{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:58:24Z","timestamp":1771865904019,"version":"3.50.1"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Rett syndrome is a neurodevelopmental disorder associated with epilepsy that influences motor\/communication skills, behavior, and other systems. Clinical experiences for these patients are not well described.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This\n                      <jats:italic>post hoc<\/jats:italic>\n                      analysis consists of a patient subgroup with Rett syndrome enrolled in an open-label, single-arm, safety study. Age- and weight-based doses of diazepam nasal spray (5\u201320\u202fmg) were administered to patients (aged 6\u201365\u202fyears) for seizure clusters. Treatment-emergent adverse events (TEAEs) were recorded, and days between seizure clusters (SEIzure interVAL [SEIVAL]) from Period 1 (P1; days 1\u201390) to Period 4 (P4; days 271\u2013360) were calculated. Caregivers completed surveys describing experiences with diazepam nasal spray and Rett syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Rates of TEAEs (87.5%), serious TEAEs (12.5%), and treatment-related TEAEs (18.8%) in patients with Rett syndrome (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f16) who received diazepam nasal spray were comparable to the overall pediatric safety population (87.2, 35.9, and 14.1%, respectively;\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f78), as was use of second doses (proxy for effectiveness) (18.4 and 11.4%). Increase in SEIVAL was also similar (P1\u202f=\u202f7.6, P4\u202f=\u202f25.0\u202fdays and P1\u202f=\u202f13.0, P4\u202f=\u202f25.9\u202fdays). Most (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f12; 75.0%) remained in the study \u226512\u202fmonths. All caregivers felt diazepam nasal spray was very\/extremely easy to use; 63.6% were able to return to normal activities within an hour of administration. Caregiver perceptions of clinical severity and caregiver affect were stable from baseline to final visits; scores for individuals using diazepam nasal spray were numerically higher.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Diazepam nasal spray has safety and effectiveness profiles consistent with the full study population and was easy to use.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>\n                      , NCT02721069.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1702423","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:01:13Z","timestamp":1771862473000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Safety and effectiveness of diazepam nasal spray in patients with Rett syndrome and seizure clusters: post hoc analyses from a long-term safety study and survey of severity and burden"],"prefix":"10.3389","volume":"17","author":[{"given":"Daniel","family":"Tarquinio","sequence":"first","affiliation":[{"name":"Center for Rare Neurological Diseases","place":["Norcross, GA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James W.","family":"Wheless","sequence":"additional","affiliation":[{"name":"Le Bonheur Children\u2019s Hospital, University of Tennessee Health Science Center","place":["Memphis, TN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric B.","family":"Segal","sequence":"additional","affiliation":[{"name":"Hackensack University Medical Center and Northeast Regional Epilepsy Group and Hackensack Meridian School of Medicine","place":["Hackensack, NJ, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian L.","family":"Rabinowicz","sequence":"additional","affiliation":[{"name":"Neurelis, Inc.","place":["San Diego, CA, United States"]},{"name":"Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University","place":["Jupiter, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Neurelis, Inc.","place":["San Diego, CA, United States"]},{"name":"John A. Burns School of Medicine, University of Hawaii","place":["Honolulu, HI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"620859","DOI":"10.3389\/fgene.2021.620859","article-title":"MeCP2: the genetic driver of Rett syndrome epigenetics","volume":"12","author":"Good","year":"2021","journal-title":"Front Genet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"14571","DOI":"10.3390\/ijms241914571","article-title":"Sex differences in brain disorders","volume":"24","author":"Ziemka-Nalecz","year":"2023","journal-title":"Int J Mol Sci"},{"key":"ref3","author":"Asuncion","year":"2025"},{"key":"ref4","article-title":"MECP2 disorders","volume-title":"GeneReviews","author":"Kaur","year":"2001"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1080\/080352501750064842","article-title":"Epilepsy in a representative series of Rett syndrome","volume":"90","author":"Steffenburg","year":"2001","journal-title":"Acta Paediatr"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/j.ejpn.2007.02.008","article-title":"Seizures in Rett syndrome: an overview from a one-year calendar study","volume":"11","author":"Jian","year":"2007","journal-title":"Eur J Paediatr Neurol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1212\/WNL.0b013e3181d6b852","article-title":"Epilepsy and the natural history of Rett syndrome","volume":"74","author":"Glaze","year":"2010","journal-title":"Neurology"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1093\/brain\/aww302","article-title":"Longitudinal course of epilepsy in Rett syndrome and related disorders","volume":"140","author":"Tarquinio","year":"2017","journal-title":"Brain"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1007\/s11011-018-0316-1","article-title":"Quality of life related to clinical features in patients with Rett syndrome and their parents: a systematic review","volume":"33","author":"Corchon","year":"2018","journal-title":"Metab Brain Dis"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1097\/NRL.0000000000000140","article-title":"Burden of seizure clusters on patients with epilepsy and caregivers: survey of patient, caregiver, and clinician perspectives","volume":"22","author":"Penovich","year":"2017","journal-title":"Neurologist"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1056\/NEJM199806253382602","article-title":"A comparison of rectal diazepam gel and placebo for acute repetitive seizures","volume":"338","author":"Dreifuss","year":"1998","journal-title":"N Engl J Med"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"2485","DOI":"10.1111\/epi.17041","article-title":"Final results from a phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy","volume":"62","author":"Wheless","year":"2021","journal-title":"Epilepsia"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1177\/08830738231185424","article-title":"Safety of diazepam nasal spray in pediatric patients with developmental epileptic encephalopathies: results from a long-term phase 3 safety study","volume":"38","author":"Tarquinio","year":"2023","journal-title":"J Child Neurol"},{"key":"ref14","volume-title":"VALTOCO\u00ae (diazepam nasal spray). Full prescribing information","year":"2025"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"Rett syndrome: revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann Neurol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1111\/epi.17177","article-title":"Use of second doses of Valtoco\u00ae (diazepam nasal spray) across 24 hours after the initial dose for out-of-hospital seizure clusters: results from a phase 3, open-label, repeat-dose safety study","volume":"63","author":"Sperling","year":"2022","journal-title":"Epilepsia"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"108013","DOI":"10.1016\/j.yebeh.2021.108013","article-title":"Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: results from an exit survey of a phase 3, open-label, repeat-dose safety study","volume":"121","author":"Penovich","year":"2021","journal-title":"Epilepsy Behav"},{"key":"ref18","first-page":"28","article-title":"The clinical global impressions scale: applying a research tool in clinical practice","volume":"4","author":"Busner","year":"2007","journal-title":"Psychiatry (Edgmont)"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.3390\/diagnostics13101708","article-title":"Evaluation tools developed for Rett syndrome","volume":"13","author":"Lotan","year":"2023","journal-title":"Diagnostics (Basel)"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1037\/\/0022-3514.54.6.1063","article-title":"Development and validation of brief measures of positive and negative affect: the PANAS scales","volume":"54","author":"Watson","year":"1988","journal-title":"J Pers Soc Psychol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"2684","DOI":"10.1111\/epi.17385","article-title":"Significant improvements in SEIzure interVAL (time between seizure clusters) across time in patients treated with diazepam nasal spray as intermittent rescue therapy for seizure clusters","volume":"63","author":"Misra","year":"2022","journal-title":"Epilepsia"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.pediatrneurol.2022.04.011","article-title":"Safety of diazepam nasal spray in children and adolescents with epilepsy: results from a long-term phase 3 safety study","volume":"132","author":"Tarquinio","year":"2022","journal-title":"Pediatr Neurol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1136\/jmedgenet-2013-102113","article-title":"Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome","volume":"51","author":"Cuddapah","year":"2014","journal-title":"J Med Genet"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1186\/s13023-024-03313-8","article-title":"Burden of illness in Rett syndrome: initial evaluation of a disorder-specific caregiver survey","volume":"19","author":"Kaufmann","year":"2024","journal-title":"Orphanet J Rare Dis"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.2147\/NDT.S376104","article-title":"Implications of seizure-cluster treatment on healthcare utilization: use of approved rescue medications","volume":"18","author":"Rabinowicz","year":"2022","journal-title":"Neuropsychiatr Dis Treat"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1038\/s41591-023-02398-1","article-title":"Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study","volume":"29","author":"Neul","year":"2023","journal-title":"Nat Med"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1229553","DOI":"10.3389\/fped.2023.1229553","article-title":"A review of the Rett syndrome behaviour questionnaire and its utilization in the assessment of symptoms associated with Rett syndrome","volume":"11","author":"Percy","year":"2023","journal-title":"Front Pediatr"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1702423\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T16:01:15Z","timestamp":1771862475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1702423\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":27,"alternative-id":["10.3389\/fneur.2026.1702423"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1702423","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]},"article-number":"1702423"}}