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There is an urgent need for the development of more effective and tolerated therapies. The multiple\u2010hit 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 (6\u03b1\u2010methylprednisolone, topiramate), as well as of the following investigative compounds: the anti\u2010inflammatory\/immunomodulatory compounds fingolimod and sivelestat, and the insulin\u2010like growth factor tripeptide IGF\u20101(1\u20103).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Postnatal day 3 (PN3) male Sprague\u2013Dawley 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 (6\u03b1\u2010methylprednisolone, IGF\u20101[1\u20103]). Blinded, vehicle\u2010controlled, dose and time response experiments were conducted. Drugs were administered as single intraperitoneal injections after spasms onset, except for IGF\u20101(1\u20103), 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Spasms frequency reduction was more consistent with the glucocorticosteroid 6\u03b1\u2010methylprednisolone 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\u2009h. Repeat administration of daily IGF\u20101(1\u20103) 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\u2010freedom rates or achieved &gt;50% reduction in spasm frequencies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our study further supports that the multiple\u2010hit model is a model of drug\u2010resistant spasms and suggests that anti\u2010inflammatory\/immunomodulatory treatments like fingolimod and sivelestat may have rapid effects on reducing spasms in the model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain language summary<\/jats:title><jats:p>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\u2010hit rat model of IESS to screen for new therapies and present here an overview of the model, which models drug\u2010resistant 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.70158","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T14:54:26Z","timestamp":1760453666000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The multiple hit model of infantile and epileptic spasms: The 2025 update"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0472-2903","authenticated-orcid":false,"given":"Aristea S.","family":"Galanopoulou","sequence":"first","affiliation":[{"name":"Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology Albert Einstein College of Medicine  Bronx New York USA"},{"name":"Isabelle Rapin Division of Child Neurology Albert Einstein College of Medicine  Bronx New York USA"},{"name":"Dominick P Purpura Department of Neuroscience Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzhu B.","family":"Mowrey","sequence":"additional","affiliation":[{"name":"Department of Epidemiology &amp; Population Health Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"Katsarou","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianyun","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4447-3312","authenticated-orcid":false,"given":"Oleksii","family":"Shandra","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Florida International University  Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9427-9476","authenticated-orcid":false,"given":"Solomon L.","family":"Mosh\u00e9","sequence":"additional","affiliation":[{"name":"Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology Albert Einstein College of Medicine  Bronx New York USA"},{"name":"Isabelle Rapin Division of Child Neurology Albert Einstein College of Medicine  Bronx New York USA"},{"name":"Dominick P Purpura Department of Neuroscience Albert Einstein College of Medicine  Bronx New York USA"},{"name":"Department of Pediatrics Albert Einstein College of Medicine  Bronx New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1111\/epi.17239","article-title":"ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE task force on nosology and definitions","volume":"63","author":"Zuberi SM","year":"2022","journal-title":"Epilepsia"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1055\/a-1909-2977","article-title":"Treatment of infantile spasm syndrome: update from the interdisciplinary guideline committee coordinated by the German\u2010speaking Society of Neuropediatrics","volume":"53","author":"Ramantani G","year":"2022","journal-title":"Neuropediatrics"},{"key":"e_1_2_10_4_1","article-title":"Treatment of infantile spasms","volume":"2013","author":"Hancock EC","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1111\/j.1528-1167.2010.02657.x","article-title":"Infantile spasms: a U.S. consensus report","volume":"51","author":"Pellock JM","year":"2010","journal-title":"Epilepsia"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2022.774828","article-title":"Etiologic classification of 541 infantile spasms cases: a cohort study","volume":"10","author":"Peng P","year":"2022","journal-title":"Front Pediatr"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/epi.12951","article-title":"How should children with west syndrome be efficiently and accurately investigated? 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