Johannes Lemke, Holger Lerche and colleagues report the identification of de novo mutations in the potassium channel gene KCNA2 in patients with epileptic encephalopathies. The authors confirm in vitro that two mutations cause dominant loss of channel function, whereas the other two mutations induce gain-of-function effects, leading to permanently open channels. Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features1,2,3,4,5,6. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

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 <2 years of age.

Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE). Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017. Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%. Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.

Problem School and preschool teachers play a key role in the care of children with epilepsy. Yet, data about their knowledge on epilepsy are scarce. Methods Assessment of knowledge and attitudes towards epilepsy in teachers by conducting a questionnaire survey in Leipzig and Blankenburg, Germany, from August 2013 to January 2014. Results 1243 questionnaires were completed by 302 school teachers, 883 preschool teachers, 56 students and two unclassified participants. Of the respondents, 140 (11%) stated to have already been actively involved in an epilepsy emergency situation, another 148 (12%) as observers. Only 214 (17%) of respondents felt sufficiently prepared for an emergency. A rescue medication had already been applied by 79 (6%) of respondents; only 186 respondents (15%) stated they would be willing to administer a prescribed rescue medication under any circumstances. In response to an open-ended question about the most common fatal outcomes of a seizure, status epilepticus and drowning were rarely mentioned. 233 (19%) of respondents assumed that epileptic seizures cannot result in death. 606 (49%) of respondents were concerned about the legal repercussions to an incorrect response to a seizure.129/403 (32%) of teachers with >20 years of professional experience claimed never to have had a child suffering from epilepsy in their care, even though the prevalence of childhood epilepsy indicates that they should. In total, 1066 (86%) respondents expressed a desire to gain more knowledge on epilepsy. Conclusions Training programmes for teachers should be established. Furthermore, a clear legal regulatory framework needs to be set up.