{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:17:07Z","timestamp":1790360227908,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T00:00:00Z","timestamp":1686787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The polyspecific intrathecal immune response (PSIIR), aka MRZ reaction (<jats:italic>M<\/jats:italic>\u2009=\u2009measles, <jats:italic>R<\/jats:italic>\u2009=\u2009rubella, <jats:italic>Z<\/jats:italic> =\u2009zoster, optionally Herpes simplex virus, HSV) is defined as intrathecal immunoglobulin synthesis (IIS) for two or more unrelated viruses. Although an established cerebrospinal fluid (CSF) biomarker for multiple sclerosis (MS), a chronic autoimmune-inflammatory neurological disease (CAIND) of the central nervous system (CNS) usually starting in young adulthood, the full spectrum of CAINDs with a positive PSIIR remains ill defined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this retrospective, cross-sectional study, patients with CSF-positive oligoclonal bands (OCB) and - to enrich for non-MS diagnoses - aged \u226550\u2009years were enrolled.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 415 with PSIIR testing results (MRZ, HSV optional), 76 were PSIIR-positive. Of these, 25 (33%) did not meet the diagnostic criteria for MS spectrum diseases (MS-S) comprising clinically or radiologically isolated syndrome (CIS\/RIS) or MS. PSIIR-positive non-MS-S phenotypes were heterogenous with CNS, peripheral nerve and motor neuron involvement and often defied unequivocal diagnostic classification. A rating by neuroimmunology experts suggested non-MS CAINDs in 16\/25 (64%). Long-term follow-up available in 13 always showed a chronically progressive course. Four of five responded to immunotherapy. Compared to MS-S patients, non-MS CAIND patients showed less frequent CNS regions with demyelination (25% vs. 75%) and quantitative IgG IIS (31% vs. 81%). MRZ-specific IIS did not differ between both groups, while additional HSV-specific IIS was characteristic for non-MS CAIND patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In conclusion, PSIIR positivity occurs frequently in non-MS-S patients \u226550\u2009years. Although sometimes apparently coincidental, the PSIIR seems to represent a suitable biomarker for previously unnoticed chronic neurologic autoimmunities, which require further characterization.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2023.1193015","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T05:58:10Z","timestamp":1686808690000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Clinical associations and characteristics of the polyspecific intrathecal immune response in elderly patients with non-multiple sclerosis chronic autoimmune-inflammatory neurological diseases \u2013 a retrospective cross-sectional study"],"prefix":"10.3389","volume":"14","author":[{"given":"Felix","family":"Brauchle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makbule","family":"Senel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Huss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Dreyhaupt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Klose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"S\u00fc\u00dfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klarissa Hanja","family":"St\u00fcrner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Leypoldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayrettin","family":"Tumani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lewerenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","article-title":"Multiple sclerosis","volume":"391","author":"Thompson","year":"2018","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1212\/01.wnl.0000237475.01655.9d","article-title":"Is late-onset multiple sclerosis associated with a worse outcome?","volume":"67","author":"Tremlett","year":"2006","journal-title":"Neurology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1212\/01.wnl.0000237343.93389.35","article-title":"Multiple sclerosis with and without CSF bands: clinically indistinguishable but immunogenetically distinct","volume":"67","author":"Imrell","year":"2006","journal-title":"Neurology"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e0181431","DOI":"10.1371\/journal.pone.0181431","article-title":"Cerebrospinal fluid humoral immunity in the differential diagnosis of multiple sclerosis","volume":"12","author":"Bernitsas","year":"2017","journal-title":"PLoS One"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2055217319901291","DOI":"10.1177\/2055217319901291","article-title":"The diagnostic value of IgG index versus oligoclonal bands in cerebrospinal fluid of patients with multiple sclerosis","volume":"6","author":"Simonsen","year":"2020","journal-title":"Mult Scler J Exp Transl Clin"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1002\/ana.410130410","article-title":"Oligoclonal IgG bands in cerebrospinal fluid in various neurological diseases","volume":"13","author":"Chu","year":"1983","journal-title":"Ann Neurol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1177\/135245859800400302","article-title":"Cerebrospinal fluid--physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases","volume":"4","author":"Reiber","year":"1998","journal-title":"Mult Scler"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1007\/s004150070130","article-title":"Incidence of CSF abnormalities in siblings of multiple sclerosis patients and unrelated controls","volume":"247","author":"Haghighi","year":"2000","journal-title":"J Neurol"},{"key":"ref9","first-page":"12","article-title":"Reference values for standard cerebrospinal fluid examinationsin multiple sclerosis. 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