Normalization and cross-sectional validation of an extended Adverse Event Profile (E AEP) in a large cohort of patients with epilepsy.

PURPOSE: The Liverpool Adverse Event Profile (L AEP) is commonly used in clinical practice and pharmacological trials for the monitoring of side effects of anti-seizure medication (ASM). However potentially unrelated, additional symptoms and normative data should be considered to put patients´ complaints into perspective. METHODS: An extended 32-item AEP (E AEP) was given to 537 healthy subjects and 1,605 patients with epilepsy as part of the Bonn ASM side effect registry. The tool was factor-analyzed, corrected for age, gender, and repeated application, and related to drug load and individual substances (with N> 100) on item and scale level (total E AEP and its subscales cognition, dizziness, energy, mood, bodily symptoms, aggression, and sexuality). RESULTS: Compared to non-normalized results, at item level, between one and two-thirds of responses suggesting impairment were found to be unlikely to be related to ASM treatment after normalization. Binary regression analyses revealed differential effects of medication choice, but also of antidepressants and neuroleptics on complaint domains. The explained variance was better for physical than psychological domains. The results reflect both known drug side effects and indications. Patients´ explicit attribution of problems to their medications barely improved the correlation of the E AEP and treatment parameters. CONCLUSION: Application of a norm-referenced AEP is highly recommended to avoid overestimation of treatment related problems in patients with epilepsy. It allows evaluation on item and scale level for individuals as well as groups in drug trials. Plausible relations to individual drugs and to drug load can be demonstrated. The explanatory power was better for physical than psychological domains. Drug-related complaint patterns reflect known drug side effects (e.g. perampanel and brivaracetam with aggression) as well as drug indications (e.g. lamotrigine for depression). This is likely to be particularly relevant when side effects may have affected treatment decisions. Longitudinal evaluation with repeated application of the E AEP with changes of drug treatment is in progress.

Levetiracetam, perampanel, and the issue of aggression: A self-report study.

This study investigated to which degree levetiracetam (LEV) and perampanel (PER), antiseizure medications (ASM) that are both known to cause aggression and irritability, share the same or different, behavioral side-effect profiles. In this self-report study, 68 participants with epilepsy treated with LEV (n = 35) or PER (n = 33) as part of their medication were asked to rate their behavioral experience with the respective drug as positive, neutral, or negative. Results of a German adaptation of the Adverse Events Profile (AEP) and of the "FPZ", a German personality questionnaire, were analyzed as a function of drug and rating. Thirty-eight percent of the LEV group and 36% of the PER group experienced negative change after the evaluated drug was introduced. By subdividing participants in the LEV sample into those who attributed the negative effects to LEV and those with neutral or positive experience with LEV, a negative evaluation of LEV was associated with significantly worse scores in cognition, mood, and physical domains (80% versus 20-40%). Subdividing participants in the PER sample into those who attributed negative the side effects to PER, and those with a neutral or positive experience with PER, significance could be shown for mood domains only (100% versus 50%), and within this domain only for increased aggression and irritability. Comparing features of the behavioral negative side effects of LEV and PER revealed that LEV appears to have a negative impact on a much broader range of behaviors than PER, which specifically seems to induce aggression and irritability and no other psychiatric side effects. Further research should aim at different expression and different mechanisms of aggression and irritability underlying the superficially similar effects of the two drugs.

Adult-onset temporal lobe epilepsy suspicious for autoimmune pathogenesis: Autoantibody prevalence and clinical correlates.

Temporal lobe adult-onset seizures (TAOS) related to autoimmunity represent an increasingly recognized disease syndrome within the spectrum of epilepsies. In this context, certain autoantibodies (autoABs) were often associated with limbic encephalitis (LE). Here, we aimed to gain insights into (a) the distribution of 'neurological' autoABs (neuroABs, defined as autoABs targeting neuronal surface structures or 'onconeuronal' ABs or anti-glutamate acid decarboxylase 65 (GAD65) autoABs) in a large consecutive TAOS patient cohort, to characterize (b) clinical profiles of seropositive versus seronegative individuals and to find (c) potential evidence for other autoABs. Blood sera/cerebrospinal fluid (CSF) of TAOS patients (n = 800) and healthy donors (n = 27) were analyzed for neuroABs and screened for other autoABs by indirect immunofluorescence on hippocampal/cerebellar sections and immunoblots of whole brain and synaptosome lysates. Serological results were correlated with clinico-neuropsychological features. 13% of TAOS patients (n = 105) were neuroAB+, with anti-GAD65 and anti-N-methyl-D-aspartate receptors (NMDAR) as most frequent autoABs in this group. In our screening tests 25% of neuroAB- patients (n = 199) were positive (screening+), whereas all control samples were negative (n = 27). Intriguingly, key clinico-neuropsychological characteristics including magnetic resonance imaging (MRI) findings, epileptiform electroencephalographic (EEG) activity, and inflammatory cellular infiltrates in CSF were shared to a greater extent by neuroAB+ with neuroAB-/screening+ patients than with neuroAB-/screening- patients. Serological testing in a large consecutive TAOS patient series revealed seropositivity for anti-GAD65 autoABs as the most frequent neuroAB. Intriguingly, neuroAB+ individuals were virtually indistinguishable from neuroAB-/screening+ patients in several major clinical features. In contrast, neuroAB-/screening- TAOS patients differed in many parameters. These data support the potential presence of so far unrecognized autoABs in patients with TAOS.

Changes in cognition after introduction or withdrawal of zonisamide versus topiramate in epilepsy patients: A retrospective study using Bayes statistics.

OBJECTIVE: We aim to evaluate the impact of zonisamide (ZNS) compared to topiramate (TPM) on cognition in patients with epilepsy. Although the risk of cognitive side effects has been clearly demonstrated for TPM, comparable side effects in ZNS have been suggested but evidence from studies is inconclusive. METHODS: In this retrospective observational study, we analyzed patients' records from before and after introduction or withdrawal of ZNS vs TPM. Data were gathered during routine clinical care protocols. Standardized monitoring of executive functions (EpiTrack), verbal memory (short version of verbaler lern- und merkfähigkeitstest, VLMT), and subjective health (extended Adverse Events Profile; quality of life in epilepsy inventory, QOLIE-10) was performed in 73 patients when TPM (n = 45) or ZNS (n = 28) was introduced and 62 patients when TPM (n = 29) or ZNS (n = 33) was withdrawn. The data were analyzed using Bayes statistics that quantify evidence for or against an effect through Bayes factors (BFs). RESULTS: There was decisive evidence for a negative effect of adjunctive ZNS and TPM on executive function (BF = 965.08) and a positive effect of their withdrawal (BF = 429.51). The ZNS effect seemed smaller, although the difference was inconclusive. Verbal memory and subjective quality of life were not significantly affected. Subjectively, ZNS was connected to lower anxiety and fewer headaches, whereas TPM had a perceived effect on weight, fluent speech and comprehension, headaches, and balance. SIGNIFICANCE: This is the first study to provide objective evidence for a considerable negative effect of ZNS treatment on executive function in a naturalistic treatment setting. Comparable to the well-known TPM effect, cognition worsens with adjunction and recovers with withdrawal of ZNS. However, the majority of patients do not show a significant negative effect, suggesting disparate susceptibilities to adverse events. The findings emphasize the need for routine monitoring of cognitive side effects to identify early on those patients who are negatively affected by new AED.

Does it actually feel right? A replication attempt of the rounded price effect.

How does the roundedness of prices affect product evaluations? The 'rounded price effect' postulates that depending on the context, rounded or non-rounded prices increase the purchase likelihood of consumers. The study presented here is a replication attempt of these findings and the proposed mediation of the effect through a sense of 'feeling right' when evaluating the product. p-Curve analysis and the R-Index are used to assess the robustness of the originally reported statistics since original data were not available. A pre-registered replication of study 5 from the original article was conducted in a sample of N=588 participants. For both the original product and one alternative product neither an interaction between price roundedness and context, nor a mediation through 'a sense of feeling right' was found. Our results suggest that the effect is either smaller than originally reported or contingent on other, not investigated factors. Further studies might investigate contingencies in larger samples.

Evaluating the longer-term cognitive effects of adjunctive perampanel compared to lacosamide in a naturalistic outpatient setting.

PURPOSE: This retrospective longitudinal study aims to compare the longer-term cognitive and behavioral side effects of adjunctive antiepileptic treatment with perampanel (PER) and lacosamide (LCM), two third generation antiepileptic drugs with suggested favorable cognitive profiles. The two drugs were monitored according to a previously established routine diagnostic protocol (Helmstaedter et al. E&B 2013;26:182-7) which facilitates the retrospective comparison of antiepileptic drug tolerability in a naturalistic outpatient setting. METHODS: Records from 94 patients were evaluated who underwent neuropsychological assessment before and under adjunctive treatment with either PER (n = 57) or LCM (n = 37). Cognition was assessed using the EpiTrack screening for executive functions and a VLMT short form for verbal memory. Subjective assessments included a German QOLIE-10 adaptation (quality of life) and an extended Adverse Events Profile (AEP). The median follow-up interval was 36 weeks. RESULTS: Multivariate repeated measures statistics revealed a non-significant trend towards an interaction effect "time - treatment arm" on both executive function and memory. When analyzed separately executive functions and memory scores significantly improved under LCM (t = -2.76 p < 0.01 and t = -2.44 p < 0.05 respectively). Subjectively, PER was associated with improvements in 2/18 physiological domains and in the LCM group 1/9 cognitive domains deteriorated. Seizure freedom was achieved for five patients treated with LCM (14%) and 15 treated with PER (26%, χ2 = 2.2, n.s.). CONCLUSION: In a naturalistic outpatient setting, chronic adjunctive treatment with PER and LCM did not negatively affect cognition and LCM may even improve cognition. Neither drug increased self-reported irritability or aggression. This suggests favorable longer-term tolerability.