The 4-Aminopyridine Model of Acute Seizures in vitro Elucidates Efficacy of New Antiepileptic Drugs

Up to date, preclinical screening for new antiepileptic substances is performed by a combination of different in vivo models of acute seizures, for which large numbers of animals are necessary. So far, little attention has been paid to in vitro models, which are also able to detect antiepileptic efficacy and in principle could likewise serve for exploratory preclinical screening. One of the established in vitro models of acute seizures is the 4-aminopyridine (4-AP) model. Previous studies have shown that the 4-AP model is capable to recapitulate the antiepileptic efficacy of standard antiepileptic drugs (AEDs) such as valproate or carbamazepine. Here, we employed a dual methodological approach using electrophysiology and optical imaging to systematically test the antiepileptic efficacy of three new-generation AEDs with distinct mechanisms of action (lacosamide, zonisamide, and levetiracetam). We found that frequency of 4-AP induced seizure like events (SLE) was the most sensitive parameter to detect dose-dependent antiepileptic effects in these compounds. Specifically, levetiracetam reduced SLE frequency while lacosamide and zonisamide at higher doses completely blocked SLE incidence. Analysis of the intrinsic optical signal additionally revealed a subiculum-specific reduction of the area involved in the propagation of ictal activity when lacosamide or zonisamide were administered. Taken together, our data adds some evidence that acute seizure models in vitro are in principle capable to detect antiepileptic effects across different mechanisms of action with efficacy similar to acute models in vivo. Further studies with negative controls, e.g., penicillin as a proconvulsant, and other clinically relevant AEDs are needed to determine if this acute in vitro model might be useful as exploratory screening tool. In view of the increasing sensitivity toward animal welfare, an affective in vitro model may help to reduce the number of laboratory animals deployed in burdening in vivo experiments and to preselect substances for subsequent testing in time- and cost-laborious models of chronic epilepsy

Etiology‐specific response to antiseizure medication in focal epilepsy

Objective: In focal epilepsy, data on the etiology-specific response to antiseizure medication (ASM) are surprisingly sparse. In this study, we sought to reappraise whether seizure outcome of pharmacological treatment is linked to the underlying etiology. Furthermore, we assessed ASM load with respect to the cause of epilepsy. Methods: Data were retrospectively obtained from the electronic database of the three sites of an academic adult epilepsy outpatient clinic. For each patient, presumed cause of epilepsy was categorized into one of nine etiological groups. Individual drug loads were calculated according to the 2020 World Health Organization Center for Drug Statistics Methodology ATC/DDD Index. Univariate and multivariate analyses were conducted to explore the association between different etiologies and outcome regarding 12-month seizure freedom as well as ASM load. Results: A total of 591 patients with focal epilepsy were included in the final analysis. Ischemic stroke was the etiology with the highest rate of 12-month terminal seizure freedom (71.2%, 95% confidence interval [CI] = 57.9-82.2) and, considering all etiological groups, was an independent predictor of seizure freedom (odds ratio = 2.093, 95% CI = 1.039-4.216). The lowest rates of seizure freedom were observed in patients with hippocampal sclerosis (28.2%, 95% CI = 15.0-44.9) and malformation of cortical development (16.7%, 95% CI = 2.1-48.4). In patients with ischemic stroke, median ASM load (1.0, interquartile range [IQR] = .5-1.8) was significantly lower compared to that in patients with hippocampal sclerosis (median = 1.8, IQR = 1.2-3.0, p = .008) and brain tumors (median = 1.7, IQR = .7-3.2, p = .049). Significance: Response to treatment with ASM is highly etiology-specific and best in patients with epilepsy due to ischemic stroke. Interestingly, this most favorable treatment outcome can be achieved by the lowest ASM load considering all etiological groups. In focal epilepsy, etiology should be taken into account when counseling patients about their expected seizure outcome with pharmacological treatment and when tailoring initial ASM doses

Valproic acid use in fertile women with genetic generalized epilepsies

Objectives: In genetic generalized epilepsies (GGE), valproic acid (VPA) is the most efficacious compound. However, due to teratogenicity and increased risk for impaired cognitive development after intrauterine exposure, its use in women of fertile age is strictly regulated but sometimes unavoidable. Methods: All patients with GGE treated at the outpatient clinic of a tertiary epilepsy center with at least one visit between January 2015 and April 2020 were included in this retrospective study. The rate of women aged 18 to 49 years taking VPA was compared to that of men of the same age group and to women > 49 years. Furthermore, in each group, clinical variables associated with VPA use were sought. Results: Twenty-eight out of 125 women of fertile age (22%) were treated with VPA, compared to 28 out of 56 men ≤ 49 years (50%; p = .002) and to 22 out of 40 female patients > 49 years (55%; p < .001). VPA dose was lower in fertile women compared to men, with no difference in seizure freedom rates. In women ≤ 49 years, multivariate analysis demonstrated age as the only variable independently associated with VPA use (OR 1.095; 95% CI 1.036-1.159). In the other two groups, no associated variables were identified. Conclusions: Despite warnings with respect to teratogenicity and impaired cognitive development with VPA, from 2015 to 2020, almost every fourth women of fertile age with GGE received this compound. Inevitably lower VPA doses in these women seem sufficient for favorable seizure freedom rates

Towards an Internationalization of the Information Systems Curriculum

Globalization has changed the requirements to professionals and students in all branches and sectors significantly in the past decade. However in the domain of Information Systems, these changes have not yet found their way into current study programs and curricula. We identify and validate core internationalization competences and their relation to IS specific competences based on an initial set of competence categories. This is the basis for designing learning services of the future. The presented study aims at validating both and identifying additional categories and competences. In this paper, we present the first results of this study focusing on the internationalization and knowledge management competences. The results can be used for different purposes exploring the human perspective on information systems development

Acute symptomatic seizures in the emergency room: predictors and characteristics

Background: When treating patients with epileptic seizures in the emergency room (ER), it is of paramount importance to rapidly assess whether the seizure was acute symptomatic or unprovoked as the former points to a potentially life-threatening underlying condition. In this study, we seek to identify predictors and analyze characteristics of acute symptomatic seizures (ASS). Methods: Data from patients presenting with seizures to highly frequented ERs of two sites of a university hospital were analyzed retrospectively. Seizures were classified as acute symptomatic or unprovoked according to definitions of the International League Against Epilepsy. Univariate and multivariate analysis were conducted to identify predictors; furthermore, characteristics of ASS were assessed. Results: Finally, 695 patients were included, 24.5% presented with ASS. Variables independently associated with ASS comprised male sex (OR 3.173, 95% CI 1.972-5.104), no prior diagnosis of epilepsy (OR 11.235, 95% CI 7.195-17.537), and bilateral/generalized tonic-clonic seizure semiology (OR 2.982, 95% CI 1.172-7.588). Alcohol withdrawal was the most common cause of ASS (74.1%), with hemorrhagic stroke being the second most prevalent etiology. Neuroimaging was performed more often in patients with the final diagnosis of ASS than in those with unprovoked seizures (82.9% vs. 67.2%, p < 0.001). Patients with ASS were more likely to receive acute antiseizure medication in the ER (55.9% vs. 30.3%, p < 0.001). Conclusions: In one quarter of patients presenting to the ER after an epileptic fit, the seizure had an acute symptomatic genesis. The independently associated variables may help to early identify ASS and initiate management of the underlying condition

Prognostic value of ‘late’ electroencephalography recordings in patients with cardiopulmonal resuscitation after cardiac arrest

Background: Electroencephalography (EEG) significantly contributes to the neuroprognostication after resuscitation from cardiac arrest. Recent studies suggest that the prognostic value of EEG is highest for continuous recording within the first days after cardiac arrest. Early continuous EEG, however, is not available in all hospitals. In this observational study, we sought to evaluate the predictive value of a 'late' EEG recording 5-14 days after cardiac arrest without sedatives. Methods: We retrospectively analyzed EEG data in consecutive adult patients treated at the medical intensive care units (ICU) of the Charite-Universitatsmedizin Berlin. Outcome was assessed as cerebral performance category (CPC) at discharge from ICU, with an unfavorable outcome being defined as CPC 4 and 5. Results: In 187 patients, a 'late' EEG recording was performed. Of these patients, 127 were without continuous administration of sedative agents for at least 24 h before the EEG recording. In this patient group, a continuously suppressed background activity < 10 mu V predicted an unfavorable outcome with a sensitivity of 31% (95% confidence interval (CI) 20-45) and a specificity of 99% (95% CI 91-100). In patients with suppressed background activity and generalized periodic discharges, sensitivity was 15% (95% CI 7-27) and specificity was 100% (95% CI 94-100). GPDs on unsuppressed background activity were associated with a sensitivity of 42% (95% CI 29-46) and a specificity of 92% (95% CI 82-97). Conclusions: A 'late' EEG performed 5 to 14 days after resuscitation from cardiac arrest can aide in prognosticating functional outcome. A suppressed EEG background activity in this time period indicates poor outcome

Dimethylethanolamine Decreases Epileptiform Activity in Acute Human Hippocampal Slices in vitro

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy with about 30% of patients developing pharmacoresistance. These patients continue to suffer from seizures despite polytherapy with antiepileptic drugs (AEDs) and have an increased risk for premature death, thus requiring further efforts for the development of new antiepileptic therapies. The molecule dimethylethanolamine (DMEA) has been tested as a potential treatment in various neurological diseases, albeit the functional mechanism of action was never fully understood. In this study, we investigated the effects of DMEA on neuronal activity in single-cell recordings of primary neuronal cultures. DMEA decreased the frequency of spontaneous synaptic events in a concentration-dependent manner with no apparent effect on resting membrane potential (RMP) or action potential (AP) threshold. We further tested whether DMEA can exert antiepileptic effects in human brain tissue ex vivo. We analyzed the effect of DMEA on epileptiform activity in the CA1 region of the resected hippocampus of TLE patients in vitro by recording extracellular field potentials in the pyramidal cell layer. Epileptiform burst activity in resected hippocampal tissue from TLE patients remained stable over several hours and was pharmacologically suppressed by lacosamide, demonstrating the applicability of our platform to test antiepileptic efficacy. Similar to lacosamide, DMEA also suppressed epileptiform activity in the majority of samples, albeit with variable interindividual effects. In conclusion, DMEA might present a new approach for treatment in pharmacoresistant TLE and further studies will be required to identify its exact mechanism of action and the involved molecular targets