Objective:The models currently available for predicting the risk of seizure recurrence after antiepileptic drug (AED) withdrawal in adult epilepsy patients include the prediction model developed by Lamberink et al (Lamberink model, 2017) and the Medical Research Council prediction model (MRC model, 1993). However, there was no external validation for the two models. The purpose of this study was to perform an independent external validation and a comparison of the Lamberink model and the MRC model in adult patients. Methods: The study population was recruited from the Wenzhou Epilepsy Follow-up Registry Database (WEFURD). All the predictors of the Lamberink and MRC models and the occurrence of seizure recurrence in the participants were collected based on the WEFURD. Participants' predicted probabilities of seizure recurrence were obtained by a Web-based tool and the prognostic index formula. The external validation of the Lamberink model and the MRC model were quantified by discrimination, calibration, and decision curve analysis (DCA). Results: Of 212 patients, 126 (59.4%) had seizure recurrence after AED withdrawal. The Lamberink 2-year model, the Lamberink 5-year model, the MRC 1-year model, and the MRC 2-year model had areas under the curve of 0.71 (95% confidence interval [CI] = 0.64-0.78), 0.68 (95% CI = 0.60-0.76), 0.60 (95% CI = 0.50-0.69), and 0.58 (95% CI = 0.50-0.66), respectively. Additionally, the Lamberink 2-year model had a significantly better integrated discrimination improvement than the MRC 2-year model (P < .001). Regarding calibration, the Lamberink 2-year model (P = .121) and the MRC 1-year model (P = .264) were well calibrated, but the Lamberink 5-year model (P = .022) and the MRC 2-year model (P = .008) were not. In the DCA, the Lamberink 2-year model performed well at threshold probabilities of 30%-65%. Significance: This external validation shows that the Lamberink 2-year model might be more accurate and has greater clinical benefit than others for guiding drug withdrawal in adult epilepsy clinics. 116 | LIN et aL. K E Y W O R D S adult epilepsy, drug withdrawal, external validation, prediction model, seizure recurrence Key Points • The Lamberink 2-year model had the highest AUC (0.71) among the models in the external validation • The Lamberink 2-year model (P = .121) and the MRC 1-year model (P = .264) were well calibrated, but the other prediction models were not • In the DCA, the Lamberink 2-year model performed well at threshold probabilities of 30%-65%
Background: Epilepsy is a common neurological disease, and neuroinflammation is one of the main contributors to epileptogenesis. Pyroptosis is a type of pro-inflammatory cell death that is related to epilepsy. Agmatine, has anti-inflammatory properties and exerts neuroprotective effects against seizures. Our study investigated the effect of agmatine on the core pyroptosis protein GSDMD in the context of epilepsy.Methods: A chronic epilepsy model and BV2 microglial cellular inflammation model were established by pentylenetetrazole (PTZ)-induced kindling or lipopolysaccharide (LPS) stimulation. H&E and Nissl staining were used to evaluate hippocampal neuronal damage. The expression of pyroptosis and inflammasome factors was examined by western blotting, quantitative real-time PCR, immunofluorescence and enzyme-linked immunosorbent assay (ELISA).Results: Agmatine disrupted the kindling acquisition process, which decreased seizure scores and the incidence of full kindling and blocked hippocampal neuronal damage. In addition, agmatine increased BV2 microglial cell survival in vitro and alleviated seizures in vivo by suppressing the levels of PTZ-induced pyroptosis. Finally, the expression of TLR4, MYD88, phospho-IκBα, phospho-NF-κB and the NLRP3 inflammasome was significantly upregulated in LPS-induced BV2 microglial cells, while agmatine suppressed the expression of these proteins.Conclusions: Our results indicate that agmatine affects epileptogenesis and exerts neuroprotective effects by inhibiting neuroinflammation, GSDMD activation, and pyroptosis. The inhibitory effect of agmatine on pyroptosis was mediated by the suppression of the TLR4/MYD88/NF-κB/NLRP3 inflammasome pathway. Therefore, agmatine may be a potential treatment option for epilepsy.
BackgroundThis active, open observational study aimed to investigate adverse drug reactions (ADRs) associated with six commonly used antiepileptic drugs (AEDs) in southern Chinese outpatients with epilepsy from 2003 to 2015.MethodsThe Wenzhou Epilepsy Follow-Up Registry Database (WEFURD) was established by a single epilepsy center in China in January 2003 to record AED efficacy and the associated ADRs by registered outpatients diagnosed with epilepsy. We reviewed the data of outpatients who had only taken one or more of six commonly used AEDs, namely, carbamazepine (CBZ), valproate (VPA), lamotrigine (LTG), oxcarbazepine (OXC), topiramate (TPM) and levetiracetam (LEV), and were registered in the WEFURD between 2003 and 2015. We evaluated the ADRs caused by the single or combined use of the above six specific AEDs based on the WHO-UMC scale. The data of the ADRs were categorized by age, sex, number of AEDs related to ADRs, medications, seriousness of ADRs, causality levels of the WHO-UMC scale and system organ class (SOC). The unit of analysis was one ADR.ResultsA total of 3069 epilepsy outpatients (1807 outpatients with 5049 eligible ADRs and 1262 outpatients without ADRs) were included. The overall ADR rate was 58.88% (1807/3069). An average of 2.79 ADRs (5049/1807) occurred per patient with an ADR; 53.8% of the 5049 ADRs were recorded in females, and 50.4% were caused by monotherapy. Of the ADRs, 10.6% (537/5049) were severe adverse reactions (SARs), including 34 serious adverse effects (SAEs). The SAR rates caused by one, two and three or more AEDs were 9.9, 10.0 and 19.6%, respectively (p < 0.001). Eighteen SOC categories were identified, and the top three were psychiatric disorders (1633/5049, 32.3%), neurological disorders (1222/5049, 24.2%) and gastrointestinal disorders (564/5049, 11.2%). Of the 537 SARs, skin and appendage disorders accounted for 24.4% (131/537). Among the 34 SAEs, serious allergies, fetal malformations, renal calculus and pancreatitis accounted for the majority.ConclusionsOur findings suggest that clinicians should pay attention to psychiatric ADRs and be alert for SARs, especially when three or more AEDs are used together. Moreover, active surveillance might provide another method of pharmacovigilance in China.Electronic supplementary materialThe online version of this article (10.1186/s40360-019-0285-y) contains supplementary material, which is available to authorized users.
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