Contributions of basic neurochemistry towards a novel concept of epilepsy

Epilepsy is an ancient disorder which treatment over the centuries has been guided by preconceptions regarding its origin. The major improvements in epilepsy management came following the discovery of the EEG and the development of seizure suppressing agents. These advances in diagnosis and anticonvulsant therapy have further ingrained the conviction that epilepsy is a disease of neurons. Evidence presented here is intended to support a different point of view which suggests that the metabolic modifications in epileptogenic tissue denote subtle alterations in the anatomical and biochemical relationship between neurons and their glial envelopes. As a result the extracellular environment of these cells contain higher than normal levels of glutamic acid. This creates an unnatural functional connectivity between neurons so that they establish abnormal synchronous activity between them and become hyperexcitable due to the depolarizing milieu. To compensate for these biochemical changes it is suggested that some thought might be given to epilepsy management by metabolic manipulation. The measures should be directed specifically towards improving the ability of glia to remove glutamic acid from the extracellular milieu. Two obvious possibilities are to enhance glial glutamine synthesis and to improve the interstitial "wash-out" of glutamic acid in epileptogenic epicenters. Such a therapy would anticipate to gradually diminish seizure incidence and susceptibility without, however, having a direct action on convulsive episodes per se. The approach must be considered an adjunct to current epilepsy treatment and not a substitute for the use of anticonvulsants.