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Mean thicknesses of: peripapillary retinal nerve fiber\u2014 (pRNFL), macular ganglion cell-inner plexiform\u2014 (mGCIPL), and inner nuclear layers (mINL) were assessed, excluding asymmetric eyes. PIRA was investigated during\u2009\u2265\u20094\u00a0years before the OCT. The associations of retinal layers with PIRA rates were estimated in linear regression adjusted for disease duration, age at onset, sex, body mass index, treatment and annualized relapse rate. In a sensitivity analysis, we investigated the associations between retinal layers and PIRMA rates (PIRA without activity on magnetic resonance imaging).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      One hundred seventy one pwMS were included (median age: 51\u00a0years(y), Expanded Disability Status Scale: 2.5, pRNFL:94\u00a0\u00b5m, mGCIPL:67.2\u00a0\u00b5m, mINL:35.4\u00a0\u00b5m, observation time:8.1y). Sixty-seven patients (39%) showed PIRA. Mean pRNFL and mGCIPL thickness decreased respectively by \u2212\u00a02.28\u00a0\u00b5m (95% CI [\u2212\u00a04.32;\u2212\u00a00.24],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.029) and \u2212\u00a01.70\u00a0\u00b5m (95% CI [\u2212\u00a02.97;\u2212\u00a00.42],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.010) for each PIRA event per decade, while mINL (beta\u2009=\u2009\u2212\u00a00.33, CI: [\u2212\u00a00.75;0.1]\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.133) did not show significant associations with PIRA. In the sensitivity analysis, all three OCT measures were associated with PIRMA (pRNFL: beta\u2009=\u2009\u2212\u00a03.70, 95% CI [\u2212\u00a06.23; \u2212\u00a01.17], p\u2009=\u20090.005; mGCIPL: beta\u2009=\u2009\u2212\u00a02.49, 95% CI [\u2212\u00a04.12; \u2212\u00a00.87],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003), mINL: beta\u2009=\u2009\u2212\u00a00.58, 95% CI [\u2212\u00a01.11; \u2212\u00a00.05],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.031).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings underline the role of retinal thinning measured by OCT as sensitive marker of progression in pwMS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-025-13185-y","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T14:15:50Z","timestamp":1749564950000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Retinal neuronal loss and progression independent of relapse activity in multiple sclerosis"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9697-8364","authenticated-orcid":false,"given":"Federico","family":"Burguet Villena","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Cerd\u00e1-Fuertes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Hofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Sch\u00e4delin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaumiya","family":"Sellathurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kean","family":"Schoenholzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"D\u2019Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Oechtering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henner","family":"Hanssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Gugleta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Cagol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Granziera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwig","family":"Kappos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Petzold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paskal","family":"Benkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Kuhle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0367-1008","authenticated-orcid":false,"given":"Athina","family":"Papadopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"issue":"10130","key":"13185_CR1","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","volume":"391","author":"AJ Thompson","year":"2018","unstructured":"Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O (2018) Multiple sclerosis. 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BMJ Open 9(2):e025077","journal-title":"BMJ Open"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-025-13185-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-025-13185-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-025-13185-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T19:05:21Z","timestamp":1757185521000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-025-13185-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,10]]},"references-count":37,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["13185"],"URL":"https:\/\/doi.org\/10.1007\/s00415-025-13185-y","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,10]]},"assertion":[{"value":"17 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"FBV received travel support by TEVA and a research grant (\u201cYoung talents in clinical research\u201d) by the Swiss Academy of Medical Sciences and of the G. & J. Bangerter-Rhyner Foundation. KS and SS are supported by the Swiss National Science Foundation (PZ00P3_216468). NCF is an employee of Neurostatus-UHB MD is CEO of Neurostatus AG and has received travel support from Bayer AG, Biogen, Teva Pharmaceuticals and Sanofi Genzyme and research support from the University Hospital of Basel. JO served on advisory boards for Roche and Merck. KG is supported by the Swiss National Science Foundation Grant No SNF212656. MD\u2019S is an employee of the University Hospital Basel and the CEO of Neurostatus-UHB Ltd. He has received research support from the University Hospital Basel. LK has received no personal compensation. His institutions (University Hospital Basel\/Foundation Clinical Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support: payments for steering committee and advisory board participation, consultancy services, and participation in educational activities from: Actelion, Bayer, BMS, df-mp Molnia & Pohlmann, Celgene, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche Ltd, Senda Biosciences Inc., Sanofi, Santhera, Shionogi BV, TG Therapeutics, and Wellmera, and license fees for Neurostatus-UHB products; grants from Novartis, Innosuisse, and Roche. AC: has received speaker honoraria from Novartis and Roche. CG: The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; (iii) research support from Siemens, GeNeuro, Roche. JK received speaker fees, research support, travel support, and\/or served on advisory boards by Swiss MS Society, Swiss National Research Foundation (320030_189140\/1 and 320030_212534\/1), University of Basel, Progressive MS Alliance, Bayer, Biogen, Bristol Myers Squibb, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi. AP received speaker fees\/fees for advisory boards\/for consulting from Sanofi Genzyme, Eli Lilly, AbbVie, Lundbeck, Pfizer and TEVA (all used for her research in the University of Basel) and travel support from Bayer AG, Abbvie, Teva and Hoffmann-LaRoche. Her research was supported by the University- and University Hospital of Basel, the Swiss Multiple Sclerosis Society, the \u201cStiftung zur F\u00f6rderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung\u201d, the \u201cFreie Akademische Gesellschaft Basel\u201d and the Swiss National Science Foundation (Project numbers: P300PB_174480 and currently: PZ00P3_216468). The other co-authors have nothing to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was approved by the local ethics committee (Ethikkommission Nordwest- und Zentralschweiz (EKNZ); under the Project ID: 2023\u201302144) and conducted in accordance with the declaration of Helsinki. All participants gave written informed consent before inclusion in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}],"article-number":"454"}}