The multiple hit model of infantile and epileptic spasms: The 2025 update

Objective Infantile and epileptic spasms syndrome (IESS) is a developmental and epileptic encephalopathy manifesting with epileptic spasms and poor neurodevelopmental outcomes. There is an urgent need for the development of more effective and tolerated therapies. The multiple‐hit model of IESS due to structural etiology has been optimized for the screening of treatments for spasms. Here, we test in this model the efficacy and tolerability of clinically available treatments (6α‐methylprednisolone, topiramate), as well as of the following investigative compounds: the anti‐inflammatory/immunomodulatory compounds fingolimod and sivelestat, and the insulin‐like growth factor tripeptide IGF‐1(1‐3). Methods Postnatal day 3 (PN3) male Sprague–Dawley rats were induced by right intracerebroventricular doxorubicin and right intracortical lipopolysaccharide infusions and underwent daily assessments of body weights, motor and developmental milestones, and intermittent monitoring for spasms. Blood glucose was measured in selected drugs (6α‐methylprednisolone, IGF‐1[1‐3]). Blinded, vehicle‐controlled, dose and time response experiments were conducted. Drugs were administered as single intraperitoneal injections after spasms onset, except for IGF‐1(1‐3), which was tested as daily injections given from PN4 to PN10. Hourly spasms frequencies, raw or normalized to pretreatment frequencies, were determined and analyzed using a mixed linear model considering repeated measures. Results Spasms frequency reduction was more consistent with the glucocorticosteroid 6α‐methylprednisolone than topiramate. Fingolimod reduced spasms during the first 2 h whereas the sivelestat had longer lasting effects in reducing spasm rates during the first 5 h. Repeat administration of daily IGF‐1(1‐3) between PN4 and PN10 had no effect on raw frequencies of spasms and only reduced the normalized frequencies during the third treatment day (PN6). None of the treatments increased the spasm‐freedom rates or achieved >50% reduction in spasm frequencies. Significance Our study further supports that the multiple‐hit model is a model of drug‐resistant spasms and suggests that anti‐inflammatory/immunomodulatory treatments like fingolimod and sivelestat may have rapid effects on reducing spasms in the model. Plain language summary Infantile and epileptic spasms syndrome (IESS) manifests with epileptic spasms and negatively affects the infants' development due to cognitive and behavioral problems. We have optimized the multiple‐hit rat model of IESS to screen for new therapies and present here an overview of the model, which models drug‐resistant IESS due to structural etiology. We also present new data on the acute effects of five drugs on spasms and a comparative assessment of all the treatments tested in this model for effects and tolerability on spasms, developmental deficits, adult epilepsy, and tolerability.