Interictal behavioral disturbances: a search for molecular substrates

Abstract

Postictal symptoms can be disabling in themselves, but their underlying substrates may endure, giving rise to epilepsy-induced interictal behavioral disorders. Chronic temporal lobe epilepsy is reported to be associated with a variety of interictal behavioral changes which often take the form of affective disturbances. Depression, among the more common interictal psychological dysfunctions suffered by patients with temporal lobe seizures, could reflect epilepsy-induced alterations in normal opioid peptide mechanisms. In experimental animal models, certain postictal behaviors have been shown to be opioid-mediated. Furthermore, an experimental model of interictal behavioral disturbance resembles stimulation-induced defensive rage, which can be relieved by intracerebral administration of opioid peptides. Defensive rage is a species-specific behavior encountered in cats. Its correlate in humans would be difficult to predict in view of the stronger cortical control; however, it may manifest rather as insecurity, irritability, and perhaps depression. Extrapolation of animal experiments would suggest that depression and certain other common postictal and interictal affective disturbances seen in patients with temporal lobe seizures reflect mechanisms more related to opiate withdrawal, than to direct opiate actions. The activity-induced plasticity associated with recurrent temporal lobe seizures, therefore, should result in changes in opioid function that predispose to withdrawal phenomena. Limbic seizures induce enhanced enkephalin synthesis lasting for up to 2 weeks. Recurrent seizures in experimental animals, however, cause paradoxical up-regulation of mu opiate receptors. Patients with temporal lobe epilepsy demonstrate enhanced mu receptor binding in the neocortex of the epileptogenic temporal lobe on PET. The reasons for this enduring interictal effect are not clear. Nevertheless, if animals or patients become dependent on enhanced endogenous opioid activity as a result of seizures, and also have up-regulation of mu receptors, then severe withdrawal effects, such as defensive rage in cats or depression in humans, might be expected when seizures do not recur frequently. Plotting the time course of mRNAenk and enkephalin expression after seizures, and the time course of symptoms of interictal behavioral disturbances, may demonstrate a temporal relationship that supports this hypothesis. For instance, depression or other withdrawal symptoms might only occur when the interval between seizures is greater than the duration of seizure-induced enkephalin synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)