The epileptic network of Lennox-Gastaut syndrome: Cortically driven and reproducible across age

Abstract

Objective: To identify brain regions underlying interictal generalized paroxysmal fast activity (GPFA), and their causal interactions, in children and adults with Lennox-Gastaut syndrome (LGS).

Methods: Concurrent scalp EEG-fMRI was performed in 2 separately analyzed patient groups with LGS: 10 children (mean age 8.9 years) scanned under isoflurane-remifentanil anesthesia and 15 older patients (mean age 31.7 years) scanned without anesthesia. Whole-brain event-related analysis determined GPFA-related activation in each group. Results were used as priors in a dynamic causal modeling (DCM) analysis comparing evidence for different neuronal hypotheses describing initiation and propagation of GPFA between cortex, thalamus, and brainstem.

Results: A total of 1,045 GPFA events were analyzed (cumulative duration 1,433 seconds). In both pediatric and older groups, activation occurred in distributed association cortical areas, as well as the thalamus and brainstem (p < 0.05, corrected for family-wise error). Activation was similar across individual patients with structural, genetic, and unknown etiologies of epilepsy, particularly in frontoparietal cortex. In both groups, DCM revealed that GPFA was most likely driven by prefrontal cortex, with propagation occurring first to the brainstem and then from brainstem to thalamus.

Conclusions: We show reproducible evidence of a cortically driven process within the epileptic network of LGS. This network is present early (in children) and late (in older patients) in the course of the syndrome and across diverse etiologies of epilepsy, suggesting that LGS reflects shared "secondary network" involvement. A cortical-to-subcortical hierarchy is postulated whereby GPFA rapidly propagates from prefrontal cortex to the brainstem via extrapyramidal corticoreticular pathways, whereas the thalamus is engaged secondarily.