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Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled identification of disease-causing genes and variants in epilepsies. In our study, 55 children with epilepsy of unknown etiology were analyzed combining clinical-exome (CES) and whole-exome sequencing (WES). Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction. Molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in 5 unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes: ASH1L, CSNK2B RHOBTB2 and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, identification of variants in ALDH7A1, KCNQ2, PNPO, SCN1A and SCN2A gene directed therapy decision of 11 children from our study, including four children who all carry novel SCN1A genetic variants. Our study emphasizes the importance of NGS in diagnosing childhood epilepsy. With an increasing number of genes associated with epilepsy, comprehensive analysis using CES and WES is crucial for high diagnostic success. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target.

Background: Childhood epilepsy with centrotemporal spikes (CECTS) is the most common epilepsy syndrome in school-aged children. However, predictors for seizure frequency are yet to be clarified using the phase lag index (PLI) analyses. We investigated PLI of scalp electroencephalography data at onset to identify potential predictive markers for seizure times. Methods: We compared the PLIs of 13 patients with CECTS and 13 age- and sex-matched healthy controls. For the PLI analysis, we used resting-state electroencephalography data (excluding paroxysmal discharges), and analyzed the mean PLIs among all electrodes and between interest electrodes (C3, C4, P3, P4, T3, and T4) and other electrodes. Furthermore, we compared PLIs between CECTS and control data and analyzed the associations between PLIs and total seizure times in CECTS patients. Results: No differences were detected in clinical profiles or visual electroencephalography examinations between patients with CECTS and control participants. In patients with CECTS, the mean PLIs among all electrodes and toward interest electrodes were higher at the theta and alpha bands and lower at the delta and gamma bands than those in control participants. Additionally, the mean PLIs toward interest electrodes in the beta frequency band were negatively associated with seizure times (P = 0.02). Conclusion: The resting-state delta, theta, alpha, and gamma band PLIs might reflect an aberrant brain network in patients with CECTS. The resting-state PLI among the selected electrodes of interest in the beta frequency band may be a predictive marker of seizure times in patients with CECTS.

Background: Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% can be attributed to genetic factors. Application of next-generation sequencing (NGS) has revolutionized diagnostics and therefore has enabled the identification of disease-causing genes and variants in childhood epilepsies. Materials and Methods: Patients who presented with epilepsy of unknown etiology in childhood, with suspicion of a genetic cause were included in this study. In total, 55 patients from unrelated non-consanguineous families were included and analyzed by NGS either using clinical-exome sequencing (MiSeq, Illumina) or whole-exome sequencing (DNBSEQ-G400, MGI). Variants were prioritized using Variant Interpreter and VarSome and classified according to the ACMG recommendations. Results: Using CES we analyzed 38 patients, and for 22 of them a diagnosis was established. Using WES we analyzed 17 patients with childhood epilepsy, which led to the identification of disease-causing genes in 11 patients. The diagnostic success rate for CES was 55.3% (21/38) and the diagnostic rate for WES was 64.7% (11/17), with the overall diagnostic rate being 58.2% (32/55). For these patients, we detected pathogenic, likely pathogenic variants or VUS in 24 epilepsy genes that correlate well to the observed phenotype. Sixteen novel genetic variants were identified and characterized using various in silico algorithms. Conclusion: This is the first study reporting the molecular-genetic basis of childhood epilepsy in Serbia. The prompt establishment of a specific diagnosis is essential in order to make available the prognosis, optimize therapy, and enable counseling on recurrence risk in future pregnancies.

Purpose of review: Drug-resistant epilepsy represents around one-quarter of epilepsies worldwide. Although ketogenic diets (KD) have been used for refractory epilepsy since 1921, the past 15 years have witnessed an explosion of KD use in the management of epilepsy. We aimed to review evidence from randomized controlled trials (RCTs) regarding the efficacy and safety of KD in drug-resistant epilepsy in children and adolescents.Recent findings: A literature search was performed in the Pubmed, Cohrane, Scopus, ClinicalTrials.gov, and Google Scholar databases. Predefined criteria were implemented regarding data extraction and study quality. Data were extracted from 14 RCTs in 1114 children and adolescents aged from 6 months to 18 years. Primary outcome was seizure reduction after the intervention. In 6 out of the 14 studies, there was a statistical significant seizure reduction by > 50% in the KD-treated group compared with the control group over a follow-up of 3-4 months. Secondary outcomes were adverse events, seizure severity, quality of life, and behavior. Gastrointestinal symptoms were the most frequent adverse events. Serious adverse events were rare. We conclude that the KD is an effective treatment for drug-resistant epilepsy in children and adolescents. Accordingly, RCTs investigating long-term impact, cognitive and behavioral effects, and cost-effectiveness are much anticipated.

Many adult diseases have their origins in early life events. Much remains unrevealed in this field, especially concerning associations between perinatal complications and early manifestation of psychiatric disorders. The aim of this work is to assess the association of early adverse life events and later psychiatric disorders in adolescence. This study sample consists of 508 adolescent inpatients aged 13–17 years in need of acute psychiatric hospitalization in an adolescent psychiatric ward of Unit 70 in Oulu University Hospital between years 2001–2006. A diagnostic semi-structured interview, the Schedule for Affective Disorder and Schizophrenia for School-Age Children Present and Lifetime (K-SADS-PL), was carried out to assess psychiatric disorders according to DSM-IV criteria. The information on obstetric complications was obtained simultaneously. Birth measures data were derived from the Medical Birth Register. Diagnoses of epilepsy and other convulsions and child psychiatric diagnoses based on hospital treatment on the child psychiatric ward were obtained from the Finnish Care Register of Health Care. Delivery complications, especially section, increased the likelihood for conduct disorders among adolescent boys. The adolescent boys were shorter and had higher ponderal index at birth compared to healthy controls. In boys high ponderal index was associated with internalizing disorders in adolescence. Febrile and other convulsions and epilepsy in childhood associated with suicide attempts among adolescent boys. The likelihood for personality disorder was 14-fold among adolescents with febrile or other convulsions in childhood and three-fold among those with childhood epilepsy. Previous child psychiatric care associated with self-mutilative behaviour and child welfare placement in adolescence. Among boys, a history of child psychiatric care was related to anxiety and conduct disorders in adolescence, and among girls, mother’s unemployment, psychiatric prob, Tiivistelmä Varhaiset terveydelle epäsuotuisat tekijät altistavat sairauksille aikuisena. Etenkin perinataalivaiheen ongelmien ja alaikäisenä puhjenneiden psykiatristen häiriöiden välisestä yhteydestä tiedetään kuitenkin vähän. Tämän työn tarkoitus on tutkia varhaisten epäsuotuisien tapahtumien yhteyttä nuoruusiässä puhjenneisiin psykiatrisiin häiriöihin. Tutkimusaineisto koostuu 508:sta, iältään 13–17-vuotiasta nuoresta, jotka on otettu Oulun yliopistollisen sairaalan nuorisopsykiatrian akuuttiosastolle (osasto 70) hoitoon vuosina 2001–2006. Osastojakson aikana nuoret tutkittiin käyttäen puolistrukturoitua K-SADS-PL-haastattelua, jolla arvioitiin psykiatrisia häiriöitä DSM-IV-tautiluokituksen mukaisesti. Samalla saatiin tieto nuoren syntymään liittyneistä obstetrisista komplikaatioista. Syntymämitat selvitettiin syntyneiden lasten rekisteristä ja tiedot lapsuusiän kuume- ja muista kouristuksista, lapsuusiän epilepsioista ja lastenpsykiatrisista hoitojaksoista poimittiin sairaaloiden hoitoilmoitusrekisteristä. Synnytyskomplikaatiot, etenkin sektio, lisäsivät poikien käytöshäiriöiden riskiä nuoruudessa. Tutkimusaineiston pojille oli tyypillisempää lyhyt syntymäpituus ja iso ponderaalimitta verrattuna samanikäisiin terveisiin kontrolleihin. Pojilla suuri ponderaalimitta lisäsi erityisesti internalisoivien häiriöiden riskiä nuoruudessa. Lapsuusiän kuume- ja muut kouristukset sekä epilepsia assosioituivat poikien itsemurhayrityksiin nuoruudessa. Kuume- ja muut kouristukset suurensivat persoonallisuushäiriön riskiä nuoruudessa 14-kertaisesti, epilepsia kolminkertaisesti. Aiempi lastenpsykiatrinen osastohoito oli yhteydessä nuorten itsensä vahingoittamiseen esimerkiksi viiltelemällä sekä sijoitukseen kodin ulkopuolelle. Lisäksi aiempi lastenpsykiatrinen hoito liittyi pojilla ahdistus- ja käytöshäiriöihin nuoruudessa ja tytöillä äidin työttömyyteen, äidin psykiatrisiin ongelmiin ja perheen huonoon toimintakykyyn GARF- mittarin perusteella arvioituna. Nämä tulokset viittaav

Objective: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. Methods: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. Results: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. Significance: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Callosotomy is a palliative surgery method for selected individuals with severe, drug-resistant epilepsy. The aim of this retrospective study was to explore parental experiences of the family's life situation before and long after their child had undergone callosotomy. Semistructured interviews of the parents of 12 children were analyzed using a combination of inductive and deductive qualitative content analysis. Before surgery, parents felt that they lived in a chaotic bubble with an unbearable situation; their child had severe and frequent seizures and had to be looked after constantly. Most parents were both satisfied and dissatisfied with the given support and information. However, if the child did not improve after surgery, parents often felt that the information before surgery had not been adequate. After surgery, they found a glimpse of hope. They felt that the family got a new life; the reduced seizure severity led to a better life situation for the family. The support was described as both good and poor. The family life situation was complex, and even if they were partly satisfied with the support, it was still not enough. However, the life situation was also very stressful because of remaining seizures, behavioral problems, and sometimes, adverse effects of surgery. The families lived in disappointment and difficulty and had to fight for their rights. This indicates that these families need more information and social service coordination both before and long after surgery. They need not only tools to manage the child's disabilities but also substantial help to care for the child and to receive the social support they need.

Severe childhood epilepsy has an impact on the whole family. For selected children, hemispherotomy is the treatment of choice. The aim of this study was to explore parents' experiences before and after hemispherotomy as reported at a long-term follow-up and their view on received information and support. This was a population-based qualitative descriptive study, using qualitative content analysis of interviews. Seven to eighteen years after hemispherotomy, parents of twenty-one operated children were interviewed about the family life situation, expectations before surgery, and support and information before and after surgery. Before surgery, the theme 'Living in a chaotic bubble' illuminates how parents felt: the family lived in isolation, they felt both dissatisfaction and satisfaction about support and information, and they experienced that surgery was a question about life or death. After surgery, the theme 'Hovering between success and disaster' illuminates how parents hovered between happiness if the surgery was successful and sadness about e.g., complications and behavior problems. They experienced both excellent and poor support, in hospital and at rehabilitation. Regardless of all concerns, parents were satisfied that the child had received an operation. The hemispherotomies were successful and generated a better life situation. However, in order to cope, families need support and information throughout the whole process, from the onset of epilepsy and for a long time after surgery. If the child has behavior problems, an assessment should be made before surgery in order for the families to get adequate support. The specialist team needs to be involved as early as possible and follow the families for several years after surgery. Focus should be on the whole family, if needed including grandparents; family-centered care might be relevant for this patient group.

Objective: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2–5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance. Methods: In this observational, multicenter, nationwide study, children (age 1 month–12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses. Results: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month–12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy. Significance: In this prospective cohort study

Nodding syndrome (NS) is an emerging epidemic neurological disease that is shrouded in mystery. It is currently only found in the post-conflict regions of South Sudan, northern Uganda, and Tanzania. NS occurs in children from the ages of five to fifteen and is characterized by a loss of motor control in the neck muscles. Seizure episodes can range in intensity from atonic to tonic-clonic, and the onset of the first episode generally marks the beginning of a decline in the child’s physical and mental health. NS is a progressive disease that generally results in physical wasting, stunted growth, behavioral difficulties, and a decline in cognitive and motor skills. The underlying cause of the disease has yet to be soundly established, but several closely correlated factors have been discovered and effective treatment methods are currently being developed. Children with NS are also susceptible to detrimental social factors such as negative perception and stigmatization. Additionally, socioeconomic conditions greatly influence the ability of healthcare workers to identify and treat the disease.

Background: From a population based study of epilepsy in Swedish children a subgroup designated well-functioning with an epilepsy diagnosis in 1997 was worked up from a medical point of view 10 years later. Aim: To describe the psychological and social outcome in this subgroup. Methods: Thirty-one patients aged 11-22 years and their parents/partners responded to a questionnaire according to Achenbach System of Empirically Based Assessment (ASEBA) to evaluate behavioural and emotional problems, and social competence. Results: Active epilepsy, diagnosed in 32%, was related to attention problems, somatic complaints, and school problems. Polytherapy, used in 16%, was related to attention problems and aggressive behaviour. School problems were found in six of seven children younger than 18 years. Internalizing, externalizing, and 'other' syndromes were found in 29% of the individuals, but a grouping of these syndromes in the clinical range only in two (6.5%), a girl with generalized tonic clonic seizures alone, and a boy with structural focal epilepsy. Both had active epilepsy and were treated with polytherapy. All ten individuals with Rolandic epilepsy were classified as normal. The answers to the ASEBA questionnaire of individuals and parents/partners were inconsistent, and parents generally stated more problems than the individuals. Summary.: This 10-year follow-up study of psychological and social outcome in well-functioning children and adolescents with childhood onset epilepsy shows some emotional, behavioural, and social problems. Thus, early information to increase knowledge about epilepsy and associated psychological co-morbidities in order to decrease risk of low self-esteem, social anxiety, and depression later in life is of importance.

Introduction: Epilepsy is one of the most common neurologic disorders in children and young adults. The prognosis depends on various conditions but the long-term prognosis regarding seizure freedom is positive in the majority of the children. Individuals with childhood-onset epilepsy are reported to have more problems in social functioning and psychological well-being compared with healthy control. The aim of this study was to investigate 10-year outcome of medical, psychological and social outcome in well-functioning individuals with childhood-onset epilepsy. Methods: Forty-five individuals and their parents completed a questionnaire regarding family history of epilepsy, febrile seizures, primary, mental retardation and behaviour disorders; and patients history of actual seizure situation, antiepileptic drug medication, febrile seizures, behaviour disorders, primary headaches, and schooling (Study I). Two families denied participation. Out of the remaining 45 families, 31 filled in a questionnaire - Achenbach System of Empirically Based Assessment (ASEBA) - assessing competence, adaptive functioning and behavioural/emotional problems (Study II). Results: The overall remission was 75.6%. Of the 11 with active epilepsy five had cryptogenic/ unknown or structural/symptomatic focal epilepsy; one had idiopathic photosensitive occipital epilepsy, one each with the diagnoses childhood absence epilepsy and juvenile absence epilepsy, and three with other idiopathic generalized epilepsies. The family history of epilepsy was 44% and of febrile seizures 17.7%. A coincidence of focal and generalized epilepsy phenotypes was found in some families. Behavioral, emotional and school problems were found in 29%. Those with active epilepsy had significantly more attention problems and somatic complaints than those in remission. Two individuals presented several problems in the clinical range. Conclusion: Longitudinal studies are of importance in epilepsy epidemiology. Early interventi

To characterize epileptic phenotype, electroencephalography (EEG) features, and epileptic evolution in patients with ring 14 r(14) syndrome.

We systematically reviewed the files of 51 infants presenting with infantile spasms and hypsarrhythmia in order to study the initial treatment strategies and the long term outcome. 80% of the infants were classified as symptomatic. In the nine participating centres, different treatment protocols were used, but the large majority of the children received vigabatrin as first line treatment. Second line options included hormonal treatment, topiramate and valproate. The time to reach cessation of infantile spasms was significantly shorter in the cryptogenic group than in the symptomatic group (50% at 13 days versus 66 days respectively) and was irrespective of the treatment used. The late follow up data (>2 years) showed that 60% of the children had epilepsy and that 75% of the children had a delay in their psychomotor development. Again, outcome in the cryptogenic group was better than in the symptomatic group, but also in the cryptogenic group, 50% of the children had a clear developmental delay, even if spasms were controlled early in the course of the disease. Our retrospective study illustrates that not only the underlying brain dysfunction is the major determinant for later outcome in infantile spasms (symptomatic group) but also even a short period of infantile spasms can be responsible for later developmental delay (cryptogenic group). (C) 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

In a previous study we reported difficulty with expressive language and visuoperceptual ability in preschool children with epilepsy and otherwise normal development. The present study analysed speech and language dysfunction for each individual in relation to epilepsy variables, ear preference, and intelligence in these children and described their auditory function. Twenty 6-year-old children with epilepsy (14 females, 6 males; mean age 6:5 y, range 6 y-6 y 11 mo) and 30 reference children without epilepsy (18 females, 12 males; mean age 6:5 y, range 6 y-6 y 11 mo) were assessed for language and auditory ability. Low scores for the children with epilepsy were analysed with respect to speech-language domains, type of epilepsy, site of epileptiform activity, intelligence, and language laterality. Auditory attention, perception, discrimination, and ear preference were measured with a dichotic listening test, and group comparisons were performed. Children with left-sided partial epilepsy had extensive language dysfunction. Most children with partial epilepsy had phonological dysfunction. Language dysfunction was also found in children with generalized and unclassified epilepsies. The children with epilepsy performed significantly worse than the reference children in auditory attention, perception of vowels and discrimination of consonants for the right ear and had more left ear advantage for vowels, indicating undeveloped language laterality.

Many people suffer from one or more epileptic seizures during life, but not all these people have epilepsy. Moreover, epilepsy is not one disease or syndrome, but a collection of different disorders, which have in common the repeated occurrence of unprovoked epileptic seizures during some time in life.There are many genetically determined and acquired causes of epilepsy. The symptomatology of the seizures can be very different. Also the course in time of epilepsies is very diverging. The cause, symptoms, signs and course are influenced to a great deal by age. Therefore, the epilepsies in childhood and in adulthood differ in many aspects. For this reason, children and adults should not be mixed in studies on epilepsy.

Purpose: We studied an eleven year-old girl with atypical, benign partial epilepsy who acutely presented a severe aphasia associated with marked EEG deterioration after lamotrigine administration. A parallel monitoring of language disorders and EEG changes during the gradual withdrawal of lamotrigine was performed in order to evaluate their possible correlation with lamotrigine administration. Methods: Detailed neuropsychological and linguistic examinations in association with awake and sleep EEG were periodically performed. Results: The evolution of the aphasic disorder was closely related to the EEG abnormalities, and disappeared after the withdrawal of lamotrigine. Conclusions: We considered the hypothesis that our case could be an expression of a paradoxical reaction to lamotrigine, in which the transitory aphasic disorder was sustained by an epileptiform electric activation.