Clinical aspects and biological bases of drug-resistant epilepsies

The definition of drug-resistant epilepsy (DRE) is elusive and still contro versial owing to some unresolved questions such as: how many drugs should b e tried before a patient is considered intractable; to which extent side-ef fects may be acceptable; how many years are necessary before establishing d rug resistance. In some cases, the view of epilepsy as a progressive disord er constitutes another important issue. Despite the use of new antiepilepti c drugs (AEDs), intractable epilepsy represents about 20-30% of all cases, probably due to the multiple pathogenetic mechanisms underlying refractorin ess. Several risk factors for pharmacoresistance are well known, even if th e list of clinical features and biological factors currently accepted to be associated with difficult-to-treat epilepsy is presumably incomplete and, perhaps, disputable. For some of these factors, the biological basis may be common, mainly represented by mesial temporal sclerosis or by the presence of focal lesions. In other cases, microdysgenesis or dysplastic cortex, wi th abnormalities in the morphology and distribution of local-circuit (inhib itory) neurons, may be responsible for the severity of seizures. The possib le influence of genes in conditioning inadequate intraparenchimal drug conc entration, and the role of some cytokines determining an increase in intrac ellular calcium levels or an excessive growth of distrophic neurites, const itute other possible mechanisms of resistance. Several hypotheses on the me chanisms involved in the generation of DRE have been indicated: (a) ontogen ic abnormalities in brain maturation; (b) epilepsy-induced alterations in n etwork, neuronal, and glial properties in seizure-prone regions such as the hippocampus; (c) kindling phenomenon; (d) reorganization of cortical tissu e in response to seizure-induced disturbances in oxygen supply. Such hypoth eses need to be confirmed with suitable experimental models of intractable epilepsy that are specifically dedicated, which have until now been lacking . (C) 1999 Elsevier Science B.V. All rights reserved.