{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:50:19Z","timestamp":1787028619646,"version":"build-2736575974"},"reference-count":21,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Increasing evidence supports the observation that multiple sclerosis (MS) has a preclinical period, with various prodromal signs and symptoms more frequently represented in patients with confirmed MS many years later. Considering the apparent gender differences in the incidence and clinical course of MS, it remains unclear whether it could be reflected in prodromal symptom features. This study aimed to compare a broad spectrum of prodromal signs and symptoms between males and females in the 7-year period before the definite diagnosis of MS. Data came from the central register of the national payer of services, financed under the public healthcare system in Poland. They covered a 7-year period of patient health record claims, from 2009 to 2016. The following groups of symptoms were significant with women: musculoskeletal (p &lt; 0.001), ophthalmic (p &lt; 0.001), laryngological (p &lt; 0.001), digestive system (p &lt; 0.001), urinary tract (p &lt; 0.001), mental (p &lt; 0.001), cardiovascular (p &lt; 0.001), complaints and headaches (p &lt; 0.001). There was also a weak correlation with head injuries (p = 0.03) while dermatological and reproductive system complaints did not appear to be significant (p &lt; 0.05). For males, the following groups of symptoms were significant: musculoskeletal (p &lt; 0.001), ophthalmic (p &lt; 0.001), laryngological (p = 0.007), cardiovascular system symptoms (p &lt; 0.001), and headaches (p &lt; 0.001). Interestingly, reproductive system problems were overrepresented in the male population (p = 0.008). There was no significant correlation with MS risk for dermatological, digestive, urinary, and mental complaints. Similarly, head injuries were not significant. Our results shed more light on well-known differences in the epidemiological and clinical characteristics between sexes in multiple sclerosis, and show differences in prodromal complaints before MS onset.<\/jats:p>","DOI":"10.3390\/jcm10173821","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T05:41:50Z","timestamp":1629956510000},"page":"3821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Gender-Related Differences in Prodromal Multiple Sclerosis Characteristics: A 7-Year Observation Study"],"prefix":"10.3390","volume":"10","author":[{"given":"Jakub","family":"Perwieniec","sequence":"first","affiliation":[{"name":"Department of Analysis and Strategy, Ministry of Health of the Republic of Poland, 00-952 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-8029","authenticated-orcid":false,"given":"Krzysztof","family":"Podw\u00f3jcic","sequence":"additional","affiliation":[{"name":"Institute of Labour and Social Studies, 01-022 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Maluchnik","sequence":"additional","affiliation":[{"name":"Department of Adult Neurology, Medical University of Gda\u0144sk, 80-211 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Szel\u0105g","sequence":"additional","affiliation":[{"name":"Department of Analysis and Strategy, Ministry of Health of the Republic of Poland, 00-952 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Walkiewicz","sequence":"additional","affiliation":[{"name":"Department of Analysis and Strategy, Ministry of Health of the Republic of Poland, 00-952 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Zakrzewski","sequence":"additional","affiliation":[{"name":"Department of Analysis and Strategy, Ministry of Health of the Republic of Poland, 00-952 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Dro\u017adzikowska","sequence":"additional","affiliation":[{"name":"Department of Analysis and Strategy, Ministry of Health of the Republic of Poland, 00-952 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-282X","authenticated-orcid":false,"given":"Bogumi\u0142","family":"Kami\u0144ski","sequence":"additional","affiliation":[{"name":"SGH Warsaw School of Economics, 02-554 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Zasybska","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Lublin, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1090-7496","authenticated-orcid":false,"given":"Marcin","family":"Wnuk","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jagiellonian University Medical College, 30-688 Krakow, Poland"},{"name":"Department of Neurology, University Hospital in Krakow, 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"S\u0142owik","sequence":"additional","affiliation":[{"name":"Department of Neurology, Jagiellonian University Medical College, 30-688 Krakow, Poland"},{"name":"Department of Neurology, University Hospital in Krakow, 30-688 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7019-6681","authenticated-orcid":false,"given":"Konrad","family":"Rejdak","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Lublin, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1002\/ana.25247","article-title":"Prodromal symptoms of multiple sclerosis in primary care","volume":"83","author":"Disanto","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1111\/ene.13925","article-title":"Prodrome in relapsing-remitting and primary progressive multiple sclerosis","volume":"26","author":"Wijnands","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41582-019-0283-0","article-title":"Mounting evidence for a multiple sclerosis prodrome","volume":"15","author":"Marrie","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1177\/1352458520914844","article-title":"The multiple sclerosis prodrome: Emerging evidence, challenges, and opportunities","volume":"27","author":"Tremlett","year":"2021","journal-title":"Mult. Scler. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S1474-4422(17)30076-5","article-title":"Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: A matched cohort study","volume":"16","author":"Wijnands","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1177\/1352458520908163","article-title":"Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome","volume":"27","author":"Wijnands","year":"2021","journal-title":"Mult. Scler. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/jnr.23955","article-title":"The importance of studying sex differences in disease: The example of multiple sclerosis","volume":"95","author":"Golden","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e2977","DOI":"10.1212\/WNL.0000000000012074","article-title":"Systematic Assessment of Medical Diagnoses Preceding the First Diagnosis of Multiple Sclerosis","volume":"96","author":"Gasperi","year":"2021","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1126\/science.283.5406.1277","article-title":"A Gender Gap in Autoimmunity","volume":"283","author":"Whitacre","year":"1999","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jns.2009.04.014","article-title":"Sex hormones, brain damage and clinical course of Multiple Sclerosis","volume":"286","author":"Tomassini","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrneurol.2012.43","article-title":"Sex-related factors in multiple sclerosis susceptibility and progression","volume":"8","author":"Voskuhl","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14813","DOI":"10.1073\/pnas.0703783104","article-title":"Differential Neuroprotective and Antiinflammatory Effects of Estrogen Receptor (ER)Alpha and ERbeta Ligand Treatment","volume":"104","author":"Morales","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1136\/jnnp.2010.208173","article-title":"The natural history of secondary progressive multiple sclerosis","volume":"81","author":"Koch","year":"2010","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1177\/1352458511422097","article-title":"Temporal trends of disability progression in multiple sclerosis: Findings from British Columbia, Canada (1975\u20132009)","volume":"18","author":"Shirani","year":"2011","journal-title":"Mult. Scler. J."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Angeloni, B., Bigi, R., Bellucci, G., Mechelli, R., Ballerini, C., Romano, C., Morena, E., Pellicciari, G., Reni\u00e8, R., and Rinaldi, V. (2021). A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073696"},{"key":"ref_16","unstructured":"International Multiple Sclerosis Genetics Consortium (2019). Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science, 365, eaav7188."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1177\/1073858414536468","article-title":"A Starring Role for Microglia in Brain Sex Differences","volume":"21","author":"Lenz","year":"2015","journal-title":"Neuroscientist"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1001\/jamaneurol.2019.3238","article-title":"Serum Neurofilament Light Chain Levels in Patients with Presymptomatic Multiple Sclerosis","volume":"77","author":"Bjornevik","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21546","DOI":"10.1073\/pnas.2003339117","article-title":"Immune signatures of prodromal multiple sclerosis in monozygotic twins","volume":"117","author":"Gerdes","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s41582-021-00519-3","article-title":"The multiple sclerosis prodrome","volume":"17","author":"Makhani","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103162","DOI":"10.1016\/j.msard.2021.103162","article-title":"Multiple Sclerosis Incidence and Prevalence in Poland: Data from Administrative Health Claims","volume":"55","author":"Wnuk","year":"2021","journal-title":"Mult. Scler. Relat. Disord."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/17\/3821\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:52:04Z","timestamp":1760165524000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/17\/3821"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,26]]},"references-count":21,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["jcm10173821"],"URL":"https:\/\/doi.org\/10.3390\/jcm10173821","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,26]]}}}