoy L.F. de Souza Delgado D. Kok F. Garzon E. Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literature. Brain Dev. 2020; 42: 211-216https://doi.org/10.1016/j.braindev.2019.09.004 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar ].

The authors regret the error below: 1. Case Report – second paragraph – Whole exome sequencing (WES) SCN3A [c.5265G>A ENST00000360093, p.(Met1765Ile)] – the correct is: c.5295G>A. The authors would like to apologise for any inconvenience caused. Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literatureBrain and DevelopmentVol. 42Issue 2PreviewSCN3A was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. We present two additional patients with a novel de novo SCN3A pathogenic variant, and a review of all published cases of de novo variants. In one of our patients brain magnetic resonance imaging (MRI) disclosed a severe polymicrogyria and in the other it was normal. The clinical phenotype was characterized by a severe developmental delay and refractory epilepsy in the patient with polymicrogyria and intellectual disability with autistic features and pharmacoresponsive epilepsy in the subject with normal MRI. Full-Text PDF

Objective: To present a cohort of 8 males and perform a systematic review of all published cases with a single copy of MECP2 carrying a pathogenic variant. Methods: We reviewed medical records of males with a single copy of MECP2 carrying a pathogenic variant. We searched in Medline (Pubmed) and Embase to collect all articles which included well characterized males with a single copy of MECP2 carrying a pathogenic or likely pathogenic variant in MECP2 (1999-2020). Results: The literature search yielded a total of 3,185 publications, of which 58 were included in our systematic review. We were able to collect information on 27 published patients with severe neonatal encephalopathy, 47 individuals with isolated or familial mental retardation X-linked 13 (XLMR13), as well as 24 individuals with isolated or familial Pyramidal signs, parkinsonism, and macroorchidism (PPM-X). In our cohort, we met eight individuals aged 4 to 19-year-old at the last evaluation. Three MECP2- associated phenotypes were seen in male carriers of a single copy of the gene: severe neonatal encephalopathy (n = 5); X-linked intellectual deficiency 13 (n = 2); and pyramidal signs, parkinsonism, and macroorchidism (PPM-X) (n = 1). Two novel de novo variants [p.(Gly252Argfs*7) and p.(Tyr132Cys)] were detected. Conclusion: In males, the MECP2 pathogenic variants can be associated with different phenotypes, including neonatal severe encephalopathy, intellectual deficiency, or late-onset parkinsonism and spasticity. The typical RS phenotype is not expected in males, except in those with Klinefelter syndrome or somatic mosaicism for MECP2. (C) 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

SCN3A was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. We present two additional patients with a novel de novo SCN3A pathogenic variant, and a review of all published cases of de novo variants. In one of our patients brain magnetic resonance imaging (MRI) disclosed a severe polymicrogyria and in the other it was normal. The clinical phenotype was characterized by a severe developmental delay and refractory epilepsy in the patient with polymicrogyria and intellectual disability with autistic features and pharmacoresponsive epilepsy in the subject with normal MRI. Polymicrogyria, a disorder of progenitor cells proliferation and migration, is an unanticipated finding for an ion channel dysfunction.

Introduction: KCNT2 was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. Case report: We present an additional observation of a 16-year-old male patient with a novel de novo KCNT2 likely pathogenic variant and review the five previously reported cases of de novo variants in this gene. Discussion: Whole exome sequencing identified the missense variant c.725C > A p.(Thr242Asn), which was confirmed by Sanger sequencing. Our patient has a refractory stereotyped and monomorphic type of hyperkinetic focal motor seizure, similar to what is seen in frontal lobe epilepsy, occurring only during sleep. This type of seizure is not usually seen in epileptic encephalopathies. (C) 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

ATP6V1B2 encodes a subunit of the lysosomal transmembrane proton pump necessary for adequate functioning of several acid hydrolases. De novo monoallelic variants of this gene have been associated with two distinct phenotypes: Zimmermann-Laband syndrome 2 (ZLS2), an intellectual deficiency/multiple malformation syndrome, and dominant deafness onychodystrophy (DDOD), a multiple malformation syndrome without cognitive involvement. Epilepsy is not observed in DDOD, is variably present in ZLS2, but is a common feature in Zimmermann-Laband syndrome 1 (ZLS1) (caused by monoallelic pathogenic variants in KCNH1) and Zimmermann-Laband syndrome-like (ZLSL) (associated with KCNK4 variants). Herein, we report a case of an infant with severe epileptic encephalopathy with microcephaly and profound developmental delay, associated with a novel de novo loss-of-function variant in ATP6V1B2, diagnosed by whole-exome sequencing. This finding expands the spectrum of ATP6V1B2-associated disorders and adds ATP6V1B2 as a new member for the growing list of early-onset epileptic encephalopathy genes. [Published with video sequence].

Research on the prevention of post-traumatic epilepsy (PTE) has seen remarkable advances regarding its physiopathology in recent years. From the search for biomarkers that might be used to indicate individual susceptibility to the development of new animal models and the investigation of new drugs, a great deal of knowledge has been amassed. Various groups have concentrated efforts in generating new animal models of traumatic brain injury (TBI) in an attempt to provide the means to further produce knowledge on the subject. Here we forward the hypothesis that restricting the search of biomarkers and of new drugs to prevent PTE by using only a limited set of TBI models might hamper the understanding of this relevant and yet not preventable medical condition.

Pacientes com epilepsia parcial refratária às drogas antiepilépticas necessitam de avaliação multidisciplinar (composta por neurofisiologistas, neurorradiologistas, neuropatologistas e neuropsicólogos) para avaliação e delimitação precisa da área epileptogênica, pois estes podem se beneficiar do tratamento cirúrgico. Este artigo discorre sobre os métodos de avaliação disponíveis.

O tratamento farmacológico para as epilepsias em geral produz o controle absoluto das crises epilépticas em apenas uma parcela de pacientes. Dependendo da etiologia e da síndrome, entre 35% e 75% destas, a despeito do tratamento clínico, continuam a apresentar as crises epilépticas. Neste artigo abordamos as definições de intratabilidade assim como outras opções de tratamento clínico, discutindo as principais indicações e efeitos colaterais das novas drogas e as formas alternativas de tratamento clínico, a dieta cetogênica e o uso do estimulador do nervo vago.

Alguns pacientes que apresentam epilepsia refratária ao tratamento medicamentoso beneficiam-se da remoção cirúrgica do foco epileptogênico. O estudo das alterações eletrofisiológicas e neuropatológicas no tecido epiléptico humano é fundamental para a compreensão dos mecanismos fisiopatogênicos e o desenvolvimento de novas drogas antiepilépticas e outras modalidades terapêuticas. A esclerose mesial temporal, lesão responsável por cerca de 65% das epilepsias do adulto, cursa com grau elevado de intratabilidade. Nela as estruturas mediais do lobo temporal, principalmente o hipocampo, participam ativamente na gênese das descargas epileptiformes. No presente trabalho, abordaremos algumas das técnicas que estão sendo atualmente utilizadas para estudo da epileptogênese na epilepsia do lobo temporal. O tecido epiléptico obtido no centro cirúrgico de seis pacientes foi transportado ao laboratório onde foram realizados, além da análise eletrofisiológica in vitro, estudos neuropatológico e imunocitoquímico. Essas técnicas permitiram a detecção de anormalidades nos registros eletrofisiológicos sob a forma de descargas interictais e ictais in vitro. Foi verificada heterogeneidade das anormalidades epileptiformes tendo sido possível, ainda, a realização de testes de resistência a drogas antiepilépticas utilizadas no tratamento de um desses pacientes. Esses dados indicam que as anormalidades epileptogênicas no tecido humano devem ser complexas e que as mesmas podem ser avaliadas pela abordagem experimental. A compreensão das mesmas pode fornecer novas perspectivas na avaliação pré-cirúrgica e no tratamento dessa forma de epilepsia.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder leading to neonatal intractable seizures and epileptic encephalopathy. Clinical seizures usually begin in the first hours of life, with poor response to anticonvulsants, evolving to refractory status epilepticus. Diagnostic assessment includes cerebrospinal fluid analysis, gene testing and clinical response to parenteral pyridoxine. Early recognition and treatment is highly desired to avoid unfavorable neurodevelopmental outcome. Electroencephalographic monitoring commonly reveals pretreatment multifocal epileptiform activity and burst suppression pattern; after pyridoxine injection, the incidence of sharp waves decreases and periods of suppression can occur. Case report of a 11-month-old girl with first seizure with 4 h after birth and delayed genetic confirmation of pyridoxine-dependent epilepsy due to the gene ALDH7A1. EEG monitoring was performed during pyridoxine infusion. A 11 month-old girl, with unremarkable gestational and delivery history, started seizures 4 h after birth. Initially treated with phenobarbital, she evolved to convulsive status epilepticus (CSE), leading to orotracheal intubation and continuous sedation for 5 days. At 3 months, she had a new CSE, being hospitalized for 4 months and started on sodium valproate, vigabatrin, clobazam and levetiracetam. Epileptic seizures remained weekly. Phenobarbital and cannabidiol were added, with no further benefit. At 9 months, seizures became daily and she had a new CSE. In the ICU, it was started midazolam, ketamine, topiramate and ketogenic diet. After 1 month, she was discharged and referred to a tertiary hospital. An exome sequencing revealed 2 copies in homozygosis in the gene ALDH7A1, variant Chr5:125.894.936 C > T, previously associated with PDE. While being admitted for pyridoxin treatment, she started a new CSE. EEG showed diffuse spikes, polyspikes and sharp waves at intervals of 1–2 s. Immediately after intravenous injection of pyridoxine 200 mg, epileptiform activity became progressively less frequent, alternating with periods of attenuattion lasting from 2 to 8 s, with no longer SE after 3 min. After 3 days, EEG showed moderate diffuse disorganization, with no epileptiform activity. Discharge was after 10 days. Outpatient EEG monitoring showed left centrotemporal sharp waves and mild disorganization of background activity. This case illustrates a clinical scenario of seizures starting in the neonatal period, with recurrent convulsive status epilepticus and little response to anticonvulsants and ketogenic diet. The delayed diagnosis can be explained by rarity of the condition and limited availability of gene testing in public health system in medium and low-income countries. It remarks the importance of empirical pyridoxine treatment in neonates with early beginning of refractory seizures and status epilepticus (SE). EEG evolution and SE cessation documents pyridoxine responsiveness.

STUDY OBJECTIVES:Sleep enuresis is one of the most common sleep disturbances in childhood. Parental perception of deeper sleep in children with sleep enuresis is not confirmed by objective studies. However, evidence of disturbed sleep has been demonstrated by questionnaire, actigraphy, and polysomnographic studies, but no neurophysiological correlation with low arousability has been found. The goal of this study was to analyze the sleep microstructure of children with sleep enuresis using cyclic alternating pattern (CAP) analysis. METHODS:Forty-nine children were recruited, 27 with enuresis (19 males and 8 females, mean age 9.78 years, 2.52 standard deviation) and 22 normal control patients (11 males and 11 females, mean age 10.7 years, 3.43 standard deviation); all subjects underwent clinical evaluation followed by a full-night polysomnographic recording. Psychiatric, neurological, respiratory, and renal diseases were excluded. RESULTS:No differences in sex, age, and apnea-hypopnea index were noted in the patients with enuresis and the control patients. Sleep stage architecture in children with sleep enuresis showed a decrease in percentage of stage N3 sleep. CAP analysis showed an increase in CAP rate in stage N3 sleep and in phase A1 index during stage N3 sleep in the sleep enuresis group, but also a significant reduction of A2% and A3% and of phases A2 and A3 indexes, supporting the concept of decreased arousability in patients with sleep enuresis. The decrease of phase A2 and A3 indexes in our patients might reflect the impaired arousal threshold of children with sleep enuresis. Sleep fragmentation might result in a compensatory increase of slow wave activity (indicated by the increase of CAP rate in stage N3 sleep) and may explain the higher arousal threshold (indicated by a decrease of phase A2 and A3 indexes) linked to an increased sleep pressure. CONCLUSIONS:The findings of this study indicate the presence of a significant disruption of sleep microstructure (CAP) in children with sleep enuresis, supporting the hypothesis of a higher arousal threshold.