Prospects for New Drug Treatment in Epilepsy: A Review

Introduction Epilepsy is the commonest of neurological disorders with prevalence rates for active epilepsy of 5 per 1000 of the population", Arguably, it has been the most fruitful of therapeutic fields for the neurologist during the course of this century, but one has to question how far we have advanced in our ability to treat patients with epilepsy over the last 20 years. In the field of pharmacology the clinician is still largely dependent on those drugs that were developed in the first half of this century. When epilepsy is compared with other major therapeutic areas such as cardiovascular or gastrointestinal medicine, the neurologist must be depressed by the knowledge that no new major antiepileptic drugs have become established as firstline agents during the last decade. Indeed, many patients continue to take phenobarbitone, a drug introduced into clinical practice in 1912, and phenytoin, an agent that has recently celebrated 50 years in clinical usel'', In the United States, even valproate is only fully licensed for the treatment of simple absence (petit mal) seizures in spite of its wellrecognized properties in the treatment of tonic clonic and partial seizures", Where pharmacological treatment has improved most is in the area of more sophisticated use of the agents that we possess. Thus, whilst major questions still remain, we are better able to decide when to start and when to stop treatment with antiepileptic drugs" and the superiority of monotherapy to polytherapy is widely recognized", Our understanding of the pharmacokinetics of the drugs we use has also benefited patients, though to some degree serum blood level estimations are overvalued and in some cases abused", How then can we expect to make progress in identifying and establishing new antiepileptic drugs? No neurologist could surely doubt the need for such agents. Whilst overall the prognosis for patients developing epilepsy is good with up to 70% achieving long-term remissions", a significant number of people with epilepsy have a chronic intractable disorder causing disability with significant socioeconomic implications. More potent and effective antiepileptic drugs are particularly needed for the treatment of partial epilepsies and drugs with similar efficacy to those available would be of value if they have more specific actions with fewer eNS side effects". Fortunately, major advances in the basic neurophysiology, neuropathology, and neuropharmacology of epilepsy would now suggest that by the end of the century new groups of antiepileptic drugs should be available for routine clinical use. There seems every hope that such drugs will be developed rationally from an understanding of the basic mechanisms ofthe epilepsies rather than by the chance discovery of antiepileptic drugs through empirical screening programmes. A century ago, Hughlings Jackson? recognized epilepsy as a disorder of hyper-excitability of the nervous system. While Jackson's original physiological definition of epilepsy holds true today, clinical definitions of seizures and epilepsy are more difficult because of the enormous heterogeneity of the clinical disorder. In pursuing the aim of controlling the abnormal electrical activity that leads to epileptic seizures two differing philosophies could be utilized. The first would recognize that epilepsy is a heterogenous disorder with many different causes. This approach would attempt to identify individual causes so as to offer specific treatment that may not be relevant to other forms of epilepsy. Whilst there is greater understanding of epileptogenesis in animal models, their relevance to human epilepsy remains uncertain. As yet such an approach cannot easily be utilized. The second approach is to recognize that the many different causes of epilepsy may well converge and operate through a common final pathway. An attack on such a final common pathway might result in a much broader spectrum antiepileptic effect. This review article will particularly focus on the latter approach and will present a clinician's view of relevant advances in basic neurophysiology and neuropharmacology that lead from studies of individual cells through to animal models and finally to clinical trials of potential antiepileptic drugs.