Clinical trials for Lennox-Gastaut syndrome: Challenges and priorities

Abstract

Objective: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes.

Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review.

Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease-modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving "drops," but should incorporate additional patient-centered outcomes, using emerging measures adapted to people with LGS.

Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient-centered clinical trials that are tailored to LGS pathophysiology and natural history.

Figure 1

Conceptualizing LGS as a secondary network disorder. Upper row: Example structural MRI findings in 8 people with LGS illustrating the diverse range of etiologies that can lead to LGS, including malformations of cortical development, acquired brain injuries, genetic abnormalities, and even combinations of multiple etiologies (e.g., both genetic and structural causes). This echoes Gastaut's original description of the syndrome as a mode of reaction of the brain to one of many possible cerebral aggressions. Lower row: Recent studies have lent support to Gastaut's view by showing that different etiologies converge upon a “secondary” brain network, which in turn gives rise to the shared electroclinical phenotype seen in LGS. LGS, Lennox–Gastaut syndrome; MRI, magnetic resonance imaging; PVNH, periventricular nodular heterotopia; GPFA,generalized paroxysmal fast activity; SSW, slow‐spike‐and‐wave.

Figure 2

Brain network correlates of GPFA and SSW revealed by simultaneous EEG‐fMRI in LGS. Functional neuroimaging modalities including EEG‐fMRI permit whole‐brain visualization of brain areas engaged at the time of epileptic events captured on scalp EEG. EEG‐fMRI studies revealed the network patterns underlying two defining EEG characteristics of LGS, GPFA and SSW. (A) EEG‐fMRI of GPFA in an individual with LGS resulting from tuberous sclerosis complex, showing bilateral fMRI signal increases in diffuse frontal and parietal cortex, thalamus, caudate, anterior putamen, pons, and cerebellum. (B) EEG‐fMRI of SSW in an individual with LGS due to a complex malformation of cortical development including bilateral PVNH, showing a mixed pattern of subcortical fMRI signal increases and cortical signal decreases, particularly in areas of the “default‐mode” network. Zoomed‐in views show concurrent activation of the individual's lesion (PVNH) with the more distributed network pattern. Images were created using previously published data and methodologies. EEG, electroencephalogram; fMRI, functional magnetic resonance imaging; GPFA, generalized paroxysmal fast activity; LGS, Lennox–Gastaut syndrome; PVNH, periventricular nodular heterotopia; SSW, slow‐spike‐and‐wave.