Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

Thiamine pyrophosphate (TPP) is an essential cofactor of the cytosolic transketolase and of three mitochondrial enzymes involved in the oxidative decarboxylation of either pyruvate, α-ketoglutarate or branched chain amino acids. Thiamine is taken up by specific transporters into the cell and converted to the active TPP by thiamine pyrophosphokinase (TPK) in the cytosol from where it can be transported into mitochondria. Here, we report five individuals from three families presenting with variable degrees of ataxia, psychomotor retardation, progressive dystonia, and lactic acidosis. Investigation of the mitochondrial energy metabolism showed reduced oxidation of pyruvate but normal pyruvate dehydrogenase complex activity in the presence of excess TPP. A reduced concentration of TPP was found in the muscle and blood. Mutation analysis of TPK1 uncovered three missense, one splice-site, and one frameshift mutation resulting in decreased TPK protein levels.

Summary:Purpose: To assess the prevalence of hyperhomocysteinemia in pediatric patients treated with antiepileptic drugs (AEDs) and to evaluate the effect of folic acid supplementation on plasma total homocysteine (tHcy) concentrations in hyperhomocysteinemic patients.Methods: 123 patients from three regional hospitals participated in the study. Patients with hyperhomocysteinemia were included in a 3-month double-blind randomized trial testing oral folic acid supplementation (1 mg/day) versus placebo.Results: Hyperhomocysteinemia (tHcy >10.4 µmol/L) was present in 19 of 123 patients. Patients with hyperhomocysteinemia were older (13.7 ± 4 vs. 11.0 ± 3.9 years) and had significantly lower folate and cobalamin concentrations. Multidrug (two or more) AED treatment and duration of therapy correlated significantly with elevated total homocysteine (tHcy) and low folate. In contrast, polymorphisms in the methylene tetrahydrofolate reductase gene (MTHFR 677 C→T, 1298 A→C, 1793 G→A) had no significant impact on tHcy. Nine of 19 patients with hyperhomocysteinemia were randomized to placebo, whereas the remaining 10 patients received folic acid supplementation. Folic acid supplementation resulted in a significant increase of folate and decrease of tHcy, whereas both parameters remained unchanged in the placebo group.Conclusions: Hyperhomocysteinemia is present in 15.5% of children receiving long-term AED treatment. Multidrug treatment and long duration of therapy enhance the risk for hyperhomocysteinemia. Folic acid supplementation significantly reduces tHcy. We recommend assessment of serum folate and plasma tHcy in children receiving AEDs.

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.

Objective This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies. Patients and Methods This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course of the first pediatric patients treated in these centers with PER was documented with the help of a questionnaire completed by the treating physicians. Effectiveness and adverse effects were evaluated. The study population consisted of 58 patients (mean age, 10.5 years; range, 2-17 years), suffering from various refractory epilepsies, classified as focal epilepsy (n ¼ 36), unclassified generalized epilepsy (n ¼ 12), Lennox-Gastaut syndrome (n ¼ 5), West syndrome (n ¼ 3), and Dravet syndrome (n ¼ 2). Results The response rate (! 50% seizure reduction) after the first 3 months of therapy was 31% (18/58 patients) in total. Complete seizure control was achieved in five patients (9% overall). Aggravation of seizures occurred in five cases (9%). The most frequently occurring adverse effects were reduced vigilance or fatigue (n ¼ 16) and behavioral changes (n ¼ 14). Discussion PER seems to be effective also in children and adolescents with pharmacorefractory epilepsies. Tolerability was acceptable.