New-generation Antiepileptic Drugs Research Articles

Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A.

More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers.

The Effect of Chronic Levetiracetam Use on Erythrocyte Deformability

ABSTRACT Background: The inhibition of carbonic anhydrase (CA) isoenzymes is one of the targets in the development of new antiepileptics. Levetiracetam (LEV) is a new-generation antiepileptic drug frequently used in pediatric patients. It has a strong inhibitory effect on CA enzymes in many tissues, including erythrocytes. Objective: Due to CA enzymes have physical connection with the erythrocyte membrane and cytoskeleton, we aimed to evaluate the probable effect of LEV on the erythrocyte deformability. Materials and Methods: This study was conducted in the Experimental Animal Laboratory of Ankara Training and Research Hospital 24 prepubertal female Wistar albino rats were divided into four groups with six animals in each group. Group I: Control (distilled water), Group II: LEV50 (50 mg/kg/day), Group III: LEV150 (150 mg/kg/day), Group IV: LEV300 (300 mg/kg/day). The calculated dose for each animal was given by oral gavage once a day for 14 days, which is accepted as chronic use in experimental models. At the end of the treatment period, erythrocyte deformability was evaluated both with whole blood viscosity at high shear rates, and osmotic fragility test. Results: No statistically significant difference was found between the groups in terms of osmotic fragility. Whole blood and plasma viscosity values also did not show any statistically significant difference between the groups. Conclusion: In this study, it has been shown that LEV does not have a negative effect on erythrocyte deformability. Therefore, we thought that it may be a good choice when an antiepileptic is needed in pediatric patients with hematological disorders.

Topiramate promotes osteogenic differentiation through AMPK-dependent phosphorylation of Smad1/5/9

Topiramate [2,3:4,5-bis-o-(1-methylethylidene) β-D-fructo-pyranose sulfamate; TPM] is one of the most used new-generation antiepileptic drugs. It has been reported to regulate the differentiation of human bone cells. However, the molecular mechanism of TPM in osteoblast differentiation is not fully elucidated. In the present study, we examined the effect of TPM on osteogenic differentiation of C3H10T1/2, MC3T3-E1, primary mouse calvarial cells, and primary bone marrow stem cells (BMSCs). Primary cells were isolated from mice calvaria and bone marrow respectively. Expression of the osteogenic gene was determined by RT-PCR. The osteogenic protein levels were measured by Western blot analysis. Alkaline phosphatase (ALP) staining experiment was performed to evaluate ALP activity. Alizarin red s (ARS) staining was performed to measure zebrafish caudal fin regeneration. Treatment of TPM up-regulated the osteogenic genes including distal-less homeobox 5 (Dlx5) and runt-related transcription factor 2 (Runx2). In addition, TPM also increased the Dlx5 and Runx2 protein levels, Smad1/5/9 phosphorylation, and alkaline phosphatase (ALP) activity. Furthermore, TPM activated AMPK, and inhibition of AMPK decreased TPM-induced osteogenic differentiation. In the zebrafish model, osteogenic effect of TPM was identified. TPM was increased amputated caudal fin rays of zebrafish. These results demonstrate that TPM enhances osteogenic differentiation via AMPK-mediated Smad1/5/9 phosphorylation.

Levetiracetam Protects Against Glutamate-Induced Excitotoxicity in SH-SY5Y Cell Line

The latest research has shown that the new generation of antiepileptic drugs has neuroprotective on nervous system. On the other hand, the effect of levetiracetam, a new generation antiepileptic drug, on GIC in SH-SY5Y cells remains uncertain. This research aims to investigate the effect of levetiracetam on GIC and oxidant and antioxidant levels in SH-SY5Y cells. It is utilized SH-SY5Y cell line at this research. Four groups were formed to assess the impact of levetiracetam on SH-SY5Y cell death following GIC. While no treatment was administered to the control group, 10 mM glutamate was administered to the glutamate group for 24 hours (10, 25, 50 and 100 μg/ml). LEV at different concentrations was given to the levetiracetam for 24 hours. The levetiracetam + glutamate was pretreated with levetiracetam at several concentrations for 1 hour (10, 25, 50, and 100 μg/ml), which was followed by a 24-hour exposure to 10 mM glutamate. TAS and TOS levels in cells and cell viability were examined. Following the GIC, a 25 μg/ml-Levetiracetam improved cell viability in neuroblastoma cells dramatically (p < 0.05). LEV (25 ug/ml) + glutamate while enhanced TAS levels in neuroblastoma cells in comparison to the glutamate (p < 0.05), significantly reduced TOS levels (p < 0.05 Levetiracetam improves cell survival by reducing cell death following GIC in neuroblastoma cells. In the acute process, levetiracetam exerts a protective effect.

Acute bilateral glaucoma related to uveal effusion syndrome associated with topiramate

AbstractPurpose: Drugs mostly sulfa‐related compounds, have produced uveal effusions, forward rotation of the iris‐lens diaphragm, transient myopia, and secondary angle closure. It has been recently encountered one case in which uveal effusions have occurred after administration of topiramate, a new anticonvulsant medication.Methods: A 54‐year‐old woman was seen in our emergency department with severe headaches, progressively blurry vision and photophobia in both eyes starting that morning. On examination, her visual acuity was hand movement in both eyes. Central corneal edema was observed, narrow chamber and anterior lens‐iris complex displacement with an unreactive middle pupil in both eyes. The funduscopic examination was difficult to assess due to the media opacity. Intraocular pressure measured with an applanation tonometer was 45 mm of mercury (mmHg) in the right eye and 50 mmHg in the left eye. Her medications included topiramate which she had started 2 weeks prior to initial examination due to headaches followed by neurology.Results: Topiramate‐induced angle closure has even been described as an idiosyncratic reaction in patients with normal depth of anterior chamber. The drug causes a prostaglandins increasement that trigger ciliary body edema at the local level but without acting at the systemic level. Ultrasound biomicroscopy shows the presence of a ciliochoroidal effusion syndrome, edema and the ciliary body anterolateral rotation, with zonular relaxation, changes that lead to iris‐lens diaphragm anterior displacement and, as a consequence, narrowing of the responsible anterior chamber with an acute glaucoma crisis.Conclusions: Topiramate is a sulfamate monosaccharide and belongs to a new generation of antiepileptic drugs, widely prescribed throughout the world as treatment of generalized tonic–clonic seizures and partial seizures. Prophylaxis of migraine, bipolar disorder, depression and neuropathic pain are other recent indications of its use. Bilateral acute glaucoma due to uveal effusion syndrome should be considered as an infrequent complication of topiramate use.References.1. Prithvi S. Sankar, MD; Louis R. Pasquale et al. Uveal Effusion and Secondary Angle‐Closure Glaucoma Associated With Topiramate Use. Arch Ophthalmol. 2001;119(8):1210–1211.

Effects of New-Generation Antiepileptic Drug Prophylaxis on Delayed Neurovascular Events After Aneurysmal Subarachnoid Hemorrhage.

Neuroelectric disruptions such as seizures and cortical spreading depolarization may contribute to the development of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). However, effects of antiepileptic drug prophylaxis on outcomes remain controversial in SAH. The authors investigated if prophylactic administration of new-generation antiepileptic drugs levetiracetam and perampanel was beneficial against delayed neurovascular events after SAH. This was a retrospective single-center cohort study of 121 consecutive SAH patients including 56 patients of admission World Federation of Neurological Surgeons grades IV - V who underwent aneurysmal obliteration within 72h post-SAH from 2013 to 2021. Prophylactic antiepileptic drugs differed depending on the study terms: none (2013 - 2015), levetiracetam for patients at high risks of seizures (2016 - 2019), and perampanel for all patients (2020 - 2021). The 3rd term had the lowest occurrence of delayed cerebral microinfarction on diffusion-weighted magnetic resonance imaging, which was related to less development of DCI. Other outcome measures were similar among the 3 terms including incidences of angiographic vasospasm, computed tomography-detectable delayed cerebral infarction, seizures, and 3-month good outcomes (modified Rankin Scale 0 - 2). The present study suggests that prophylactic administration of levetiracetam and perampanel was not associated with worse outcomes and that perampanel may have the potential to reduce DCI by preventing microcirculatory disturbances after SAH. Further studies are warranted to investigate anti-DCI effects of a selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist perampanel in SAH patients in a large-scale prospective study.

A Systematic Review of the Cost-effectiveness of Perampanel in the Treatment of Epilepsy

A Systematic Review of the Cost-effectiveness of Perampanel in the Treatment of Epilepsy

Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel

Perampanel (PER), a new-generation antiepileptic drug effective against different types of seizures, has already demonstrated a potential in status epilepticus therapy. Considering the growing interest of intranasal (IN) administration for nose-to-brain delivery, PER could be envisioned as a good candidate for this route, especially if formulated in a lipid-based nanosystem. With that purpose, a hydrophobic formulation (FO1.2) and a self-microemulsifying drug delivery system (SMEDDS) (FH5) loaded with PER were developed and characterized. Following PER IN administration (1 mg/kg) to mice, its pharmacokinetics was characterized and compared with intravenous and oral routes. Histopathological toxicity was also examined after a 7-day repeated dose study. FH5 homogeneously formed nanodroplets upon dispersion (20.07 ± 0.03 nm), showing a sustained in vitro PER release profile up to 4 h. By IN route, PER brain delivery was more extensive with FH5 (Cmax and AUC of 52.32 ng/g and 190.35 ng.h/g for FO1.2; 93.87 ng/g and 257.75 ng.h/g for FH5). Maximum brain concentration and total brain exposure were higher than those obtained after oral dosage, with maximum PER concentrations reached significantly faster than post-oral administration (15 min vs 2 h). An improvement in PER plasmatic concentration was also obtained, demonstrated by high relative bioavailability values (134.1% for FH5 and 107.8% for FO1.2). PER absolute plasma bioavailability after IN delivery was 55.5% for FH5 and 44.6% for FO1.2, ensuring a somewhat improved targeting of PER to the brain by the IN route compared to the IV route. No signs of toxicity were found by histopathologic evaluation. Results suggest that IN administration of PER might be a feasible and safe approach for acute and chronic epilepsy management, especially using delivery systems as SMEDDS.

Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model

New-generation antiepileptic drugs as perampanel, rufinamide and stiripentol emerged as alternatives in chronic epilepsy polytherapy. Hence, their metabolic stability and potential involvement in relevant drug-drug interactions (DDI) are of great clinical interest, being HepaRG cells herein used as an in vitro human model.To characterize their metabolic stability profiles, HepaRG cells were incubated with perampanel (1 μM), rufinamide (100 μM) or stiripentol (5 μM) for 12-h. HepaRG cells, pretreated with known CYP450 isoenzymes inducers (rifampicin, phenytoin, phenobarbital, omeprazole and carbamazepine), were also incubated with perampanel, rufinamide or stiripentol to assess possible DDI mediated by CYP450 induction.Results suggest a considerable decrease in perampanel and stiripentol concentrations over 12-h; contrary, rufinamide concentrations did not variated. Cells pretreatment with all inducers significantly decreased stiripentol concentrations (between 20.3% and 31.9%), suggesting a considerable potential for DDI. Rufinamide concentrations only decreased when preincubated with rifampicin and with the highest tested concentrations of the remaining inducers. Perampanel levels decreased with rifampicin, carbamazepine and phenobarbital, supporting the involvement of CYP3A4-mediated metabolism.Besides relevant information concerning the metabolic stability profile and potential DDIs of the new antiepileptics here studied, it was also reinforced the HepaRG cells suitability as a reliable in vitro model to foresee in vivo metabolism in humans.

Determinants of Health-Related Quality of Life of Epilepsy Patients in Jeddah, Saudi Arabia.

BackgroundEpilepsy puts an enormous burden on the physical and mental health of patients and can negatively impact their Health-Related Quality of Life (HRQoL). Previous studies have identified multiple factors impacting patients’ HRQoL; however, a consensus has not been reached, as these factors vary among different populations. This has not been sufficiently investigated in Saudi Arabia. Thus, this study aims to assess the HRQoL of epilepsy patients, as measured by the Quality Of Life In Epilepsy-31 (QOLIE-31) questionnaire, to determine the effects of demographics, disease characteristics, and antiepileptic drugs (AEDs) on patients in Jeddah, Saudi Arabia.MethodsThis was a cross-sectional, questionnaire-based study of adult epilepsy patients receiving AEDs who followed up at the epilepsy clinic at King Abdulaziz University Hospital between April 2018 and June 2018. Recruited individuals participated by phone interview.ResultsA total of 200 participants fulfilled our inclusion criteria and consented to participate; 57.4% were males. The average age was 32.8 years. The total average score on the QOLIE-31 was 61.56 (±17.52). QOLIE-31 scores correlated inversely with seizure frequency (p<.000) while the class of medication used, and the number of drugs administered did not correlate with HRQoL.ConclusionWhereas previous work has suggested a better quality of life when using newer generation AEDs, our study found no significant difference between the class of medication and whether monotherapy or polytherapy is used. Our findings suggest that efforts to improve HRQoL should be directed toward proper control of seizures regardless of medication class, as the frequency of attacks has the most detrimental effect on patients’ quality of life.

Eski ve Yeni Kuşak Antiepileptik İlaçların Hemogram Parametrelerine Etkileri Farklı Mı?

Aim: There are different comments related to hematological side effects caused by antiseizure drugs (ASDs). In our study, we investigated the effects of ASDs on hemogram parameters. Materials and Methods: Hemogram values of 293 patients including 156 women, who used ASDs for at least six months, were compared with the values of 36 healthy control participants group who did not. In addition, the hemogram values of the patients using old-generation antiepileptic drugs such as phenytoin (PHT), carbamazepine (CBZ), valproic acid were compared with those using new-generation antiepileptic drugs as levetiracetam, oxcarbazepine, pregabalin (PGB), gabapentin and two ASDs in combination. Results: Comparison of the patients using ASDs with the control group revealed that white blood cell (WBC) values of only PHT users were lower than the control group (p=0.045). Red cell distribution width (RDW) values were found to be higher in healthy controls than those using AEDs (p&amp;lt;0.001). When the groups using ASDs were compared among themselves, it was found that the WBC values of the users of old- generation ASDs as PHT and CBZ were significantly lower than those using PGB (p=0.006; P=0.005, respectively). Conclusion: As hematological side effects, ASDs may decrease WBC counts. The WBC decreasing effects of PHT and CBZ, which are older generation antiepileptics, are more pronounced than pregabalin, which is a new- generation antiepileptic drug. The effects of antiepileptic drugs on hemogram parameters of the patients should be taken into consideration while choosing appropriate ASDs and also while following the patient.

The antiepileptic drug lacosamide and memory – A preclinial study

ObjectiveLacosamide (LC) belongs to a new generation of antiepileptic drugs (AEDs) and demonstrates unique mechanism of action. The drug also shows neuroprotective activity on the hippocampus. In this study, the impact of LC on learning processes was assessed. MethodsAdult male Wistar rats (n = 40) were used. Lacosamide was administered p.o. as a single (25 mg/kg or 75 mg/kg) or repeated doses (75 mg/kg). The effect of the drug was assessed in the Morris water maze (spatial memory) and the passive avoidance (PA) (emotional memory). ResultsLacosamide administered at a single dose or repeatedly did not impair spatial memory in Morris water maze. Higher swimming speed was observed in rats after administration of acute doses of LC. In PA, the disturbance of emotional memory was observed only after the single high dose of LC. ConclusionLacosamide does not impair memory and learning processes. The emotional memory impairment observed after the acute high dose appears to be temporary and did not occur after repeated administration.

Acute withdrawal of new-generation antiepileptic drugs in epilepsy monitoring units: Safety and efficacy

IntroductionAcute withdrawal of antiepileptic drugs (AEDs) is a safe and effective approach to provoking seizures in order to complete video-electroencephalogram (V-EEG) studies in a timely manner. Previous studies have focused only on withdrawal from conventional AEDs, and the effects of withdrawal from new-generation AEDs have not been extensively studied. Materials and MethodsThis study examined adult patients with drug-resistant epilepsy admitted to an epilepsy monitoring unit between 2015 and 2018. Patients were classified according to whether they received conventional AEDs (Con; n = 13) or new-generation AEDs (N-Gen; n = 26). We then compared the effects of withdrawing these two types of AEDs over a period of one week in terms of efficacy (time to complete V-EEG monitoring) and safety, including the incidence of cluster seizures (CS), focal to bilateral tonic-clonic seizures (FBTCS) and status epilepticus (SE). ResultsIn both groups, approximately one week was required to complete V-EEG analysis: N-Gen group (5.6 days) and Con group (6.3 days). No differences were observed between the two groups in terms of the median number of seizures, the onset of the 1st seizure, the distribution of CS, FBTCS, or SE. Following acute withdrawal of medication, a high percentage of patients with a history of CS or FBTCS, respectively, presented CS or FBTCS. ConclusionsWe did not observe significant differences between patients taking new-generation AEDs and those taking conventional AEDs following withdrawal during V-EEG recording. In the current study, we employed a standard protocol for the rapid withdrawal of AEDs (daily dose reduction of 50%), which was sufficient for 80% of patients to complete V-EEG monitoring within one week.

A combo-strategy to improve brain delivery of antiepileptic drugs: Focus on BCRP and intranasal administration

The breast cancer resistance protein (BCRP) is an efflux transporter expressed at the apical surface of human brain endothelial cells of the blood-brain barrier (BBB). It was proposed as one of the transporters responsible for the development of drug resistance to several central nervous system (CNS) drugs, including antiepileptic drugs (AEDs). In this context, the present work aimed to characterize the interaction between new-generation AEDs, lacosamide, levetiracetam and zonisamide, and BCRP, in order to investigate whether intranasal administration can successfully avoid the impact of BCRP on brain drug distribution, preventing the development of refractory epilepsy. Firstly, BCRP substrates and/or inhibitors were identified resorting to intracellular accumulation and bidirectional transport assays on Madin-Darby canine kidney (MDCK) cells and the transfected cell line with human ABCG2 (MDCK-BCRP). Furthermore, in vivo pharmacokinetic studies were carried out for BCRP substrates with and without elacridar, a well-known P-gp and BCRP modulator, to assess the impact of efflux inhibition on brain drug distribution. The extent of drug equilibration between plasma and brain was compared after intravenous (IV) and intranasal administration to mice. Among the three tested AEDs, zonisamide was the only AED identified as BCRP substrate in vitro, as demonstrated by the net flux ratio of 2.73, which decreased 53.85 % in the presence of a BCRP inhibitor, Ko143. Lacosamide revealed to inhibit BCRP in all tested concentrations (2.5-75µM), exhibiting a significant increase (p<0.001) of the intracellular accumulation of a BCRP substrate (Hoechst 33342) in MDCK-BCRP cells. Levetiracetam did not behave as a BCRP substrate nor inhibitor. After IV administration, the plasma concentrations of zonisamide were unaffected by elacridar, but its extent of brain exposure increased three-fold (as assessed by AUCt, 674.12 vs 284.47µg.min/mL). These results corroborate the previous in vitro findings, suggesting that BCRP is involved in the transport of zonisamide through the BBB. In opposition, no significant changes were found in plasma or brain concentrations after the administration of zonisamide by intranasal route, indicating that the influence of BCRP is less relevant than for IV route. In addition, direct nose-to-brain delivery of zonisamide, given by the direct transport percentage, was approximately 49 %. Altogether, these assays demonstrated that the impact of BCRP on the delivery of zonisamide to the brain is lower after intranasal administration, probably due to direct nose-to-brain transport. Therefore, the intranasal administration of AEDs may be a relevant strategy to avoid the impact of efflux transporters at the BBB and the development of drug resistance.

P.435 Further psychometric evaluation of a patient-reported outcome measure: patient-reported experience of cognitive impairment in schizophrenia (PRECIS)

We aimed to gauge the burden of epilepsy in China from a societal perspective by estimating the direct, indirect and intangible costs.Patients with epilepsy and controls were enrolled from two tertiary hospitals in China. Patients were asked to complete a Cost-of-Illness (COI), Willingness-to-Pay (WTP) questionnaires, two utility elicitation instruments and Mini Mental State Examination (MMSE). Healthy controls only completed WTP questionnaire, and utility instruments. Univariate analyses were performed to investigate the differences in cost on the basis of different variables, while multivariate analysis was undertaken to explore the predictors of cost/cost component.In total, 141 epilepsy patients and 323 healthy controls were recruited. The median total cost, direct cost and indirect cost due to epilepsy were US$949.29, 501.34 and 276.72, respectively. Particularly, cost of anti-epileptic drugs (AEDs) (US$394.53) followed by cost of investigations (US$59.34), cost of inpatient and outpatient care (US$9.62) accounted for the majority of the direct medical costs. While patients’ (US$103.77) and caregivers’ productivity costs (US$103.77) constituted the major component of indirect cost. The intangible costs in terms of WTP value (US$266.07 vs. 88.22) and utility (EQ-5D, 0.828 vs. 0.923; QWB-SA, 0.657 vs. 0.802) were both substantially higher compared to the healthy subjects.Epilepsy is a cost intensive disease in China. According to the prognostic groups, drug-resistant epilepsy generated the highest total cost whereas patients in seizure remission had the lowest cost. AED is the most costly component of direct medical cost probably due to 83% of patients being treated by new generation of AEDs.

New-generation antiepileptic drugs during pregnancy and the risk of attention-deficit hyperactivity disorder: A scoping review.

The use of maternal antiepileptic drug (AED) during pregnancy is associated with an increased risk of cognitive adverse effects among the offspring. As new-generation AEDs continue to enter the market, evidence on their safety during pregnancy is limited yet necessary. To date, there are no published reviews summarizing the evidence of new-generation AED exposure in utero and the development of attention deficit-hyperactivity disorder (ADHD) in the offspring. The objective of this scoping review is to summarize the available evidence on the risk of ADHD after maternal exposure to new-generation AEDs during pregnancy. We searched EMBASE and MEDLINE for articles published from January 1988 to April 2020. New-generation AEDs were considered if marketed after 1988. ADHD was defined as attention-deficit hyperactivity disorder, hyperkinetic disorder, hyperkinesis, or conduct disorder. Of the total articles screened (n = 805), eight publications were finally included (seven cohort studies and one systematic review). Across the studies, the sample size of pregnant women exposed to AEDs ranged from 1 to 1383. Monotherapy was examined in six studies (mostly lamotrigine), while only two studies examined polytherapy. The included studies reported a range of adjusted relative risks, from 0.84 [0.59-1.19] to 1.63 [0.41-6.06]. Lamotrigine monotherapy holds the largest body of evidence, concluding that no significant risk of ADHD exists among the offspring. However, the available evidence is considered scarce and has several methodological limitations. Disentangling the effect of AEDs from epilepsy itself and examining polytherapies are challenges that merit additional investigations. Further comparative safety studies with longer follow-up periods and large sample sizes are needed to accurately quantify the true impact of new-generation AED exposure during pregnancy and ADHD in children.

HLAs associated with perampanel-induced psychiatric adverse effects in a Korean population

Perampanel (PER) is a new-generation antiepileptic drug that has an occasional but significant shortcoming, psychiatric adverse effects (PAEs). Recently, antiepileptic drug-related adverse reactions, such as skin rash and even PAEs, have been discovered to be correlated with certain human leukocyte antigen (HLA) types. Thus, we aimed to analyze specific HLA alleles as risk factors for PER-PAEs. We prospectively enrolled 17 patients with epilepsy who were prescribed PER between May 2016 and Jul 2018 at Seoul National University Hospital and developed PAEs while taking PER. Their HLA types were analyzed compared to those of 19 patients in the PAE-tolerant group and the general Korean population. In silico docking was performed with two different computational programs, AutoDock Vina and SwissDock, to theoretically evaluate the binding affinity of PER in the grooves of the specific HLA alleles. The HLA-DQB1*06:01, DRB1*08:03, and B*54:01 alleles were significantly associated with the patients who developed PER-PAEs compared with the general Korean population (odds ratio [OR] 3.94, p = 0.008, OR 9.24, p = 0.037, and OR 3.25, p = 0.041, respectively). As a haplotype, the combination of the three alleles was significantly more frequent in the PER-PAE group than in both the PER-tolerant group and the general Korean population. DQB1*06:01 and B*54:01 also demonstrated higher docking scores with PER than other alleles. This is the first study to analyze the association of PER-PAEs with specific HLA genotypes. Our results suggest that an HLA-associated genetic predisposition and a possible immunological mechanism are involved in the occurrence of PER-PAEs.

Effects of antiepileptic drugs on electroencephalography (EEG): Insights and applicability

ObjectiveThe objective of the study was to assess the effects of antiepileptic drugs (AEDs) on posterior alpha rhythm and determine whether they produce pathological slow waves in patients with epilepsy. MethodsOutpatient electroencephalographs (EEGs) in alert patients were selected. The three compared groups include 1) patients with an interested AED (monotherapy or combined with other AEDs); 2) patients with AEDs other than the interested AED; and 3) patients who did not take AEDs. Outcomes were frequency of posterior alpha rhythm and presence of generalized continuous (CSWs) and generalized intermittent slow waves (ISWs). Analysis of variance was used to assess which AED was associated with slower posterior alpha rhythm. Chi-square and logistic regression were employed to assess association and odds ratio (OR) with 95% confidence interval (CI) between pathological generalized slow waves and each AED. ResultsAmong 1050 EEG tracings, 638 EEGs met our criteria. Electroencephalographs requested because of cognitive decline and psychiatric symptoms were excluded, leaving 616 EEGs for analysis. Four hundred thirty-seven patients received at least one AED, whereas the remaining 179 patients did not take AED. Conventional AEDs [carbamazepine (CBZ), p = 0.024; phenobarbital (PB), p = 0.013; phenytoin (PHT), p = 0.001] except valproic acid (VPA) were associated with slower alpha frequency. Carbamazepine [adjusted OR: 5.74 (95% CI: 2.07, 15.94)] and PB [adjusted OR: 2.58 (95% CI: 1.15, 5.78)] were significantly associated with generalized ISWs. None were associated with generalized CSWs. ConclusionsPhenytoin, CBZ, and PB are associated with slower posterior alpha frequency. The latter 2 AEDs also produced pathological generalized ISWs. Valproic acid, benzodiazepines, and new-generation AEDs are not associated with either outcome. The presence of generalized ISWs in patients taking CBZ or PB should be cautiously interpreted since there can be drug effects. Association with cognitive side effects of these slow waves should be further studied.

Current trends in epileptology: priorities, challenges, tasks and solutions

Within a field meeting of experts from the Russian branch of the League Against Epilepsy (RLAE), diagnostic and treatment aspects of epilepsy were discussed with the emphasis on the female population (girls, women of childbearing and older ages). All experts underscored the special features and unique needs of female patients with epilepsy. Experimental and clinical studies on efficacy and safety of traditional and novel antiepileptic drugs (AEDs) applied to women with epilepsy were discussed. It was commonly agreed that the new generation of AEDs did not yet find an appropriate place in the clinical practice, and that they were mainly used as add-on therapy in order to overcome drug resistance. The current use of AEDs in the treatment of epilepsy is, by large, not gender-specific and is not related enough to age, sociodemographic characteristics, and comorbid disorders. It should be noted that the new AEDs are addressed specifically to individual, socio-demographic, gender and clinical features of the patient. The potential of some AEDs (lamotrigine), in fact, remains underestimated by practitioners. Due to the current restrictions in using valproic acid, lamotrigine is the alternative medication for women with epilepsy. Having a balanced profile of efficacy and safety, lamotrigine is recommended as the first choice drug for initial therapy, as well as an alternative monotherapy for epilepsy in women.These data were presented at the Russian League Against Epilepsy (RLAE) on-site meeting “Epilepsy and Woman” 18 September 2019 (Ohrid, Makedonia).

Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment.

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of TDM of newer generation AEDs in epilepsy. We performed a randomized, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study endpoint was reached (inefficacy or adverse events). The primary outcome was the proportion of participants followed 1 year without reaching one of the predefined endpoints. A total of 151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic, and 53% in the rescue TDM arm, p = 0.6, Cox regression). There was no difference in terms of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit. This study provides class A evidence that systematic drug level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as when there are compliance issues. ANN NEUROL 2020;87:22-29.