Summary:This article is a summary of a workshop held by the ILAE concerning the issue of the epilepsy treatment gap in developing countries. The gap is defined in terms of those people with epilepsy who are not being appropriately treated and is the result of an array of medical, political, social, economic, and cultural factors. The situation regarding the treatment gap for various countries is reviewed, along with some of its causes. Although the overall gap is estimated to be large, a number of recent projects and interventions have been effective in delivering appropriate treatment to people with epilepsy in underresourced countries of the developing world. It is hoped that these may be transferable elsewhere and that, combined with the ILAE/IBE/WHO Global Campaign against Epilepsy and increased support from the worldwide epilepsy community, the treatment gap will begin to be bridged.

Summary: Purpose:To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy.Methods: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies.Results: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.71. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using >1,000 mg VPNday were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed G600 mg VPNday (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and G600 mg/day.Conclusions: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.

Summary:Purpose: When monothempy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which cornbinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches.Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers.Results: Thirty-nine papers were identified reporting on twodrug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. Conclusions:There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seeins less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.

Summary: Purpose:We reviewed the literature to determine whether an analysis of published data could clarify the relationship between antiepileptic drug (AED) polytherapy and adverse affects (AE). We highlight the problems encountered.Methods: We made a Medline-search for articles published between 1974 and 1994 reporting the number of AE and doses or serum levels of every AED, per patient or treatment group, and used the PDD/DDD ratio to calculate AED load per patient from doses or the OSL/AToxL ratio to do so from serum levels of individual drugs. The PDD/ DDD is the sum of ratios of the actual prescribed daily doses divided by the published average therapeutic dose of each drug. The OSL/AToxL is the sum of each observed serum level divided by its average toxic level.Results: We retrieved 118 trial reports. Most had to be excluded because of incomplete reporting of concomitant medication or AE. The data of the 15 articles selected for further analysis indicate a relationship between drug load and number of AE. We noted no relationship between the number of AEDs administered and AE. In add-on studies, the difference in neurotoxicity between the active and placebo arm may be obscured if the relative increase in drug load is small, as exemplified by the study of McGuire et al. (35).Conclusions: Articles reporting add-on trials of new AEDs generally do not provide detailed information about the basic medication to which the new AED is added, which makes calculation of total drug load impossible. Furthermore, often only frequency of A E is reported, not severity or development of tolerance, making it difficult to judge the impact of AE. However, despite the paucity of available information, we present some evidence that toxicity in AED polytherapy may be related to total drug load, rather than to the number of drugs administered. Therefore, the present trend to reject polytherapy for fear of increased toxicity is not warranted, which removes one of the objections to initiating specific research to prove or disprove the value of AED combinations as long as the drug load is appropriate. Key Words: PolytherapyAntiepileptic drugs-Adverse effects-Drug loadEpilepsy.Antiepileptic drug (AED) pharmacotherapy is aimed at reducing seizure frequency and severity without producing adverse effects (AE). However, the reporting of AE in clinical trials lacks quantitative data because AE are often described in terms of frequency and rarely in terms of severity (1). Although the incidence of AE is important, the degree to which they occur also determines the acceptability of individual AEDs. When quantitative data are presented, a comparison is complicated because of the different rating scales used (2,3).The risk of development of chronic toxicity has been one of the arguments against use of polypharmacy in epilepsy (4). Much of this toxicity is believed Accepted January 13, 1997. Address correspondence and reprint requests to Dr. H. Meinardi, c/o P.O. Box 21,2100 AA Heemstede, The Netherlands.to be directly related to the number ...

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