{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T10:40:57Z","timestamp":1789814457392,"version":"4.0.1"},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2017,7,10]],"date-time":"2017-07-10T00:00:00Z","timestamp":1499644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4\u2010aminopyridine (4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied ictal and interictal intracranial electrographic activity (<jats:styled-content style=\"fixed-case\">iEEG<\/jats:styled-content>) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4\u2010<jats:styled-content style=\"fixed-case\">AP)<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">iEEG<\/jats:styled-content> was recorded continuously before, during, and after seizures induced by 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content> infusion into the hippocampus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The control group (n = 5) was monitored for 2\u20133 months, and the weekly baseline <jats:styled-content style=\"fixed-case\">iEEG<\/jats:styled-content> recordings showed long\u2010term stability. The low\u2010dose group (1 \u03bcL 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>, 40 m<jats:sc>m<\/jats:sc>, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high\u2010dose group (5 \u03bcL 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>, 40 m<jats:sc>m<\/jats:sc>, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal <jats:styled-content style=\"fixed-case\">iEEG<\/jats:styled-content> flattening. The group that received high\u2010dose 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content> without brainstem implantation (n = 5) had similar seizure\u2010related respiratory difficulties. Finally, five rats that received high\u2010dose 4\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content> without <jats:styled-content style=\"fixed-case\">EEG<\/jats:styled-content> recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups <jats:styled-content style=\"fixed-case\">III<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> IV,<\/jats:styled-content> and V, manual respiratory resuscitation was successful in five of 13 animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13846","type":"journal-article","created":{"date-parts":[[2017,7,10]],"date-time":"2017-07-10T06:35:37Z","timestamp":1499668537000},"page":"1637-1644","source":"Crossref","is-referenced-by-count":22,"title":["Mortality with brainstem seizures from focal 4\u2010aminopyridine\u2013induced recurrent hippocampal seizures"],"prefix":"10.1111","volume":"58","author":[{"given":"Muhammad Tariqus","family":"Salam","sequence":"first","affiliation":[{"name":"Krembil Research Institute University of Toronto Toronto Ontario Canada"},{"name":"Departments of Electrical and Computer Engineering University of Toronto Toronto Ontario Canada"},{"name":"Hospital for Sick Children University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaspard","family":"Montandon","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Genov","sequence":"additional","affiliation":[{"name":"Departments of Electrical and Computer Engineering University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orrin","family":"Devinsky","sequence":"additional","affiliation":[{"name":"Department of Neurology New York University Medical Center New York New York U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Del Campo","sequence":"additional","affiliation":[{"name":"Krembil Research Institute University of Toronto Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3339-8102","authenticated-orcid":false,"given":"Peter L.","family":"Carlen","sequence":"additional","affiliation":[{"name":"Krembil Research Institute University of Toronto Toronto Ontario Canada"},{"name":"Department of Physiology University of Toronto Toronto Ontario 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