Conceptualizing Lennox–Gastaut Syndrome as a Secondary Network Epilepsy

Abstract

Lennox–Gastaut Syndrome (LGS) is a category of severe, disabling epilepsy, characterized by frequent, treatment-resistant seizures, and cognitive impairment. Electroencephalography (EEG) shows characteristic generalized epileptic activity that is similar in those with lesional, genetic, or unknown causes, suggesting a common underlying mechanism. The condition typically begins in young children, leaving many severely disabled with recurring seizures throughout their adult life. Scalp EEG of the tonic seizures of LGS is characterized by a diffuse high-voltage slow transient evolving into generalized low-voltage fast activity, likely reflecting sustained fast neuronal firing over a wide cortical area. The typical interictal discharges (runs of slow spike-and-wave and bursts of generalized paroxysmal fast activity) also have a “generalized” electrical field, suggesting widespread cortical involvement. Recent brain mapping studies have begun to reveal which cortical and subcortical regions are active during these “generalized” discharges. In this critical review, we examine findings from neuroimaging studies of LGS and place these in the context of the electrical and clinical features of the syndrome. We suggest that LGS can be conceptualized as “secondary network epilepsy,” where the epileptic activity is expressed through large-scale brain networks, particularly the attention and default-mode networks. Cortical lesions, when present, appear to chronically interact with these networks to produce network instability rather than triggering each individual epileptic discharge. LGS can be considered as “secondary” network epilepsy because the epileptic manifestations of the disorder reflect the networks being driven, rather than the specific initiating process. In this review, we begin with a summation of the clinical manifestations of LGS and what this has revealed about the underlying etiology of the condition. We then undertake a systematic review of the functional neuroimaging literature in LGS, which leads us to conclude that LGS can best be conceptualized as “secondary network epilepsy.”

The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2)

“…Functional neuroimaging has indicated that epileptic activity in LGS recruits widespread areas of association cortex and that tonic seizures are expressed through the reticular formation of the pons (Archer et al, 2014). LGS has been recently conceptualized as "secondary network epilepsy" in which the epileptic activity is expressed through largescale brain networks; cortical lesions, when present, appear to chronically interact with these networks to produce M. Koutroumanidis, et al network instability rather than triggering each individual epileptic discharge (Archer et al, 2014). There is significant overlap between LGS and other epilepsy syndromes (Kaminska and Oguni, 2013), making the differential diagnosis particularly challenging.…”

Abnormal cognitive network interactions in Lennox‐Gastaut syndrome: A potential mechanism of epileptic encephalopathy

“…1 Given that diverse causes result in a shared electroclinical profile, we and others have hypothesized that the epileptic process in LGS may engage common brain systems. [2][3][4][5] Clinical observations suggest that epileptic activity can contribute directly to impaired cognition in LGS, a process termed "epileptic encephalopathy." 5 Patients with LGS typically experience cognitive regression at seizure onset, and intellectual decline often continues if seizures remain poorly controlled.…”

Brainstem dysfunction in patients with late-onset Lennox-Gastaut syndrome: Voxel-based morphometry and tract-based spatial statistics study

“…[12] Although paroxysmal fast activities are not pathognomonic for LGS because these activities may also be observed in focal lesional epilepsy, paroxysmal fast activities are suggestive of LGS, especially with bilateral GPFA. [29] All of our patients had GPFA. Interestingly, GPFA were especially observed during sleep, which was consistent with the previous study.…”