{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:33:53Z","timestamp":1790210033361,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.<\/jats:p>","DOI":"10.3390\/microorganisms9081716","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T02:40:14Z","timestamp":1628736014000},"page":"1716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["No Metagenomic Evidence of Causative Viral Pathogens in Postencephalitic Parkinsonism Following Encephalitis Lethargica"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8063-2766","authenticated-orcid":false,"given":"D\u00e1niel","family":"Cadar","sequence":"first","affiliation":[{"name":"Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt A.","family":"Jellinger","sequence":"additional","affiliation":[{"name":"Institute of Clinical Neurobiology, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Riederer","sequence":"additional","affiliation":[{"name":"Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Strobel","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Institute for Pathology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camelia-Maria","family":"Monoranu","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Institute for Pathology, University of W\u00fcrzburg, 97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Tappe","sequence":"additional","affiliation":[{"name":"Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.jcv.2014.07.013","article-title":"Medical and molecular perspectives into a forgotten epidemic: Encephalitis lethargica, viruses, and high-throughput sequencing","volume":"61","author":"Tappe","year":"2014","journal-title":"J. Clin. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1002\/mds.22908","article-title":"A historical analysis of the relationship between encephalitis lethargica and postencephalitic parkinsonism: A complex rather than a direct relationship","volume":"25","author":"Vilensky","year":"2010","journal-title":"Mov. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1002\/mds.22991","article-title":"Does the historical literature on encephalitis lethargica support a simple (direct) relationship with postencephalitic Parkinsonism?","volume":"25","author":"Vilensky","year":"2010","journal-title":"Mov. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dickson, D.W., and Weller, R.O. (2011). Postencephalitic Parkinsonism. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, Wiley. [2nd ed.].","DOI":"10.1002\/9781444341256"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s00401-009-0537-9","article-title":"Absence of \u03b1-synuclein pathology in postencephalitic parkinsonism","volume":"118","author":"Jellinger","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1212\/WNL.59.4.645","article-title":"Alpha-synuclein studies are negative in postencephalic parkinsonism of von Economo","volume":"59","author":"Josephs","year":"2002","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00401-015-1511-3","article-title":"Neurotropic virus infections as the cause of immediate and delayed neuropathology","volume":"131","author":"Ludlow","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1056\/NEJMoa1415627","article-title":"A Variegated Squirrel Bornavirus Associated with Fatal Human Encephalitis","volume":"373","author":"Hoffmann","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1056\/NEJMc1803115","article-title":"Fatal Encephalitic Borna Disease Virus 1 in Solid-Organ Transplant Recipients","volume":"379","author":"Schlottau","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s007020050086","article-title":"Postencephalitic parkinsonism\u2014A review","volume":"105","author":"Casals","year":"1998","journal-title":"J. Neural Transm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.bbadis.2008.08.001","article-title":"Viral parkinsonism","volume":"1792","author":"Jang","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jviromet.2015.02.002","article-title":"Virus characterization and discovery in formalin-fixed paraffin-embedded tissues","volume":"214","author":"Bodewes","year":"2015","journal-title":"J. Virol. Methods"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature07390","article-title":"Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960","volume":"455","author":"Worobey","year":"2008","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1126\/science.275.5307.1793","article-title":"Initial genetic characterization of the 1918 \u201cSpanish\u201d influenza virus","volume":"275","author":"Taubenberger","year":"1997","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1093\/jnen\/60.7.696","article-title":"Influenza RNA not Detected in Archival Brain Tissues from Acute Encephalitis Lethargica Cases or in postencephalitic parkinson Cases","volume":"60","author":"McCall","year":"2001","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s00428-003-0795-1","article-title":"Lack of detection of influenza genes in archived formalin-fixed, paraffin wax-embedded brain samples of encephalitis lethargica patients from 1916 to 1920","volume":"442","author":"Lo","year":"2003","journal-title":"Virchows Arch."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1080\/22221751.2021.1902752","article-title":"Introduction and spread of variegated squirrel bornavirus 1 (VSBV-1) between exotic squirrels and spill-over infections to humans in Germany","volume":"10","author":"Cadar","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/path.4145","article-title":"High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded autopsy lung tissue sample from the 1918 influenza pandemic","volume":"229","author":"Xiao","year":"2013","journal-title":"J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Carrick, D.M., Mehaffey, M.G., Sachs, M., Altekruse, S., Camalier, C., Chuaqui, R., Cozen, W., Das, B., Hernandez, B.Y., and Lih, C.-J. (2015). Robustness of Next Generation Sequencing on Older Formalin-Fixed Paraffin-Embedded Tissue. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127353"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Tomazatos, A., Marschang, R.E., Maranda, I., Baum, H., Bialonski, A., Sp\u00eenu, M., L\u00fchken, R., Schmidt-Chanasit, J., and Cadar, D. (2020). Letea Virus: Comparative Genomics and Phylogenetic Analysis of a Novel Reassortant Orbivirus Discovered in Grass Snakes (Natrix natrix). Viruses, 12.","DOI":"10.3390\/v12020243"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lorenzo, R.H., Cadar, D., Koundouno, F., Juste, J., Bialonski, A., Baum, H., Garc\u00eda-Mudarra, J., Hakamaki, H., Bencsik, A., and Nelson, E. (2021). Metagenomic Snapshots of Viral Components in Guinean Bats. Microorganisms, 9.","DOI":"10.3390\/microorganisms9030599"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1007\/s00702-020-02230-x","article-title":"Correction to: Coronaviruses: A challenge of today and a call for extended human postmortem brain analyses","volume":"127","author":"Riederer","year":"2021","journal-title":"J. Neural Transm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"656","DOI":"10.2174\/156720510793611592","article-title":"Tau in Alzheimer Disease and Related Tauopathies","volume":"7","author":"Iqbal","year":"2010","journal-title":"Curr. Alzheimer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00401-015-1507-z","article-title":"Propagation of tau pathology: Hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies","volume":"131","author":"Lewis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1017\/S0317167100005370","article-title":"West Nile Virus Encephalomyelitis with Polio-like Paralysis & Nigral Degeneration","volume":"33","author":"Schafernak","year":"2006","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/0197-4580(96)00069-3","article-title":"On the relationship between measles virus and Alzheimer neurofibrillary tangles in subacute sclerosing panencephalitis","volume":"17","author":"Bancher","year":"1996","journal-title":"Neurobiol. Aging"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s00401-016-1591-8","article-title":"Neuropathological criteria of anti-IgLON5-related tauopathy","volume":"132","author":"Gelpi","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/S1474-4422(18)30244-8","article-title":"Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: A prospective observational study and retrospective analysis","volume":"17","author":"Armangue","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41586-019-1769-z","article-title":"NLRP3 inflammasome activation drives tau pathology","volume":"575","author":"Ising","year":"2019","journal-title":"Nature"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/8\/1716\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:44:27Z","timestamp":1760165067000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/8\/1716"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,12]]},"references-count":29,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["microorganisms9081716"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms9081716","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,12]]}}}