Authors :
Presenting Author: Kayla Vieira, M.S. – New York Medical College
Antonia Schonwald, M.S. – New York Medical College
Chian-Ru Chern, Ph.D. – New York Medical College
Jana Velíšková, M.D., Ph.D. – New York Medical College
Libor Velíšek, M.D., Ph.D., FAES – New York Medical College
Rationale:
Infantile Epilepsy Spasms Syndrome (IESS) is a rare, severe epilepsy diagnosed in approximately 1 in 3,000 children between three and twenty-four months of age annually. Clinically, IESS is marked by myoclonic-tonic seizures (spasms), developmental regression, and a hallmark interictal EEG pattern of hypsarrhythmia, characterized by asynchronous high-amplitude slow waves and multifocal spikes. Current FDA-approved management including adrenocorticotropic hormone (ACTH) and vigabatrin, demonstrate efficacy in only 50–60% of cases and often carry significant side effects, such as immunosuppression and visual field deficits. Despite therapy, IESS is associated with a poor prognosis, including developmental delays, increased early life mortality, and progression to other devastating epilepsies such as Lennox-Gastaut Syndrome (LGS), underscoring the need for more effective therapies. Emerging evidence indicates that sigma-1 receptor (SIGMAR1) agonists have anticonvulsant properties. Blarcamesine restores cellular homeostasis via SIGMAR1 and muscarinic receptors, making it a promising candidate. Based on the established efficacy of SIGMAR1, we hypothesized that blarcamesine would suppress spasms, normalize EEG patterns, and prevent development of delayed spontaneous seizures in our validated model of IESS.
Methods:
Our lab has established a rat model of IESS, which recapitulates the clinical features and associated EEG signatures. In our model, rat pups are exposed to betamethasone during the prenatal period followed by N-methyl-D-aspartic acid (NMDA) induction of spasms on postnatal (P) days P12, P13, and P15, which then leads to spontaneous seizures after P21. EEG recordings are critical since effective treatment of IESS necessitates clinical and electrographic resolution. Thus, we obtained EEG-video recordings during NMDA-induced spasms (P12–P15) and during a period of spontaneous seizures (P22–P28). Blarcamesine or vehicle were administered after cessation of the first bout of spasms (P12), with subsequent doses on P13 and P14.
Results:
In vehicle-control animals, acute EEG-video recordings (P12–P15) revealed interictal hypsarrhythmia with large-amplitude waves and ictal electrodecrement. Further chronic recordings (P22–P28) showed spontaneous ictal activity, including slow (< 2.5 Hz) spike-and-wave discharges, associated with episodes of staring and subtle motor symptoms such as twitching or slow forelimb movements, mimicking the atypical absence seizures in LGS. Blarcamesine significantly increased latency to seizure onset, reduced spasm frequency, and normalized EEG activity by P15 as well as prevented the development of spontaneous seizures with preserved normal EEG activity.