{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T10:14:31Z","timestamp":1789812871793,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS130385"],"award-info":[{"award-number":["NS130385"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS21671"],"award-info":[{"award-number":["NS21671"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS25605"],"award-info":[{"award-number":["NS25605"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100029697","name":"Whitaker Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100029697","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>In status epilepticus there are concerns that the prolonged high\u2010intensity electrographic seizure activity causes neuronal death and poorer outcomes. In animal models of status epilepticus, early treatment that stops the seizures prevents the later development of epilepsy. We wished to determine if that same treatment prevents the neuronal damage that is associated with the prolonged seizures and later epilepsy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In adult male rats, status epilepticus was induced by continuous electrical stimulation of the hippocampus. Some rats received phenobarbital to stop the seizure activity. They were compared to rats that did not receive treatment. At set intervals after status epilepticus (1\u2009week and 8\u2009weeks) the rats were examined for N\u2010acetyl aspartate (NAA) concentrations, a biochemical marker for neurons, in selected brain regions with magnetic resonance spectroscopic imaging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Rats treated with phenobarbital had no decrease in NAA levels compared to untreated controls, which had significant decreases in the examined limbic regions. The decreases corresponded with neuronal loss seen by histological evalutation of the ventral hippocampus, olfactory cortex, and amygdala but not in the neocortex.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>This study shows that early intervention to stop the status epilepticus prevents the neuronal loss that is associated with the development of epilepsy. The findings reinforce the principle of early and aggressive treatment for status epilepticus to improve long\u2010term outcomes. The findings support recent clinical reports that tie early, aggressive treatment to improved neurological outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70448","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:40:17Z","timestamp":1789810817000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early treatment prevents neuronal loss in experimental status epilepticus: A magnetic resonance spectroscopic imaging study"],"prefix":"10.1002","author":[{"given":"Yue","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering School of Engineering and Applied Sciences, University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik J.","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering School of Engineering and Applied Sciences, University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1922-195X","authenticated-orcid":false,"given":"Edward H.","family":"Bertram","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine, University of Virginia  Charlottesville Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1111\/epi.13121","article-title":"A definition and classification of status epilepticus\u2013 report of the ILAE task force on classification of status epilepticus","volume":"56","author":"Trinka E","year":"2015","journal-title":"Epilepsia"},{"key":"e_1_2_13_3_1","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1111\/epi.17614","article-title":"Early timing of anesthesia in status epilepticus is associated with complete recovery: a 7\u2010year retrospective two\u2010center study","volume":"64","author":"De Stefano P","year":"2023","journal-title":"Epilepsia"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.08.05.25332982"},{"key":"e_1_2_13_5_1","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/0920-1211(90)90085-A","article-title":"Recurrent spontaneous hippocampal seizures in the rat as a chronic sequela to limbic status epilepticus","volume":"6","author":"Lothman E","year":"1990","journal-title":"Epilepsy Res"},{"key":"e_1_2_13_6_1","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1212\/WNL.0b013e31824f807a","article-title":"Long\u2010term risk of devloping epilepsy after febrile seizures","volume":"78","author":"Neligan A","year":"2012","journal-title":"Neurology"},{"key":"e_1_2_13_7_1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1212\/WNL.0b013e318266fcc5","article-title":"MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study","volume":"79","author":"Shinnar S","year":"2012","journal-title":"Neurology"},{"key":"e_1_2_13_8_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/ana.10085","article-title":"Phenobarbital and MK\u2010801 but not phenytoin improve long term outcome in status epilepticus","volume":"51","author":"Prasad A","year":"2002","journal-title":"Ann Neurol"},{"key":"e_1_2_13_9_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/S0920-1211(98)00048-5","article-title":"Differential changes in hippocampal AMPA and NMDA mRNA levels and subunit immunoreactivity in human temporal lobe epilepsy and a rodent model of chronic limbic epilepsy","volume":"32","author":"Mathern GW","year":"1998","journal-title":"Epilepsy Res"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105183"},{"key":"e_1_2_13_11_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0021-9258(18)65008-2","article-title":"Studies on the distribution of N\u2010acetyl\u2010Laspartic acid in brain","volume":"224","author":"Tallan HH","year":"1957","journal-title":"J Biol Chem"},{"key":"e_1_2_13_12_1","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1111\/j.1471-4159.1984.tb12854.x","article-title":"N\u2010acetyl\u2010aspartyl\u2010glutamate regional levels in rat brain and the effects of brain lesions as determined by a new HPLC method","volume":"43","author":"Koller KJ","year":"1984","journal-title":"J Neurochem"},{"key":"e_1_2_13_13_1","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1111\/j.1471-4159.1966.tb04266.x","article-title":"Distribution of N\u2010acetyl\u2010L\u2010aspartic acid, in the rat brain","volume":"13","author":"Marcucci M","year":"1966","journal-title":"J Neurochem"},{"key":"e_1_2_13_14_1","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/0006-8993(93)91751-D","article-title":"Assessing chronic brain damage by quantification of regional volumes in postischemic rat brain","volume":"605","author":"Beck T","year":"1993","journal-title":"Brain Res"},{"key":"e_1_2_13_15_1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1097\/00006123-199601000-00030","article-title":"Mapping of lactate and N\u2010acety\u2010L\u2010aspartate predicts infarction during focal ischemia in\u00a0vivo 1H magnetic resonance spectroscopy in rats","volume":"38","author":"Higuchi T","year":"1996","journal-title":"Neurosurgery"},{"key":"e_1_2_13_16_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/jcbfm.1994.48","article-title":"N\u2010acetylaspartate as an in\u00a0vivo marker of neuronal viability in kainate\u2010induced status epilepticus: 1H magnetic resonance spectroscopic imaging","volume":"14","author":"Ebisu T","year":"1994","journal-title":"J Cereb Blood Flow Metab"},{"key":"e_1_2_13_17_1","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1097\/00001756-199409080-00011","article-title":"Reduced N\u2010acetylaspartate concentration in temporal lobe epilepsy by quantitative 1H MRS in\u00a0vivo","volume":"5","author":"Vainio P","year":"1994","journal-title":"Neuroreport"},{"issue":"6","key":"e_1_2_13_18_1","first-page":"S3","article-title":"Pathological substrate for limbic epilepsy: is the medial dorsal thalamic nucleus the unifying abnormality","volume":"41","author":"Bertram EH","year":"2000","journal-title":"Epilepsia"},{"key":"e_1_2_13_19_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/0920-1211(89)90038-7","article-title":"Self\u2010sustaining limbic status epilepticus induced by \u201ccontinuous\u201d hippocampal stimulation: electrographic and behavioral characteristics","volume":"3","author":"Lothman EW","year":"1989","journal-title":"Epilepsy Res"},{"key":"e_1_2_13_20_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0920-1211(90)90036-U","article-title":"NMDA receptor antagonists and limbic status epilepticus: comparison with standard anticonvulsants","volume":"5","author":"Bertram E","year":"1990","journal-title":"Epilepsy Res"},{"key":"e_1_2_13_21_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/mrm.1910370106","article-title":"Histological and 1H MRSI analysis of quinolinic acid\u2010induced damage to the rat striatum","volume":"37","author":"Strauss I","year":"1997","journal-title":"Magn Reson Med"},{"key":"e_1_2_13_22_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0149-7634(89)80048-X","article-title":"N\u2010acetyl\u2010L aspartic acid: a literature review of a compound prominent in 1H NMR spectroscopic studies of brain","volume":"13","author":"Birken DL","year":"1989","journal-title":"Neurosci Biobehav Rev"},{"key":"e_1_2_13_23_1","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/mrm.1910030123","article-title":"Neurometabolic effetss of an inborn error of metabolism demonstrated in\u00a0vivo by 1H NMR","volume":"3","author":"Gadian DG","year":"1986","journal-title":"Magn Reson Med"},{"key":"e_1_2_13_24_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1126\/science.1251187","article-title":"Brain acetylcholine control by dietary choline","volume":"191","author":"Cohen CL","year":"1976","journal-title":"Science"},{"key":"e_1_2_13_25_1","volume-title":"The rat brain in stereotactic coordinates","author":"Paxinos G","year":"1996"},{"key":"e_1_2_13_26_1","unstructured":"MaudsleyAA WuZ WeinerMW.Automatic processing of MR spectroscopic images. Proc SMRM 12th Annual Meeting. 5101993."},{"key":"e_1_2_13_27_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/0006-8993(93)91071-Y","article-title":"The ontogeny of seizures in a rat model of limbic epilepsy: Evidence for a kindling process in the development of chronic spontaneous seizures","volume":"625","author":"Bertram EH","year":"1993","journal-title":"Brain Res"},{"key":"e_1_2_13_28_1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0006-8993(94)91192-4","article-title":"The evolution of a rat model of chronic limbic epilepsy","volume":"661","author":"Bertram EH","year":"1994","journal-title":"Brain Res"},{"key":"e_1_2_13_29_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/ana.410270108","article-title":"The hippocampus in experimental chronic epilepsy: a morphometric analysis","volume":"27","author":"Bertram E","year":"1990","journal-title":"Ann Neurol"},{"key":"e_1_2_13_30_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0006-8993(93)91295-4","article-title":"Morphometric effects of intermittent kindled seizures and limbic status epilepticus in the dentate gyrus","volume":"603","author":"Bertram EH","year":"1993","journal-title":"Brain Res"},{"key":"e_1_2_13_31_1","first-page":"499","article-title":"Epilepsy and the temporal lobes. A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes","volume":"89","author":"Margerison JH","year":"1966","journal-title":"Brain"},{"key":"e_1_2_13_32_1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.yebeh.2009.02.033","article-title":"Neuropathology of focal epilepsies: A critical review","volume":"15","author":"Blumcke I","year":"2009","journal-title":"Epilepsy Behav"},{"key":"e_1_2_13_33_1","volume-title":"The Neuropathology of Temporal Lobe Epilepsy","author":"Bruton CJ","year":"1988"},{"key":"e_1_2_13_34_1","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1093\/jnen\/61.6.510","article-title":"Cytoarchitectural abnormalities in hippocampal sclerosis","volume":"61","author":"Thom M","year":"2002","journal-title":"J Neuropathol Exp Neurol"},{"key":"e_1_2_13_35_1","first-page":"1149","article-title":"Transient MR signal changes in patients with generalized Tonicoclonic seizure or status epilepticus: Periictal diffusion\u2010weighted imaging","volume":"22","author":"Kim J\u2010A","year":"2001","journal-title":"Am J Neuroradiol"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.78076"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000214774"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14082711"},{"key":"e_1_2_13_39_1","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0006-8993(98)00605-2","article-title":"Time course for kindling\u2010induced changes in the hilar area of the dentate gyrus: reactive gliosis as a potential mechanism","volume":"804","author":"Adams B","year":"1998","journal-title":"Brain Res"},{"key":"e_1_2_13_40_1","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1073\/pnas.93.9.3908","article-title":"Hippocampal atrophy in recurrent major depression","volume":"93","author":"Sheline YI","year":"1996","journal-title":"Proc Natl Acad Sci"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2018.05.017"},{"issue":"4","key":"e_1_2_13_42_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1528-1167.2007.01236.x","article-title":"Magnetic resonance imaging in animal models of epilepsy\u2014Noninvasive detection of structural alterations","volume":"48","author":"Gr\u00f5hn O","year":"2007","journal-title":"Epilepsia"},{"key":"e_1_2_13_43_1","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1046\/j.1528-1157.2001.27500.x","article-title":"Propofol and midazolam in the treatment of refractory status epilepticus","volume":"42","author":"Prasad A","year":"2001","journal-title":"Epilepsia"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70448","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/epi.70448","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70448","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:40:22Z","timestamp":1789810822000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi.70448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":42,"alternative-id":["10.1002\/epi.70448"],"URL":"https:\/\/doi.org\/10.1002\/epi.70448","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]},"assertion":[{"value":"2026-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"epi.70448"}}