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Wolf-Hirschhorn syndrome (WHS) is araredisorderwithan estimated prevalence being around 1 in 50,000 births. The syndrome is caused by the deletion of a critical region (Wolf-Hirschhorn Syndrome Critical region- WHSCR) on chromosome 4p16.3. WHS is clinically characterized by pre-and postnatal growth restriction, hypotonia, intellectual disability, craniofacial dysmorphismand congenital fusion anomalies. The clinical aspects are variable due to the deletion size.Consistently, epilepsy is one of the major concerns for parents and professionals caring for children with WHS. Seizures tend to occur in over 90% of patients, with onset within the first 3 years of life, and a peak incidence at around 6-12 months of age. Approximately 20% of patients had the first seizure onset within the first 6 months of age, almost 50% at 6 to 12 months of age and about 25% later than 12 months of age. The main types of epileptic seizures occurring in patients with WHS were generalized tonic-clonic seizures (around 70%). These were followed by tonic spasms (20%); focal seizures with impaired awareness (12%) and clonicseizures in 7% of patients.Seizures are often triggered by fever, followed by infections of various systems. Particularly, half of WHS patients experience status epilepticus in the first years of life, which can be fatal. Due to limited number of reports on the topic of EEG abnormalities in epilepsy among WHS patients, it is difficult to determine whether there are any characteristic deviations for WHS. Although more than 300 persons with WHS have been reported in the literature, there is sparse knowledge about epilepsy and methods of its anti-seizure medication (ASM) management with an assessment of their effectiveness. The purpose of this systematic review is to briefly summarize achievements and advances in the field of epilepsy in Wolf-Hirschhorn syndrome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Recently, precision medicine has attracted much attention in the management of epilepsies, but it remains unclear if the increasingly utilized ketogenic diet approaches can truly be considered precision medicine in all epilepsy treatment. Currently, it is the standard treatment for patients with GLUT1 deficiency and the latest NICE guidelines highlight ketogenic diet as a therapeutic option for multi-drug resistant epilepsy patients. Ketogenic diet is presumed to be a precision medicine tool when applied to the treatment of seizures secondary to GLUT1 transporter deficiency. In contrast, the genetic and epigenetic mechanisms modulated by ketogenic diet and underlying its efficacy in other epilepsy types can only be hypothesized to relate to mechanisms of neuroprotection, neuromodulation, and reduction of neuroinflammation. Early ketogenic diet initiation in well-selected patients, would allow immediate action in the direction of neuroprotection and modulation of neuroinflammation, ensuring higher success rates and lower "cost" to the patient in terms of quality of life and comorbidities. These considerations have fueled an increasing interest in investigating the efficacy, side effects, and adherence to long-term use of the ketogenic diet in epilepsy treatment in large contemporary cohorts, available within the scope of multicentric collaborations, such as the European Network for Therapy in Rare Epilepsies (NETRE). Future directions should involve the use of precision medicine, applied to each patient with the help of "omics", whose use should be expanded and inclusive., Competing Interests: Declaration of competing interest I declare that all authors have agreed to this final version of the paper being submitted to the journal and that all contributed equally or give details on the differences of contribution and that there are no conflicts of interest., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Objective: Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy., Methods: This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified., Results: A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity., Significance: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Epilepsy is a challenging multifactorial disorder with a complex genetic background. Our current understanding of the pathophysiology and treatment of epilepsy has substantially increased due to animal model studies, including canine studies, but additional basic and clinical research is required. Drug-resistant epilepsy is an important problem in both dogs and humans, since seizure freedom is not achieved with the available antiseizure medications. The evaluation and exploration of pharmacological and particularly non-pharmacological therapeutic options need to remain a priority in epilepsy research. Combined efforts and sharing knowledge and expertise between human medical and veterinary neurologists are important for improving the treatment outcomes or even curing epilepsy in dogs. Such interactions could offer an exciting approach to translate the knowledge gained from people and rodents to dogs and vice versa. In this article, a panel of experts discusses the similarities and knowledge gaps in human and animal epileptology, with the aim of establishing a common framework and the basis for future translational epilepsy research., Competing Interests: Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported., Methods: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp)., Results: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period., Conclusion: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Background: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline., Methods: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings., Findings: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits., Interpretation: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment., Funding: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation., Competing Interests: Declaration of interests SW received consultancy and speaker fees from UCB, Biocodex, Xenon, Zogenix, Lundbeck, Knopp Biosciences, Encoded MT received consultancy fees from Xenon. ECC received consultancy fees from Xenon, Knopp, these activities have been reviewed and approved by Baylor College of Medicine according to its policy on disclosure of outside interests. RSM received consultancy and speaker fees from EISAI and UCB. The remaining authors have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy., Methods: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified., Results: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures., Significance: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment., (© 2022 International League Against Epilepsy.)

Background: Childhood stroke is rare and can predispose to post-stroke epilepsy. The purpose of this study was to evaluate long-term quality of life (QoL) in patients with childhood stroke, focusing on epileptic aspects., Method: This involves a retrospective study of 98 patients with childhood stroke (pre- and neonatal strokes excluded), who had been inpatients between 1986 and 2003 for early rehabilitation. Data were obtained via interviews using a standardized questionnaire: QoL evaluation with KINDL, functional outcome with Barthel Index, and motor handicaps-assessment with modified Rankin Score., Results: Forty-nine of 98 patients (31 males, mean follow-up 16 years, range 8-25 years) were included. Six patients passed away (three of sudden unexpected death in epilepsy). At least one epileptic seizure occurred in 27/49 patients (occurrence: 2 days-13 years.; mean 3.3 years.). Epilepsy manifested in 19/49 patients. No correlation was found between the development of epilepsy and the location or etiology of the stroke. The presence of functional independence was significantly higher in seizure-free patients and in patients without epilepsy. For the external assessment (filled in for the patient by the parent/caregiver), there was no significant difference in QoL in patients with and without epilepsy; however, in the in-person KINDL questionnaire a significantly lower QoL was noted in epilepsy patients compared with patients without epilepsy., Conclusion: One important finding in our study is that in the long-term course 39% of patients developed epilepsy after a childhood stroke. It occurred as late as 13 years after the acute episode and affected the QoL especially in cognitively less handicapped patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC., Methods: We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence., Results: TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs., Conclusions: The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.

Nicolaides-Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via "Network Therapy of Rare Epilepsies (NETRE)" and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: None

The objective of this study was to gather evidence-based data on the educational needs of neuropediatricians. A needs assessment was conducted to identify the clinical challenges of physicians when diagnosing, medically treating, and managing pediatric patients with epilepsy; which could be addressed through educational interventions. A two-phase mixed-methods approach was used to conduct the needs assessment in Germany, Spain, and the US. Phase 1 consisted of qualitative data collection through multiple sources: a literature review, semi-structured interviews with clinicians and nurses working in pediatric epilepsy, and interpretation and input from faculty experts. Qualitative data were coded (NVivo) and analyzed using a thematic analysis, and findings were then used to design the second phase. Phase 2 consisted of quantitative data collection through an online survey that aimed to validate the identified challenges and underlying causes using a larger sample than in Phase 1. Data from the survey were analyzed using frequency tabulations and chi-square tests (SPSS). A total of 267 participants were included in the study. Phase 1 included 88 participants (neurologists, pediatricians, neuropediatricians, and nurses). Phase 2 included 179 participants (neurologists, pediatricians, and neuropediatricians). The main areas of challenge which emerged from the triangulated data included: the integration of guidelines into practice, identification of epilepsy and epilepsy events, integration of genetic testing into practice, integration of non-pharmacological treatments, transition from pediatric to adult care, and involvement and engagement with caregivers. Underlying causes of these challenges are reported, along with supporting qualitative findings. This study identified the educational needs of physicians working in pediatric epilepsy in Germany, Spain and the USA. Increasingly, educational interventions are required to be evidence-based. The results of this study could be used to design such interventions to support neuropediatricians who wish to specialize in pediatric epileptology, in order to manage the identified challenges.

Purpose: To identify risk factors for the development of epilepsy after pediatric stroke., Methods: Retrospective analysis of hospital charts of 93 children and adolescents with post-neonatal non-traumatic stroke and a minimum follow-up of two years. Seizures during the first 48 h after onset of stroke symptoms were defined as "early seizures"; when two or more seizures occurred after this period, the patient was classified as "epileptic"., Results: Early seizures, young age at stroke and MRI evidence of cortical involvement were observed more frequently in the children who developed epilepsy. These factors were, however, significantly interrelated; a stepwise multiple regression analysis in 46/93 patients with complete datasets identified only the occurrence of early seizures as a significant risk factor: 15/19 (79%) children with early seizures developed epilepsy, as opposed to only 7/53 (13%) without early seizures., Conclusion: Children with stroke who show seizures during the first 48 h after onset of stroke symptoms have a high risk to develop post-stroke epilepsy, whereas in children without early seizures, post-stroke epilepsy is rare., (Copyright © 2016. Published by Elsevier Ltd.)

Objective: To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment., Methods: Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire., Results: 7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion)., Conclusions: Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome., (Copyright © 2017 European Paediatric Neurology Society. All rights reserved.)

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To examine the role of mutations in GABRB3 encoding the β 3 subunit of the GABA A receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes., Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs., Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant β 3 , together with α 5 and γ 2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations., Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism., (© 2017 American Academy of Neurology.)

Objective: Most studies on seizure detection systems focus more on the effectiveness of devices than on their practicability in and impact on everyday life. Our study investigated the impact of a technical monitoring system on subjective quality of sleep and the lives of affected families. Furthermore, we evaluated the impact of anxiety levels on seizure monitoring and vice versa., Methods: Forty-three patients with newly diagnosed epilepsy were included. Initially, the families decided whether they did (group 1, n=27) or did not (group 2, n=16) want to use a monitoring device. In group 1, patients were randomly assigned to using Epi-Care® (group 1A, n=14) or an audio baby monitor (group 1B, n=13). Quality of life was assessed at two points (t1, at the start of the study and t2, at 5-7months of follow-up) using the SF-12, Kindl-R, and "Familien-Belastungs-Fragebogen" (German version of the "Impact on Family Scale"). In addition, parental anxiety was measured using the State-Trait Anxiety-Inventory, and subjective quality of sleep was measured using the Pittsburgh Sleep Quality Index. Statistical analysis focused on the possible differences between groups 1 and 2 that may influence parents' decisions and the effects of the presence and types of technical monitoring over time., Results: Anxiety levels were not significantly different between the groups with and without monitoring (group 1 vs. group 2). We also found no statistically significant, substantial baseline differences between the Epi-Care® and audio baby monitor groups, with at least medium effect sizes (group 1A vs. group 1B). Parents' health-related mental quality of life measured via the SF-12 increased significantly over time in all groups. By tendency, the fear of further seizures as well as the frequency of cosleeping arrangements in the monitoring group decreased during the study and approached the stable values of the control group., Significance: Individual parental anxiety levels are not crucial in the decision regarding the use of a monitoring device. A monitoring system may help some families in certain aspects of daily life. During the first months following a diagnosis of epilepsy, quality of life increases independently of the use of a monitoring system., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations., Methods: We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10.6 years)., Results: The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year., Significance: The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder., Method: Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months., Results: The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions., Significance: Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation., (Copyright © 2015. Published by Elsevier Ltd.)

Seizures are rarely reported in Williams-Beuren syndrome (WBS)--a contiguous-gene-deletion disorder caused by a 7q11.23 heterozygous deletion of 1.5-1.8 Mb--and no previous study evaluated electro-clinical features of epilepsy in this syndrome. Furthermore, it has been hypothesized that atypical deletion (e.g., larger than 1.8 Mb) may be responsible for a more pronounced neurological phenotypes, especially including seizures. Our objectives are to describe the electro-clinical features in WBS and to correlate the epileptic phenotype with deletion of the 7q11.23 critical region. We evaluate the electro-clinical features in one case of distal 7q11.23 deletion syndrome and in eight epileptic WBS (eWBS) patients. Additionally, we compare the deletion size-and deleted genes-of four epileptic WBS (eWBS) with that of four non-epileptic WBS (neWBS) patients. Infantile spasms, focal (e.g., motor and dyscognitive with autonomic features) and generalized (e.g., tonic-clonic, tonic, clonic, myoclonic) seizures were encountered. Drug-resistance was observed in one patient. Neuroimaging discovered one case of focal cortical dysplasia, one case of fronto-temporal cortical atrophy and one case of periventricular nodular heterotopia. Comparison of deletion size between eWBS and neWBS patients did not reveal candidate genes potentially underlying epilepsy. This is the largest series describing electro-clinical features of epilepsy in WBS. In WBS, epilepsy should be considered both in case of typical and atypical deletions, which do not involve HIP1, YWHAG or MAGI2., (© 2015 Wiley Periodicals, Inc.)

Objective: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations., Methods: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data., Results: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges., Conclusion: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent., (© 2015 American Academy of Neurology.)

Purpose: The literature on the efficacy and safety of rufinamide in childhood-onset epilepsy syndromes currently includes approximately 600 paediatric patients. This paper summarizes the views of a panel of experienced European epileptologists with regard to the current role of rufinamide in the treatment of childhood epilepsies., Results: Rufinamide is effective in decreasing the seizure frequency in the Lennox-Gastaut syndrome (LGS), especially tonic and atonic seizures. It might consequently be preferred to other drugs as a second-line treatment for LGS when drop-attacks are frequent. The mean responder rate in the published studies is 38% with seizure freedom achieved in 2.4% of patients. Rufinamide has shown some efficacy in epileptic encephalopathies other than LGS. It can be also effective as adjunctive therapy in children and adolescents with drug-resistant partial seizures. The available data suggest that rufinamide has an acceptable risk/benefit ratio with quite a low risk of aggravating seizures. Common adverse effects (somnolence, nausea and vomiting) are usually mild and self-limiting; they are more frequently observed during titration than in the maintenance phase, suggesting that low escalation rates might be associated with fewer adverse effects. Rufinamide appears to have a favourable cognitive profile compared with other antiepileptic drugs., Conclusion: Rufinamide is only approved for adjunctive treatment of seizures associated with LGS in children 4 years of age and older. There are very few data on rufinamide treatment at the onset of LGS or early in the course of the disorder; whether early treatment will improve outcome has yet to be determined., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To report on six patients with SCN1A mutations and malformations of cortical development (MCDs) and describe their clinical course, genetic findings, and electrographic, imaging, and neuropathologic features., Methods: Through our database of epileptic encephalopathies, we identified 120 patients with SCN1A mutations, of which 4 had magnetic resonance imaging (MRI) evidence of MCDs. We collected two further similar observations through the European Task-force for Epilepsy Surgery in Children., Results: The study group consisted of five males and one female (mean age 7.4 ± 5.3 years). All patients exhibited electroclinical features consistent with the Dravet syndrome spectrum, cognitive impairment, and autistic features. Sequencing analysis of the SCN1A gene detected two missense, two truncating, and two splice-site mutations. Brain MRI revealed bilateral periventricular nodular heterotopia (PNH) in two patients and focal cortical dysplasia (FCD) in three, and disclosed no macroscopic abnormality in one. In the MRI-negative patient, neuropathologic study of the whole brain performed after sudden unexpected death in epilepsy (SUDEP), revealed multifocal micronodular dysplasia in the left temporal lobe. Two patients with FCD underwent epilepsy surgery. Neuropathology revealed FCD type IA and type IIA. Their seizure outcome was unfavorable. All four patients with FCD exhibited multiple seizure types, which always included complex partial seizures, the area of onset of which co-localized with the region of structural abnormality., Significance: MCDs and SCN1A gene mutations can co-occur. Although epidemiology does not support a causative role for SCN1A mutations, loss or impaired protein function combined with the effect of susceptibility factors and genetic modifiers of the phenotypic expression of SCN1A mutations might play a role. MCDs, particularly FCD, can influence the electroclinical phenotype in patients with SCN1A-related epilepsy. In patients with MCDs and a history of polymorphic seizures precipitated by fever, SCN1A gene testing should be performed before discussing any epilepsy surgery option, due to the possible implications for outcome., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Childhood epilepsies comprise a heterogeneous group of disorders and syndromes that vary in terms of severity, prognosis and treatment requirements. Effective management requires early, accurate recognition and diagnosis, and a holistic approach that addresses each individual's medical and psychosocial needs within the context of their overall health status and quality of life. With increasing understanding of underlying aetiologies, new approaches to management and treatment are emerging. For example, genetic testing is beginning to provide a tool to aid differential diagnosis and a means of predicting predisposition to particular types of epilepsy. Despite the availability of an increasing number of antiepileptic drugs (AEDs)--due not only to the development of new AEDs, but also to changes in regulatory requirements that have facilitated clinical development--seizure control and tolerability continue to be suboptimal in many patients, and there is therefore a continuing need for new treatment strategies. Surgery and other non-pharmacological treatments (e.g. vagus nerve stimulation, ketogenic diet) are already relatively well established in paediatric epilepsy. New pharmacological treatments include generational advances on existing AEDs and AEDs with novel modes of action, and non-AED pharmacological interventions, such as immunomodulation. Emerging technologies include novel approaches allowing the delivery of medicinal agents to specific areas of the brain, and 'closed-loop' experimental devices employing algorithms that allow treatment (e.g., electrical stimulation) to be targeted both spatially and temporally. Although in early stages of development, cell-based approaches (e.g., focal targeting of adenosine augmentation) and gene therapy may also provide new treatment choices in the future., (Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: This multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy., Method: This study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months., Results: A total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean±SD age was 15.9±6.80 years and the age range was 4-38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p=0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p=0.4612) and 51 (47.4% group A; 39% group B; p=0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p=1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B., Conclusion: Lacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures., (Copyright © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Aim: Febrile infection-related epilepsy syndrome (FIRES) is an enigmatic seizure disorder in childhood with an innocuous febrile infection triggering severe and intractable multifocal epilepsy, mostly with status epilepticus. FIRES shares several phenotypic features with epilepsies seen in patients with protocadherin 19 (PCDH19), sodium channel protein type 1 subunit alpha (SCN1A), and DNA polymerase subunit gamma-1 (POLG) mutations. The aim of the study was the mutation analysis of these prime candidate genes in a cohort of patients with FIRES. Additionally, given that rare copy number variations (CNVs) have recently been established as important risk factors for epilepsies, we performed a genome-wide CNV analysis., Method: We analysed the protein coding region, including splice sites of the three candidate genes in 15 patients (eight males, seven females) with FIRES (age at onset 3-15 y, median 6) using Sanger sequencing. Inclusion criteria were a status epilepticus without identifiable cause and a preceding febrile infection in previously healthy children. In addition, we performed genome-wide human single-nucleotide polymorphism 6.0 arrays in a subset of 10 patients to identify pathological CNVs., Results: We could not identify the most likely pathogenic mutations or CNVs in FIRES., Interpretation: Mutations in PCDH19, SCN1A, POLG, or CNVs are not responsible for FIRES., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

Febrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1,000,000. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: This open-label extension evaluated the long-term efficacy and tolerability of rufinamide in patients with Lennox-Gastaut syndrome (LGS) who had previously completed a 12-week double-blind study., Materials and Methods: In total, 124 patients (aged 4-37 years), receiving 1-3 concomitant antiepileptic drugs, were treated with rufinamide approximately 25-60 mg/kg/day. Efficacy was assessed by seizure frequency; tolerability by adverse events (AEs) and laboratory tests., Results: Overall, patients were treated with rufinamide for a median (range) of 432 (10-1149) days. Reductions in seizure frequency were observed throughout the study; during the last 12 months of treatment, 41.0% and 47.9% of patients had > or = 50% reduction in total and tonic-atonic seizure frequency, respectively. The most common AEs were vomiting (30.6%) and pyrexia (25.8%)., Conclusions: In this open-label extension, rufinamide appeared to be an effective long-term adjunctive therapy for the treatment of LGS-associated seizures in children and young adults.

Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3-15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2-14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2-42 cells/microl (median 5 cells/microl) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy-refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection-related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term "febrile infection-related epilepsy syndrome" (FIRES).

Objective: Recently, we published the first postmarketing European experience with rufinamide (RUF) in a retrospective 12-week observational study. This follow-up report summarizes the long-term effectiveness and tolerability of RUF after 18 months for the same patient sample., Methods: In total, 52 of 60 initially included patients from eight centers in Germany and Austria (45 children and 15 adults aged 1-50 years) with various severe and inadequately controlled epilepsy syndromes continued treatment with RUF after the initial 3-month observation period (mean final dose: 38.2+/-17.3mg/kg/day). Efficacy was assessed by seizure frequency evaluated by comparison with baseline frequency. Tolerability was evaluated by analysis of parental report of adverse events and laboratory tests. Responders were defined as patients who achieved a 50% or greater decrease in countable seizures within 18 months of initiating RUF therapy., Results: Mean overall duration of RUF treatment was 14.5 months (range: 3-18 months). Retention rate, defined as the percentage of patients still taking RUF after 18 months, was 41.7% (n=25/60). The overall response rate after 18 months was 26.7% (16/60 patients). The highest response rates were found in the subgroup of patients with Lennox-Gastaut syndrome (LGS, 35.5%) and in patients with other generalized epilepsy syndromes. Complete seizure control was maintained in one patient (1.6%). A total of 73 adverse events were reported in 37 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (15.0%), and loss of appetite (10.0%). Only 4 new adverse events were reported after week 12. No serious adverse events were observed., Conclusions: The present data suggest that RUF is efficacious and well tolerated in the long-term treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

This prospective, observational, single arm, monocentric study explored efficacy and tolerability outcomes of rapid oral initiation of topimarate in children with difficult to treat epilepsy. The study population consisted of 19 multiply handicapped children (mean age 4.4 years, range 0.6-15.3 years). The observation period was 12 weeks and included 7 visits. The mean initial dose of topiramate was 1.1 mg/kg body weight/d (range: 0.66-2.67 mg/kg/d) following rapid titration. The mean final dose was 3.3 mg/kg/d (range 0.5-6.7 mg/kg/d). An at least 50% reduction of seizure frequency compared to baseline was observed in 9 of 19 patients (47.4%). Six patients (31.6%) had a slight reduction of seizure frequency (<50%) and 4 patients (21.1%) experienced an increase of seizure frequency. A total number of 29 adverse events were documented in 17 of 19 patients. Most frequently captured were fatigue (26.3% of patients), decreased appetite (15.8%) and psychiatric disturbances (15.8%). No serious adverse events were reported. These data might suggest that in certain clinical circumstances rapid dose escalation with topiramate followed by a low maintenance dose might be a good therapeutic option for pediatric patients with difficult to treat epilepsy., ((c) Georg Thieme Verlag KG Stuttgart, New York.)

Objective: The aim of the study was to explore the effectiveness and tolerability of rufinamide in a heterogeneous group of patients with refractory epilepsies in Europe, immediately after the drug became available as an orphan drug for the adjunctive treatment of Lennox-Gastaut syndrome (LGS)., Methods: This observational study was conducted as a collection of retrospective data from multiple centers in Germany and Austria. Clinical course in patients treated with rufinamide was documented. Initial dosage and titration schedule of rufinamide were at the discretion of the treating physician according to medical need. The observation period was 12 weeks. Effectiveness was evaluated by comparing the frequency of seizures with limitations to the countability between baseline and the last 4-week period of observation., Results: The study population consisted of 45 children and 15 adults (mean age: 14.5+/-11.6 years, range: 1-50) with various severe and inadequately controlled epilepsy syndromes, that is, LGS (n=31), idiopathic generalized epilepsy syndromes (n=5), cryptogenic unclassified generalized epilepsy (n=7), and partial epilepsy (n=17). The response rate (50% reduction in countable seizures) was 46.7% (28 of 60 patients) in total; 25.0% experienced a 75% reduction in seizure frequency and 21.7% experienced a 50-75% reduction. Complete seizure control was achieved by 8.3%. The highest response rate was observed in patients with LGS (17/31, 54.8%), and the lowest in patients with partial epilepsy (4/17, 23.5%). Response rate in patients with unclassified generalized epilepsy was 42.8% (3/7 patients). A total of 67 adverse events were reported by 35 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (13.3%), and loss of appetite (10.0%). No serious adverse events were observed., Conclusions: These preliminary data suggest that rufinamide may be effective and well tolerated in the treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures. The results of our study suggest that the efficacy of rufinamide in patients with generalized epilepsy might be comparable to that in patients with LGS, whereas rufinamide was less effective in patients with partial epilepsy.

Lennox-Gastaut syndrome is one of the most severe epileptic encephalopathies of childhood onset. The cause of this syndrome can be symptomatic (ie, secondary to an underlying brain disorder) or cryptogenic (ie, has no known cause). Although Lennox-Gastaut syndrome is commonly characterised by a triad of signs, which include multiple seizure types, slow spike-wave complexes on electroencephalographic (EEG) recordings, and impairment of cognitive function, there is debate with regard to the precise limits, cause, and diagnosis of the syndrome. Tonic seizures, which are thought to be a characteristic sign of Lennox-Gastaut syndrome, are not present at onset and the EEG features are not pathognomonic of the disorder. There are few effective treatment options for the multiple seizures and comorbidities, and the long-term outlook is poor for most patients. Probably as a result of the complexity of the disorder, only a few randomised trials have studied Lennox-Gastaut syndrome, and thus many of the drugs that are more commonly used have little or no supporting evidence base from controlled trials. In this Review, we discuss the main issues with regard to the diagnosis and treatment options available. We also suggest key considerations for future trials and highlight the importance of a comprehensive approach to the assessment and management of this syndrome.

From the 15th century to the present day, Christian art has portrayed people who suffer from epilepsy as attributes in illustrations of Saint Valentine (SV). The objective of our study was to interpret the works of art from a modern epileptological perspective on the basis of a collection of portrayals of SV in Europe that was as comprehensive as possible. The people depicted as attributes were analyzed with respect to their age, gender, social status, and possible seizure semiology. Three hundred forty-one illustrations of SV from Austria, Belgium, Croatia, Czech Republic, France, Germany, Hungary, Ireland, Italy, Luxembourg, Poland, Scotland, Slovakia, and Switzerland were systematically analyzed. Irrespective of the age of the work of art, among the 143 pictures of people with possible epilepsy characteristics, there were more males than females from various levels of society. As far as could be interpreted, there were 17 infants, 35 children, 7 adolescents, and 84 adults. With respect to possible seizure semiology, infantile spasms (n=10), atonic seizures (n=13), tonic seizures (n=53), absences (n=2), psychogenic seizures (n=4), and postictal or undefinable states (n=61) were differentiated in a subjective assessment. Despite the fact that from a modern perspective, the 15th to 20th centuries in Europe seemed to be dominated by a rather superstitious attitude toward epilepsy, there is striking accuracy in the detail of the semiology in many of the historic portrayals, and a well-founded knowledge of epilepsy is apparent.

Background: Lennox-Gastaut syndrome is a catastrophic pediatric epilepsy syndrome characterized by multiple types of treatment-resistant seizures and high rates of seizure-related injury. Current available treatments are inadequate, leaving patients with few treatment options and opportunities., Methods: We conducted a double-blind, randomized, placebo-controlled trial of the antiepileptic drug rufinamide in patients with Lennox-Gastaut syndrome. Eligible patients between 4 and 30 years of age had multiple types of seizures (including tonic-atonic and atypical absence seizures) with a minimum of 90 seizures in the month before baseline and a recent history of a slow spike-and-wave pattern on EEG., Results: After a 28-day baseline period, 139 eligible patients were randomized; 138 patients received either rufinamide (n = 74) or placebo (n = 64) in addition to their other antiepileptic drugs. The median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7% vs 11.7%, p = 0.0015). There was a difference (p < 0.0001) in tonic-atonic ("drop attack") seizure frequency with rufinamide (42.5% median percentage reduction) vs placebo (1.4% increase). The rufinamide group had a greater improvement in seizure severity (p = 0.0041) and a higher 50% responder rate compared with placebo for total seizures (p = 0.0045) and tonic-atonic seizures (p = 0.002). The common adverse events (reported by >or=10% of patients receiving rufinamide) were somnolence (24.3% with rufinamide vs 12.5% with placebo) and vomiting (21.6% vs 6.3%)., Conclusions: Rufinamide was an effective and well-tolerated treatment for seizures associated with Lennox-Gastaut syndrome.

Objective: To assess the efficacy and tolerability of Levetiracetam (LEV) in children and adolescents with refractory epilepsy with a special interest in the long-term retention rate., Method: One hundred and twenty-nine patients (83 male, 46 female; mean age 10.6 years/range: 6 months-39 years 9 months) were included in a prospective, open-label, add-on trial of LEV for up to 3 years. All patients had severe forms of epilepsy starting before the age of 10 often accompanied by mental retardation. Primary outcome measures were changes in seizure frequency after 6 months on the medication with LEV, with initial responders (>50% seizure reduction). Further objective was the retention rate of LEV therapy after 3 years defined as percentage of patients still taking LEV., Results: Thirty-five patients (27.1%) were initial responders of which 5 became seizure free. The average maximum LEV dosage was 39.8 mg/kg/day (range: 6-70 mg/kg/day) with no difference responders vs. no responders. The retention rate for responders after 3 years was 22.5%. The rate of side effects was 39.8% in all patients, with the most frequent side effects being fatigue (12.5%), aggressiveness (7.8%) and gastrointestinal disorders (13.3%)., Conclusions: Our study in patients with refractory epilepsy suggests that our initial responders were very likely to be still taking LEV after 3 years. We therefore consider treatment with LEV in this special group of patients with refractory epilepsy a promising therapeutic option, because of its favourable tolerance profile, the option of fast titration and the absence of drug interactions.

Background: It is known that most adult patients with epilepsy often have poor knowledge of their disorder, treatment options, and social and vocational consequences, despite the huge amount of information available. Being pressed for time, health care professionals often are not able to provide the repetitive counseling and instruction necessary to address epilepsy care adequately. Therefore educational programs are considered extremely important in filling the gap., Method: For German-speaking countries, two educational programs called famoses, modulares Schulungsprogramm Epilepsie fur Familien [modular service package epilepsy for families], were developed by a multidisciplinary group of neuropediatricians, psychologists, social workers, and educators. The aims of the famoses programs are to improve children's and parents' knowledge about epilepsy and to help patients of childhood age and their parents achieve a better understanding of their disease, gain more self-confidence, and reduce specific fears regarding epilepsy. famoses comprises two different educational programs: famoses for kids with epilepsy within the developmental period of ages 7 to 13, and famoses for parents or caretakers. The programs are designed for interactive small-group education., Results: The child-centered educational program is based on a fictional story: The children are sailors on a virtual cruise, sailing from island to island, accompanied by educated trainers. On each island there is something new to discover about epilepsy. The parent (and caretaker)-centered educational program covers different topics-overview and content of the program, basic knowledge, diagnostics, therapy, prognosis and development, and living with epilepsy-within six modules. The program was implemented in Germany and Switzerland in the spring of 2005 and is now operating in different epilepsy centers., Conclusion: Within comprehensive therapeutic management of epilepsy, educational programs for patients, and for parents (caretakers) of children with epilepsy, are considered to be extremely important. Such educational programs have two main goals: to increase knowledge about the disorder, and to strengthen the patients' responsibility for themselves, with the consequence of living with as few limitations as possible. famoses is an effective component of this comprehensive care. The program has been operating successfully in different epilepsy centers in Germany and Switzerland since the spring of 2005.

Purpose: Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. We provide an update on hepatotoxic side effects in Germany between 1994 and 2003., Methods: We mailed a questionnaire to all members of the German Section of the International League Against Epilepsy, asking for VPA-induced side effects, especially severe side effects such as hepatopathy., Results: As a result of our questionnaire, we found 31 cases of reversible hepatotoxicity and nine cases of lethal hepatopathies in Germany from 1994 to 2003., Conclusions: The outcome of patients with severe hepatotoxicity is better than that in the past. The risk of a VPA-induced hepatopathy is not limited to patients younger than 2 years, receiving polytherapy, or patients with congenital or acquired metabolic diseases.

Purpose: To evaluate the efficacy and tolerability of Levetiracetam (LEV) in a large pediatric cohort with drug-resistant epilepsy from a prospective multicenter observational study., Methods: We report the results of a multicenter observational survey of a cohort of 285 pediatric patients (mean: 9.9 years, range: 0; 6-17; 11) with refractory generalized and focal epilepsy who received Levetiracetam as an add-on open label treatment trial. The average duration of epilepsy was 6.0 years and the patients were treated with a mean of 7.0 antiepileptic drugs (AED) before LEV was introduced., Results: No serious persistent adverse events were reported. Reversible colitis and an apnoea syndrome in a child with phosphorylase-A-kinase-deficiency were noted. Mild to moderate side effects were reported in 128 patients (44.9%), consisting most frequently of somnolence (23.9%), general behavioral changes (15.4%), aggression (10.5%) and sleep disturbances (3.2%). In 209 patients, efficacy was analyzed over a treatment period of at least 12 weeks compared to a baseline of 2 weeks. Thirteen patients (6.2%) became seizure free, 39 (18.7%) responded with a seizure reduction of more than 50% following introduction of LEV. No response to LEV was reported in 65.1% (n=136). A decrease of initial treatment effect was seen in 37 patients (17.8%) while in 6.7% the seizure frequency doubled to the baseline (n=14). In seven patients (3.3%), the effect of LEV on seizure frequency could not be evaluated. A positive psychotropic effect was observed in 18 patients (8.6%). Mental retardation was associated with poor response and associated with more side effects and earlier discontinuation of LEV therapy., Conclusion: LEV is a well-tolerated new AED that may effectively improve seizure control as an add-on drug in resistant epilepsy in childhood with good tolerability. However, neurologically handicapped children appear at increased risk for reversible neurocognitive side effects and have a poorer treatment response.

Our purpose was to compare the initial efficacy and retention at 5 years of lamotrigine (LTG) and vigabatrin (VGB) in patients with severe childhood-onset epilepsies, especially with regard to loss of efficacy. Add-on therapy in 95 young patients with severe epilepsies in a neuropaediatric department was prospectively followed in open label studies for up to 5 years. VGB group: 56 patients (mean age: 11.1 years). LTG group: 39 patients (mean age: 13.6 years). Definition of initial responders: more than 50% reduction in seizure-frequency after 6 weeks of VGB treatment or after 4 months of LTG treatment. Definition of retention at 5 years: percentage of patients still taking LTG or VGB after 5 years. Definition of loss of efficacy: return to the baseline seizure frequency. The results were: VGB group: after 6 weeks 18 of 56 patients (32%) were initial responders. The retention at 5 years was five of 56 patients (8.9%). One patient (1.8%) was still seizure free. A loss of efficacy occurred in 10 of the 18 initial responders, usually within the first 9 months after the initial response. In the LTG group, after 4 months, 11 of 39 patients (28%) were initial responders. The retention at 5 years was 10 of 39 patients (25.6%). Five patients (12.8%) were still seizure free. The rate of adverse events was equal in both groups (41%). All but one occurred within the first 6 months of treatment. Our study in patients with difficult to treat childhood epilepsies suggests that in clinical practice patients were less likely to be discontinued from LTG than from VGB within 5 years, after similiar initial efficacy. This was mainly due to a loss of efficacy in VGB treatment early after initial response.

We used two strategies to investigate a possible link between predisposition for epilepsy and mutations in the fragile X mental retardation-1 gene. The first entailed performing electroencephalography on 14 patients with an amplification in the fragile X mental retardation-1 gene, and the second involved molecular genetic analysis of the fragile X mental retardation-1 gene in 16 children with benign childhood epilepsy with centrotemporal spikes (BECT, Rolandic epilepsy). Fourteen young male patients with fragile X syndrome, verified by a full mutation in exon 1 of the fragile X mental retardation-1 gene, were studied by electroencephalography. In eight boys aged between 4-8 years we observed focal sharp waves, activated by sleep. In six of these patients, partial seizures occurred during sleep. We detected no epileptiform electroencephalographic abnormalities under the age of 4 and over the age of 8. In 16 children with Rolandic epilepsy who were studied for fragile X gene mutations, one boy proved to carry a fragile X premutation. In the waking state electroencephalography of a 5-year-old girl with a premutation in one of her fragile X mental retardation-1 genes, we found groups of generalized spike wave complexes. Our observations suggest a possible impact of the fragile X mental retardation-1 gene mutations on brain maturation and epileptogenesis.

This article, published in the journal Neuropediatrics, discusses the use of videos taken by parents as a diagnostic tool for the diagnosis of KCNQ2-related self-limiting familial neonatal epilepsy (SLFNE). The study analyzed videos taken by parents of three affected families, which showed neonates experiencing seizures with focal onset and changing manifestation throughout the seizure. The family history of each affected neonate was conclusive, as one parent in each family had also experienced seizures in the same timeframe after birth. Genetic testing confirmed a mutation in the KCNQ2 gene in the affected children and at least one parent in all three families. The authors suggest that analyzing these videos, along with the positive family history, can aid in the diagnosis of SLFNE and promote early genetic testing and treatment initiation. [Extracted from the article]

Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A -associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. We report 21 patients with SCN2A -associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1–2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype–phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A -associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Our study describes the heterogeneous clinical spectrum of SCN2A -associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%. • Pathogenic variants in SCN2A are associated with episodic ataxia (EA). • EA is often accompanied by early-infantile onset epilepsy. • Developmental outcome is favorable in most of these patients. • Two mutational hotspots for SCN2A -associated EA were identified. • Acetazolamide shows positive treatment effects in around half of the patients. [ABSTRACT FROM AUTHOR]

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We report on a male proband with pyridoxine-dependent epilepsy (PDE) and neonatal seizure onset. At the age of 31 months, a prolonged status epilepticus led to severe neurological regression with cortical blindness, loss of speech and muscular hypotonia with slow recovery over the following 3 months. At 33 months of age pyridoxine therapy was initiated with excellent response and the boy remained seizure-free on pyridoxine monotherapy, except for two occasions with seizure recurrence 10 days after accidental pyridoxine withdrawal. alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) deficiency was indicated by elevated pipecolic acid concentrations in plasma and alpha-aminoadipic semialdehyde excretion in urine. Molecular analysis of the antiquitin gene revealed a novel missense mutation c.57insA, while the mutation of the other allele remained unidentified so far. Despite the delay in diagnosis and prolonged status epilepticus, neuropsychological evaluations at the ages of 11 and 18 years demonstrated full-scale IQ of 93 and 92, respectively, with better verbal IQ (103 and 101) than performance IQ (85 and 82). [ABSTRACT FROM AUTHOR]

We report on a 5-year-old boy with methylmalonic aciduria, an autosomal recessive inborn error of metabolism leading to accumulation of methylmalonic-CoA and thereby causing intoxication with leading symptoms of hyperammonaemia and metabolic acidosis. l-lyperammonemia itself causes brain oedema. In our patient, this led to a vast metabolic stroke of the left hemisphere and subsequent pharmacoresistant epilepsy. Guided by his main seizures - drop attacks - the orphan drug rufinamide (RUF) was introduced as "off-label use" and led to freedom of drop attacks and tonic-clonic seizures over a period of 14 months as well as normalisation of the electroencephalogramm. Only once during an episode of fever and diarrhoea with reduced level of RUF did some provoked seizures with focal complex semiology for the time period of infection occur. In the 16 months follow-up, the patient also improved in his development, showing a more stable gait with the hemiparesis and understanding more complex sentences. [ABSTRACT FROM AUTHOR]