Development and validation of the NEOS2 score for prediction of long-term outcomes and improvement after first-line immunotherapy in patients with anti-NMDAR encephalitis: an international cohort study
Year: 2025
Type: article
Study design: Observational Study
Abstract: Background: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a severe disease that primarily affects young people and can improve with adequate treatment. We aimed to refine the anti-NMDAR Encephalitis One-year functional Status (NEOS) score by developing NEOS2, an updated model using readily available data at the time of diagnosis. We assessed the predictive value of the NEOS2-score for (1) improvement following first-line treatment, (2) functional outcome at one-year follow-up, and (3) resumption of school or work within three years. Methods: In this international (France, Germany, Japan, the Netherlands and Spain) cohort study in patients with a definite anti-NMDAR encephalitis diagnosis (according to the clinical criteria plus antibody testing in CSF), we performed logistic regression analyses to develop and validate multivariable models to predict -based upon variables available at diagnosis- short (ΔmRS two weeks after first-line treatment), middle (modified Rankin Scale [mRS] at one year), and long-term (return to school or work within three years) outcomes. We included clinical variables and biomarkers available at diagnosis. Findings: We included 702 patients (mean age 23 years, 95%-CI 2-69; 79% female, 21% male) diagnosed between the discovery of the disease in 2007 and 2022. Most patients (96%; 672/702) had received first-line immunotherapy, and 38% (233/615) showed improvement within two weeks. One year after diagnosis, 80% (517/644) had a favourable functional outcome (mRS≤2). At three years, 73% (203/278) had resumed work/school. In multivariable analysis, higher age (odds ratio [OR] 0·35, 95%-CI 0·29-0·43, p < 0·0001), treatment delay (OR 0·49, 95%-CI 0·41-0·58, p < 0·0001), movement disorders (OR 0·32, 95%-CI 0·24-0·41, p < 0·0001), ICU-requirement (OR 0·34, 95%-CI 0·26-0·44, p < 0·0001) and increased CSF leucocyte count (OR 0·65, 95%-CI 0·60-0·71, p < 0·0001) independently predicted poorer outcomes (NEOS2, accuracy AUC 80%, 95%-CI 75-86%). The same variables, excluding age, were relevant in predicting improvement following first-line immunotherapy (NEOS2-T AUC 81-84%, 95%-CI 77-86%). Return-to-work or -school served as a useful measure of longer-term outcomes, predicted with equal accuracy as one-year functional outcome (NEOS2-W AUC 80%, 95%-CI 75-85%). The NEOS2-score, applied as an ordinal measure, enabled nuanced predictions of outcome probabilities across the score spectrum, ranging from a high (80%; n = 20/25) likelihood of improving after first-line immunotherapy and achieving a good outcome (100%; n = 32/32) to a high risk of first-line treatment failure (97%; n = 77/79) and no return to school/work (94%; n = 15/16). Interpretation: The NEOS2-score, readily available at diagnosis and easy to apply, can identify patients with either a favourable or poor prognosis, and those who may benefit from early intensified treatment. The value of the NEOS2-score for guiding treatment decisions and as a stratification tool in studies on optimal treatment regimens, should be confirmed in further prospective studies. Funding: This study was funded by Dioraphte (charity; project 2001 0403).
Authors: Juliette Brenner, Anna E.M. Bastiaansen, Mar Guasp, Sergio Muñiz-Castrillo, Takahiro Iizuka, Marienke A.A.M. de Bruijn, Amaia Muñoz-Lopetegi, Eugenia Martínez-Hernández, Géraldine Picard, Alberto Vogrig, Mathilde Millot, Carsten Finke, Christian Geis, Jan Lewerenz, Nico Melzer, Harald Prüss, Saskia Räuber, Marius Ringelstein, Kevin Rostàsy, Kurt-Wolfram Sühs, Franziska S. Thaler, Klaus-Peter Wandinger, Katharina Wurdack, Yvette S. Crijnen, Jeroen Kerstens, Robin W. van Steenhoven, Sharon Veenbergen, Marco W.J. Schreurs, Robert van den Berg, Victor Volovici, Rinze F. Neuteboom, Juna M. de Vries, Peter A.E. Sillevis Smitt, Mariska M.P. Nagtzaam, Suzanne C. Franken, Dominica Ratuszny, Til Menge, Annikki Bertolini, Christian Bien, Robert Berger, Simone Tauber, Klemens Angstwurm, Thomas Seifert-Held, Andrea Kraft, Jaqueline Klausewitz, Ilya Ayzenberg, Katharina Eisenhut, Rosa Rößling, Martha Heiden, Tania Kümpfel, Josep Dalmau, Frank Leypoldt, Jérôme Honnorat, Maarten J. Titulaer
Institutions: Erasmus MC, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Lyon 1 Université, Hospices Civils de Lyon, Hospital Universitario 12 De Octubre, Kitasato University, Elisabeth-TweeSteden Ziekenhuis, University of Udine, Azienda sanitaria universitaria Friuli Centrale, Charité - Universitätsmedizin Berlin, Jena University Hospital, University Hospital Ulm, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, German Center for Neurodegenerative Diseases, Witten/Herdecke University, Medizinische Hochschule Hannover, Institut für Klinische Neuroimmunologie, Ludwig-Maximilians-Universität München, University Hospital Schleswig-Holstein, Centre for Biomedical Network Research on Rare Diseases, Centro de Investigación Biomédica en Red, CaixaResearch Institute, Christian-Albrechts-Universität zu Kiel
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,930
Funders: Fundació Clinic per la Recerca Biomèdica, Agence Nationale de la Recherche, Bundesministerium für Bildung und Forschung, Université Claude Bernard Lyon 1, Stichting Dioraphte, Research and Innovative Technology Administration, Instituto de Salud Carlos III, European Regional Development Fund
Awards: CONNECT-GENERATE - Deutsches Netzwerk zur Erforschung autoimmuner Enzephalitiden - Teilprojekt 1 Register, Teilprojekt 3 Genetische Ursachen, CONNECT-GENERATE 2.0 - Forschungsverbund zur Aufklärung, Kategorisierung und Behandlung autoimmuner Hirnentzündungen und verwandter Erkrankungen - Koordination, Register und genetische Analysen, G5631366207, Investigaciones en la encefalitis anti-NMDAR: Nuevo test diagnóstico, papel de la inflamación en un modelo animal, y modulación alostérica de NMDAR como estrategia terapéutica, Construction, Fonction Cognitive et Réhabilitation du Cerveau, G7238145507, La encefalitis mediada por anticuerpos LGI1: síntomas, biomarcadores y mecanismos de la fase crónica de la enfermedad, Déficits neuropsiquiátricos y cognitivos y el papel de la disfunción del sistema inmunitario adaptativo en la fase post-aguda de la encefalitis anti-NMDAR, Biomarkers in autoimmune EncephaliTis and Paraneoplastic neurological SYndromes
OpenAlex ID: W7114807449