Temporal lobe epilepsy: where do the seizures really begin?

Abstract

Defining precisely the site of seizure onset has important implications for our understanding of the pathophysiology of temporal lobe epilepsy, as well as for the surgical treatment of the disorder. Removal of the limbic areas of the medial temporal lobe has led to a high rate of seizure control, but the relatively large number of patients for whom seizure control is incomplete, as well as the low rate of surgical cure, suggests that the focus extends beyond the usual limits of surgical resection. Reevaluation of the extent of the pathology, as well as new data from animal models, suggests that the seizure focus extends, at least in some cases, beyond the hippocampus and amygdala, which are usually removed at the time of surgery. In this review, we examine current information about the pathology and physiology of mesial temporal lobe epilepsy syndrome, with special emphasis on the distribution of the changes and patterns of seizure onset. We then propose a hypothesis for the nature of the seizure focus in this disorder and discuss its clinical implications, with the ultimate goal of improving surgical outcomes and developing nonsurgical therapies that may improve seizure control.

Figure 1

Basic circuitry of a neocortical seizure focus with a cortical excitatory driver, a subcortical seizure synchronizer and a number of neuromodulatory inputs (NM) that regulate excitability of synchronizer, driver or both.

Figure 2

Summary of Gloor’s absence circuitry experiments. A. Regular spike wave activity occurs in intact thalamocortical circuit. B. Separating cortex from the thalamus prevents regular spike and wave activity. C. Removal of cortex prevents abnormal activity from developing in the thalamus.

Figure 3

Connections between limbic structures and medial dorsal and midline thalamic nuclei. Simplified outline of significant known pathways between limbic sites that are strongly associated with seizure activity and the medial dorsal (MD) and midline thalamic nuclei. Direction of arrows indicates efferent and afferent pathways.

Figure 4

Modulation of limbic seizure activity through manipulation of the midline region of the thalamus. Seizure induced in anesthetized rat by stimulation of contralateral CA 3 in the hippocampus, with simultaneous seizure activity in CA 1 of the hippocampus and the medial dorsal thalamic nucleus (MD) before and after infusion of the GABA-A antagonist bicuculline. Seizure duration is significantly lengthened by bicuculline (arrows). First 10 seconds of each recording is stimulation artifact.

Figure 5

Variable pattern of limbic seizure onset according to the multiple independent generator hypothesis of limbic epilepsy. A. shows the situation in which all three sites contribute equally to seizure onset. B. displays a theoretical amygdala dominant seizure onset, whereas C. depicts a seizure in which the amygdala would play a minor role in relation to the other sites.