{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:14:38Z","timestamp":1780100078095,"version":"3.54.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2016-02349"],"award-info":[{"award-number":["2016-02349"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2020-01998"],"award-info":[{"award-number":["2020-01998"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006636","name":"Forskningsr\u00e5det om H\u00e4lsa, Arbetsliv och V\u00e4lf\u00e4rd","doi-asserted-by":"publisher","award":["2015-00195"],"award-info":[{"award-number":["2015-00195"]}],"id":[{"id":"10.13039\/501100006636","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006636","name":"Forskningsr\u00e5det om H\u00e4lsa, Arbetsliv och V\u00e4lf\u00e4rd","doi-asserted-by":"publisher","award":["2019-00697"],"award-info":[{"award-number":["2019-00697"]}],"id":[{"id":"10.13039\/501100006636","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003792","name":"Swedish Brain Foundation","doi-asserted-by":"crossref","award":["FO2020-0077"],"award-info":[{"award-number":["FO2020-0077"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003792","name":"Swedish Brain Foundation","doi-asserted-by":"crossref","award":["FO2024-0344"],"award-info":[{"award-number":["FO2024-0344"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100018163","name":"Margareta af Ugglas Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018163","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018367","name":"Swedish Foundation for MS Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018367","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006310","name":"Medicinska Forskningsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006310","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurol"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Multiple sclerosis (MS) has heterogeneous clinical presentations at onset. We aimed to investigate determinants of MS onset-symptom type, and the prognostic relevance of onset categories for long-term disability outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed 1385 incident MS cases from a Swedish population-based case\u2013control study. Onset symptoms were hierarchically categorized as pyramidal\/motor, brainstem\/cerebellar, visual, or sensory, with sensory used as the reference. Associations with sex, ancestry, age at onset, smoking and body mass index were assessed using multinomial logistic regression. Disability progression was analyzed with Kaplan\u2013Meier curves and Cox proportional hazards models for time to EDSS 3, 4, and 6.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Male sex was associated with higher odds of motor (OR 1.54, 95% CI 1.07\u20132.20) and brainstem\/cerebellar onset (OR 1.36, 95% CI 1.00\u20131.84). Non-Nordic ancestry was linked to motor onset (OR 1.75, 95% CI 1.21\u20132.51). Obesity was strongly associated with visual onset (OR 2.22, 95% CI 1.41\u20133.40), and smoking with motor and brainstem\/cerebellar onset. Motor onset consistently predicted shorter times to EDSS milestones. Brainstem\/cerebellar onset conferred increased risk of reaching EDSS 4. In supplementary analyses, multifocal onset was associated with faster progression, but this effect was largely driven by concomitant motor involvement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The first clinical manifestation of MS varies by demographic and lifestyle characteristics and carries prognostic value for subsequent disability progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-025-13536-9","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T06:05:07Z","timestamp":1764655507000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Determinants and prognostic value of onset symptoms in multiple sclerosis"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-4749","authenticated-orcid":false,"given":"Anna Karin","family":"Hedstr\u00f6m","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Olsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Alfredsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"13536_CR1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1093\/brain\/116.1.117","volume":"116","author":"B Runmarker","year":"1993","unstructured":"Runmarker B, Andersen O (1993) Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 116:117\u2013134","journal-title":"Brain"},{"key":"13536_CR2","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1212\/WNL.53.3.473","volume":"53","author":"TL Sorensen","year":"1999","unstructured":"Sorensen TL, Frederiksen JL, Bronnum-Hansen H et al (1999) Optic neuritis as onset manifestation of multiple sclerosis: a nationwide, long-term survey. Neurology 53:473\u2013478","journal-title":"Neurology"},{"key":"13536_CR3","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1177\/1352458520926955","volume":"27","author":"L Minh","year":"2021","unstructured":"Minh L, Malpas C, Sharmin S et al (2021) Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis. Mult Scler 27:755\u2013766","journal-title":"Mult Scler"},{"key":"13536_CR4","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.874388","volume":"13","author":"Y Yang","year":"2022","unstructured":"Yang Y, Wang M, Xu L et al (2022) Cerebellar and\/or brainstem lesions indicate poor prognosis in multiple sclerosis: a systematic review. Front Neurol 13:874388","journal-title":"Front Neurol"},{"key":"13536_CR5","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1001\/jamaneurol.2019.4271","volume":"77","author":"M Rosso","year":"2020","unstructured":"Rosso M, Chitnis T (2020) Association between cigarette smoking and multiple sclerosis: a review. JAMA Neurol 77:245\u2013253","journal-title":"JAMA Neurol"},{"key":"13536_CR6","doi-asserted-by":"publisher","first-page":"1038393","DOI":"10.3389\/fimmu.2022.1038393","volume":"13","author":"J Correale","year":"2022","unstructured":"Correale J, Marrodan M (2022) Multiple sclerosis and obesity: the role of adipokines. Front Immunol 13:1038393","journal-title":"Front Immunol"},{"key":"13536_CR7","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200334","volume":"12","author":"J Wu","year":"2025","unstructured":"Wu J, Alfredsson L, Olsson T et al (2025) Obesity affects disease activity and progression, cognitive functioning, and quality of life in people with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 12:e200334","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"13536_CR8","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1002\/ana.20703","volume":"58","author":"CH Polman","year":"2005","unstructured":"Polman CH, Reingold SC, Edan G et al (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the \u201cMcDonald Criteria.\u201d Ann Neurol 58:840\u2013846","journal-title":"Ann Neurol"},{"key":"13536_CR9","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1002\/ana.22366","volume":"69","author":"CH Polman","year":"2011","unstructured":"Polman CH, Reingold SC, Banwell B et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Ann Neurol 69:292\u2013302","journal-title":"Ann Neurol"},{"key":"13536_CR10","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1136\/jnnp-2022-330848","volume":"94","author":"J Wu","year":"2023","unstructured":"Wu J, Olsson T, Hillert J et al (2023) Influence of oral tobacco versus smoking on multiple sclerosis disease activity and progression. J Neurol Neurosurg Psychiatry 94:859\u2013596","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"11","key":"13536_CR11","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","volume":"33","author":"JF Kurtzke","year":"1983","unstructured":"Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33(11):1444\u20131452","journal-title":"Neurology"},{"key":"13536_CR12","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1007\/s10654-025-01276-z","volume":"40","author":"P Alping","year":"2025","unstructured":"Alping P, Frisell T, He A et al (2025) Completeness and generalizability of the Swedish MS register. Eur J Epidemiol 40:905\u2013913","journal-title":"Eur J Epidemiol"},{"key":"13536_CR13","doi-asserted-by":"publisher","first-page":"175628642095649","DOI":"10.1177\/1756286420956495","volume":"13","author":"PS Rommer","year":"2020","unstructured":"Rommer PS, Ellenberger D, Hellwig K et al (2020) Relapsing and progressive MS: the sex-specific perspective. Ther Adv Neurol Disord 13:1756286420956495","journal-title":"Ther Adv Neurol Disord"},{"key":"13536_CR14","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1212\/01.wnl.0000188880.17038.1d","volume":"65","author":"H Tremlett","year":"2005","unstructured":"Tremlett H, Paty D, Devonshire V (2005) The natural history of primary progressive MS in British Columbia, Canada. Neurology 65:1919\u20131923","journal-title":"Neurology"},{"key":"13536_CR15","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1002\/acn3.646","volume":"5","author":"L Amezcua","year":"2018","unstructured":"Amezcua L, Beecham AH, Delgado SR et al (2018) Native ancestry is associated with optic neuritis and age of onset in Hispanics with multiple sclerosis. Ann Clin Transl Neurol 5:1362\u20131371","journal-title":"Ann Clin Transl Neurol"},{"key":"13536_CR16","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1212\/01.WNL.0000145762.60562.5D","volume":"63","author":"BAC Cree","year":"2004","unstructured":"Cree BAC, Khan O, Bourdette D et al (2004) Clinical characteristics of African Americans vs. Caucasian Americans with multiple sclerosis. Neurology 63:2039\u20132045","journal-title":"Neurology"},{"key":"13536_CR17","first-page":"24","volume":"329","author":"M Alrouji","year":"2019","unstructured":"Alrouji M, Manouchehrinia A, Gran B et al (2019) Effects of cigarette smoking on immunity, neuroinflammation and multiple sclerosis. J Neuroinflamm 329:24\u201334","journal-title":"J Neuroinflamm"},{"key":"13536_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.693440","volume":"12","author":"V Ajdacic-Gross","year":"2021","unstructured":"Ajdacic-Gross V, Steinemann N, Horw\u00e1th G et al (2021) Onset symptom clusters in multiple sclerosis: characteristics, comorbidities, and risk factors. Front Neurol 12:693440","journal-title":"Front Neurol"},{"key":"13536_CR19","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1001\/jamaneurol.2020.3502","volume":"77","author":"T Braithwaite","year":"2020","unstructured":"Braithwaite T, Subramanian A, Petzold A et al (2020) Trends in optic neuritis incidence and prevalence in the UK and association with systemic and neurologic disease. JAMA Neurol 77:1514\u20131523","journal-title":"JAMA Neurol"},{"key":"13536_CR20","doi-asserted-by":"publisher","DOI":"10.1016\/j.pdpdt.2024.104074","volume":"46","author":"E Celik","year":"2024","unstructured":"Celik E, Polat E, Togac M et al (2024) Retinal thickness changes in preobese and obese patients without hyperglycemia: optical coherence tomography study. Photodiagnosis Photodyn Ther 46:104074","journal-title":"Photodiagnosis Photodyn Ther"},{"key":"13536_CR21","doi-asserted-by":"publisher","first-page":"1133965","DOI":"10.3389\/fped.2023.1133965","volume":"11","author":"J Dezor-Garus","year":"2023","unstructured":"Dezor-Garus J, Niechcial E, Kedzia A et al (2023) Obesity-induced ocular changes in children and adolescents: a review. Front Pediatr 11:1133965","journal-title":"Front Pediatr"},{"key":"13536_CR22","doi-asserted-by":"publisher","first-page":"3262","DOI":"10.1111\/dom.16344","volume":"27","author":"MG Inam","year":"2025","unstructured":"Inam MG, Inam O, Gucer D et al (2025) Obesity-related early structural alterations in the retina detected by optical coherence tomography. Diabetes Obes Metab 27:3262\u20133273","journal-title":"Diabetes Obes Metab"},{"key":"13536_CR23","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1177\/1352458519900942","volume":"26","author":"AG Filippatou","year":"2020","unstructured":"Filippatou AG, Lambe J, Sotirchos ES et al (2020) Association of body mass index with longitudinal rates of retinal atrophy in multiple sclerosis. Mult Scler 26:843\u2013854","journal-title":"Mult Scler"},{"key":"13536_CR24","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/jcp.25855","volume":"233","author":"G Maurizi","year":"2018","unstructured":"Maurizi G, Della Guardia L, Maurizi A et al (2018) Adipocytes properties and crosstalk with immune system in obesity-related inflammation. J Cell Physiol 233:88\u201389","journal-title":"J Cell Physiol"},{"key":"13536_CR25","doi-asserted-by":"publisher","first-page":"8626","DOI":"10.3390\/ijms25168626","volume":"25","author":"TH Yang","year":"2024","unstructured":"Yang TH, Chen KJ, Lin CW et al (2024) Mitochondria in retinal ganglion cells: unravelling the metabolic nexus and oxidative stress. Int J Mol Sci 25:8626","journal-title":"Int J Mol Sci"},{"key":"13536_CR26","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/bs.adgen.2024.11.002","volume":"113","author":"DM Garc\u00eda","year":"2025","unstructured":"Garc\u00eda DM (2025) Retinal physiology in metabolic syndrome. Adv Genet 113:76\u2013101","journal-title":"Adv Genet"},{"key":"13536_CR27","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1007\/s00018-016-2399-3","volume":"74","author":"Y Endo","year":"2017","unstructured":"Endo Y, Yokote K, Nakayama T (2017) The obesity-related pathology and Th17 cells. Cell Mol Life Sci 74:1231\u20131245","journal-title":"Cell Mol Life Sci"},{"key":"13536_CR28","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.celrep.2015.07.014","volume":"12","author":"Y Endo","year":"2015","unstructured":"Endo Y, Asou HK, Matsugae N et al (2015) Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep 12:1042\u20131055","journal-title":"Cell Rep"},{"issue":"3","key":"13536_CR29","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1212\/WNL.51.3.765","volume":"51","author":"O Kantarci","year":"1998","unstructured":"Kantarci O, Siva A, Eraksoy M et al (1998) Survival and predictors of disability in Turkish MS patients. Turkish Multiple Sclerosis Study Group (TUMSSG). Neurology 51(3):765\u2013772","journal-title":"Neurology"},{"issue":"3","key":"13536_CR30","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1111\/j.1600-0404.1992.tb04031.x","volume":"85","author":"T Riise","year":"1992","unstructured":"Riise T, Gronning M, Fernandez O et al (1992) Early prognostic factors for disability in multiple sclerosis, a European multicenter study. Acta Neurol Scand 85(3):212\u2013218","journal-title":"Acta Neurol Scand"},{"issue":"3","key":"13536_CR31","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1136\/jnnp.58.3.300","volume":"58","author":"M Trojano","year":"1995","unstructured":"Trojano M, Avolio C, Manzari C et al (1995) Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events. J Neurol Neurosurg Psychiatry 58(3):300\u2013306","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"13536_CR32","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1212\/WNL.0b013e3181feb26f","volume":"75","author":"M Tintore","year":"2010","unstructured":"Tintore M, Rovira A, Arrambide G et al (2010) Brainstem lesions in clinically isolated syndromes. Neurology 75:1933\u20131938","journal-title":"Neurology"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-025-13536-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-025-13536-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-025-13536-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:57:04Z","timestamp":1773665824000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-025-13536-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["13536"],"URL":"https:\/\/doi.org\/10.1007\/s00415-025-13536-9","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,2]]},"assertion":[{"value":"15 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 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":"The authors have nothing to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}}],"article-number":"2"}}