Author(s)
David Thumim (student)1
Kayla Vieira MS (student)1
Chian-Ru Chern PhD (faculty)1
Antonia Schonwald MS (student)1
Jana Velíšková MD PhD (faculty)1 2 4
Libor Velíšek MD PhD (faculty)1 3 4
Affiliation(s)
1 Department of Cell Biology & Anatomy, 2 Department of Obstetrics and Gynecology, 3 Department of Pediatrics, 4 Department of Neurology, New York Medical College, Valhalla, NY
Abstract:
Developmental and epileptic encephalopathies (DEE) are devastating epilepsy syndromes of childhood associated with significant morbidity and mortality. Of the DEEs, infantile epileptic spasms syndrome (IESS) is a severe DEE marked by increased risk of premature mortality, developmental regression, and progression to other epilepsies, including 20-50% of cases that evolve to Lenox-Gastaut syndrome (LGS). LGS is a debilitating DEE affecting approximately one million children with 350 new cases annually in the United States. Current treatments, including anti-seizure medications (ASMs), ketogenic diet, surgery, and neuromodulation, neither fully alleviate the condition nor are without severe side effects. Despite emerging therapies, the prognosis for LGS patients remains poor with a markedly elevated sudden unexplained death in epilepsy (SUDEP) risk relative to all DEEs combined. Although existing LGS models capture specific genetic features, they incompletely reflect its electroclinical heterogeneity and its developmental relationship with IESS, underscoring the need for improved translational models.
Our laboratory has developed a rat model of IESS that recapitulates both the electrographic (EEG) and clinical features of the disorder, and importantly, its progression to LGS. In this model, rat pups are prenatally exposed to betamethasone with post-natal (P) induction of spasms by N-methyl-D-aspartate (NMDA) on P12, P13, and P15. During NMDA-induced spasms, pups exhibit ictal electrodecrement and interictal asynchronous large-wave activity, consistent with hypsarrhythmia characteristic of IESS. We implanted cortical electrodes at P19, and EEG-video recorded pups continuously from P22-P33. We hypothesized that animals experiencing early-life spasms (P12-P15) would develop spontaneous seizures after P21 with EEG correlates compared to saline controls.
We found that pups with P12-P15 spasms developed different spontaneous seizure types, including tonic and clonic seizures as well as absence-like events, corresponding to the multiple seizure types observed in LGS. Furthermore, these pups displayed EEG abnormalities with slow-wave activity <3 Hz and fast activity >10 Hz, consistent with LGS-associated EEG patterns. None of the prenatal-betamethasone postnatal-saline control pups exhibited behavioral seizures or aberrant EEG activity.
This preclinical model represents the first developmental model of LGS. Future studies can use this model to investigate the underlying disease mechanisms, evaluate targeted therapies, identify potential biomarkers, and ultimately improve patient outcomes.