{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:51:38Z","timestamp":1791816698218,"version":"4.3.4"},"reference-count":56,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.<\/jats:p>","DOI":"10.3390\/v13061040","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T21:42:06Z","timestamp":1622497326000},"page":"1040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection"],"prefix":"10.3390","volume":"13","author":[{"given":"Nina","family":"Hautala","sequence":"first","affiliation":[{"name":"Medical Research Center, PEDEGO Research Unit, Department of Ophthalmology, Oulu University Hospital and University of Oulu, 90029 Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terhi","family":"Partanen","sequence":"additional","affiliation":[{"name":"Research Unit of Internal Medicine, Department of Internal Medicine, Division of Infectious Diseases, Oulu University and Oulu University Hospital, 90014 Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Maria","family":"Kubin","sequence":"additional","affiliation":[{"name":"Medical Research Center, PEDEGO Research Unit, Department of Ophthalmology, Oulu University Hospital and University of Oulu, 90029 Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikki","family":"Kauma","sequence":"additional","affiliation":[{"name":"Research Unit of Internal Medicine, Department of Internal Medicine, Division of Infectious Diseases, Oulu University and Oulu University Hospital, 90014 Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Hautala","sequence":"additional","affiliation":[{"name":"Research Unit of Internal Medicine, Department of Internal Medicine, Division of Infectious Diseases, Oulu University and Oulu University Hospital, 90014 Oulu, Finland"},{"name":"Research Unit of Biomedicine, University of Oulu, 90029 Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.1111\/1469-0691.12291","article-title":"Hantavirus Infections","volume":"21","author":"Saksida","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/rmv.1722","article-title":"Hantavirus infections in Europe and their impact on public health","volume":"23","author":"Vaheri","year":"2013","journal-title":"Rev. Med. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S1473-3099(03)00774-6","article-title":"Hantavirus infections in Europe","volume":"3","author":"Vapalahti","year":"2003","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1136\/bjo.2010.185413","article-title":"Prospective study on ocular findings in Acute Puumala Hantavirus infection in hospitalised patients","volume":"95","author":"Hautala","year":"2011","journal-title":"Br. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1086\/340859","article-title":"Hypophyseal hemorrhage and panhypopituitarism during Puumala Virus infection: Magnetic resonance imaging and detection of viral antigen in the hypophysis","volume":"35","author":"Hautala","year":"2002","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"344","DOI":"10.3109\/07853890.2010.480979","article-title":"Central nervous system-related symptoms and findings are common in Acute Puumala Hantavirus infection","volume":"42","author":"Hautala","year":"2010","journal-title":"Ann. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3109\/00365549509047057","article-title":"Four fatal cases of Nephropathia Epidemica","volume":"27","author":"Valtonen","year":"1995","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1007\/s10875-020-00834-2","article-title":"Heterozygous TLR3 mutation in patients with Hantavirus Encephalitis","volume":"40","author":"Partanen","year":"2020","journal-title":"J. Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0163-4453(98)80004-2","article-title":"Central nervous system and ophthalmic involvement in nephropathia epidemica (European type of haemorrhagic fever with renal syndrome)","volume":"36","author":"Ahlm","year":"1998","journal-title":"J. Infect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/clinids\/20.2.255","article-title":"Neurological manifestations of hemorrhagic fever with renal syndrome caused by Puumala virus: Review of 811 cases","volume":"20","author":"Alexeyev","year":"1995","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1365-2796.1992.tb00555.x","article-title":"Complications of Nephropathia Epidemica: Three cases","volume":"232","author":"Forslund","year":"1992","journal-title":"J. Intern. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1210\/jc.2008-0311","article-title":"High risk of hypopituitarism in patients who recovered from Hemorrhagic Fever with renal syndrome","volume":"93","author":"Stojanovic","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hautala, T., Hautala, N., M\u00e4h\u00f6nen, S.-M., Sironen, T., P\u00e4\u00e4kk\u00f6, E., Karttunen, A., Salmela, P.I., Vainio, O., Rytky, S., and Plyusnin, A. (2011). Young male patients are at elevated risk of developing serious central nervous system complications during Acute Puumala Hantavirus infection. BMC Infect. Dis., 11.","DOI":"10.1186\/1471-2334-11-217"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1053\/jinf.2002.1014","article-title":"Encephalitis due to a Hantavirus Infection","volume":"45","author":"Bergmann","year":"2002","journal-title":"J. Infect."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1093\/cid\/cit458","article-title":"Case definitions, diagnostic algorithms, and priorities in encephalitis: Consensus statement of the International Encephalitis Consortium","volume":"57","author":"Venkatesan","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1212\/WNL.0000000000000999","article-title":"TLR3 Deficiency in Herpes Simplex Encephalitis: High allelic heterogeneity and recurrence risk","volume":"83","author":"Lim","year":"2014","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e532","DOI":"10.1212\/NXG.0000000000000532","article-title":"Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation","volume":"6","author":"Hautala","year":"2020","journal-title":"Neurol Genet"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gao, D., Ciancanelli, M.J., Zhang, P., Harschnitz, O., Bondet, V., Hasek, M., Chen, J., Mu, X., Itan, Y., and Cobat, A. (2021). TLR3 Controls constitutive IFN-\u03b2 antiviral immunity in human fibroblasts and cortical neurons. J. Clin. Investig., 131.","DOI":"10.1172\/JCI134529"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.coi.2020.01.004","article-title":"Human inborn errors of immunity to herpes viruses","volume":"62","author":"Jouanguy","year":"2020","journal-title":"Curr. Opin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"R488","DOI":"10.1016\/j.cub.2011.05.039","article-title":"Toll-like receptors","volume":"21","author":"Moresco","year":"2011","journal-title":"Curr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1002\/jmv.21021","article-title":"Case report: Severe neurological manifestation of Dobrava Hantavirus infection","volume":"79","author":"Cerar","year":"2007","journal-title":"J. Med. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1080\/13550280802491485","article-title":"Central nervous system complications following Hanta virus cardiopulmonary syndrome","volume":"15","author":"Huisa","year":"2009","journal-title":"J. Neurovirol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s13365-010-0011-4","article-title":"Hantavirus pulmonary syndrome: Encephalitis caused by virus Andes","volume":"17","author":"Talamonti","year":"2011","journal-title":"J. Neurovirol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.3201\/eid2506.181966","article-title":"Infection with New York Orthohantavirus and associated respiratory failure and multiple cerebral complications","volume":"25","author":"Fernando","year":"2019","journal-title":"Emerg. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1080\/23744235.2016.1274421","article-title":"Kidney disease in Puumala Hantavirus infection","volume":"49","author":"Mustonen","year":"2017","journal-title":"Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"727","DOI":"10.3389\/fmicb.2014.00727","article-title":"The fundamental role of Endothelial cells in Hantavirus pathogenesis","volume":"5","author":"Hepojoki","year":"2014","journal-title":"Front. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"634632","DOI":"10.1155\/2013\/634632","article-title":"Elevated cerebrospinal fluid neopterin concentration is associated with disease severity in Acute Puumala Hantavirus infection","volume":"2013","author":"Hautala","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"196432","DOI":"10.1155\/2013\/196432","article-title":"Neopterin in diagnosis and monitoring of infectious diseases","volume":"2013","author":"Eisenhut","year":"2013","journal-title":"J. Biomark."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0022-510X(00)00501-3","article-title":"Cerebrospinal fluid analysis: Disease-related data patterns and evaluation programs","volume":"184","author":"Reiber","year":"2001","journal-title":"J. Neurol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.jcv.2007.08.008","article-title":"Puumala Virus RNA in cerebrospinal fluid in a patient with uncomplicated nephropathia epidemica","volume":"40","author":"Sironen","year":"2007","journal-title":"J. Clin. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/cen.12863","article-title":"Long-term hormonal follow-up after human Puumala Hantavirus infection","volume":"84","author":"Partanen","year":"2016","journal-title":"Clin. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s10096-010-0918-y","article-title":"Hormonal deficiencies during and after Puumala Hantavirus infection","volume":"29","author":"Jaatinen","year":"2010","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tarvainen, M., M\u00e4kel\u00e4, S., Mustonen, J., and Jaatinen, P. (2016). Autoimmune polyendocrinopathy and Hypophysitis after Puumala Hantavirus Infection. Endocrinol. Diabetes Metab. Case Rep., 2016.","DOI":"10.1530\/EDM-16-0084"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Bhoelan, S., Langerak, T., Noack, D., van Schinkel, L., van Nood, E., van Gorp, E.C.M., Rockx, B., and Goeijenbier, M. (2019). Hypopituitarism after Orthohantavirus infection: What is currently known?. Viruses, 11.","DOI":"10.3390\/v11040340"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1177\/0284185119889564","article-title":"Puumala Hantavirus: An imaging review","volume":"61","author":"Lebecque","year":"2020","journal-title":"Acta Radiol."},{"key":"ref_36","first-page":"1","article-title":"Nephropathia epidemica in Finland. A clinical histological and epidemiological study","volume":"3","year":"1971","journal-title":"Ann. Clin. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/0002-9394(76)90301-9","article-title":"Acute Glaucoma in Hemorrhagic Fever with Renal Syndrome (nephropathia Epidemica)","volume":"81","author":"Saari","year":"1976","journal-title":"Am. J. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/j.1755-3768.1984.tb08400.x","article-title":"Ophthalmological findings in Nephropathia Epidemica in Lapland","volume":"62","author":"Saari","year":"1984","journal-title":"Acta Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1001\/jama.1977.03280090038018","article-title":"Nephropathia epidemica. The Scandinavian form of hemorrhagic fever with renal syndrome","volume":"238","author":"Saari","year":"1977","journal-title":"JAMA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/00006982-198808020-00007","article-title":"Acute posterior multifocal placoid pigment Epitheliopathy in connection with Acute Nephritis","volume":"8","author":"Laatikainen","year":"1988","journal-title":"Retina"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0002-9394(89)90025-1","article-title":"Tonic pupillary reaction after Epidemic Nephropathy and Transient Myopia","volume":"108","author":"Kuronen","year":"1989","journal-title":"Am. J. Ophthalmol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1136\/bjo.78.12.903","article-title":"Myopic shift and its mechanism in Nephropathia Epidemica or Puumala Virus infection","volume":"78","author":"Kontkanen","year":"1994","journal-title":"Br. J. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1016\/S0161-6420(95)30789-0","article-title":"Intraocular pressure changes in Nephropathia Epidemica. A prospective study of 37 patients with Acute Systemic Puumala virus infection","volume":"102","author":"Kontkanen","year":"1995","journal-title":"Ophthalmology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/j.1600-0420.1996.tb00748.x","article-title":"Ocular Characteristics in Nephropathia Epidemica or Puumala Virus infection","volume":"74","author":"Kontkanen","year":"1996","journal-title":"Acta Ophthalmol. Scand."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1111\/j.1755-3768.1993.tb04972.x","article-title":"Ophthalmic manifestations of Epidemic Nephropathy","volume":"71","author":"Klemetti","year":"1993","journal-title":"Acta Ophthalmol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s004170050146","article-title":"Hemorrhagic fever (Puumala Virus Infection) with Ocular involvement","volume":"236","author":"Kontkanen","year":"1998","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"378","DOI":"10.4103\/0301-4738.33827","article-title":"Ocular features of Hantavirus infection","volume":"55","author":"Mehta","year":"2007","journal-title":"Indian J. Ophthalmol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/IJG.0b013e318287ac5d","article-title":"Bilateral simultaneous angle-closure glaucoma associated with septic condition of Korean Hemorrhagic fever (KHF)","volume":"24","author":"Cho","year":"2015","journal-title":"J. Glaucoma"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"NP4","DOI":"10.1177\/1120672119858895","article-title":"Acute angle-closure glaucoma with choroidal effusion revealing a Hantavirus infection: Description of ultrasound biomicroscopy imagery and optical coherence tomography visante","volume":"31","author":"Baillieul","year":"2021","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1007\/s00347-010-2311-8","article-title":"Bilateral acute angle-closure glaucoma due to an infection with Hantavirus","volume":"108","author":"Zimmermann","year":"2011","journal-title":"Ophthalmologe"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/clinids\/13.1.97","article-title":"Mechanisms of disease in Hantavirus infection: Pathophysiology of hemorrhagic fever with renal syndrome","volume":"13","author":"Cosgriff","year":"1991","journal-title":"Rev. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1099\/0022-1317-74-3-515","article-title":"Susceptibility of human cells to Puumala virus infection","volume":"74","author":"Temonen","year":"1993","journal-title":"J. Gen. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/(SICI)1099-1654(199804\/06)8:2<67::AID-RMV217>3.0.CO;2-U","article-title":"Pathogenesis of Puumala and other Hantavirus infections","volume":"8","author":"Kanerva","year":"1998","journal-title":"Rev. Med. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1016\/j.jcjo.2016.09.017","article-title":"Hantavirus retinitis and concurrent hemorrhagic fever with renal syndrome","volume":"52","author":"Cao","year":"2017","journal-title":"Can. J. Ophthalmol."},{"key":"ref_55","first-page":"27698","article-title":"Risk factors and potential preventive measures for Nephropatia Epidemica in Sweden 2011\u20132012: A Case-Control Study","volume":"5","author":"Gherasim","year":"2015","journal-title":"Infect. Ecol. Epidemiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1093\/oxfordjournals.aje.a009769","article-title":"Puumala Virus infections in Finland: Increased occupational risk for farmers","volume":"149","author":"Vapalahti","year":"1999","journal-title":"Am. J. Epidemiol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/6\/1040\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:23Z","timestamp":1760162963000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/6\/1040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,31]]},"references-count":56,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["v13061040"],"URL":"https:\/\/doi.org\/10.3390\/v13061040","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,31]]}}}