Prefrontal cortex in the driving seat of epileptic networks in Lennox-Gastaut syndrome

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy characterized by multiple drug-resistant seizure types, bursts of diffuse slow spike-waves (1.5–2.5 Hz), and generalized paroxysmal fast activity (GPFA) on EEG, as well as intellectual disability.¹ Despite diverse underlying etiologies, and regardless of the presence or absence of a brain lesion, the electroclinical phenotype of LGS is stereotypical, suggesting the involvement of a common epileptic brain network. Indeed, LGS has been conceptualized as a secondary network epilepsy, where the clinical and electrophysiologic manifestations reflect the activated network while often not revealing the specific initiating process or site.² Imaging and electrophysiologic studies pointed to widely distributed network components residing in multilobar cortical regions, brainstem, and thalamus. The fact that surgical resection of a cortical lesion can alleviate seizures in some patients with LGS³ strongly supports the key role of cortex in LGS-associated epilepsy. However, conventional methodologies did not allow the identification of brain structures initiating epileptic activity, and the exact origin of LGS-related seizures remains enigmatic.