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The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22-25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes.

The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22-25, 2022 and was attended by 157 delegates from 26 countries representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK-001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients 2 years of age and older.

OBJECTIVE: Optimal choice of antiseizure medication (ASM) depends on seizure type, syndrome, age, gender, comorbidities and co-medications. There are no fixed rules on how to weigh these factors; choices are subjective and experience-driven. We investigated agreement among experts in selecting ASM as monotherapy and used their prevailing choices to validate a web-based decision-support application.METHODS: Twenty-four international experts, blinded to the app, selected the optimal ASM for 25 individual patient-cases covering a wide variation of seizure types and other factors influencing ASM selection. The app ranked ASMs in order of likely appropriateness for each case. In a second step, experts rated anonymously the choices of the app.RESULTS: Of the 25 patient-cases (age 13-74 years), 13 were female, 18 (72%) had comorbidities, six (24%) were on contraceptives, and 13 (52%) had other co-medications. The median number of experts who selected the same ASM for a given case was 15 (62.5%) and interquartile range (IQR) 13-18 (54%-75%). Gwet's agreement coefficient among experts was 0.38 (95% confidence interval [CI] 0.32-0.44), corresponding to a "fair" agreement. Agreement between the app and the prevailing expert choice for each case was 0.48 (95% CI 0.29-0.67), corresponding to a "moderate" beyond chance agreement. The percent agreement between the highest ranked selections of the app and the expert selections was 73% (95% CI 64%-82%). Ninety-five percent of the experts considered that no incorrect or potentially harmful ASMs were ranked highest by the app, and most experts strongly agreed with the app's selections.SIGNIFICANCE: This app, now validated by experts, provides an objective, reproducible method for selecting ASM that accounts for relevant clinical features. It is freely available at: https://epipick.org.

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.

The lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing. In this paper we assembled an expert panel to discuss the nature of these needs, current limitations, and obstacles based on a survey amongst these experts who were queried about the most important issues regarding the use of electroencephalography (EEG) parameters as endpoints in clinical drug and device development.A structured survey was sent to a group of experts in the design and conduct of epilepsy trials in adults and children. This was followed by a virtual in-person meeting discussing the results of the trial and identifying a list of most important issues.Six clinical trialists and 5 individuals from pharmaceutical companies returned the survey containing 14 questions, and 8 clinical trialists and 10 pharma-representatives attended the meeting. Three main issues were identified (1) lack of accuracy of seizure diaries due to nocturnal seizures, subtle motor seizures, impairment of consciousness and lack of awareness of the seizure by the patient (2) inter-rater variability of EEG assessment (3) lack of standardization regarding definition(s) of seizures (clinical and electrographic), EEG recording methods and EEG data management. Recommended solutions included (1) validation of EEG parameters as biomarkers and use of wearables (2) development of a manual that describes EEG rating criteria, protocol for validation by 1 central reader and use of a resolution of disagreements reporting template (3) standardization of EEG recording, data management and reporting.Current developments in research and technology seem promising to advance the use of EEG parameters as potential endpoints and offer partial solutions to the current needs. However, continuous, focused and collaborative efforts of all stakeholders (academia, industry and regulatory agencies) are needed to formulate guidelines, validate emerging technologies and approve them for use in trials. It is the intent of this opinion "position paper" to stimulate those efforts.

Objective: To develop and validate a pragmatic algorithm that classifies seizure types, to facilitate therapeutic decision-making. Methods: Using a modified Delphi method, five experts developed a pragmatic classification of nine types of epileptic seizures or combinations of seizures that influence choice of medication, and constructed a simple algorithm, freely available on the internet. The algorithm consists of seven questions applicable to patients with seizure onset at the age of 10 years or older. Questions to screen for nonepileptic attacks were added. Junior physicians, nurses, and physician assistants applied the algorithm to consecutive patients in a multicenter prospective validation study (ClinicalTrials.gov identifier: NCT03796520). The reference standard was the seizure classification by expert epileptologists, based on all available data, including electroencephalogram (EEG), video-EEG monitoring, and neuroimaging. In addition, physicians working in underserved areas assessed the feasibility of using the web-based algorithm in their clinical setting. Results: A total of 262 patients were assessed, of whom 157 had focal, 51 had generalized, and 10 had unknown onset epileptic seizures, and 44 had nonepileptic paroxysmal events. Agreement between the algorithm and the expert classification was 83.2% (95% confidence interval = 78.6%–87.8%), with an agreement coefficient (AC1) of.82 (95% confidence interval =.77–.87), indicating almost perfect agreement. Thirty-two health care professionals from 14 countries evaluated the feasibility of the web-based algorithm in their clinical setting, and found it applicable and useful for their practice (median = 6.5 on 7-point Likert scale). Significance: The web-based algorithm provides an accurate classification of seizure types, which can be used for selecting antiseizure medications in adolescents and adults.

We review data on the comparative teratogenicity of antiepileptic drugs (AEDs), focusing on major congenital malformations (MCMs), intrauterine growth restriction, impaired cognitive development, and behavioral adverse effects following prenatal exposure.Prospective registries and meta-analyses have better defined the risk of MCMs in offspring exposed to individual AEDs at different dose levels. Valproate is the drug with the highest risk, whereas prevalence of MCMs is lowest with lamotrigine, levetiracetam, and oxcarbazepine. For valproate, phenobarbital, phenytoin, carbamazepine, and lamotrigine, the risk of MCMs is dose-dependent. Prenatal exposure to valproate has also been confirmed to cause an increased risk of cognitive impairments and autistic traits. In a population-based study, the risk of AED-induced autistic traits was attenuated by periconceptional folate supplementation.The risk of adverse fetal effects differs in relation to the type of AED and for some AEDs also the daily dose. Although for MCMs the risk is primarily associated with the first trimester of gestation, influences on cognitive and behavioral development could extend throughout pregnancy. Available information now permits a more rational AED selection in women of childbearing potential, and evidence-based counseling on optimization of AED treatment before conception.

We thank Dr. Bruzzone for her interest in our article.1 We agree that participation in the study per se could have impacted outcomes. In particular, as pointed out in our Discussion, patients in the control group were also administered the questionnaire, and therefore, they might have been sensitized to report adverse effects that otherwise could have been neglected. We also agree that screening for adverse effects should be part of the routine management of people with epilepsy. Ideally, this should be supplemented by other measures aimed at raising awareness about the impact of adverse effects on quality of life, and about the strategies that can be applied to optimize drug treatment according to individual needs.

The International League Against Epilepsy (ILAE) / American Epilepsy Society (AES) Task Force on the cardiac effects of lamotrigine was convened in response to a recent addition to the lamotrigine label by the US Food and Drug Administration (FDA). 1 Lamotrigine is the nonproprietary name for a medicine that is sold under its generic name and several brand names including Lamictal™. The present advisory is based on an assessment of currently available evidence. It is not intended to replace regulatory requirements, nor is it intended to be an exhaustive review. Its purpose is to advise healthcare professionals worldwide on how to minimize cardiac safety risks associated with lamotrigine use.

Introduction Spontaneous reports of adverse drug reactions (ADRs) are a valuable supplement to clinical studies in informing about the safety of medications. This is especially relevant for pediatric populations, which are not often included in large-scale clinical trials. Objectives To evaluate patterns of pediatric ADRs to antiseizure medications (ASMs) reported to the Italian Spontaneous Reporting System (SRS) database during the period November 1, 2001─May 31, 2019. Methods Suspected ADRs ascribed to medications listed under ATC code N03, plus clobazam (code N05BA09), and affecting individuals below age 18 years were sourced from the Italian SRS database, categorized based on a modification of the MedDRA® high-level term, and analyzed using descriptive statistics. Results A total of 956 reports listing a total of 1806 ADRs ascribed to one or more ASMs were received for individuals in pediatric age. The most commonly reported ADRs were skin rashes (24.0% of all reports), epileptic seizures (12.6%), gastrointestinal disturbances (11.8%), and somnolence (10.6%). A more detailed analysis was conducted on 675 reports listing a single ASM as suspected drug and occurring in patients with a specified or presumed diagnosis of epilepsy. Adverse drug reaction patterns differed widely across ASMs. Skin rashes were the most commonly reported ADR for lamotrigine (62.3%), carbamazepine (50.3%), phenobarbital (42.3%), and oxcarbazepine (33.0%). Other most commonly reported ADRs were gastrointestinal symptoms for ethosuximide (44%), irritability/aggression for levetiracetam (25.0%), epileptic seizures for valproic acid (16.1%), fever (often associated with hypohidrosis) for topiramate (17.9%), and utilization error (mostly accidental drug administration) for clonazepam (34.6%). Conclusions Patterns of spontaneous ADR reports are indicative of major differences in safety profile among individual ASMs. Most, but not all, frequently reported ADRs were in line with findings from clinical trials and observational studies.

Background When use of a single antiseizure medication (ASM) fails to induce seizure remission, add-on therapy is justified. Perampanel (PER) is approved in Europe as adjunctive therapy for focal, focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures. Aim of the study was to establish whether PER is suitable for first add-on use. Methods A Delphi methodology was adopted to assess consensus on a list of 39 statements produced by an Expert Board of 5 epileptologists. Using an iterative process, statements were finalized by a Delphi Panel of 84 Italian pediatric and adult neurologists. Each statement was rated anonymously to determine level of agreement on a 9-point Likert scale. Consensus was established as agreement by at least 80% of the panelists. The relevance of each statement was also assessed on a 3-point scale. Results Consensus was achieved for 37 statements. Characteristics of PER considered to justify its use as first add-on include evidence of a positive impact on quality of life based on long term retention data, efficacy, tolerability, and ease of use; no worsening of cognitive functions and sleep quality; a low potential for drug interactions; a unique mechanism of action. Potential unfavorable factors are the need for a relatively slow dose titration; the potential occurrence of behavioral adverse effects; lack of information on safety when used in pregnancy; limited access to plasma PER levels. Conclusion Perampanel has many features which justify its use as a first add-on. Choice of an ASM as first add-on should be tailored to individual characteristics.

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r2 = .78, P

Objective Antiseizure medications (ASMs) are the first-line treatment for epilepsy. Many ASMs are available; this offers the opportunity to improve therapy by tailoring it to individual characteristics, but also increases the possibility of healthcare professionals making inappropriate treatment choices. To assist healthcare professionals, we developed a pragmatic algorithm aimed at facilitating medication selection for individuals whose epilepsy begins at age 10 years and older. Methods Utilizing available evidence and a Delphi panel-based consensus process, a group of epilepsy experts developed an algorithm for selection of ASMs, depending on the seizure type(s) and the presence of relevant clinical variables (age, gender, comorbidities, and comedications). The algorithm was implemented into a web-based application that was tested and improved in an iterative process. Results The algorithm categorizes ASMs deemed to be appropriate for each seizure type or combination of seizure types into three groups, with group 1 ASMs considered preferred, group 2 considered second line, and group 3 considered third line. Depending on the presence of relevant clinical variables, the ranking of individual ASMs is adjusted in the prioritization scheme to tailor recommendations to the characteristics of the individual. The algorithm is available on a web-based application at: https://epipick.org/#/. Significance The proposed algorithm is user-friendly, requires less than 2 minutes to complete, and provides the user with a range of appropriate treatment options from which to choose. This should facilitate its broad utilization and contribute to improve epilepsy management for healthcare providers who desire advice, particularly those who lack special expertise in the field.

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p

Objective To access the effect of vagus nerve stimulation (VNS) on the outcome of pregnancy. Methods We used the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) and its network to search for women receiving adjunctive VNS during pregnancy. Data on maternal and fetal outcomes were extracted from the registry databases and outcomes were evaluated. Results Twenty-six pregnancies were identified in 25 women. All women were exposed to a relative high VNS stimulation level (mean duty cycle 18%, range 5%–51%). Most women had seizures during pregnancy and almost 70% were on antiepileptic drug (AED) polytherapy. The proportion of women with obstetrical interventions was 53.9% (95% confidence interval [CI] 33.4%–73.4%) which was higher compared to the EURAP average (48.2%; 95% CI 47.2%–49.1%). One infant (3.9%; 95% CI 0.1%–19.6%) was born with a major malformation (unilateral congenital glaucoma), which is within the range expected among offspring of AED-treated women. Conclusion Although the present series of VNS-exposed pregnancies is the largest reported to date, the sample size is insufficient to draw any firm conclusions on the safety of VNS in pregnancy but the findings suggest an increased rate of obstetrical interventions, and no clear signal of VNS-related teratogenicity.

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes.

Perampanel, a new specific non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist, has been recently approved in the United States and the European Union for the adjunctive treatment of focal seizures and primary generalized tonic-clonic seizures associated with idiopathic generalized epilepsy. A positive relationship between plasma perampanel concentration and improvement in seizure control has been identified in regulatory trials, suggesting that therapeutic drug monitoring could be useful in optimizing clinical response in patients with epilepsy treated with perampanel. The development of a simple and broadly applicable method for measuring plasma perampanel concentrations is desirable to permit the use of TDM for this drug in clinical practice.A high-performance liquid chromatographic method with ultraviolet detection for the quantitative determination of perampanel in small aliquots of human plasma (200 μL) has been developed and validated. Sample preparation involves a simple precipitation step followed by solvent evaporation. High-performance liquid chromatographic separation is achieved on 2 reverse-phase monolithic columns in sequence connected to an ultraviolet detector (320 nm), using as mobile phase water/acetonitrile (60:40 vol/vol) mixed with 1 mL/L phosphoric acid, at a flow rate of 1.5 mL/min. Promethazine hydrochloride is used as internal standard.Calibration curves were linear over a perampanel concentration range of 25-1000 ng/mL, with correlation coefficients equal or greater than 0.998 ± 0.001 and a limit of quantitation set at 25 ng/mL. Intra- and inter-day coefficients of variation did not exceed 7.4%, and the accuracy ranged from 96.4% to 113.3%. No interference was observed from commonly coprescribed drugs.The present assay is simple, specific, and cost effective with performance characteristics suitable for TDM use.

Since 1989, 18 second-generation antiseizure medications have reached the market, resulting in a greatly increased range of treatment options for patients and prescribers. 30 years have passed and now is the time for an appraisal of the effect of these medications on clinical outcomes. Every antiseizure medication needs to be assessed individually, but overall second-generation drugs are less likely to cause pharmacokinetic interactions than their older counterparts. Some second-generation antiseizure medications have shown advantages in tolerability and safety, particularly in the treatment of older patients and women of childbearing potential. Disappointingly, however, none of these medications appear to be more efficacious than first-generation antiseizure medications, highlighting the need for novel strategies in epilepsy drug development. Although second-generation antiseizure medications have not substantially reduced the proportion of patients with pharmacoresistant epilepsy, their availability has enabled more opportunities to tailor treatment choice to the characteristics of the individual.

Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938-1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970-1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology. The last period (1989-2019) was dominated by the introduction of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials. The expansion of the pharmacological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inadequate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second-generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies.

International audience; Pharmacoresistance is a major clinical challenge for approximately 30% of patients with epilepsy. Previous studies indicate nuclear receptors (NRs), drug efflux transporters, and cytochrome P450 enzymes (CYPs) control drug passage across the blood-brain barrier (BBB) in drug-resistant epilepsy. Here, we (1) evaluate BBB changes, neurovascular nuclear receptors, and drug transporters in lesional/epileptic (EPI) and non-lesional/non-epileptic (NON-EPI) regions of the same brain, (2) examine regional CYP expression and activity, and (3) investigate the association among CYP brain expression, seizure frequency, duration of epilepsy, and antiepileptic drug (AED) combination. We used surgically resected brain specimens from patients with medically intractable epilepsy (n = 22) where the epileptogenic loci were well-characterized by invasive and non-invasive methods; histology confirmed distinction of small NON-EPI regions from EPI tissues. NRs, transporters, CYPs, and tight-junction proteins were assessed by western blots/immunohistochemistry, and CYP metabolic activity was determined and compared. The relationship of CYP expression with seizure frequency, duration of epilepsy, and prescribed AEDs was evaluated. Decreased BBB tight-junction proteins accompanied IgG leakage in EPI regions and correlated with upregulated NR and efflux transporter levels. CYP expression and activity significantly increased in EPI compared to NON-EPI tissues. Change in EPI and NON-EPI CYP3A4 expression increased in patients taking AEDs that were CYP substrates, was downregulated when CYP- and non-CYP-substrate AEDs were given together, and correlated with seizure frequency. Our studies suggest focal neurovascular CYP-NR-transporter alterations, as demonstrated by the relationship of seizure frequency and AED combination to brain CYP3A4, might together impact biotransformation machinery of human pharmacoresistant epilepsy.

Despite the availability of many antiepileptic drugs (AEDs) (old and newly developed) and, as recently suggested, their optimization in the treatment of patients with uncontrolled seizures, more than 30% of patients with epilepsy continue to experience seizures and have drug-resistant epilepsy; the management of these patients represents a real challenge for epileptologists and researchers. Resective surgery with the best rates of seizure control is not an option for all of them; therefore, research and discovery of new methods of treating resistant epilepsy are of extreme importance. In this article, we will discuss some innovative approaches, such as P-glycoprotein (P-gp) inhibitors, gene therapy, stem cell therapy, traditional and novel antiepileptic devices, precision medicine, as well as therapeutic advances in epileptic encephalopathy in children; these treatment modalities open up new horizons for the treatment of patients with drug-resistant epilepsy.

The last decade saw impressive advances not only in the discovery of gene mutations causing epilepsy, but also in unraveling the molecular mechanisms underlying the clinical manifestations of the disease. Increasing evidence is emerging that understanding these mechanisms is relevant for selection of the most appropriate treatment in the affected individual(s). The present article discusses the therapeutic implications of epilepsy-causing variants affecting a broad range of targets, from ion channels to genes controlling cellular metabolism and cell signaling pathways. Identification of a precise genetic etiology can direct physicians to (i) prescribe treatments that correct specific metabolic defects (e.g., the ketogenic diet for GLUT1 deficiency, or pyridoxine for pyridoxine-dependent epilepsies); (ii) avoid antiepileptic drugs (AEDs) that can aggravate the pathogenic defect (e.g., sodium channel blocking drugs in SCN1A-related Dravet syndrome), or (iii) select AEDs that counteract the functional disturbance caused by the gene mutation (e.g., sodium channel blockers for epilepsies due to gain-of-function SCN8A mutations). In some instances, different pathogenic variants of the same gene can have opposite functional effects, which determines whether certain treatments can be beneficial or deleterious (e.g., gain-of-function versus loss-of-function variants in SCN2A determine whether sodium channel blockers improve or worsen seizure control). There are also cases where functional disturbances caused by the gene defect may not be corrected by existing AEDs, but can be countered by medications already available in the market for other indications (e.g., memantine has been used to treat the epileptic encephalopathy caused by a specific gain-of-function GRIN2A mutation), thus making 'drug repurposing' a valuable tool for personalized epilepsy therapies. As our understanding of pathogenic mechanisms improve, opportunities arise for development of treatments targeting the specific gene defect or its consequences. Everolimus, an mTOR inhibitor approved for the treatment of focal seizures associated with tuberous sclerosis complex, is an example of a medication targeting the etiological mechanisms of the disease. Several treatments aimed at correcting specific pathogenic defects responsible for rare genetic epilepsies are currently in development, and range from traditional small molecules to novel approaches involving peptides, antisense oligonucleotides, and gene therapy.

Background Although therapeutic drug monitoring of antiepileptic drugs is typically based on the analysis of plasma samples, alternative matrices, such as dried plasma spots (DPSs), may offer specific advantages. The aims of this work were to (1) develop and validate a bioanalytical method for the quantitative determination of the second-generation antiepileptic drug perampanel in DPSs; (2) assess short- and long-term stability of perampanel in DPSs; and (3) test the clinical applicability of the developed method. Methods Two hundred microliters of plasma were dispensed on a glass paper filter and dried. Glass paper filter discs were then inserted into clean tubes. After addition of the internal standard (ie, promethazine), the analytes were extracted with 5-mL methanol, dried at room temperature (23 ± 2°C), and reconstituted. Separation and quantification were achieved on 2 serial reverse-phase monolithic columns connected to an UV detector (λ = 320 nm). Results Calibration curves were linear in the validated concentration range (25-1000 ng/mL). Intraday and interday accuracy were in the range of 99.2%-111.4%, whereas intraday and interday precision (coefficient of variation) ranged from 2.8% to 8.6%. The lowest limit of quantitation was 25 ng/mL. The stability of the analyte in DPSs was assessed and confirmed under different storage conditions. Perampanel concentrations estimated in DPS samples from patients receiving therapeutic doses were equivalent to those measured in plasma samples. Conclusions This simple method enables the quantitation of perampanel in DPSs with adequate accuracy, precision, specificity, and sensitivity. The short- and long-term stabilities of perampanel in DPSs are highly beneficial for sample shipment or storage at ambient temperature. Moreover, DPSs decreases the costs associated with storage and transportation compared with conventional wet samples.

Objective: To evaluate interrater agreement in categorizing treatment outcomes and drug responsiveness status according to the International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy. Methods: A total of 1053 adults with focal epilepsy considered by the investigators to meet ILAE criteria for drug resistance were enrolled consecutively at 43 centers and followed up prospectively for 18-34months. Treatment outcomes for all antiepileptic drugs (AEDs) used up to enrollment (retrospective assessment), and on an AED newly introduced at enrollment, were categorized by individual investigators and by 2 rotating members of a 16-member expert panel (EP) that reviewed the patient records independently. Interrater agreement was tested by Cohen’s kappa (k) statistics and rated according to Landis and Koch’s criteria. Results: Agreement between EP members in categorizing outcomes on the newly introduced AED was almost perfect (90.1%, k=0.84, 95% confidence interval [CI] 0.80-0.87), whereas agreement between the EP and individual investigators was moderate (70.4%, k=0.57, 95% CI 0.53-0.61). Similarly, categorization of outcomes on previously used AEDs was almost perfect between EP members (91.7%, k=0.83, 95% CI 0.81-0.84) and moderate between the EP and investigators (68.2%, k=0.50, 95% CI 0.48-0.52). Disagreement was related predominantly to outcomes considered to be treatment failures by the investigators but categorized as undetermined by the EP. Overall, 19% of patients classified as having drug-resistant epilepsy by the investigators were considered by the EP to have “undefined responsiveness.”. Significance: Interrater agreement in categorizing treatment outcomes according to ILAE criteria ranges from moderate to almost perfect. Nearly 1 in 5 patients considered by enrolling neurologists to be “drug-resistant” were classified by the EP as having “undefined responsiveness.”.

Summary Objective Although many studies have attempted to describe treatment outcomes in patients with drug‐resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug‐resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. Methods This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug‐resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). Results A seizure‐free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a “treatment failure” as compared to the judgment of the investigator (46.7% vs 62.9%, P

Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials.

Objective Among people with epilepsy, levetiracetam (LEV) can cause neuropsychiatric adverse events (NPAEs) that impact negatively on quality of life. It has been suggested that pyridoxine can ameliorate LEV-related NPAEs. We conducted a systematic review of studies on the use of pyridoxine supplementation to relieve NPAEs associated with LEV therapy. Methods The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, EMBASE, Scholar, Cochrane-CENTRAL (2000–2019), and EThOS platform were searched for studies on the use of pyridoxine in patients with LEV-related NPAEs. Proportions of patients reported to benefit from pyridoxine supplementation were tabulated, and a random-effect model meta-analysis was conducted. Results Eleven retrospective studies/case reports and one randomized prospective study, mostly including pediatric populations, were identified. Retrospective studies, which were rated as low quality due to failure to control for bias, reported an overall improvement of NPAEs after pyridoxine supplementation in 72.5% (108/149) of patients. The proportion of patients showing improvement in a pooled analysis of the four largest retrospective studies (n = 134) was 72.1% (95% confidence interval (CI) 47.1–88.3), although there was high heterogeneity across studies (I2 = 82%, pheterogeneity Conclusion This systematic review suggests that pyridoxine might be of benefit in relieving LEV-related NPAEs. However, the quality of the evidence is poor, and better-designed prospective studies that include quantitative as well as qualitative data are needed to define the role of pyridoxine in the management of LEV-related NPAEs.

Healthcare administrative databases of Italy's Lombardy Region were analyzed with the aim to assess perinatal outcomes and healthcare resource utilization during the first year of life in infants exposed to antiepileptic drugs (AEDs) during pregnancy. Drug prescriptions dispensed in the 12 months before delivery to women, who delivered between 2005 and 2011, were analyzed. Neonates were classified as cases if exposed to AEDs, and each case was randomly matched to seven controls. No significant differences were observed in the risk of congenital malformations between 526 cases and 3682 controls except for valproic acid (odds ratio (OR): 2.29; 95% confidence interval (CI): 1.24–4.22) where cases were more likely to be small for gestational age (χ2 = 7.66; p = 0.006). Cases also had a higher probability than controls of needing at least one specialist visit in a child neuropsychiatry outpatient service (OR: 1.74; 95% CI: 1.22–2.49).

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium-chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec-butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older. The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo-controlled randomized controlled trials, with promising efficacy and safety results.

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from preclinical or early (phase I) clinical studies were presented. The compounds reviewed include adenosine and adenosine kinase inhibitors, BIS-001 (huperzine A), 2-deoxy-d-glucose, FV-082, FV-137, JNJ-40411813, JNJ-55511118 and analogs, ketone-enhanced antiepileptic drugs, oxynytones, OV329, TAK-935 (OV935), XEN901, and XEN1101. Many innovative approaches to drug development were presented. For example, some compounds are being combined with traditional antiepileptic drugs based on evidence of synergism in seizure models, some act as inhibitors of enzymes involved in modulation of neuronal activity, and some interact in novel ways with excitatory receptors or ion channels. Some of the compounds in development target the etiology of specific epilepsy syndromes (including orphan conditions) through precision medicine, and some offer hope of producing disease-modifying effects rather than symptomatic seizure suppression. Overall, the results summarized in the report indicate that important advances are being made in the effort to develop compounds with potentially improved efficacy and safety profiles compared with existing agents.

Objective To evaluate long-term safety/tolerability and seizure outcomes in patients with focal seizures treated with adjunctive perampanel in the open-label extension (OLEx) Study 307 (ClinicalTrials.gov identifier: NCT00735397). Methods Patients could enter the OLEx after completing one of the double-blind, phase III studies. Safety/tolerability and seizure outcomes (median percent reduction in seizure frequency per 28 days, and 50% responder and seizure freedom rates) were analyzed during the OLEx in cohorts with the same minimum perampanel exposure for all focal seizures and secondarily generalized seizures (SGS). An additional sensitivity analysis accounted for early dropouts from the OLEx. Results Of 1480 patients randomized across the double-blind studies, 1218 enrolled in the OLEx. The majority of patients (65.4%-80.9%) received a last daily dose of perampanel 12 mg and completed long-term assessment on the same, or one fewer, concomitant antiepileptic drug compared with baseline. The long-term safety/tolerability profile was consistent with the double-blind studies. Treatment-emergent adverse events (TEAEs) leading to discontinuation in >1% of patients were dizziness, irritability, and fatigue; TEAEs of clinical interest were stable for 4 years. In all cohorts, seizure outcome improvements were sustained over time. Median percent seizure reductions per 28 days reached 62.0% and 70.6% for patients with ≥3 (n = 436) or ≥4 (n = 78) years of exposure, respectively; corresponding 50% responder rates were 59.6% and 67.9%. The largest median percent seizure reduction per 28 days occurred in SGS for patients with SGS at baseline: 88.0% and 100.0% for patients with ≥3 (n = 190) or ≥4 (n = 28) years of exposure, respectively; in these cohorts 40.0% and 53.6% of patients, respectively, attained freedom from SGS. Median percent seizure reductions per 28 days were similar when early dropouts were accounted for. Significance Long-term (≤4 years) adjunctive perampanel treatment did not raise new safety/tolerability signals and was associated with markedly improved seizure control, particularly in patients with SGS at baseline.

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain from May 13th to 16th 2018. Again, presentations on new medical devices and neuromodulation and discussions on device-related regulatory aspects were included in the programme. The virtual special issue on "neuromodulation" summarises the presentations focusing firstly, on the pre-clinical developments and the difficulties of clinical trial designs for neuromodulatory therapies, including vagus nerve stimulation (VNS) and Brain-Responsive Neurostimulation (RNS), and the use of transcutaneous vagus nerve stimulation (tVNS) as a potential screening tool for determining the efficacy of neuromodulatory treatments in individual patients; secondly, on wearable devices for seizure monitoring through indices of peripheral sympathetic nervous activity, the use of such devices in combination with biofeedback for the treatment of epilepsy, and its potential for improving epilepsy specialist services, particularly in remote areas.

Phenytoin, a widely prescribed old-generation antiepileptic drug, requires careful individualization of dosage to compensate for its prominent pharmacokinetic variability. This article reviews the contribution of genetic polymorphisms affecting the activity of CYP2C9, the main enzyme responsible for phenytoin metabolism, to the variation in phenytoin clearance and susceptibility to adverse effects.Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile.There is extensive evidence that CYP2C9 polymorphisms are an important determinant of the rate of phenytoin metabolism, although other factors including expression of other enzymes such as CYP2C19 and the influence of drug interactions, physiological and disease-related factors may also play a role. Patients carrying CYP2C9 genotypes associated with reduced phenytoin clearance are at greater risk of developing CNS adverse effects as well as serious cutaneous adverse reactions when given usual dosages of phenytoin. The clinical value and cost-effectiveness of CYP2C9 genotyping in improving the safety of phenytoin therapy, however, have not been clearly established and require formal testing in well-designed prospective studies.

The Twelfth Eilat Conference on New Antiepileptic Drugs (AEDs) - EILAT XII, took place in Madrid, Spain from August 31st to September 3rd 2014. About 130 basic scientists, clinical pharmacologists and neurologists from 22 countries attended the conference, whose main themes included "Conquering pharmacoresistant epilepsy", "Innovative emergency treatments", "Progress report on second-generation treatment" and "New methods and formulations". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 2004. Like the EILAT X and EILAT XI reports, the current article focuses on the preclinical and clinical pharmacology of AEDs that are currently in development. These include adenosine-releasing silk, allopregnanolone (SAGE-547), AMP-X-0079, brivaracetam, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-glucose, everolimus, ganaxolone, huperzine A, imepitoin, minocycline, NAX 801-2, pitolisant, PRX 0023, SAGE-217, valnoctamide and its homologue sec-butyl-propylacetamide (SPD), and VLB-01. Since the previous Eilat conference, perampanel has been introduced into the market and twelve novel potential epilepsy treatments are presented for the first time.

Epilepsy affects 65 million people worldwide and entails a major burden in seizure-related disability, mortality, comorbidities, stigma, and costs. In the past decade, important advances have been made in the understanding of the pathophysiological mechanisms of the disease and factors affecting its prognosis. These advances have translated into new conceptual and operational definitions of epilepsy in addition to revised criteria and terminology for its diagnosis and classification. Although the number of available antiepileptic drugs has increased substantially during the past 20 years, about a third of patients remain resistant to medical treatment. Despite improved effectiveness of surgical procedures, with more than half of operated patients achieving long-term freedom from seizures, epilepsy surgery is still done in a small subset of drug-resistant patients. The lives of most people with epilepsy continue to be adversely affected by gaps in knowledge, diagnosis, treatment, advocacy, education, legislation, and research. Concerted actions to address these challenges are urgently needed.

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.

Objective A previous European cost-utility study reported that use of buccal midazolam in the community setting for the treatment of prolonged seizures (ie, seizures lasting ≥5 minutes) in children was associated with an overall €12 507 399 reduction in annual costs charged to the Italian national health service compared with rectal diazepam. We re-evaluated these findings by applying a more conservative approach. Methods The Italian Delphi panel reconvened to apply a more conservative assessment of available reports. A decision-tree model was used, allowing for different treatment pathways depending on whether or not a caregiver administers treatment, an ambulance is required for transport of the child to hospital, and an inpatient stay is required. Direct medical costs were derived from Italian healthcare system data. Estimates of the annual number of prolonged tonic-clonic seizures expected in the country were based on studies which assessed seizure duration using video-EEG recordings and medical records. Results Although drug acquisition costs were greater for buccal midazolam than for rectal diazepam, the acquisition cost difference was outweighed by larger cost savings resulting mostly from a reduction in hospital admissions. Assuming that 1.2% of tonic and/or clonic seizures occurring in children and adolescents over a 12-month period are prolonged, the annual nationwide reduction in costs from preferring buccal midazolam to rectal diazepam was estimated at €3 577 587.9. Conclusions In this more conservative revised analysis, the high cost of buccal midazolam is still counteracted by greater cost savings compared with rectal diazepam, but cost reduction was less than previously estimated.

Summary Objective To better understand the relationship between efficacy and perampanel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period; open-label Maintenance Period) were analyzed. Methods Seizure frequency data were analyzed in patients who were randomized to and completed the 13-week Maintenance Period of the phase III studies on perampanel 8 mg, and who received an actual (last) dose of 12 mg during (1) the extension 16-week blinded Conversion Period or (2) weeks 1–13 of the extension Maintenance Period. Due to a treatment-by-region interaction (p = 0.042), analyses excluded patients from the Latin America region (n = 162/1,480; 10.9% of the treated cohort). Results Of 372 patients randomized to 8 mg in the phase III studies, 273 completed the Maintenance Period at 8 mg and 267 entered the extension study. In patients who then had an actual (last) dose of 12 mg during the extension blinded Conversion Period (n = 217), median percent change in seizure frequency per 28 days improved from −32.4% (8 mg, phase III Maintenance Period) to −44.2% (12 mg, extension blinded Conversion Period); 50% responder rates increased slightly from 37.3% to 42.9%. In patients who completed the phase III studies on 8 mg and had an actual (last) dose of 12 mg during weeks 1–13 of the extension Maintenance Period (n = 181), median percent change in seizure frequency per 28 days improved from −34.1% (phase III Maintenance Period) to −46.0% (weeks 1–13 extension Maintenance Period); 50% responder rates were 39.2% and 46.4%. Seizure control remained substantially unchanged in patients who completed the phase III studies at 12 mg and continued on that dose during the extension. Significance Increasing perampanel dose from 8 to 12 mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose.

Between 30% and 50% of patients with brain tumors first present with a seizure, and up to 30% more will develop seizures later. Therefore, optimal management of these patients requires a rational approach to the use of antiseizure medications. Based on current evidence, prophylactic prescription of long-term antiepileptic drugs (AEDs) in patients with brain tumors in patients who did not present with seizures is not justified. Because of the high risk of recurrence, however, AED treatment should be strongly considered after a single seizure considered to be due to a tumor. Because of the lack of well-controlled randomized trials, the decision on which AED provides the best risk-benefit ratio in the individual patient is based mostly on physician's judgment rather than sound scientific evidence. In patients who may require chemotherapy, a non-enzyme-inducing AED is preferred for initial treatment to minimize the risk of drug interactions that impact adversely on the outcome of anticancer chemotherapy. Several retrospective studies in seizure patients with glioblastoma treated with chemotherapy have provided evidence for a moderately improved survival with the use of valproic acid, possibly due to inhibition of histone deacetylase. However, valproic acid may also increase the hematologic toxicity of antineoplastic drugs, presumably by inhibiting their metabolism, and may independently impair hemostasis, which is of some concern for patients who require surgical intervention. Among newer generation AEDs, levetiracetam has a number of advantageous features, including availability of a parenteral formulation, but other agents such as gabapentin, lamotrigine, oxcarbazepine, topiramate, and zonisamide may also be considered. Potentially more effective treatments targeting specific mechanisms of epileptogenesis and ictogenesis are being investigated. Resection of the tumor, radiation therapy, or chemotherapy can bring refractory seizures under control or prolong the duration of seizure freedom, an effect that does not appear to be necessarily related to removal or shrinkage of the tumor mass. In patients with a successfully treated tumor and an overall good prognosis for long-term survival, gradual discontinuation of AEDs may be considered.

Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs' pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new-generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2-3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging-related pharmacokinetic changes could be predicted by measuring creatinine clearance (CLCR). Overall, most recent findings confirm that age is a major factor influencing the pharmacokinetic profile of AEDs. However, pharmacokinetic variability at any age can be considerable, and the importance of other factors should not be disregarded. These include genetic factors, co-morbidities, and drug interactions, particularly those caused by concomitantly administered AEDs which induce or inhibit drug-metabolizing enzymes.

OBJECTIVE Perampanel (PER), a selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor antagonist, exhibits broad-spectrum anticonvulsant activity in several seizure models, but its potential disease-modifying effects have not been investigated. Because of the relevance of AMPA receptors in epileptogenesis and psychiatric comorbidities, we studied the effects of PER in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and depressive-like comorbidity. METHODS We investigated the effects of acute, subchronic, and chronic treatment with PER (0.25-3 mg/kg) on absence seizures, their development, and related psychiatric/neurologic comorbidity in WAG/Rij rats. Depression-related behavior was studied by using the forced swimming and the sucrose preference test; anxiety-related behavior by using the open field and elevated plus maze test; and memory by using the passive avoidance test. RESULTS PER (3 mg/kg/day orally for 17 weeks starting from P30) significantly reduced the development of absence seizures at 6 months of age (1 month after treatment withdrawal), but this effect was not maintained when reassessed 4 months later. Attenuated absence seizure development was accompanied by reduced depressive-like behavior in the forced swimming test (FST), whereas no effects were observed on anxiety-related behavior and memory. Subchronic (1 and 3 mg/kg/day orally for 1 week) and acute PER (0.25-1 mg/kg, i.p.) dosing did not affect established absence seizures and behavior. SIGNIFICANCE These results suggest that AMPA receptors are involved in mechanisms of epileptogenesis in an established model of absence epilepsy, and that these mechanisms differ from those responsible for seizure generation and spread when epilepsy has become established.

Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the last 2 decades, the proportion of individuals with pharmacoresistant epilepsy has not been reduced substantially compared with the late 1960s. All currently available AEDs also have limitations in terms of adverse effects and susceptibility to be involved in clinically important drug-drug interactions. Therefore, the search for potentially more effective and better tolerated agents is continuing. This article reviews the pharmacological and clinical profile of the latest compounds to receive marketing authorization. Since the beginning of 2008, three novel AEDs, lacosamide, eslicarbazepine acetate and retigabine (also known as ezogabine), have become commercially available in Europe, with lacosamide and retigabine also being licensed in the US. All three agents are indicated for the adjunctive treatment of focal seizures in adults. Eslicarbazepine acetate is a produg for eslicarbazepine, which acts by blocking voltage-dependent sodium channels. Lacosamide enhances the slow inactivation phase of voltage-dependent sodium channels, and retigabine potentiates neuronal M-currents by opening Kv 7.2-7.5 potassium channels. All three agents, which are well absorbed from the gastrointestinal tract, exhibit linear pharmacokinetics. Lacosamide is also available as an intravenous formulation intended as replacement therapy for patients temporarily unable to take oral medications. All three drugs are eliminated partly unchanged in urine and partly by biotransformation through glucuronide conjugation (eslicarbazepine, retigabine), N-acetylation (retigabine) and oxidative demethylation (lacosamide). The half-life is in the order of 8-20 hours for eslicarbazepine, 12-16 hours for lacosamide and 6-10 hours for retigabine. Based on the limited information available to date, the ability of these agents to cause pharmacokinetic drug interactions appears to be relatively modest, although eslicarbazepine can cause a significant decrease in the blood levels of ethinylestradiol, levonorgestrel and simvastatin. The approved effective dose ranges are 200-400 mg/day in two divided doses for lacosamide, 800-1200 mg/day once daily for eslicarbazepine acetate, and 600-1200 mg/day in three divided doses for retigabine. In phase III, randomized, double-blind, adjunctive therapy trials, responder rates (proportion of patients with ≥50% reduction in seizure frequency vs baseline) at the highest approved dose were comparable for the three drugs (eslicarbazepine acetate: 37-43% vs 13-20% for placebo; lacosamide: 38-41% vs 18-26% for placebo; retigabine: 33-44% vs 16-18% for placebo). The adverse events most commonly reported with active treatment compared with placebo included dizziness, diplopia and nausea for lacosamide; dizziness, somnolence and nausea for eslicarbazepine acetate; and dizziness, somnolence and fatigue for retigabine. The role of these agents in the treatment algorithm will be increasingly defined as clinical experience accumulates. At present, their use is largely restricted to the adjunctive treatment of focal seizures, with or without secondary generalization, in adults with epilepsy who failed to achieve seizure freedom after having tried two or more first-line agents.