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Abstract Genetic variants in relevant genes coexisting with MRI lesions in children with drug‐resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. Still, presurgical evaluation does not include genetic diagnostics routinely. Here, we report our presurgical evaluation algorithm that includes routine genetic testing. We analyzed retrospectively the data of 68 children with DRE operated at a mean age of 7.8 years (IQR: 8.1 years) at our center. In 49 children, genetic test results were available. We identified 21 gene variants (ACMG III: n = 7, ACMG IV: n = 2, ACMG V: n = 12) in 19 patients (45.2%) in the genes TSC1, TSC2, MECP2, DEPDC5, HUWE1, GRIN1, ASH1I, TRIO, KIF5C, CDON, ANKD11, TGFBR2, ATN1, COL4A1, JAK2, KCNQ2, ATP1A2, and GLI3 by whole‐exome sequencing as well as deletions and duplications by array CGH in six patients. While the results did not change the surgery indication, they supported counseling with respect to postoperative chance of seizure freedom and weaning of antiseizure medication (ASM). The presence of genetic findings leads to the postoperative retention of at least one ASM. In our cohort, the International League against Epilepsy (ILAE) seizure outcome did not differ between patients with and without abnormal genetic findings. However, in the 7/68 patients with an unsatisfactory ILAE seizure outcome IV or V 12 months postsurgery, 2 had an abnormal or suspicious genetic finding as a putative explanation for persisting seizures postsurgery, and 3 had received palliative surgery including one TSC patient. This study highlights the importance of genetic testing in children with DRE to address putative underlying germline variants as genetic epilepsy causes or predisposing factors that guide patient and/or parent counseling on a case‐by‐case with respect to their individual chance of postoperative seizure freedom and ASM weaning. Plain Language Summary Genetic variants in children with drug‐resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. However, presurgical evaluation does not include genetic diagnostics routinely. This retrospective study analyzed the genetic testing results of the 68 pediatric patients who received epilepsy surgery in our center. We identified 21 gene variants by whole‐exome sequencing as well as deletions and duplications by array CGH in 6 patients. These results highlight the importance of genetic testing in children with DRE to guide patient and/or parent counseling on a case‐by‐case with respect to their individual chance of postoperative seizure freedom and ASM weaning.

Abstract Although epilepsy surgery is the only curative therapeutic approach for lesional drug‐resistant epilepsy (DRE), there is reluctance to operate on infants due to a fear of complications. A recent meta‐analysis showed that epilepsy surgery in the first 6 months of life can achieve seizure control in about two thirds of children. However, robust data on surgical complications and postoperative cognitive development are lacking. We performed a retrospective multicenter study of infants who underwent epilepsy surgery in the first 6 months of life. 15 infants underwent epilepsy surgery at a median age of 134 days (IQR: 58) at four centers. The most common cause was malformation of cortical development, and 13 patients underwent a hemispherotomy. Two thirds required intraoperative red blood transfusions. Severe intraoperative complications occurred in two patients including death in one infant due to cardiovascular insufficiency. At a median follow‐up of 1.5 years (IQR: 1.8), 57% of patients were seizure‐free. Three patients where reoperated at a later age, resulting in 79% seizure freedom. Anti‐seizure medication could be reduced in two thirds, and all patients improved in their development. Our findings suggest that early epilepsy surgery can result in good seizure control and developmental improvement. However, given the perioperative risks, it should be performed only in specialized centers.

Abstract Objective Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox‐Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes. Methods In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. Results The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0‐72) years (235 children and adolescents, 76 adults). Therapy with CBD was off‐label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co‐medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). Significance Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children

Anti-neuronal autoantibodies can be transplacentally transferred during pregnancy and may cause detrimental effects on fetal development. It is unclear whether autoantibodies against synapsin-I, one of the most abundant synaptic proteins, are associated with developmental abnormalities in humans. We recruited a cohort of 263 pregnant women and detected serum synapsin-I IgG autoantibodies in 13.3% using cell-based assays. Seropositivity was strongly associated with abnormalities of fetal development including structural defects, intrauterine growth retardation, amniotic fluid disorders and neuropsychiatric developmental diseases in previous children (odds ratios of 3–6.5). Autoantibodies reached the fetal circulation and were mainly of IgG1/IgG3 subclasses. They bound to conformational and linear synapsin-I epitopes, five distinct epitopes were identified using peptide microarrays. The findings indicate that synapsin-I autoantibodies may be clinically useful biomarkers or even directly participate in the disease process of neurodevelopmental disorders, thus being potentially amenable to antibody-targeting interventional strategies in the future.

IntroductionEpilepsy patients with intellectual disability often suffer from drug-resistant epilepsy (DRE), which severely affects patients’ quality of life. Cenobamate (CNB) is a recently approved novel and effective ASM that can achieve high rates of seizure freedom in previously drug-resistant patients.MethodsWe performed a retrospective data analysis of the first patients treated with CNB at a single center. Outcome and treatment response were assessed at two different time points, and ASM burden was calculated.ResultsA 12 patients (7 males and 5 females) began treatment at a median age of 43 years, six of whom had developmental and epileptic encephalopathies. Prior to treatment with CNB, patients had tried a median of 13 different ASM. At the start of CNB therapy, patients were taking a median of 3 ASM. Treatment outcomes were available for 11 patients. After the first follow-up period (median 9 months), 55% of patients showed a significant seizure reduction of more than 50%, with three patients showing a reduction of more than 75% (27%). One patient achieved complete seizure freedom, while one patient did not respond to treatment. These response rates were consistently maintained at second follow-up after a median of 22 months. Ten patients (83%) reported adverse events (AE), the most common of which were dizziness and fatigue. No cases of drug reactions with eosinophilia and systemic symptoms (DRESS) were observed. The majority of AEs were mild and resolved over time. In addition, most patients were able to reduce their concomitant ASM.DiscussionCenobamate has been shown to be an effective ASM in patients with DRE and in patients with intellectual disabilities. After more than 1 year of treatment with CNB, close monitoring and management of drug–drug interactions may reduce enzyme-inducing ASMs and lead to better long-term outcomes. With CNB treatment, many patients can achieve a reduced overall drug burden while maintaining a reduction in seizures.

Maternal autoantibodies can be transmitted diaplacentally, with potentially deleterious effects on neurodevelopment. Synapsin 1 (SYN1) is a neuronal protein that is important for synaptic communication and neuronal plasticity. While monoallelic loss of function (LoF) variants in the SYN1 gene result in X-linked intellectual disability (ID), learning disabilities, epilepsy, behavioral problems, and macrocephaly, the effect of SYN1 autoantibodies on neurodevelopment remains unclear. We recruited a clinical cohort of 208 mothers and their children with neurologic abnormalities and analyzed the role of maternal SYN1 autoantibodies. We identified seropositivity in 9.6% of mothers, and seropositivity was associated with an increased risk for ID and behavioral problems. Furthermore, children more frequently had epilepsy, macrocephaly, and developmental delay, in line with the SYN1 LoF phenotype. Whether SYN1 autoantibodies have a direct pathogenic effect on neurodevelopment or serve as biomarkers requires functional experiments.

IntroductionIn one third of all patients with epilepsy, seizure freedom is not achieved through anti-seizure medication (ASM). These patients have an increased risk of earlier death, poorer cognitive development, and reduced quality of life. Cenobamate (CNB) has recently been approved as a promising novel ASM drug for the treatment of adults with focal-onset epilepsy. However, there is little experience for its application in pediatric patients.MethodsIn a multicenter study we evaluated retrospectively the outcome of 16 pediatric patients treated “off label” with CNB.ResultsIn 16 patients with a mean age of 15.38 years, CNB was started at an age of 15.05 years due to DRE. Prior to initiation of therapy, an average of 10.56 (range 3–20) ASM were prescribed. At initiation, patients were taking 2.63 (range 1–4) ASM. CNB was increased by 0.47 ± 0.27mg/kg/d every 2 weeks with a mean maximum dosage of 3.1 mg/kg/d (range 0.89–7) and total daily dose of 182.81 mg (range 50–400 mg). Seizure freedom was achieved in 31.3% and a significant seizure reduction of >50% in 37.5%. Adverse events occurred in 10 patients with fatigue/somnolence as the most common. CNB is taken with high adherence in all but three patients with a median follow-up of 168.5 daysConclusionCenobamate is an effective ASM for pediatric patients suffering from drug-resistant epilepsy. In addition to excellent seizure reduction or freedom, it is well-tolerated. Cenobamate should be considered as a novel treatment for DRE in pediatric patients.

Background: Neonatal drug-resistant epilepsy is often caused by perinatal epileptogenic insults such as stroke, ischemia, hemorrhage, and/or genetic defects. Rapid seizure control is particularly important for cognitive development. Since early surgical intervention and thus a short duration of epilepsy should lead to an optimal developmental outcome, we present our experience with hemispherotomy in an infant at the corrected age of 1 week.Methods: We report successful hemispherotomy for drug-resistant epilepsy in an infant with hemimegalencephaly at a corrected age of 1 week.Results: The infant was diagnosed with drug-resistant lesional epilepsy due to hemimegalencephaly affecting the left hemisphere. Given congruent electroclinical findings, we performed a left vertical parasagittal transventricular hemispherotomy after critical interdisciplinary discussion. No complications occurred during the surgery. Intraoperatively; 118 ml of red blood cells (30 ml/kg) and 80 ml of plasma were transfused. The patient has been seizure-free since discharge without further neurological deficits.Conclusion: We demonstrate that early epilepsy surgery is a safe procedure in very young infants if performed in a specialized center experienced with age-specific surgical conditions and perioperative management. The specific surgical difficulties should be weighed against the risk of life-long developmental drawbacks of ongoing detrimental epilepsy.

Background: Hemispherotomy is an epilepsy surgery procedure applied to cure particularly pharmacorefractory lesional epilepsy due to unihemispheric pathologies. Such a disconnection of an entire hemisphere is followed by reorganizational processes.Methods: We describe an acute aggravation of behavioral problems following a hemispherotomy in a patient treated with valproic acid, which subsided once valproate was discontinued.Results: A 9-year-old boy with drug-resistant epilepsy caused by the residua of a perinatal stroke treated for several years with valproic acid and lamotrigine underwent hemispherotomy. Shortly after surgery, minimal preoperative behavioral problems intensified dramatically, and aggression occurred as a new symptom. Assuming a correlation between valproate treatment and the postoperative altered neuronal network, we tapered off valproate. The behavioral problems decreased in intensity with the reduction of valproate dose and disappeared after drug discontinuation.Conclusion: We describe severe behavioral problems after hemispherotomy that subsided when valproate was tapered off. While we cannot rule out a spontaneous correction of a post-hemispherotomy network dysregulation, our report raises awareness to possible altered effects of the anticonvulsant valproic acid parallel to reorganizational processes after hemispherotomy.