{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:02:52Z","timestamp":1789380172367,"version":"build-2803163510"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Study Objectives<\/jats:title>\n                    <jats:p>We evaluated the diagnostic potential of detecting narcolepsy type 1 (NT1) by systematically measuring cerebrospinal fluid hypocretin-1 (CSF-HCRT1) in patients with suspected central disorder of hypersomnolence (CDH), after the multiple sleep latency test (MSLT) was negative for narcolepsy criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Consecutive untreated patients with suspected CDH were hospitalized at the Bologna Narcolepsy Center (Italy) from 2013 to 2024. They underwent a standardized protocol of 2-day continuous polysomnography (PSG), MSLT, and systematic CSF-HCRT1 measurement. Our focus was the identification of additional NT1 cases through the detection of low CSF-HCRT1\u2009&amp;lt;\u2009110\u00a0pg\/mL among those with negative PSG-MSLT for narcolepsy (i.e. mean sleep latency&amp;gt;8\u00a0min or sleep onset REM periods-SOREMPs&amp;lt;2). Features of patients with CSF-HCRT1\u2009&amp;lt;\u2009110\u00a0pg\/mL and negative PSG-MSLT were explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Out of 870 patients with suspected CDH (all with CSF-HCRT1 assay, 52% males, 30.1% pediatric), 342 had PSG-MSLT criteria consistent with narcolepsy with cataplexy (NT1). Sixty-four had PSG-MSLT criteria consistent with narcolepsy but did not have cataplexy (31.3% with CSF-HCRT1 deficiency). In the remaining 464 cases with a PSG-MSLT negative for narcolepsy, CSF-HCRT1\u2009&amp;lt;\u2009110 was detected in 34 (five without cataplexy), increasing NT1 diagnoses by 9.9% and re-classifying 7.3% of MSLT negative cases (p\u2009&amp;lt;\u20090.001 vs. PSG-MSLT+cataplexy). Among the 378 cases with CSF-HCRT1\u2009&amp;lt;\u2009110, the 34 patients with negative PSG-MSLT carried HLA-DQB1*0602 less often (88.2% vs. 96.5%, p\u2009=\u20090.046), had fewer SOREMPs, and higher CSF-HCRT1 values in comparison to the 344 positive at the first PSG-MSLT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In suspected CDH, systematically measuring CSF-HCRT1 in the presence of a negative PSG-MSLT identifies about 10% additional NT1 cases (of which 15% without cataplexy), otherwise possibly misdiagnosed.<\/jats:p>\n                    <jats:p>Statement of Significance In clinical practice, cerebrospinal fluid hypocretin-1 measurement (diagnostic for narcolepsy type 1 if below 110\u00a0pg\/mL) is not routinely performed in patients with suspected central disorders of hypersomnolence when the multiple sleep latency test (MSLT) is negative. Therefore, in this large consecutive cohort of adults and children with suspected hypersomnolence, we systematically performed hypocretin-1 assay after MSLT negative for narcolepsy, significantly improving the diagnostic yield by correctly identifying narcolepsy type 1 in cases unrecognized by MSLT alone. These patients have subtle phenotypical differences from those with MSLT positive for narcolepsy. We also provided some highly sensitive markers that can suggest the presence of narcolepsy type 1 despite a negative MSLT, guiding the physician to second-line assessments, to reduce misdiagnosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/sleep\/zsag142","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:14:12Z","timestamp":1779794052000},"source":"Crossref","is-referenced-by-count":1,"title":["To diagnose narcolepsy type 1 after a negative multiple sleep latency test: the contribution of systematic hypocretin measurement"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9756-6470","authenticated-orcid":false,"given":"Francesco","family":"Biscarini","sequence":"first","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna ,","place":["Italy"]},{"name":"Narcolepsy Center, IRCCS Istituto delle Scienze Neurologiche di Bologna , Bologna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Vandi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna ,","place":["Italy"]},{"name":"Narcolepsy Center, IRCCS Istituto delle Scienze Neurologiche di Bologna , Bologna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Neccia","sequence":"additional","affiliation":[{"name":"Narcolepsy Center, IRCCS Istituto delle Scienze Neurologiche di Bologna , Bologna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Gnazzo","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neuroscience, University of Modena and Reggio Emilia , Modena ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5194-375X","authenticated-orcid":false,"given":"Francesca","family":"Ingravallo","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna , Bologna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6928-5310","authenticated-orcid":false,"given":"Emmanuel","family":"Mignot","sequence":"additional","affiliation":[{"name":"Stanford University Center for Sleep Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine , Palo Alto, CA ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Plazzi","sequence":"additional","affiliation":[{"name":"Narcolepsy Center, IRCCS Istituto delle Scienze Neurologiche di Bologna , Bologna ,","place":["Italy"]},{"name":"Department of Biomedical, Metabolic and Neuroscience, University of Modena and Reggio Emilia , Modena ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Pizza","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna , Bologna ,","place":["Italy"]},{"name":"Narcolepsy Center, IRCCS Istituto delle Scienze Neurologiche di Bologna , Bologna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"2026091405064834500_ref1","volume-title":"International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR)","author":"American Academy of Sleep Medicine"},{"issue":"9","key":"2026091405064834500_ref2","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1038\/79690","article-title":"A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains","volume":"6","author":"Peyron","year":"2000","journal-title":"Nat Med"},{"issue":"8","key":"2026091405064834500_ref3","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1093\/sleep\/32.8.993","article-title":"Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy","volume":"32","author":"Thannickal","year":"2009","journal-title":"Sleep."},{"issue":"7","key":"2026091405064834500_ref4","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000213473","article-title":"Use of portable 24-hour polysomnography as alternative diagnostic tool for narcolepsy type 1 in adults and children","volume":"104","author":"Biscarini","year":"2025","journal-title":"Neurology."},{"issue":"1","key":"2026091405064834500_ref5","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207815","article-title":"Role of daytime continuous polysomnography in the diagnosis of pediatric narcolepsy type 1","volume":"102","author":"Pizza","year":"2024","journal-title":"Neurology."},{"issue":"11","key":"2026091405064834500_ref6","doi-asserted-by":"publisher","first-page":"e012799","DOI":"10.1136\/bmjopen-2016-012799","article-title":"STARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration","volume":"6","author":"Cohen","year":"2016","journal-title":"BMJ Open"},{"issue":"12","key":"2026091405064834500_ref7","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsae189","article-title":"The actigraphic evaluation of daytime sleep in central disorders of hypersomnolence: comparison with polysomnography","volume":"47","author":"Biscarini","year":"2024","journal-title":"Sleep."},{"issue":"1","key":"2026091405064834500_ref8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1111\/j.1365-2869.2012.01032.x","article-title":"Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin","volume":"22","author":"Pizza","year":"2013","journal-title":"J Sleep Res"},{"issue":"12","key":"2026091405064834500_ref9","doi-asserted-by":"publisher","first-page":"2489","DOI":"10.5664\/jcsm.9620","article-title":"Recommended protocols for the multiple sleep latency test and maintenance of wakefulness test in adults: guidance from the American Academy of Sleep Medicine","volume":"17","author":"Krahn","year":"2021","journal-title":"J Clin Sleep Med"},{"key":"2026091405064834500_ref10","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.sleep.2017.08.021","article-title":"A standardized test to document cataplexy","volume":"53","author":"Vandi","year":"2019","journal-title":"Sleep Med"},{"issue":"10","key":"2026091405064834500_ref11","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1001\/archneur.59.10.1553","article-title":"The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias","volume":"59","author":"Mignot","year":"2002","journal-title":"Arch Neurol"},{"key":"2026091405064834500_ref12","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6578-6_27","volume-title":"International Classification of Sleep Disorders","author":"American Academy of Sleep Medicine","year":"2014"},{"issue":"7","key":"2026091405064834500_ref13","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1001\/jamaneurol.2013.1589","article-title":"Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy\/hypocretin deficiency","volume":"70","author":"Andlauer","year":"2013","journal-title":"JAMA Neurol"},{"issue":"1","key":"2026091405064834500_ref14","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsac247","article-title":"Rapid eye movement sleep duration during the multiple sleep latency test to diagnose hypocretin-deficient narcolepsy","volume":"46","author":"Lopez","year":"2023","journal-title":"Sleep."},{"key":"2026091405064834500_ref15","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.sleep.2018.12.003","article-title":"Use and safety of nitrous oxide during lumbar puncture for the diagnosis of childhood narcolepsy","volume":"59","author":"Testoni","year":"2019","journal-title":"Sleep Med"},{"issue":"9197","key":"2026091405064834500_ref16","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/S0140-6736(99)05582-8","article-title":"Hypocretin (orexin) deficiency in human narcolepsy","volume":"355","author":"Nishino","year":"2000","journal-title":"Lancet."},{"issue":"9","key":"2026091405064834500_ref17","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.5665\/sleep.2080","article-title":"Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy","volume":"35","author":"Andlauer","year":"2012","journal-title":"Sleep."},{"issue":"9","key":"2026091405064834500_ref18","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/s41582-019-0226-9","article-title":"Narcolepsy \u2014 clinical spectrum, aetiopathophysiology, diagnosis and treatment","volume":"15","author":"Bassetti","year":"2019","journal-title":"Nat Rev Neurol"},{"issue":"Pt 12","key":"2026091405064834500_ref19","doi-asserted-by":"publisher","first-page":"3477","DOI":"10.1093\/brain\/awr244","article-title":"Complex movement disorders at disease onset in childhood narcolepsy with cataplexy","volume":"134","author":"Plazzi","year":"2011","journal-title":"Brain."},{"issue":"7","key":"2026091405064834500_ref20","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/nrneurol.2014.97","volume":"10","author":"Dauvilliers","year":"2014","journal-title":"Nat Rev Neurol"},{"issue":"6","key":"2026091405064834500_ref21","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1111\/jsr.12420","article-title":"Diagnostic delay in narcolepsy type 1: combining the patients\u2019 and the doctors\u2019 perspectives","volume":"25","author":"Taddei","year":"2016","journal-title":"J Sleep Res"},{"key":"2026091405064834500_ref22","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.2147\/NSS.S359980","article-title":"Idling for decades: a European study on risk factors associated with the delay before a narcolepsy diagnosis","volume":"14","author":"Zhang","year":"2022","journal-title":"Nat Sci Sleep"},{"issue":"5","key":"2026091405064834500_ref23","doi-asserted-by":"publisher","first-page":"e70118","DOI":"10.1111\/jsr.70118","article-title":"Present and future of central disorders of hypersomnolence","volume":"34","author":"Biscarini","year":"2025","journal-title":"J Sleep Res"},{"issue":"19","key":"2026091405064834500_ref24","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1056\/NEJMoa2405847","article-title":"Oveporexton, an oral orexin receptor 2-selective agonist, in narcolepsy type 1","volume":"392","author":"Dauvilliers","year":"2025","journal-title":"N Engl J Med"},{"issue":"1","key":"2026091405064834500_ref25","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1212\/01.wnl.0000101725.34089.1e","article-title":"Effect of age on MSLT results in patients with narcolepsy-cataplexy","volume":"62","author":"Dauvilliers","year":"2004","journal-title":"Neurology."},{"issue":"12","key":"2026091405064834500_ref26","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14124379","article-title":"Impact of age at narcolepsy onset on sleep-onset REM periods in the multiple sleep latency test","volume":"14","author":"Sunwoo","year":"2025","journal-title":"J Clin Med"},{"issue":"12","key":"2026091405064834500_ref27","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsaf296","article-title":"Orexin 1-16 as the stable metabolite behind low CSF orexin\/hypocretin immunoreactivity in narcolepsy","volume":"48","author":"Mignot","year":"2025","journal-title":"Sleep."},{"issue":"1","key":"2026091405064834500_ref28","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36942-8","article-title":"HPLC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy","volume":"9","author":"Sakai","year":"2019","journal-title":"Sci Rep"},{"issue":"12","key":"2026091405064834500_ref29","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsaf237","article-title":"16-mer hypocretin-1\/orexin-a in cerebrospinal fluid to diagnose narcolepsy","volume":"48","author":"Vialaret","year":"2025","journal-title":"Sleep."},{"key":"2026091405064834500_ref30","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.sleep.2022.10.004","article-title":"Repeated measures of hypocretin-1 in Danish and Italian patients with narcolepsy and in controls","volume":"101","author":"Torstensen","year":"2023","journal-title":"Sleep Med"},{"issue":"5","key":"2026091405064834500_ref31","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsac052","article-title":"Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1","volume":"45","author":"Van Der Hoeven","year":"2022","journal-title":"Sleep."},{"issue":"8","key":"2026091405064834500_ref32","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.5665\/sleep.4908","article-title":"Nocturnal sleep dynamics identify narcolepsy type 1","volume":"38","author":"Pizza","year":"2015","journal-title":"Sleep."},{"issue":"1","key":"2026091405064834500_ref33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07229-3","article-title":"Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy","volume":"9","author":"Stephansen","year":"2018","journal-title":"Nat Commun"},{"issue":"2","key":"2026091405064834500_ref34","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsae241","article-title":"Probabilistic sleep staging in MSLTs across hypersomnia disorders","volume":"48","author":"Hjuler Andersen","year":"2025","journal-title":"Sleep."},{"issue":"3","key":"2026091405064834500_ref35","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsaa203","article-title":"Combining information on nocturnal rapid eye movement sleep latency and atonia to facilitate diagnosis of pediatric narcolepsy type 1","volume":"44","author":"Silvani","year":"2021","journal-title":"Sleep."},{"issue":"2","key":"2026091405064834500_ref36","doi-asserted-by":"publisher","first-page":"245","DOI":"10.5664\/jcsm.6944","article-title":"Nocturnal REM sleep without atonia is a diagnostic biomarker of pediatric narcolepsy","volume":"14","author":"Bin-Hasan","year":"2018","journal-title":"J Clin Sleep Med"},{"issue":"7","key":"2026091405064834500_ref37","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsab021","article-title":"Stability of nocturnal wake and sleep stages defines central nervous system disorders of hypersomnolence","volume":"44","author":"Maski","year":"2021","journal-title":"Sleep."},{"issue":"2","key":"2026091405064834500_ref38","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsac288","article-title":"Differentiation of central disorders of hypersomnolence with manual and artificial-intelligence-derived polysomnographic measures","volume":"46","author":"Cesari","year":"2023","journal-title":"Sleep."}],"container-title":["SLEEP"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/sleep\/advance-article-pdf\/doi\/10.1093\/sleep\/zsag142\/68397230\/zsag142.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/49\/9\/zsag142\/68397230\/zsag142.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/sleep\/article-pdf\/49\/9\/zsag142\/68397230\/zsag142.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:06:56Z","timestamp":1789376816000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/sleep\/article\/doi\/10.1093\/sleep\/zsag142\/8694651"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5,26]]},"published-print":{"date-parts":[[2026,9,9]]}},"URL":"https:\/\/doi.org\/10.1093\/sleep\/zsag142","relation":{},"ISSN":["0161-8105","1550-9109"],"issn-type":[{"value":"0161-8105","type":"print"},{"value":"1550-9109","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,5,26]]},"article-number":"zsag142"}}