{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:43:34Z","timestamp":1787319814059,"version":"build-2736575974"},"reference-count":121,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T00:00:00Z","timestamp":1777680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union-NextGenerationEU","award":["BG-RRP-2.004-0004-C01"],"award-info":[{"award-number":["BG-RRP-2.004-0004-C01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurology International"],"abstract":"<jats:p>The conventional classification of multiple sclerosis (MS) into relapsing\u2013remitting, secondary progressive, and primary progressive phenotypes has long guided diagnosis, prognosis, and therapeutic decision-making. However, accumulating evidence indicates that disability accumulation frequently occurs independently of clinical relapses, challenging relapse-centric and phenotype-based models of disease evolution. The concept of progression independent of relapse activity (PIRA) has emerged as a clinically relevant framework capturing this phenomenon across MS phenotypes. In this state-of-the-art narrative review, we propose a spectrum-based reinterpretation of MS, integrating PIRA with concepts of smouldering-associated worsening and neurologic reserve. We highlight the heterogeneity of relapse-independent worsening, distinguishing transient from persistent PIRA, and discuss how ageing-related decline in compensatory capacity contributes to the clinical unmasking of progression over time. Within this framework, secondary progressive MS is redefined as the clinically recognizable accumulation of persistent relapse-independent worsening, while primary progressive MS is conceptualized as early predominance of clinically manifest progression due to limited reserve rather than a distinct disease entity. Finally, we examine diagnostic and therapeutic implications of a spectrum-based model in the contemporary era, emphasizing the limitations of relapse-centric treatment strategies and unmet needs in addressing progression-related biology. By reframing MS as a dynamic continuum shaped by the interaction between ongoing pathology and evolving neurologic reserve, this review aims to support earlier recognition of clinically meaningful progression and to inform more biology-aware approaches to disease monitoring and therapy.<\/jats:p>","DOI":"10.3390\/neurolint18050086","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:06:21Z","timestamp":1777860381000},"page":"86","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From Phenotypes to Spectrum: Rethinking RRMS, SPMS and PPMS in the Era of PIRA\u2014A Framework Integrating PIRA, Smouldering-Associated Worsening, and Neurologic Reserve to Facilitate Earlier Recognition of Progression"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-5060","authenticated-orcid":false,"given":"Georgi V.","family":"Vasilev","sequence":"first","affiliation":[{"name":"Clinic for Movement Disorders, University Multiprofile Hospital for Treatment in Neurology and Psychiatry \u201cSt. Naum\u201d, 1113 Sofia, Bulgaria"},{"name":"Department of Neurology, Medical University, 1431 Sofia, Bulgaria"},{"name":"Clinic of Neurology, Multiprofile Hospital for Active Treatment \u201cUni Hospital\u201d, 4500 Panagyurishte, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Clinic for Movement Disorders, University Multiprofile Hospital for Treatment in Neurology and Psychiatry \u201cSt. Naum\u201d, 1113 Sofia, Bulgaria"},{"name":"Department of Neurology, Medical University, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4522-4070","authenticated-orcid":false,"given":"Ivan","family":"Milanov","sequence":"additional","affiliation":[{"name":"Clinic for Movement Disorders, University Multiprofile Hospital for Treatment in Neurology and Psychiatry \u201cSt. Naum\u201d, 1113 Sofia, Bulgaria"},{"name":"Department of Neurology, Medical University, 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/S1474-4422(25)00270-4","article-title":"Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria","volume":"24","author":"Montalban","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1093\/brain\/awac016","article-title":"How patients with multiple sclerosis acquire disability","volume":"145","author":"Lublin","year":"2022","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0140-6736(23)01473-3","article-title":"Multiple sclerosis","volume":"403","author":"Jakimovski","year":"2024","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S1474-4422(12)70059-5","article-title":"Disability outcome measures in multiple sclerosis clinical trials: Current status and future prospects","volume":"11","author":"Cohen","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1177\/1352458520973618","article-title":"Quantifying cognition and fatigue to enhance the sensitivity of the EDSS during relapses","volume":"27","author":"Morrow","year":"2021","journal-title":"Mult. 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