{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:23:17Z","timestamp":1778217797088,"version":"3.51.4"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100024157","name":"Neurelis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100024157","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>In epilepsy, daily treatment provides only symptomatic seizure control, leaving a significant unmet need for a treatment that affects the underlying predisposition to seizures. Here, in a first\u2010of\u2010its\u2010kind study, we test the hypothesis that intermittent treatment of seizure clusters with diazepam in the kainic acid post\u2010status epilepticus rat model of acquired epilepsy has an enduring effect on the seizure cluster phenotype, suggestive of potential disease modification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Following kainic acid\u2010induced status epilepticus, rats with epilepsy were monitored for occurrence of seizure clusters (\u22652 seizures in 24\u2009h) for a 3\u2010week baseline period before entering a 6\u2010week treatment period using a previously established multidose regimen of diazepam (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097) or vehicle (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20099) upon identification of a seizure cluster. In a subsequent 2\u2010week outcome period during which no rats received diazepam, we evaluated changes in seizure cluster size, burden (cluster size\u2009\u00d7\u2009severity), duration, and other phenotype parameters.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 3396 seizures and 216 seizure clusters were included for analysis. During the outcome period, time between seizures in a cluster (also interseizure interval [ISI]) was significantly longer in the diazepam group (log ISI = .25 longer, SE = .08,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.0001), and the proportion of clustered seizures with an ISI of \u226430\u2009min increased in the outcome period in the vehicle group (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.023) but was stable in the diazepam group. Despite the occurrence of rebound seizures during the treatment period, improvement in several phenotypical parameters, including severity and proportion of seizures in a cluster, supported a positive impact of intermittent diazepam treatment on seizure cluster biology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Changes in several seizure cluster phenotypical parameters were suggestive of an enduring disease\u2010modifying effect of diazepam, despite an apparent rebound effect of intermittent diazepam treatment on seizure frequency. Further study is warranted using a model incorporating a background antiseizure medication regimen to potentially attenuate the unexpected rebound seizures.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70051","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:39:15Z","timestamp":1770035955000},"page":"1497-1508","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Preclinical signal for a disease\u2010modifying effect on seizure cluster severity with intermittent diazepam treatment"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6259-7434","authenticated-orcid":false,"given":"Qian","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Center for Epilepsy Drug Discovery University of Washington  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4788-0175","authenticated-orcid":false,"given":"Michelle","family":"Guignet","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Epilepsy Drug Discovery University of Washington  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Vuong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Epilepsy Drug Discovery University of Washington  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4550-4408","authenticated-orcid":false,"given":"H. Steve","family":"White","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Epilepsy Drug Discovery University of Washington  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5546-5951","authenticated-orcid":false,"given":"Wesley T.","family":"Kerr","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Biomedical Informatics University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-0231","authenticated-orcid":false,"given":"Evelyn K.","family":"Shih","sequence":"additional","affiliation":[{"name":"Neurelis  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8184-1367","authenticated-orcid":false,"given":"Leock Y.","family":"Ngo","sequence":"additional","affiliation":[{"name":"Neurelis  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8788-0722","authenticated-orcid":false,"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Neurelis  San Diego California USA"},{"name":"John A. Burns School of Medicine University of Hawaii  Honolulu Hawaii USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1299-0606","authenticated-orcid":false,"given":"Adrian L.","family":"Rabinowicz","sequence":"additional","affiliation":[{"name":"Neurelis  San Diego California USA"},{"name":"Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science Florida Atlantic University  Boca Raton Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12526"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.3949"},{"issue":"3","key":"e_1_2_12_4_1","first-page":"S13","article-title":"An update on the seizures beget seizures theory","volume":"64","author":"Jiruska P","year":"2023","journal-title":"Epilepsia"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2014.05.031"},{"key":"e_1_2_12_6_1","article-title":"Do seizures damage the brain?\u2010cumulative effects of seizures and epilepsy: a 2025 perspective","author":"Klein P","year":"2025","journal-title":"Epilepsy Curr"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25956"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31419-2"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2023.08.005"},{"issue":"1","key":"e_1_2_12_10_1","first-page":"S6","article-title":"Recognizing seizure clusters in the community: the path to uniformity and individualization in nomenclature and definition","volume":"63","author":"Haut SR","year":"2022","journal-title":"Epilepsia"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199806253382602"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-023-01060-1"},{"key":"e_1_2_12_13_1","volume-title":"VALTOCO\u00ae (diazepam nasal spray). 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