{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:03:18Z","timestamp":1791511398463,"version":"4.3.4"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clocks &amp; Sleep"],"abstract":"<jats:p>Kleine\u2013Levin syndrome (KLS) is characterized by episodes of hypersomnia. Additionally, these patients can present with hyperphagia, hypersexuality, abnormal behavior, and cognitive dysfunction. Functional neuroimaging studies such as fMRI-BOLD, Positron Emission Tomography (PET) or SPECT help us understand the neuropathological bases of different disorders. We conducted a systematic review to investigate the neuroimaging features of KLS patients and their clinical correlations. This systematic review was conducted by following the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and PRISMA protocol reporting guidelines. We aim to investigate the clinical correlation with neuroimaging among patients with KLS. We included only studies written in the English language in the last 20 years, conducted on humans; 10 studies were included. We excluded systematic reviews, metanalysis, and case reports. We found that there are changes in functional imaging studies during the symptomatic and asymptomatic periods as well as in between episodes in patients with K.L.S. The areas most reported as affected were the hypothalamic and thalamic regions, which showed hypoperfusion and, in a few cases, hyperperfusion; areas such as the frontal, parietal, occipital and the prefrontal cortex all showed alterations in cerebral perfusion. These changes in cerebral blood flow and regions vary according to the imaging (SPECT, PET SCAN, or fMRI) and the task performed while imaging was performed. We encountered conflicting data between studies. Hyper insomnia, the main feature of this disease during the symptomatic periods, was associated with decreased thalamic activity. Other features of K.L.S., such as apathy, hypersexuality, and depersonalization, were also correlated with functional imaging changes. There were also findings that correlated with working memory deficits seen in this stage during the asymptomatic periods. Hyperactivity of the thalamus and hypothalamus were the main features shown during the asymptomatic period. Additionally, functional imaging tends to improve with a longer course of the disease, which suggests that K.L.S. patients outgrow the disease. These findings should caution physicians when analyzing and correlating neuroimaging findings with the disease.<\/jats:p>","DOI":"10.3390\/clockssleep4020025","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T09:24:29Z","timestamp":1653989069000},"page":"287-299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neuroimaging in the Rare Sleep Disorder of Kleine\u2013Levin Syndrome: A Systematic Review"],"prefix":"10.3390","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7512-6140","authenticated-orcid":false,"given":"Juan Fernando","family":"Ortiz","sequence":"first","affiliation":[{"name":"California Institute of Behavioral Neuroscience & Psychology, Fairfield, CA 94534, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Argudo","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences, School of Medicine, Universidad de Cuenca, Cuenca 010107, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Y\u00e9pez","sequence":"additional","affiliation":[{"name":"School of Medicine, Universidad Cat\u00f3lica Santiago de Guayaquil, Guayaquil 090615, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1547-8747","authenticated-orcid":false,"given":"Juan Andr\u00e9s","family":"Moncayo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Pontificia Universidad Cat\u00f3lica del Ecuador Quito, Quito 170143, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyder","family":"Tamton","sequence":"additional","affiliation":[{"name":"Neurology Department, Larkin Community Hospital, South Miami, FL 33143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4866-4925","authenticated-orcid":false,"given":"Alex S.","family":"Aguirre","sequence":"additional","affiliation":[{"name":"School of Medicine, Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Quito 170901, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8657-6884","authenticated-orcid":false,"given":"Ghanshyam","family":"Patel","sequence":"additional","affiliation":[{"name":"Mercy Health Internal Medicine Residency, Javon Bea Hospital, Rockford, IL 61114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9116-0397","authenticated-orcid":false,"given":"Meghdeep","family":"Sen","sequence":"additional","affiliation":[{"name":"School of Medicine, American University of Antigua, Osbourn, Antigua and Barbuda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayushi","family":"Mistry","sequence":"additional","affiliation":[{"name":"Pramukh Swami Medical College, Karamsad 388325, Gujarat, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ray","family":"Yuen","sequence":"additional","affiliation":[{"name":"Neurology Department, Larkin Community Hospital, South Miami, FL 33143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Eissa-Garces","sequence":"additional","affiliation":[{"name":"School of Medicine, Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Quito 170901, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Ojeda","sequence":"additional","affiliation":[{"name":"School of Medicine, Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Quito 170901, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-8944","authenticated-orcid":false,"given":"Samir","family":"Ruxmohan","sequence":"additional","affiliation":[{"name":"Neurology Department, Larkin Community Hospital, South Miami, FL 33143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1001\/archneurpsyc.1929.02220060069006","article-title":"Narcolepsy (G\u00e9lineau\u2019s syndrome) and other varieties of morbid somnolence","volume":"22","author":"Levin","year":"1929","journal-title":"Arch. Neurol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.braindev.2017.04.003","article-title":"Kleine-Levin syndrome: An update and mini-review","volume":"39","author":"Gadoth","year":"2017","journal-title":"Brain Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/ana.21333","article-title":"Kleine-Levin syndrome: A systematic study of 108 patients","volume":"63","author":"Arnulf","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.sleep.2007.06.015","article-title":"Clinical characteristics and HLA typing of a family with Kleine-Levin syndrome","volume":"9","author":"BaHammam","year":"2008","journal-title":"Sleep Med."},{"key":"ref_5","first-page":"9","article-title":"Kleine-Levin Syndrome","volume":"25","author":"Mason","year":"2018","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1093\/brain\/awh620","article-title":"Kleine-Levin syndrome: A systematic review of 186 cases in the literature","volume":"128","author":"Arnulf","year":"2005","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s11325-017-1617-z","article-title":"Kleine-Levin syndrome: Clues to aetiology","volume":"22","author":"AlShareef","year":"2018","journal-title":"Sleep Breath."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"241","DOI":"10.4103\/0972-2327.74185","article-title":"Kleine-Levin syndrome: Etiology, diagnosis, and treatment","volume":"13","author":"Ramdurg","year":"2010","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_9","first-page":"CD006685","article-title":"Pharmacological treatment for Kleine-Levin syndrome","volume":"2016","author":"Conti","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Moher, D., Liberati, A., Tetzlaff, J., and Altman, D.G. (2009). PRISMA Group: Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000097"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1001\/jamasurg.2021.0522","article-title":"MOOSE Reporting Guidelines for Meta-analyses of Observational Studies","volume":"156","author":"Brooke","year":"2021","journal-title":"JAMA Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1093\/sleep\/28.8.955","article-title":"SPECT findings in the Kleine-Levin syndrome","volume":"28","author":"Huang","year":"2005","journal-title":"Sleep"},{"key":"ref_14","first-page":"58","article-title":"Neuroimaging in the Kleine-Levin Syndrome. Curr. Neurol","volume":"18","author":"Latini","year":"2018","journal-title":"Neurosci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Vigren, P., Tisell, A., Engstr\u00f6m, M., Karlsson, T., Dahlqvist, O.L., Lundberg, P., and Landtblom, A.-M. (2013). Low Thalamic NAA-Concentration Corresponds to Strong Neural Activation in Working Memory in Kleine-Levin Syndrome. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056279"},{"key":"ref_16","first-page":"140","article-title":"Brain and effort: Brain activation and effort-related working memory in healthy participants and patients with working memory deficits","volume":"7","author":"Landtblom","year":"2013","journal-title":"Front. Hum. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"178","DOI":"10.3389\/fneur.2014.00178","article-title":"SPECT in the Kleine-Levin Syndrome, a Possible Diagnostic and Prognostic Aid?","volume":"5","author":"Vigren","year":"2014","journal-title":"Front. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1093\/brain\/awu112","article-title":"Feeling unreal: A functional imaging study in patients with Kleine-Levin syndrome","volume":"137","author":"Kas","year":"2014","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"fcab130","DOI":"10.1093\/braincomms\/fcab130","article-title":"Functional brain imaging using 18F-fluorodeoxyglucose positron emission tomography\/computerized tomography in 138 patients with Kleine\u2013Levin syndrome: An early marker?","volume":"3","author":"Dudoignon","year":"2021","journal-title":"Brain Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/jsr.12428","article-title":"New hypothesis on pontine-frontal eye field connectivity in Kleine-Levin syndrome","volume":"25","author":"Landtblom","year":"2016","journal-title":"J. Sleep Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dauvilliers, Y., Bayard, S., Lopez, R., Comte, F., Zanca, M., and Peigneux, P. (2014). Widespread hypermetabolism in symptomatic and asymptomatic episodes in Kleine-Levin syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093813"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.5665\/sleep.3420","article-title":"Thalamic Activation in the Kleine-Levin Syndrome","volume":"37","author":"Karlsson","year":"2014","journal-title":"Sleep"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1093\/sleep\/32.5.681","article-title":"Working Memory in 8 Kleine-Levin Syndrome Patients: An fMRI Study","volume":"32","author":"Engstrom","year":"2009","journal-title":"Sleep"},{"key":"ref_24","unstructured":"Yandrapalli, S., and Puckett, Y. (2022). SPECT Imaging, StatPearls Publishing."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.nec.2010.11.001","article-title":"Overview of Functional Magnetic Resonance Imaging","volume":"22","author":"Glover","year":"2011","journal-title":"Neurosurg. Clin. N. Am."},{"key":"ref_26","unstructured":"Kapoor, M., and Kasi, A. (2021). PET Scanning, StatPearls Publishing."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/j.1365-2869.2006.00533.x","article-title":"Cognitive deficits in narcolepsy","volume":"15","author":"Naumann","year":"2006","journal-title":"J. Sleep Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/S0896-6273(00)80593-0","article-title":"A common network of functional areas for attention and eye movements","volume":"21","author":"Corbetta","year":"1998","journal-title":"Neuron"},{"key":"ref_29","first-page":"42","article-title":"Reduced Thalamic and Pontine Connectivity in Kleine\u2013Levin Syndrome","volume":"5","author":"Karlsson","year":"2014","journal-title":"Front. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9878","DOI":"10.1523\/JNEUROSCI.1138-17.2019","article-title":"The Salience Network: A Neural System for Perceiving and Responding to Homeostatic Demands","volume":"39","author":"Seeley","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_31","unstructured":"(2022, February 14). Central Executive Network\u2014An Overview. ScienceDirect Topics. Available online: https:\/\/www.sciencedirect.com\/topics\/psychology\/central-executive-network."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/NRL.0000000000000047","article-title":"Bilateral Paramedian Thalamic Infarction","volume":"20","author":"Hawkes","year":"2015","journal-title":"Neurologist"},{"key":"ref_33","first-page":"2324709619867355","article-title":"Artery of Percheron Infarction: A Short Review","volume":"7","author":"Kichloo","year":"2019","journal-title":"J. Investig. Med. High Impact Case Rep."},{"key":"ref_34","first-page":"19","article-title":"Kleine-Levin syndrome: A review","volume":"6","author":"Miglis","year":"2014","journal-title":"Nat. Sci. Sleep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1212\/WNL.0b013e318271f85a","article-title":"Kleine-Levin syndrome: Functional imaging correlates of hypersomnia and behavioral symptoms","volume":"79","author":"Prior","year":"2012","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e261","DOI":"10.1097\/RLU.0000000000001616","article-title":"FDG Brain PET\/CT Revealing Bilateral Thalamostriatal Activation During a Symptomatic Episode in a Patient with Kleine-Levin Syndrome","volume":"42","author":"Drouet","year":"2017","journal-title":"Clin. Nucl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.sleep.2010.03.002","article-title":"Greater reduction of striatal dopamine transporter availability during the symptomatic than asymptomatic phase of Kleine-Levin syndrome","volume":"11","author":"Hoexter","year":"2010","journal-title":"Sleep Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1034\/j.1600-0404.2003.00171.x","article-title":"Short-term memory dysfunction in Kleine-Levin syndrome","volume":"108","author":"Landtblom","year":"2003","journal-title":"Acta Neurol. Scand."}],"container-title":["Clocks &amp; Sleep"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2624-5175\/4\/2\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:22:32Z","timestamp":1760138552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2624-5175\/4\/2\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,31]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["clockssleep4020025"],"URL":"https:\/\/doi.org\/10.3390\/clockssleep4020025","relation":{},"ISSN":["2624-5175"],"issn-type":[{"value":"2624-5175","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,31]]}}}