{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:09:17Z","timestamp":1792066157019,"version":"4.4.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T00:00:00Z","timestamp":1689379200000},"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":[[2023,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Patients with herpes simplex virus (HSV) encephalitis (HSE) often develop neuronal autoantibody-associated encephalitis (AE) post-infection. Risk factors of AE are unknown. We tested the hypotheses that predisposition for AE post-HSE may be involved, including genetic variants at specific loci, human leucocyte (HLA) haplotypes, or the blood innate immune response against HSV, including type I interferon (IFN) immunity. Patients of all ages with HSE diagnosed between 1 January 2014 and 31 December 2021 were included in one of two cohorts depending on whether the recruitment was at HSE onset (Spanish Cohort A) or by the time of new neurological manifestations (international Cohort B). Patients were assessed for the type of neurological syndromes; HLA haplotypes; blood type I-IFN signature [RNA quantification of 6 or 28 IFN-response genes (IRG)] and toll-like receptor (TLR3)-type I IFN-related gene mutations. Overall, 190 patients (52% male) were recruited, 93 in Cohort A and 97 in Cohort B. Thirty-nine (42%) patients from Cohort A developed neuronal autoantibodies, and 21 (54%) of them developed AE. Three syndromes (choreoathetosis, anti-NMDAR-like encephalitis and behavioural-psychiatric) showed a high (\u226595% cases) association with neuronal autoantibodies. Patients who developed AE post-HSE were less likely to carry the allele HLA-A*02 (4\/21, 19%) than those who did not develop AE (42\/65, 65%, P = 0.0003) or the Spanish general population (2005\/4335, 46%, P = 0.0145). Blood IFN signatures using 6 or 28 IRG were positive in 19\/21 (91%) and 18\/21 (86%) patients at HSE onset, and rapidly decreased during follow-up. At Day 21 after HSE onset, patients who later developed AE had higher median IFN signature compared with those who did not develop AE [median Zs-6-IRG 1.4 (0.6; 2.0) versus 0.2 (\u22120.4; 0.8), P = 0.03]. However, a very high median Zs-6-IRG (&amp;gt;4) or persistently increased IFN signature associated with uncontrolled viral infection. Whole exome sequencing showed that the percentage of TLR3-IFN-related mutations in patients who developed AE was not different from those who did not develop AE [3\/37 (8%) versus 2\/57 (4%), P = 0.379]. Multivariate logistic regression showed that a moderate increase of the blood IFN signature at Day 21 (median Zs-6-IRG &amp;gt;1.5 but &amp;lt;4) was the most important predictor of AE post-HSE [odds ratio 34.8, interquartile ratio (1.7\u2013691.9)]. Altogether, these findings show that most AE post-HSE manifest with three distinct syndromes, and HLA-A*02, but not TLR3-IFN-related mutations, confer protection from developing AE. In addition to neuronal autoantibodies, the blood IFN signature in the context of HSE may be potentially useful for the diagnosis and monitoring of HSE complications.<\/jats:p>","DOI":"10.1093\/brain\/awad238","type":"journal-article","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T14:16:29Z","timestamp":1689430589000},"page":"4306-4319","source":"Crossref","is-referenced-by-count":91,"title":["Neurologic complications in herpes simplex encephalitis: clinical, immunological and genetic studies"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6192-6171","authenticated-orcid":false,"given":"Tha\u00eds","family":"Armangu\u00e9","sequence":"first","affiliation":[{"name":"Neuroimmunology Program, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Pediatric Neuroimmunology Unit, Neurology Department, Sant Joan de D\u00e9u Children\u2019s Hospital, University of Barcelona , 08950 Esplugues de Llobregat, Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Oliv\u00e9-Cirera","sequence":"additional","affiliation":[{"name":"Neuroimmunology Program, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Pediatric Neurology Unit, Parc Taul\u00ed Hospital Universitari , 08208 Sabadell, Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Mart\u00ednez-Hernandez","sequence":"additional","affiliation":[{"name":"Neuroimmunology Program, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Neuroimmunology Unit, Service of Neurology, Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rodes","sequence":"additional","affiliation":[{"name":"Neuroimmunology Program, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Peris-Sempere","sequence":"additional","affiliation":[{"name":"Center for Sleep Science and Medicine, Stanford University , Stanford, CA 94304 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Guasp","sequence":"additional","affiliation":[{"name":"Neuroimmunology Program, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Neuroimmunology Unit, Service of Neurology, Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Immunology Department, Hospital Cl\u00ednic, Centre de Diagn\u00f2stic Biom\u00e8dic , 08036 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Palou","sequence":"additional","affiliation":[{"name":"Immunology Department, Hospital Cl\u00ednic, Centre de Diagn\u00f2stic Biom\u00e8dic , 08036 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azucena","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Immunology Department, Hospital Cl\u00ednic, Centre de Diagn\u00f2stic Biom\u00e8dic , 08036 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma \u00c1ngeles","family":"Marcos","sequence":"additional","affiliation":[{"name":"Service of Microbiology, Hospital Cl\u00ednic, Centre de Diagn\u00f2stic Biom\u00e8dic , 08036 Barcelona , Spain"},{"name":"ISGlobal Barcelona Institute for Global Health , 08036 Barcelona , Spain"},{"name":"CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III , 28222 Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Elena","family":"Erro","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario de Navarra , 31008 Pamplona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Bataller","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitari i Polit\u00e8cnic La Fe , 46026 Valencia , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00cd\u00f1igo","family":"Corral-Corral","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universitario Ramon y Cajal , 28034 Madrid , 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Bastard","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY 10065 , USA"},{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children , 75015 Paris , France"},{"name":"Paris City University, Imagine Institute , 75015 Paris , France"},{"name":"Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP , 75015 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Materna","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children , 75015 Paris , France"},{"name":"Paris City University, Imagine Institute , 75015 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Marchal","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Necker Hospital for Sick Children , 75015 Paris , France"},{"name":"Paris City University, Imagine Institute , 75015 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Abel","sequence":"additional","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY 10065 , 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de D\u00e9u , 08950 Barcelona , Spain"},{"name":"Department of Pediatrics, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Study Group for Immune Disfunction Diseases in Children, Institut de Recerca Sant Joan de D\u00e9u (IRSJD) , 08950 Esplugues de Llobregat, Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e0udia","family":"Fortuny","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Infectious Diseases Department, Institut de Recerca Sant Joan de D\u00e9u (IRSJD) , 08950 Esplugues de Llobregat, Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Saiz","sequence":"additional","affiliation":[{"name":"Neuroimmunology Program, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Neuroimmunology 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Dalmau","sequence":"additional","affiliation":[{"name":"Neuroimmunology Program, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Hospital Cl\u00ednic, Universitat de Barcelona , 08036 Barcelona , Spain"},{"name":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 , USA"},{"name":"Catalan Institute for Research and Advanced Studies (ICREA) , 08010 Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,15]]},"reference":[{"key":"2023100302121396500_awad238-B1","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1086\/521262","article-title":"Herpes simplex encephalitis in Sweden, 1990-2001: Incidence, morbidity, and mortality","volume":"45","author":"Hjalmarsson","year":"2007","journal-title":"Clin Infect 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