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BACKGROUND/AIMS: As epilepsy is a complex disease group, it is difficult to diagnose and classify. Oxidative stress plays a vital role in the pathogenesis of epilepsy. This study investigated the total oxidant/antioxidant status levels in patients with focal onset and generalized onset seizures. The results we obtained may help find the etiological cause in patients with seizure complaints and may guide their treatment. In addition, knowing the seizure type of the patient can give an idea about the prognosis of their disease.MATERIALS AND METHODS: The total number of patients included in this prospective study was 58. There were also 57 people in a control group. The patients were classified according to their type of seizure: focal or generalized onset. The serum oxidative stress index (OSI) and total oxidant/antioxidant status values of all patients and control group members were measured. The patients (focal/generalized groups) and control group members were compared.RESULTS: This prospective study was completed with 58 eligible patients who met the inclusion criteria. There were 57 people in the control group. Total oxidant status (TOS) and OSI levels were higher in the seizure groups compared to the control group (p

Purpose Resective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). Methods We present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up. Results All patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded. Conclusion This protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences. Trial registration number www.trialregister.nl: NTR7536.

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access) PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

2nd International Behcet Uz Children's Congress -- MAR 04-07, 2020 -- Izmir, TURKEY Background. We aimed to investigate the effectiveness of ketogenic diet (KD) in children with various types of refractory epilepsy. Methods. A total of 91 children (49 females) aged 3 to 193 months (median, 52 months) with drug resistant epilepsy who received KD treatment for at least 12 months were enrolled in the study. Seizure frequency, adherence to diet, reason for discontinuation of KD, and adverse effects were recorded. Response was defined as >= 50% improvement in seizure frequency compared to baseline. We also searched for influences of different variables on the outcome. Results. Intent-to-treat analysis revealed an improvement in seizure frequency for >= 50% in 73.6%, 80.2%, 75.8%, 73.6%, and 70.3% of patients at month-1,-3,-6,-9, and month-12, respectively. Overall, 32 (35.2%) patients remained seizure-free at month-12. There was no significant differences between responders and non responders in terms of age at onset of epilepsy, age at onset of KD, gender, or etiology. Mild hyperlipidemia was associated with a higher response rate. At the last follow-up (median: 20 months), 38 (41.8%) patients were still maintained on KD. While 15.4% of patients completed the diet with a success in seizure control, remainder discontinued KD due to lack of efficacy (23.1%), non-adharence to diet (11%), intercurrent infection (4.4%), adverse effects (3.3%), and death (1.1%). Conclusion. Ketogenic diet treatment appears to be effective in about two-thirds of children with various types of drug-resistant epilepsy, including one-third remaining seizure free. Mild hyperlipidemia seems to be associated with a higher response rate. Discontinuation of KD is mostly due to lack of efficacy or nonadherence, and rarely side effects.

The ketogenic diet (KD), containing high levels of fat and low levels of carbohydrates, has been used to treat refractory epilepsy since the 1920s. In the past few decades, there has been more interest in less restrictive KDs such as the modified Atkins diet (MAD). Our aim was to review all evidence regarding the efficacy and tolerability of the KD and MAD from randomized controlled trials (RCTs) in children and adolescents with refractory epilepsy. We reviewed the current literature using Cochrane, EMBASE, and MEDLINE (using PubMed). We implemented predefined criteria regarding dataextraction and study quality. We identified five RCTs that generated seven publications and recruited 472 children and adolescents with refractory epilepsy (≤ 18 years). The primary outcome (seizure frequency reduction (SFR) ≥ 50%) was attained in 35–56.1% of the participants in the intervention group, compared with 6–18.2% in the control group. Our meta-analysis underlined the significant efficacy of the KD compared with the control group: RR = 5.1 (95% CI 3.18–8.21, p

Background COVID-19 disease was first seen in December 2019 and was declared a pandemic soon after. To fight the pandemic, there is an immense need for effective vaccines. The purposes of our study were to investigate the effect of coronavirus vaccines on seizures in people with epilepsy (PWE) and assess the adverse events of COVID-19 vaccine in PWE. Methods This was a cross-sectional study. We included epilepsy patients who got vaccinated with two or three doses at least 1 month earlier. We gathered the data using a standardized form. The form contained questions about patients' demographic features, clinical features, and information about the vaccination and its adverse events. The questionnaire included questions about epilepsy-related adverse events. Results We included 178 people with epilepsy in our study. The frequency of adverse events was lower than clinical studies of the vaccines. The mean number of seizures in the month before the vaccination was 1.62, between the doses was 1.61, and after vaccination was 1.64. There was no significant difference in the number of monthly seizures before the vaccination, the month between the doses, or the month after the vaccination (p = 0.46). Conclusions The vaccines under consideration in our study were tolerated well by the epilepsy patients. The vaccines did not affect the monthly number of seizures of the PWE. A small number of patients had more seizures than normal after vaccination. We think that benefits of the vaccines outweigh the slightly increased possibility of having a seizure after vaccination.

Aim To determine neurocognitive performance and behavioural problems in children with Panayiotopoulos syndrome. Method All 18 children (10 females, 8 males; mean age 4y 7mo; SD 1y 10mo) diagnosed with Panayiotopoulos syndrome at the Kempenhaeghe Epilepsy Center in the Netherlands between 2010 and 2017 were analysed retrospectively. All underwent a neuropsychological/behavioural assessment, an academic assessment, and a 24-hour electroencephalogram. Results Mean full-scale IQ (93.5; range 76-123; p=0.04) and performance IQ (93.2; range 76-126; p=0.04) were within the normal range, although significantly lower compared to the normative mean. Verbal IQ (96.3; range 76-118) and processing speed (96.1; range 74-114) were not significantly lower. Simple auditory/visual reaction times, visual attention, visual-motor integration, and verbal memory were significantly lower compared to normative values. On average, patients with Panayiotopoulos syndrome were 8 months behind in arithmetic speed and 11 months behind in reading speed for the number of months in school. Behavioural questionnaires revealed significantly higher scores on reported internalizing behavioural problems. Interpretation Children with Panayiotopoulos syndrome demonstrated diffuse cognitive dysfunction in full-scale IQ, performance IQ, visual attention, visual-motor integration, and verbal memory. A high incidence of internalizing behavioural problems was reported. This strongly suggests neuropsychological and behavioural comorbidity in children with Panayiotopoulos syndrome. What this paper addsChildren with Panayiotopoulos syndrome are at risk for cognitive deficits in various cognitive domains. Children with Panayiotopoulos syndrome are also prone to internalizing behavioural problems. Mild-to-severe academic underachievement was present in more than half of the children with Panayiotopoulos syndrome.

Absence epilepsy (AE) has been associated with lower than average cognitive functioning, which are clinically relevant in some and may predispose to problems later in life. This study aimed to assess cognitive development during long-term follow-up in children with AE. Thirty-one children with AE, who had undergone two neuropsychological assessments between 2010 and 2017 were analyzed retrospectively. Cognitive measurements were 1.7 +/- 0.95 years apart. The difference in neurocognitive test scores was assessed on a group level and on an individual level using reliable change methodology. Results show that sustained attention was lower at the first measurement compared to the normative mean. Sustained attention improved during follow-up and 7 out of 14 children showed improvement after correction for practice effects. Receptive vocabulary showed a decline over time, but did not differ from the normative mean. Significant lower mean group scores were present for performance IQ, perceptual organization, processing speed, simple reaction times, and visual motor integration, while being stable over time in the majority of children. Cognitive development was not associated with seizure freedom. Mild-to-severe academic underachievement was present in 65% and comorbidities that might affect learning in 38%. This study in children with AE showed improvement in sustained attention during long-term follow-up while other cognitive weaknesses persisted over time, regardless of seizure freedom.

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the mu-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the mu-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2 mu conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

Objective To investigate the occurrence of psychosis and serious behavioral problems in females with protocadherin 19 gene (PCDH19) pathogenic variants. Methods We evaluated whether psychosis and serious behavioral problems had occurred in 60 females (age 2-75 years) with PCDH19 pathogenic variants belonging to 35 families. Patients were identified from epilepsy genetics databases in Australia, New Zealand, the United States, and Canada. Neurologic and psychiatric disorders were diagnosed using standard methods. Results Eight of 60 females (13%) from 7 families developed a psychotic disorder: schizophrenia (6), schizoaffective disorder (1), or an unspecified psychotic disorder (1). Median age at onset of psychotic symptoms was 21 years (range 11-28 years). In our cohort of 39 females aged 11 years or older, 8 (21%) developed a psychotic disorder. Seven had ongoing seizures at onset of psychosis, with 2 continuing to have seizures when psychosis recurred. Psychotic disorders occurred in the setting of mild (4), moderate (2), or severe (1) intellectual disability, or normal intellect (1). Preexisting behavioral problems occurred in 4 patients, and autism spectrum disorder in 3. Two additional females (3%) had psychotic features with other conditions: an adolescent had recurrent episodes of postictal psychosis, and a 75-year-old woman had major depression with psychotic features. A further 3 adolescents (5%) with moderate to severe intellectual disability had onset of severe behavioral disturbance, or significant worsening. Significance We identify that psychotic disorders, including schizophrenia, are a later-onset manifestation of PCDH19 Girls Clustering Epilepsy. Affected girls and women should be carefully monitored for later-onset psychiatric disorders.

ObjectiveThis nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis.MethodsAnti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects.ResultsOf 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27–160), and 28 days from start of immunotherapy (IQR 9–71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis.ConclusionEpilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial.

Background: Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. Methods: Biochemical and electrophysiological methods were used to assess the role of GSK3β in regulating neuronal transmission and epileptogenesis. GSK3β activity was increased genetically in GSK3β[S9A] mice. Its effects on neuronal transmission and epileptogenesis induced by kainic acid were assessed by field potential recordings in mice brain slices and video electroencephalography in vivo. The ion channel expression was measured in brain samples from mice and followed by analysis in samples from patients with temporal lobe epilepsy or focal cortical dysplasia in correlation to GSK3β phosphorylation. Findings: Higher GSK3β activity decreased the susceptibility to kainic acid-induced epileptiform discharges and the progression of epileptogenesis. At the biochemical level, higher GSK3β activity increased the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 4 and decreased phosphorylation of the glutamate α±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1. The phosphorylation of GluA1 at Serine 831 and Serine 845 was lower in GSK3β[S9A] mice than in wildtype controls, under basal conditions and in the epileptic mouse brain, respectively. Moreover, we found a significant correlation between higher inhibitory GSK3β phosphorylation at Serine 9 and higher activating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients. Interpretation: Our data imply GSK3β activity in the protection of neuronal networks from hyper-activation and indicate that the anti-epileptogenic function of GSK3I² involves decreasing the synaptic AMPA receptors pool. Funding: Research was supported by the Polish National Science Centre (no. 2011/01/N/NZ3/05409 to MU; no. 2017/26/D/NZ4/00159 to PK-G) and FP7 European Union grants (no. 223276, “NeuroGSK3” to FvL and JJ; no. 229676, “HealthProt” to JJ; no. 602102, “Epitarget” to EV and EA.). This study was also co-financed by European Union funds from the European Social Fund (MU). The work of MU was partially financed by IUVENTUS IP2012 037872. The work of MU, KKotulska, SJ, EA and JJ was partly supported by 7FP grant “EPISTOP” (grant agreement no. 602391), and the Polish Ministerial funds for science (years 2014-2019) for the implementation of international co-financed projects. The work of AG was financed by the Polish National Science Centre (grant no. 2011/01/B/NZ3/05397). KKotulska, SJ and JJ were partly financed by the Polish National Center for Research and Development (grant EPIMARKER, no. STRATEGMED3/306306/4/2017). MU was a recipient of a L’OrealUNESCO for Women and Science Fellowship in Poland and EMBO Short Term Fellowship. JJ and MU were also recipients of a Foundation for Polish Science "Mistrz" Professorial Subsidy and Fellowship, respectively. Declaration of Interest: SJ received Advisory Board honoraria from Novartis Oncology. The other 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. Ethical Approval: The study was approved by the local Ethics Board in Warsaw (approval no. 223/KBE/2015).

RATIONALE: Resective epilepsy surgery is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is detection of an epileptogenic lesion by magnetic resonance imaging (MRI). Application of ultra-high field (UHF) MRI, i.e. field strengths ≥ 7 Tesla (T), may increase the sensitivity to detect such a lesion.METHODS: A keyword search strategy was submitted to Pubmed, EMBASE, Cochrane Database and clinicaltrials.gov to select studies on UHF MRI in patients with epilepsy. Follow-up study selection and data extraction were performed following PRISMA guidelines. We focused on I) diagnostic gain of UHF- over conventional MRI, II) concordance of MRI-detected lesion, seizure onset zone and surgical decision-making, and III) postoperative histopathological diagnosis and seizure outcome.RESULTS: Sixteen observational cohort studies, all using 7T MRI were included. Diagnostic gain of 7T over conventional MRI ranged from 8% to 67%, with a pooled gain of 31%. Novel techniques to visualize pathological processes in epilepsy and lesion detection are discussed. Seizure freedom was achieved in 73% of operated patients; no seizure outcome comparison was made between 7T MRI positive, 7T negative and 3T positive patients. 7T could influence surgical decision-making, with high concordance of lesion and seizure onset zone. Focal cortical dysplasia (54%), hippocampal sclerosis (12%) and gliosis (8.1%) were the most frequently diagnosed histopathological entities.SIGNIFICANCE: UHF MRI increases, yet variably, the sensitivity to detect an epileptogenic lesion, showing potential for use in clinical practice. It remains to be established whether this results in improved seizure outcome after surgical treatment. Prospective studies with larger cohorts of epilepsy patients, uniform scan and sequence protocols, and innovative post-processing technology are equally important as further increasing field strengths. Besides technical ameliorations, improved correlation of imaging features with clinical semiology, histopathology and clinical outcome has to be established.

Highlights • This review discusses 16 studies using 7T MRI to evaluate patients with chronic focal epilepsy. • UHF MRI increases the sensitivity to detect an epileptogenic lesion. • Diagnostic gain of 7T over conventional MRI was between 8 and 67%, pooled gain was 31% • FCD, gliosis and HS were the most frequently diagnosed histopathological lesions. • No conclusion can be drawn whether 7T improves surgical treatment and seizure outcome., Rationale Resective epilepsy surgery is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is detection of an epileptogenic lesion by magnetic resonance imaging (MRI). Application of ultra-high field (UHF) MRI, i.e. field strengths ≥ 7 Tesla (T), may increase the sensitivity to detect such a lesion. Methods A keyword search strategy was submitted to Pubmed, EMBASE, Cochrane Database and clinicaltrials.gov to select studies on UHF MRI in patients with epilepsy. Follow-up study selection and data extraction were performed following PRISMA guidelines. We focused on I) diagnostic gain of UHF- over conventional MRI, II) concordance of MRI-detected lesion, seizure onset zone and surgical decision-making, and III) postoperative histopathological diagnosis and seizure outcome. Results Sixteen observational cohort studies, all using 7T MRI were included. Diagnostic gain of 7T over conventional MRI ranged from 8% to 67%, with a pooled gain of 31%. Novel techniques to visualize pathological processes in epilepsy and lesion detection are discussed. Seizure freedom was achieved in 73% of operated patients; no seizure outcome comparison was made between 7T MRI positive, 7T negative and 3T positive patients. 7T could influence surgical decision-making, with high concordance of lesion and seizure onset zone. Focal cortical dysplasia (54%), hippocampal sclerosis (12%) and gliosis (8.1%) were the most frequently diagnosed histopathological entities. Significance UHF MRI increases, yet variably, the sensitivity to detect an epileptogenic lesion, showing potential for use in clinical practice. It remains to be established whether this results in improved seizure outcome after surgical treatment. Prospective studies with larger cohorts of epilepsy patients, uniform scan and sequence protocols, and innovative post-processing technology are equally important as further increasing field strengths. Besides technical ameliorations, improved correlation of imaging features with clinical semiology, histopathology and clinical outcome has to be established.

The purpose of this study was to determine a possible association between two GABA transporter (GAT) single-nucleotide polymorphisms (SNPs), rs2697153 G>A in SLC6A1 (GAT-1) and rs2272400 C>T in SLC6A11 (GAT-3), and drug-resistant temporal lobe epilepsy (TLE). DNA was isolated from 138 TLE patients (from the neocortex) and 94 non-epileptic controls (from blood/buccal swaps), and amplified by polymerase chain reaction and subjected to restriction fragment length polymorphism assays. A subgroup of patients with a positive history of febrile seizures (FS+) and traumatic brain injury (TBI+) were investigated in a separate analysis. P values were obtained using the Chi-Square test and Fishers exact test. The GAT-1 SNP was different between patients and controls (p

Highlights • The functional network of children with childhood absence epilepsy is less efficiently organized in terms of clustering and small-worldness. • Longer path lengths (i.e. less efficient organization) of the functional network relate to a longer duration of childhood absence epilepsy. • Longer path lengths of the functional network relate to a higher seizure frequency in childhood absence epilepsy., While cognitive impairments are not generally considered to be part of the childhood absence epilepsy (CAE) syndrome, some recent studies report cognitive, mainly attentional, deficits. Here we set out to investigate the whole brain functional network of children with CAE and controls. Furthermore, the possible relation of the functional network abnormalities with epilepsy and neurocognitive characteristics is studied. Seventeen children with childhood CAE (aged 9.2 ± 2.1 years) and 15 controls (aged 9.8 ± 1.8 years) were included. Resting state functional MRI was acquired to study the functional network. Using graph theoretical analysis, three global metrics of the functional network were investigated: the characteristic path length, the clustering coefficient, and the small-worldness. A multivariable linear regression model including age, sex, and subject motion as covariates was used to investigate group differences in the graph metrics. Subsequently, relations of the graph metrics with epilepsy and neurocognitive characteristics were assessed. Longer path lengths, weaker clustering and a lower small-world network topology were observed in children with CAE compared to controls. Moreover, longer path lengths were related to a longer duration of CAE and a higher number of absence seizure per hour. Clustering and small-worldness were not significantly related to epilepsy or neurocognitive characteristics. The organization of the functional network of children with CAE is less efficient compared to controls, and is related to disease duration. These preliminary findings suggest that CAE is associated with alterations in the functional network.

Idiopathic or genetic generalized epilepsies (IGE) constitute an electroclinically well-defined group that accounts for almost one third of all people with epilepsy. They consist of four well-established syndromes and some other rarer phenotypes. The main four IGEs are juvenile myoclonic epilepsy, childhood absence epilepsy, juvenile absence epilepsy and IGE with generalized tonic-clonic seizures alone. There are three main seizure types in IGE, namely generalized tonic-clonic seizures, typical absences and myoclonic seizures, occurring either alone or in any combination. Diagnosing IGEs requires a multidimensional approach. The diagnostic process begins with a thorough medical history with a specific focus on seizure types, age at onset, timing and triggers. Comorbidities and family history should be questioned comprehensively. The EEG can provide valuable information for the diagnosis, including specific IGE syndromes, and therefore contribute to their optimal pharmacological treatment and management.

International audience; Objective: Fibroblast-growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 gene encodes a cytosolic protein that interacts with neuronal sodium channel. Aim of this study is to report the largest series of patients with pathogenic FHF1 genetic variants in order to define electro-clinical phenotype, genotype-phenotype correlation, and information about management and prognosis. Methods: Through an international collaboration, we retrospectively collected detailed clinical, genetic, neurophysiologic and neuroimaging data of 17 patients with FHF1-related epilepsy. Results: Fourteen patients carried heterozygous missense variant c.341G>A (p.Arg114His) in FHF1 gene, two patients heterozygous missense variant c.334G>A (p.Gly112Ser) and one patient carried a chromosomal microduplication involving FHF1 gene. The majority of variants were de novo, although in 29% of cases somatic or germline parent mosaicism occurred. Patients with c.341G>A variant presented with a phenotype consisting of early onset DEE. Drug resistant epilepsy, intellectual disability, psychiatric features and status epilepticus were also common features. Tonic seizures were the most frequent seizure type. Patients who carried c.334G>A variant and FHF1 gene duplication showed a delayed epilepsy onset compared with patients carring the hotspot variant (c.341G>A). Brain MRI was normal at onset while a mild cerebral and/or cerebellar atrophy appeared during follow-up in 8 out of 17 patients (47%). Conclusion: FHF1-related DEE is characterized by an almost homogeneous clinical phenotype characterized by early-onset and drug-resistant epilepsy, intellectual disability, and psychiatric features in patients with c.334G>A variant. Few cases with a milder phenotype can occur, although a genotype-phenotype correlation had been identified. Because of the possibility of germline or somatic mosaicism, it is appropriate to offer prenatal diagnosis to couples with a child with FHF1related DEE.

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

Purpose of review: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery. Recent findings: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed. Examples of precision medicine in epilepsy targeting gain-of-function mutations in KCNT1, GRIN2A, GRIN2D and SCN8A are presented. Potential reasons for the paucity of examples of precision medicine for loss-of-function mutations or in non-ion channel epilepsy genes are explored. We highlight how systems genetics and gene network analyses have suggested that pathways disrupted in epilepsy overlap with those of other neurodevelopmental traits including human cognition. We review how network-based computational approaches are now being applied to epilepsy drug discovery. Summary: We are living in an unparalleled era of epilepsy gene discovery. Advances in clinical care from this progress are already materializing through improved clinical diagnosis and stratified medicine. The application of targeted drug repurposing based on single gene defects has shown promise for epilepsy arising from gain-of-function mutations in ion-channel subunit genes, but important barriers remain to translating these approaches to non-ion channel epilepsy genes and loss-of-function mutations. Gene network analysis offers opportunities to discover new pathways for epilepsy, to decipher epilepsy's relationship to other neurodevelopmental traits and to frame a new approach to epilepsy drug discovery.

Purpose: While levetiracetam (LEV) usage is a known risk factor for psychosis in epilepsy, the modulating effect of certain patient and treatment characteristics on the risk of psychosis has yet to be fully elucidated.Methods: In our tertiary epilepsy center, 84 patients with psychotic symptoms during LEV usage and 100 controls without psychotic symptoms during LEV usage were selected. Patient records were reviewed including demographics, medical history, antiepileptic drug use, and cognitive abilities. Univariate comparisons were performed, and variables with p Results: The total incidence of psychosis during LEV therapy in our population was 3.7%. The timing of psychotic symptoms was classified as postictal in 20 (19.8%), interictal in 14 (15.4%), postepilepsy surgery in 1 (1.1%), and unknown in 18 cases (19.8%). In 31 cases (34.1%), psychotic symptoms were classified as an antiepileptic druginduced psychotic disorder (AIPD) as a result of LEV. In 7 cases (7.7%), AIPD occurred as a result of a different antiepileptic drug. A significant association was found between the experience of psychotic symptoms and status epilepticus (p = 0.002), a history of psychotic symptoms (p Conclusion: Our retrospective study found that psychotic symptoms during LEV therapy were significantly associated with status epilepticus, a history of psychotic symptoms, a history of psychiatric illness other than psychosis, and concomitant PHT usage, whereas concomitant LTG usage was protective. Psychotic symptoms specifically as an adverse drug reaction to LEV were significantly associated with female gender, intellectual disability, status epilepticus, and a history of psychotic symptoms. (C) 2019 Elsevier Inc. All rights reserved.

Objective The frontal lobe in childhood absence epilepsy (CAE) might be affected due to the suggested involvement of the frontal lobe during absence seizures and reports on attentional deficits. Previously, subtle white matter abnormalities have been reported in CAE. However, the impact of one of the most characteristic components of the white matter, the myelin content, remains underdetermined. Therefore, this study investigated whether the myelin content in frontal areas is adversely affected in CAE compared to controls. Methods Seventeen children with childhood absence epilepsy (mean age +/- standard deviation [SD], 9.2 +/- 2.1 years) and 15 age- and sex-matched controls (mean age +/- SD, 9.8 +/- 1.8 years) underwent neuropsychological assessment and a magnetic resonance imaging (MRI) examination. T2 relaxometry scans were used to distinguish myelin-water from tissue water and to determine the myelin-water fraction (MWF) in the frontal, temporal, parietal, occipital, and insular lobes. A linear regression model including age and sex as covariates was used to investigate group differences. Furthermore, the relationship of MWF with cognitive performance and epilepsy characteristics was determined. Results The frontal lobe revealed a significantly lower myelin-water content in children with CAE compared to controls over the developmental age range of 6-12 years (5.7 +/- 1.0% vs 6.6 +/- 1.1%, P = 0.02). This association was not found for any of the other four lobes (P > 0.10). No significant relation was found between myelin-water content and cognitive performance or epilepsy characteristics. Significance The lower frontal myelin-water content of children with CAE in comparison with healthy controls probably reflects an altered neurodevelopmental aspect in CAE, of which the underlying mechanisms still need to be unraveled.

BACKGROUND AND PURPOSE: Drug-resistant idiopathic generalized epilepsy (IGE) remains challenging despite a favourable overall prognosis of IGE, and little is known about basic epidemiology and long-term outcome of drug-resistant IGE. The aim of the study was to describe the incidence, prevalence and outcome of IGE in an unbiased, population-based cohort.METHODS: In 2014-2018, all patients (≥17 years) with IGE inhabiting the island of Funen (496 000 inhabitants) were recruited. The socioeconomic and clinical information available for 406 individuals was assessed. Median follow-up was 15 years.RESULTS: The average IGE incidence (2008-2017) was 2.9/100 000 inhabitants/year. The point prevalence of identifiable IGE patients was 1.0/1000 adults (juvenile myoclonic epilepsy 0.4/1000; absence epilepsy 0.3/1000, epilepsy with generalized tonic-clonic seizures alone 0.3/1000); 92.1% of the patients were diagnosed before 25 years of age. When correcting for unequal age distribution in the cohort, 1102 people on the island of Funen fulfilled the diagnostic criteria for IGE at the age of 25 (estimated prevalence 2.7/1000 adults). In the year before data closure, 121 patients reported seizures. Fifty patients met the definition of drug-resistant IGE (12.1% of the cohort, 4.5% of the estimated 1102 IGE patients). The average seizure burden of all patients with drug-resistant IGE was 2.2 generalized tonic-clonic seizures per year; only 14 patients suffered more than two generalized tonic-clonic seizures per year. Drug-resistant IGE was associated with an increased risk of requiring treatment for affective disorders and a reduced probability of working full time.CONCLUSION: Idiopathic generalized epilepsy was associated with a low risk of persistent drug-resistant seizures requiring specialist medical attention. Drug resistance was associated with a negative socioeconomic outcome.

Epileptic seizures are caused by a disturbance in the electrical activity of the brain and classified as many different types of epileptic seizures based on the characteristics of EEG and other parameters. Till now research has been conducted to classify EEG as seizure and non-seizures, but the classification of seizure types has not been explored. Thus, in this paper, we have proposed the 8-class classification problem in order to classify different seizure types using convolutional neural networks (CNN). This research study suggests a CNN based framework for classification of epileptic seizure types that include simple partial, complex partial, focal non-specific, generalized non-specific, absence, tonic, and tonic-clonic, and non-seizures. EEG time series was converted into spectrogram stacks and used as input for CNN. To the best of authors knowledge, ours is the very first study that classified the seizures types using the computational algorithm. The four CNN models, namely AlexNet, VGG16, VGG19, and basic CNN model was applied to study the performance of 8-class classification problem. The proposed study showed a classification accuracy of 84.06%, 79.71%, 76.81%, and 82.14% using AlexNet, VGG16, VGG19 and basic CNN models respectively. The experimental results suggest that the proposed framework could be helpful to the neurology community for recognition of seizures types.

Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 x 10(-9)). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Background Seizures and their consequences contribute to the burden of epilepsy because they can cause health loss (premature mortality and residual disability). Data on the burden of epilepsy are needed for health-care planning and resource allocation. The aim of this study was to quantify health loss due to epilepsy by age, sex, year, and location using data from the Global Burden of Diseases, Injuries, and Risk Factors Study. Methods We assessed the burden of epilepsy in 195 countries and territories from 1990 to 2016. Burden was measured as deaths, prevalence, and disability-adjusted life-years (DALYs; a summary measure of health loss defined by the sum of years of life lost [YLLs] for premature mortality and years lived with disability), by age, sex, year, location, and Socio-demographic Index (SDI; a compound measure of income per capita, education, and fertility). Vital registrations and verbal autopsies provided information about deaths, and data on the prevalence and severity of epilepsy largely came from population representative surveys. All estimates were calculated with 95% uncertainty intervals (UIs). Findings In 2016, there were 45.9 million (95% UI 39. 9-54 .6) patients with all-active epilepsy (both idiopathic and secondary epilepsy globally; age-standardised prevalence 621.5 per 100 000 population; 540.1-737.0). Of these patients, 24.0 million (20.4-27.7) had active idiopathic epilepsy (prevalence 3 26 7 per 100 000 population; 278.4-378.1). Prevalence of active epilepsy increased with age, with peaks at 5-9 years (374.8 [280 .1-490 .0]) and at older than 80 years of age (545.1 [444. 2-652. 0]). Age-standardised prevalence of active idiopathic epilepsy was 329.3 per 100 000 population (280.3-381. 2) in men and 318.9 per 100 000 population (271.1-369.4) in women, and was similar among SDI quintiles. Global age-standardised mortality rates of idiopathic epilepsy were 1.74 per 100 000 population (1.64-1.87; 1.40 per 100 000 population [1. 23-1.54] for women and 2.09 per 100 000 population [1.96-2.25] for men). Age-standardised DALYs were 182.6 per 100 000 population (149. 0-223 .5; 163.6 per 100 000 population [130.6-204.3] for women and 201.2 per 100 000 population [166. 9-241. 4] for men). The higher DALY rates in men were due to higher YLL rates compared with women. Between 1990 and 2016, there was a non-significant 6.0% (-4.0 to 16.7) change in the age-standardised prevalence of idiopathic epilepsy, but a significant decrease in age-standardised mortality rates (24.5% [10.8 to 31.8]) and age-standardised DALY rates (19.4% [9.0 to 27.6]). A third of the difference in age-standardised DALY rates between low and high SDI quintile countries was due to the greater severity of epilepsy in low-income settings, and two-thirds were due to a higher YLL rate in low SDI countries. Interpretation Despite the decrease in the disease burden from 1990 to 2016, epilepsy is still an important cause of disability and mortality. Standardised collection of data on epilepsy in population representative surveys will strengthen the estimates, particularly in countries for which we currently have no or sparse data and if additional data is collected on severity, causes, and treatment. Sizeable gains in reducing the burden of epilepsy might be expected from improved access to existing treatments in low-income countries and from the development of new effective drugs worldwide. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.

Objective: We aimed to identify the possible causes of myoclonus and related electrophysiological features in a cohort of young patients. Patients and Methods: We performed a retrospective analysis of all clinical and electrophysiological recordings of patients who had myoclonus and were under 60 years between 2005 and 2018. The clinical data included age at examination, gender, age at onset, and main neurological or systemic findings, underlying cause and electrophysiological features constituted surface electromyogram, long-loop reflexes, electroencephalography, and somatosensory-evoked potentials. Results: In the study period, we identified 155 patients with myoclonus. Myoclonus was most commonly related with epilepsy and movement disorders. Myoclonus with epilepsy was the leading cause between 10 and 30 years, whereas myoclonus with movement disorders was more common after 30 years. In our country, SSPE was an important cause of myoclonus under the 20 years of age. We identified cortico-subcortical subtype followed by cortical, cortical reflex, subcortical-basal ganglia, subcortical-brainstem and propriospinal subtypes, and correlated these subtypes with relevant disorders. Conclusion: The electrophysiological classification provides anatomical subtyping, which is favorable in diagnosing certain cases such as brainstem and propriospinal myoclonus. Certain characteristics such as reflex nature of myoclonus and accompanying features narrow the list of differentials and help in making the diagnosis.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

OBJECTIVES:The clinical profile of children who had possible seizures is heterogeneous, and accuracy of diagnostic testing is limited. We aimed to develop and validate a prediction model that determines the risk of childhood epilepsy by combining available information at first consultation.METHODS:We retrospectively collected data of 451 children who visited our outpatient department for diagnostic workup related to 1 or more paroxysmal event(s). At least 1 year of follow-up was available for all children who were diagnosed with epilepsy or in whom diagnosis remained inconclusive. Clinical characteristics (sex, age of first seizure, event description, medical history) and EEG report were used as predictor variables for building a multivariate logistic regression model. Performance was validated in an external cohort (n = 187).RESULTS:Model discrimination was excellent, with an area under the receiver operating characteristic curve of 0.86 (95% confidence interval [CI]; 0.80–0.92), a positive predictive value of 0.93 (95% CI 0.83–0.97) and a negative predictive value of 0.76 (95% CI 0.70–0.80). Model discrimination in a selective subpopulation of children with uncertain diagnosis after initial clinical workup was good, with an area under the receiver operating characteristic curve of 0.73 (95% CI 0.58–0.87).CONCLUSIONS:This model may prove to be valuable because predictor variables together with a first interictal EEG can be available at first consultation. A Web application is provided (http://epilepsypredictiontools.info/first-consultation) to facilitate the diagnostic process for clinicians who are confronted with children with paroxysmal events, suspected of having an epileptic origin.

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies., tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

Item does not contain fulltext Background: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. Methods: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). Results: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. Conclusions: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.) 9 p.

In 2008, a group of Belgian epilepsy experts published recommendations for antiepileptic drug (AED) treatment of epilepsies in adults and children. Selection of compounds was based on the registration and reimbursement status in Belgium, the level of evidence for efficacy, common daily practice and the personal views and experiences of the authors. In November 2011 the validity of these recommendations was reviewed by the same group of Belgian epilepsy experts who contributed to the preparation of the original paper. The recommendations made in 2008 for initial monotherapy in paediatric patients were still considered to be valid, except for the first choice treatment for childhood absence epilepsy. This update therefore focuses on the treatment recommendations for initial monotherapy and add-on treatment in adult patients. Several other relevant aspects of treatment with AEDs are addressed, including considerations for optimal combination of AEDs (rational polytherapy), pharmacokinetic properties, pharmacodynamic and pharmacokinetic interaction profile, adverse effects, comorbidity, treatment of elderly patients, AED treatment during pregnancy, and generic substitution of AEDs. © 2012 The Author(s)., SCOPUS: re.j, info:eu-repo/semantics/published