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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 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 from June 26th to 29th 2016. For the first time, the last day of the conference focused solely on new medical devices and neuromodulation. The current article summarises the presentations of that day, focusing first on EEG- and ECG based methods and devices for seizure detection. These methodologies form the basis for novel cardiac-based methods of vagal nerve and responsive deep brain stimulation that rely on the prediction or early detection of seizures and that are also included in this article.

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.

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.

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.

In a study that applied a nonlinear mixed effect model to evaluate factors affecting steady-state serum carbamazepine concentrations in elderly nursing home residents, co-administration of iron supplements was reported to reduce serum carbamazepine concentrations by approximately one third. Although these findings suggest that iron ions reduce the oral bioavailability of carbamazepine, the influence of confounders cannot be excluded. Further studies are required to confirm this interaction.

SummaryThe Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included “Indications overlapping with epilepsy” and “Securing the successful development of an investigational antiepileptic drug in the current environment”. 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 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.

To assess whether levetiracetam elimination is influenced by enzyme inducing antiepileptic drugs (EIAEDs), serum levetiracetam levels were determined at frequent intervals after a single oral 1000mg dose in 15 subjects co-medicated with EIAEDs and 15 matched controls. The EIAED group showed a higher levetiracetam oral clearance (p=0.01) and a shorter half-life (p=0.02) than controls. Although the magnitude of interaction is relatively modest, it could have clinical significance for some patients.

The Tenth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT X, took place in Eilat, Israel from the 25th to 29th of April 2010. About 200 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included learning from the past: Lessons learnt after 18 years of Eilat Conferences and Detecting assessing and preventing adverse effects of AEDs. 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 1994. Like the previous EILAT (EILAT IX) manuscript, the current (EILAT X) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate, 2-deoxy-glucose, ganaxolone, huperizine A, ICA-105665, NAX-5055, retigabine, perampanel, T-2007, valnoctamide and YK3089. Since the previous Eilat Conference (EILAT IX-2008) two new AEDs; eslicarbazepine acetate and lacosamide have been marketed and three new AEDs in development not included in the EILAT IX manuscript were added: ICA-105665, perampanel and valnoctamide. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in Tables 1 and 2 and their proposed mechanism of action at summarized in Table 3.

The Ninth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT IX, took place in Sitges, Barcelona from the 15th to 19th of June 2008. Over 300 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included old and new AEDs in generalized epilepsies, novel formulations and routes of administration of AEDs, common targets and mechanisms of action of drugs for treating epilepsy and other central nervous system (CNS) disorders, and opportunities and perspectives in new AED discovery. Consistent with previous formats of this conference, a large part of the programme was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1989. Unlike previous EILAT manuscripts, the current (EILAT IX) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate (RWJ-333369), 2-deoxy-d-glucose, eslicarbazepine acetate (BIA-2-093), ganaxolone, huperzine, JZP-4, lacosamide, NAX-5055, propylisopropylacetamide (PID), retigabine, T-2000, tonabersat, valrocemide and YKP-3089. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in first and second tables and their proposed mechanisms of action are summarized in the third table.

The Eigth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT VII, took place in Sitges, Barcelona from the 10th to 14th September, 2006. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference, whose main themes included a focus on status epilepticus (epidemiology, current and future treatments), evidence-based treatment guidelines and the potential of neurostimulation in refractory epilepsy. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on marketed AEDs introduced since 1989. This article summarizes the information presented on drugs in development, including brivaracetam, eslicarbazepine acetate (BIA-2-093), fluorofelbamate, ganaxolone, huperzine, lacosamide, retigabine, rufinamide, seletracetam, stiripentol, talampanel, valrocemide, JZP-4, NS1209, PID and RWJ-333369. Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and new extended release oxcarbazepine formulations, pregabalin, tiagabine, topiramate, vigabatrin, zonisamide and new extended release valproic acid formulations, and the antiepileptic vagal stimulator device are also presented.

Purpose To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication. Methods The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged ≥65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/ F ) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20–50 years and matched for gender, body weight and antiepileptic drug (AED) comedication. Results A total of 71 elderly patients aged 70.0±4.4 years, including 20 receiving enzyme inducing AEDs, was included in the main evaluation. In the absence of enzyme inducing comedication, VPA CL/ F in the elderly was similar to that found in non-elderly controls (9.7±4.6 versus 10.2±4.6mlh −1 kg −1 ). Elderly patients on enzyme inducing comedication, on the other hand, had lower CL/ F values than enzyme induced younger controls (11.7±5.4 versus 16.0±6.3mlh −1 kg −1 , p F is known to increase with increasing dosage, a lower VPA dosage in elderly patients comedicated with enzyme inducers compared with controls may have contributed to differences in CL/ F between the two groups. Conclusions In the absence of enzyme inducing comedication, VPA clearance in the elderly was comparable to that observed in controls. VPA clearance in elderly patients receiving enzyme inducing AEDs was lower than in controls, the difference being probably due to an influence of age as well as to the fact that mean VPA dosage was lower in these patients than in controls. Since our measurements of clearance were based on total serum VPA concentrations and VPA binding to plasma proteins is known to be reduced in old age, it is likely that the clearance of unbound, pharmacologically active, VPA was decreased to an important extent in the elderly, presumably as a result of a decline in drug metabolizing capacity.

Recent years have witnessed an increased interest from pediatric neurologists, neuropediatricians, epileptologists and general neurologists in the use of the ketogenic diet (KD) for the management of refractory epilepsies, particularly in children and adolescents. This article summarizes current knowledge on various issues related to its use, as discussed at a recent international workshop. Aspects discussed in some detail include (i) the putative mechanisms responsible for the diet’s anticonvulsant effects, based on results of biochemical and neurophysiological studies in experimental models; (ii) consensus and controversies on the modalities of initiation of the diet, and different protocols of implementation; (iii) indications and contraindications; (iv) efficacy data, also in relation to seizure type, syndromic form and patients age; (v) adverse effects; (vi) methodological aspects related to assessment of the diet’s clinical effects, and perspectives for future research. Overall, the data reviewed indicate that considerable advances have been made in understanding the modes of action of the diet, its efficacy and tolerability profiles and its potential role in different types of epilepsy. Although clinical studies performed to date have important methodological limitations, including suboptimally characterized patients’ populations and an uncontrolled design, a number of innovative, prospective randomized study protocols have been recently proposed and are being implemented. The results of these will hopefully provide much needed high-quality information to better define the role of the diet in the treatment algorithms in different epilepsy syndromes.

In this article, epidemiological and clinical aspects related to the use of antiepileptic drugs (AEDs) in the elderly are highlighted. Studies have shown that people with epilepsy receiving AED treatment show important deficits in physical and social functioning compared with age-matched people without epilepsy. To what extent these deficits can be ascribed to epilepsy per se or to the consequences of AED treatment remains to be clarified. The importance of characterizing the effects of AEDs in an elderly population is highlighted by epidemiological surveys indicating that the prevalence of AED use is increased in elderly people, particularly in those living in nursing homes. Both the pharmacokinetics and the pharmacodynamics of AEDs may be altered in old age, which may contribute to the observation that AEDs are among the drug classes most commonly implicated as causing adverse drug reactions in an aged population. Age alone is one of several contributors to alterations in AED response in the elderly; other factors include physical frailty, co-morbidities, dietary influences, and drug interactions. Individualization of dosage, avoidance of unnecessary polypharmacy, and careful observation of clinical response are essential for an effective and safe utilization of AEDs in an elderly population.

The purpose of this study was to determine the influence of levetiracetam on the steady-state serum concentrations of other commonly used antiepileptic drugs (AEDs). Serum AED concentrations were measured at baseline and after adjunctive therapy with levetiracetam (1000-4000 mg/day) or placebo in four phase III trials in patients with refractory partial epilepsy receiving stable AED dosages. The data were pooled, and repeated measures covariance analysis was used to calculate the ratio (and 90% confidence intervals) of the geometric mean serum drug concentrations during adjunctive levetiracetam therapy relative to baseline. Levetiracetam did not increase or decrease mean steady-state serum concentrations of carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. For each of these AEDs, the 90% confidence interval of the geometric mean drug concentrations ratio was included within the 80-125% bioequivalence range. Serum concentrations of these AEDs did not change over time after adjunctive levetiracetam therapy, irrespective of the dosage of levetiracetam used. For vigabatrin, there was no evidence for a significant change in serum drug concentration after the addition of levetiracetam, but the number of observations was too small for the limits of the confidence interval to fall within the 80-125% range. Thus, adjunctive therapy with levetiracetam does not influence the steady-state serum concentrations of concomitantly administered carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. Consequently, no need for adjusting the dosages of these AEDs is anticipated when levetiracetam is added on or removed from a patient's therapeutic regimen.

The Seventh Eilat Conference on New Antiepileptic Drugs (AEDs) (EILAT VII) took place in Villasimius, Sardinia, Italy from the 9th to 13th May 2004. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference, whose main themes included advances in pathophysiology of drug resistance, new AEDs in pediatric epilepsy syndromes, modes of AED action and spectrum of adverse effects and a re-appraisal of comparative responses to AED combinations. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on second-generation AEDs. This article summarizes the information presented on drugs in development, including atipamezole, BIA-2-093, fluorofelbamate, NPS 1776, pregabalin, retigabine, safinamide, SPM 927, stiripentol, talampanel

OBJECTIVE: To evaluate the value of alternative monotherapy versus adjunctive therapy in partial epilepsy refractory to single antiepileptic drug (AED) therapy. DESIGN AND METHODS: In a multicentre, parallel-group, open-label study, patients with cryptogenic or symptomatic partial epilepsy not controlled after single or sequential AED monotherapies were randomised to monotherapy with an alternative AED or to adjunctive therapy with a second AED. The AED to be added/substituted and dose adjustments were determined by the physician's best judgement. Patients were followed up until withdrawal from the allocated treatment or for 12 months, whichever first. Outcome measures included proportion of patients continuing on the assigned treatment strategy, proportion of patients seizure-free after achieving the target maintenance dose, and adverse effects rates. Data were analysed by actuarial life tables, Kaplan-Meier survival analysis and Cox proportional hazard regression model. RESULTS: Of a total of 157 patients (including 94 previously exposed to only one AED), 76 were randomised to alternative monotherapy and 81 to adjunctive therapy. The two groups were balanced in clinical characteristics. The 12-month cumulative probability of remaining on the assigned treatment was 55% in patients randomised to alternative monotherapy and 65% in those randomised to adjunctive therapy (P=0.74). The 12-month probability of remaining seizure-free was 14 and 16%, respectively (P=0.74). Adverse effects were similar in the two groups. No significant differences in outcome within or between groups were identified based on etiology of epilepsy and previous AED exposure. CONCLUSIONS: Although these findings should be interpreted with caution due to the low statistical power resulting from the relatively small sample size, alternative monotherapy and adjunctive therapy were associated with similar outcomes. Further work is required to determine whether outcome could be improved through identification of specific AED combinations with synergistic activity.

Purpose : To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state. Methods : Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000–4000mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose). Results : Estimated pharmacokinetic values, normalized to a dose of 1mgkg −1 b.i.d., were: concentration at 1h ( C 1h ) 2.1μgml −1 , concentration at 12h ( C 12h ) 0.8μgml −1 , area under the curve from 0 to 12h (AUC 0–12h ) 17.1μgml −1 h, half-life ( t 1/2 ) 8.1h, and apparent oral clearance (CL/F) 0.97mlmin −1 kg −1 . Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t 1/2 tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest. Conclusions : Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.

The Sixth Eilat Conference on New Antiepileptic Drugs (AEDs) took place in Taormina, Sicily, Italy from 7th to 11th April, 2002. Basic scientists, clinical pharmacologists and neurologists from 27 countries attended the conference, whose main themes included dose-response relationships with conventional and recent AEDs, teratogenic effects of conventional and recent AEDs, update on clinical implications of AED metabolism, prevention of epileptogesis, and seizure aggravation by AEDs. According to tradition, the central part of the conference was devoted to a review of AEDs in development, as well to updates on AEDs, which have been marketed in recent years. This article summarizes the information presented on drugs in preclinical and clinical development, including carabersat (SB-204269), CGX-1007 (Conantokin-G), pregabalin, retigabine (D-23129), safinamide, SPD421 (DP-VPA), SPM 927, talampanel and valrocemide (TV 1901). Updates on fosphenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, new formulations of valproic acid, and the antiepileptic vagal stimulator device are also presented.

The Fifth Eilat Conference on New Antiepileptic Drugs (AEDs) took place at the Dan Hotel, Eilat, Israel, 25-29 June 2000. Basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included recognition of unexpected adverse effects, new indications of AEDs, and patient-tailored AED therapy. According to tradition, the central part of the conference was devoted to a review of AEDs in development, as well to updates on AEDs that have been marketed in recent years. This article summarizes the information presented on drugs in preclinical and clinical development, including AWD 131-138, DP-valproate, harkoseride, LY300164, NPS 1776, NW 1015, pregabalin, remacemide, retigabine, rufinamide and valrocemide. The potential value of an innovative strategy, porcine embryonic GABAergic cell transplants, is also discussed. Finally, updates on felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, and the antiepileptic vagal stimulator device are presented.

Tiagabine is currently recommended mainly as add-on therapy in adults and children above 12 years with partial epilepsy not satisfactorily controlled with other antiepileptic drugs. Based on available evidence and our clinical experience, tiagabine should be used preferably in patients sharing one or more of the following additional features, (i) a history of drug-induced cutaneous adverse events; (ii) mild to moderate epilepsy allowing for a slow titration and gradual onset of anticonvulsant action over a few weeks; (iii) patients for whom it is particularly important to avoid a deterioration in cognitive performance; and, (iv) patients who failed to respond to previous treatment with sodium channel blocker agents as they may particularly benefit from the introduction of tiagabine, due to its GABAergic mechanism of action. Tiagabine can also be used successfully in other patients with refractory partial epilepsy. Tiagabine is not indicated for patients with generalized or unclassified epilepsies and for patients with severely impaired liver function.

The Fourth Eilat Conference on New Antiepileptic Drugs (AEDs) was held at the Royal Beach Hotel, Eilat, Israel, from 6th to 10th September 1998. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss a number of issues in drug development, including outcome assessment in epilepsy (long-term efficacy, quality of life, safety), cost-effectiveness, an update on drugs in development, a progress report on recently marketed AEDs, and controversies in strategies for drug development. This review focuses on drugs in development and recently marketed AEDs. Drugs in development include ADCI, AWD 131-138, DP16, ganaxolone (CCD 1042), levetiracetam (ucb L059), losigamone, pregabalin (isobutyl GABA [CI-1008]), remacemide hydrochloride, retigabine (D-23129), rufinamide (CGP 33101), soretolide (D2916), TV1901, and 534U87. New information on the safety and efficacy of recently marketed drugs (felbamate, fosphenytoin, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide) and of a new antiepileptic device, the neurocybernetic prosthesis (NCP), has become available. This paper summarizes the presentations made at the conference.

Traditional randomized clinical trials for the monotherapy assessment of antiepileptic drugs (AED) involve allocation of newly diagnosed patients to long-term treatment with different AEDs in order to determine remission rates and side effect profile. Apart from being time-consuming, however, these trials are unlikely to show significant differences in seizure control between the various drugs, which may lead some regulatory agencies to argue that remission rates could be related to the natural history of the disease rather than to efficacy of the administered drugs. To circumvent this problem, a number of innovative designs for the monotherapy assessment of new AEDs have been developed in recent years. They all share the common feature of being aimed at demonstrating a difference in response rate over a short treatment period between a high dosage of a new AED and some form of suboptimal treatment (placebo or low-dose active control). Patients allocated to suboptimal treatment show unacceptable seizure control more rapidly than patients on high-dose active treatment and therefore they exit the trial at a faster rate: evidence of antiepileptic activity is therefore based on demonstration of differences in rate of deterioration rather than improvement. These trials are conducted with titration schedules, dosages and durations of treatment which are totally unrelated to optimal use of the same AEDs in routine clinical practice. No comparative data with an established reference agent are provided, and allocation of patients to suboptimal treatment raises serious ethical concerns. For these reasons, justification for the continued implementation of these trials is questionable. Randomized long-term comparative trials should be considered the gold-standard for the monotherapy assessment of new AEDs. A review of the literature, however, reveals that long-term trials with new AEDs completed to date had significant shortcomings in their design, including excessively rigid or inappropriate dosing schedules, enrollment of patients with heterogeneous seizure disorders, low statistical power and insufficient duration of follow-up. Because these studies are usually aimed at addressing regulatory requirements, the information obtained cannot be meaningfully applied to routine clinical practice. Large longer-term randomized comparative trials using more pragmatic approaches are highly needed to determine the real value of first-line therapy with new AEDs in patients with well defined seizure disorders.

The Third Eilat Conference on New Antiepileptic Drugs was held at the Royal Beach Hotel from May 27 to May 30, 1996. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss critical issues i n drug development, new antiepileptic drugs (AEDs) in development, progress reports and recent findings of newly marketed AEDs, the use of AEDs in special populations and their utilization in non-epileptic disorders. Over the last seven years, six new AEDs have been introduced worldwide and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate and vigabatrin. Drugs in development include those at an advanced stage, such as remacemide and tiagabine, as well as those just entering clinical trials, such as rufinamide (CGP 331010) and levetiracetam (ucb LO59). The following is a summary of the presentations for drugs in development and recent findings on newly marketed drugs.

The Second Eilat Conference on New Antiepileptic Drugs was held at the King Solomon's Palace Hotel from October 31 to November 3, 1994. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss new trial designs, drug approval, early use of new antiepileptic drugs, and new drugs in development. Over the last six years, several novel antiepileptic drugs have been introduced worldwide, and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, and vigabatrin. Drugs in development include those at an advanced stage, such as topiramate and tiagabine, as well as those just entering clinical trials, such as remacemide and levetiracetam. The following is a summary of the presentations for drugs in development and newly marketed drugs. The meeting concluded with a presentation, 'Still Searching for the Magic Bullet'.

To evaluate the pharmacokinetics of eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs).Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400mg (n=7), 800mg (n=26) or 1200mg (n=18) once-daily. Most patients (n=29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n=34, 66.7%) and valproic acid (n=19, 37.3%). Plasma concentrations of ESL and its metabolites eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry.Similarly to earlier findings in healthy subjects, plasma ESL concentrations were consistently below the lower limit of quantification (50ng/mL). The major compound in plasma was the active metabolite eslicarbazepine, which reached maximum concentrations (C(max)) 2h post-dose; thereafter, its plasma concentrations declined with a mean apparent half-life of 13, 14, and 20h in patients receiving ESL doses of 400, 800, and 1200mg once daily, respectively. Eslicarbazepine C(max) were 9.7, 15.5 and 23.0μg/mL, and areas under the plasma concentration-time curve over the dosing interval (AUC(0-24)) were 132.5, 205.4 and 336.1μgh/mL in patients receiving ESL doses of 400, 800 and 1200mg once-daily, respectively. Eslicarbazepine main pharmacokinetic parameters (C(max) and AUC(0-24)) were dose-proportional. R-licarbazepine and OXC were minor metabolites.Following once-daily oral administration of ESL 400mg, 800mg and 1200mg to epilepsy patients treated concomitantly with one or two other AEDs, ESL was rapidly converted to eslicarbazepine, which was the primary active compound found in plasma. Systemic exposure to eslicarbazepine was dose-proportional.

Summary Purpose To evaluate the potential anticonvulsant activity of α-lactalbumin (ALAC), a whey protein rich in tryptophan (TRP) relative to other large neutral aminoacids (LNAAs), in rodent models of seizures and epilepsy. Methods The effects of ALAC administered per os were evaluated by standard protocols against audiogenic seizures in Genetic Epilepsy Prone Rats (GEPR-9 rats), maximal electroshock (MES)-induced seizures in rats, pilocarpine-induced seizures in mice, spontaneous chronic seizures in mice exposed to pilocarpine-induced status epilepticus (SE), and absence seizures in WAG/Rij rats. In some models, carbamazepine (CBZ) was included as an active control. Plasma TRP/LNAAs ratios were measured by GC–MS. Results Single doses of ALAC up to 500 or 6000 mg/kg were devoid of anticonvulsant activity in all models tested. Conversely, 5- and 12-day treatment with ALAC (250–1000 mg/kg/day) in GEPR rats reduced dose-dependently seizure scores and prolonged latency to clonus onset, with full persistence of the effect for up to 12 h. ALAC (125–500 mg/kg/day for 15 days) protected against seizures induced by 250 mg/kg pilocarpine, but was less effective against higher pilocarpine doses. Similarly to CBZ, ALAC (125–500 mg/kg/day for 15 days) was also effective against spontaneous seizures in the post-pilocarpine SE model. ALAC (up to 6000 mg/kg/day for 12 days) did not prevent MES-induced seizures, although it reduced the duration of tonic extension at doses between 250 and 1000 mg/kg/day. Absence seizures in WAG/Rij rats were not significantly affected by ALAC. Plasma TRP/LNAAS ratios increased 2- to 3-fold after dosing with ALAC (250 mg/kg/day) for 7 and 14 days, respectively. Conclusions ALAC exerts significant protective activity against seizures in animal models, the effect being especially prominent against audiogenic seizures in GEPR-9 rats, seizures induced by low-dose pilocarpine in mice, and spontaneous seizures in mice exposed to pilocarpine-induced SE. This action is likely to be mediated by increased availability of TRP in the brain, with a consequent increase in 5-HT mediated transmission.

The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/F) in 75 patients aged 65-90 years (mean, 71.7 +/- 5.3 years) receiving phenytoin alone (n = 58) or in combination with phenobarbital (n = 17) and in an equal number of control patients aged 20-50 years (mean, 36.7 +/- 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/F values compared with controls (14.6 +/- 4.7 ml h(-1) kg(-1) versus 13.1 +/- 4.2 ml h(-1) kg(-1), P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 +/- 1.1 mg kg(-1)day(-1) versus 5.3 +/- 1.1 mg kg(-1) day(-1), P < 0.001) and had lower serum phenytoin concentrations (14.1 +/- 5.7 microg ml(-1) versus 18.6 +/- 6.8 microg ml(-1), P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/F. By contrast, in the elderly group, CL/F values were negatively correlated with age. On average, CL/F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug. Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.

The most important determinant of quality of life in patients with epilepsy is complete seizure control, and therefore this should be the ultimate goal of pharmacological therapy. Seizure freedom, or a reduction in seizure frequency, however, should not be sought at all costs, and the situation should never arise where a person with epilepsy is made to suffer more from the side effects of treatment than from the consequences of the underlying disease. Overtreatment is not uncommon in patients taking antiepileptic drugs, and it may occur in many forms and with a variety of mechanisms. Long-term use (or continuation) of anticonvulsant therapy in situations where it is not indicated (e.g. in children with simple febrile seizures, or in non-epileptic seizure-free patients who underwent brain surgery) constitutes a blatant case of overtreatment. Other forms of overtreatment include the use of unnecessarily fast dose escalation rates, which may expose the patient to potentially serious or severe side effects, or the prescription of unnecessarily high maintenance dosages. The latter occurrence may result from inadequate understanding of dose-response relationships, from misinterpretation of serum drug concentrations (e.g. targeting concentrations within the 'range' in patients who are well controlled at lower concentrations) or, at times, from failure to recognize a paradoxical increase in seizure frequency as a manifestation of drug toxicity. The most common form of overtreatment, however, involves the unnecessary use of combination therapy (polypharmacy) in patients who could be treated optimally with a single drug. Adverse effects associated with polypharmacy often result from undesirable drug-drug interactions. While pharmacokinetic interactions are somewhat predictable and can be minimized or controlled by monitoring serum drug concentrations and/or dose adjustment, pharmacodynamic interactions leading to enhanced neurotoxicity (as seen, for example, in some patients given a combination of lamotrigine and carbamazepine) can only be identified by careful clinical observation. There is evidence that not all antiepileptic drug combinations are equally adverse, and that the combined use of specific drugs (e.g. lamotrigine and valproic acid) may even exhibit an improved therapeutic index compared with either agent given alone, provided appropriate dose adjustments are made. Although the suggestion has been made that adverse effects are more likely to result from combining anticonvulsants having a similar mode of action, our knowledge of the pharmacology of individual agents is insufficient to allow a reliable prediction of the clinical effects of specific drug combinations.

The chronic nature of most seizure disorders requires that antiepileptic drugs (AEDs) be administered for many years. Therefore, new drugs should be evaluated over a period sufficient to assess potential development of tolerance as well as long-term safety. While patients and prescribers desire extensive long-term data prior to registration, too stringent requirements would discourage industry's investment into new treatments, and a compromise between these stakes should be sought. In add-on studies, it is recommended that patients completing double-blind assessment be offered indefinite open-label treatment, and that safety data be collected prospectively. Monotherapy trials in refractory patients include presurgical and conversion to monotherapy studies. Duration of assessment in these studies rarely exceeds few weeks, and endpoints relate to seizure deterioration rather than improvement; this surrogate measure of efficacy is not necessarily predictive of clinical usefulness and, in view of ethical concerns, the rationale for these studies should be questioned. There may be scope, however, for alternative study designs whereby refractory patients are converted to monotherapy and followed up for several months. Active-control long-term monotherapy trials in newly diagnosed patients represent the mainstay for evaluating efficacy and safety. In patients with partial or generalized tonic-clonic seizures, most trials conducted to date had a duration of 6-12 months, but this period may be insufficient to assess seizure freedom rates at optimized dosages, and at least one 2-year trial would be desirable. With respect to open-label follow-up, many protocols require that the randomization code not be broken until the database has been sealed. Patients completing blind assessment are often forced through unblinding procedures which involve tapering of trial medication and institution of an open-label therapy which may differ, in dosage or type of medication, from that taken previously. In view of ethical concerns, the rationale for this practice should also be questioned.

Epilepsy in the elderly differs from that in younger people in several respects. The incidence of seizures increases sharply with age and the seizures are more often symptomatic of underlying brain disease. The handling of antiepileptic drugs (AEDs) may be impaired by diminishing hepatic and renal function as age advances, and the pharmacodynamic response to drug therapy may be altered. In consequence, the elderly are more likely to experience adverse drug effects. Whether their seizures respond to drug treatment in a different way from younger patients is uncertain, but there are, nevertheless, convincing arguments for clinical trials being undertaken specifically in this population during the Phase II/IV development programme.

Assessment of risk to benefit ratio in patients with epilepsy is crucial in determining the need for treatment, the choice of drugs and the use of monitoring tools such as laboratory tests and other investigations. Active epilepsy per se carries significant risks in terms of increased mortality, susceptibility to psychopathology and physical injury, and reduced quality of life as a result of restricted lifestyle, stigma and prejudice. By preventing the occurrence of seizures, antiepileptic drugs (AEDs) attenuate or eliminate altogether seizure-related risks, but other risks may arise due to the side effects of the drugs, all of which have a relatively narrow therapeutic index. While there are no major differences in the degree of efficacy between AEDs which are effective in any given seizure type, side effect profiles differ considerably from one agent to another and represent a major factor in determining choice of treatment. Assessment of risk to benefit ratio should also take into consideration patient-specific factors such as type and severity of the epilepsy, age, sex, childbearing potential, medical and drug history, associated disease, use of concomitant medication (including the contraceptive pill) and the prospected patient's compliance. In some benign epilepsy syndromes, such as idiopathic partial epilepsy with centro-temporal spikes, the risk of side effects from AEDs may outweigh potential benefits in terms of seizure control, and treatment is generally not indicated. At the opposite end of the spectrum, the serious morbidity and mortality associated with severe epileptic encephalopathies, such as the Lennox-Gastaut syndrome, justifies aggressive treatment even with drugs associated with a relatively high risk of life threatening side effects such as felbamate. The present article will provide an overview of specific risks associated with epilepsy and with the various drugs used for its treatment, and will attempt to evaluate the complex balance between these risks and therapeutic benefits in different categories of patients.

Clinical trial endpoints often extend beyond conventional efficacy and tolerability measures. While it is generally assumed that seizure control without major adverse drug effects is by far the most important determinant of quality of life, other factors also are important. Pharmacokinetic endpoints could also provide relevant information for optimal drug use. Outcome measures could reveal drug effects on mood, headache, and sleep disorders, as well as overall quality of life and seizure severity.

The pharmacokinetics of a single oral dose of carbamazepine-10,11-epoxide (CBZ-E, 100 mg) were compared in 10 patients on chronic monotherapy with lamotrigine (LTG, 200–300 mg/day) and in 10 drug-free healthy control subjects. CBZ-E pharmacokinetic parameters in LTG-treated patients were found to be similar to those observed in controls (half-life: 7.2 ± 1.6 vs 6.1 ± 0.9 h ; apparent oral clearance: 110.8 ± 53.1 vs 120.5 ± 29.9 ml / h / kg ; apparent volume of distribution: 1.08 ± 0.37 vs 1.04 ± 0.25 l / kg respectively; means ± s.d.). These data indicate that, contrary to previous suggestions, LTG has no effect on the metabolic disposition of CBZ-E.

Women of childbearing age have been viewed as a 'vulnerable population' and have been systematically excluded from early clinical trials. A change in attitude and policies occurred in the last decade, with a consequent increase of women participating in clinical trials. The implications are increasing respect for the woman's capacity to make her own risk-benefit choices, early evaluation of patients that represent the ultimate user of a drug and equal opportunities for women to benefit from the therapeutic potential of new drugs. Drug trials should be designed to identify sex-related effects and to analyse the efficacy and tolerability of antiepileptic drugs (AEDs) by gender. Further aspects should be considered, including changes in response in relation to the menstrual cycle and over the various stages of reproductive life; interactions between hormonal therapies and AEDs; the effect of AEDs on reproductive function and possible consequences of prenatal exposure to AEDs. These considerations become even more critical when pregnant and lactating women are considered, since any risk for the offspring is unacceptable unless drug administration is likely to have major medical benefits for the mother.