1. Introduction
Multiple sclerosis (MS) is a chronic autoimmune disease that targets the central nervous system (CNS) and causes multifocal inflammation, demyelinating lesions, and axonal loss. It affects more than two million people around the world, with women being affected more frequently than men [ 1 , 2 ]. The MS diagnostic criteria have been recently revised, and according to the 2024 McDonald criteria, the diagnosis of MS is based on a combination of clinical features, CSF (cerebrospinal fluid) biomarkers, and ruling out diseases that mimic MS. Brain and spinal cord magnetic resonance imaging (MRI) is the most useful modality for confirming and monitoring CNS demyelinating lesions [ 3 , 4 ]. Conventional MRI techniques can reveal white matter lesions (WMLs) on T2- and T1-weighted images and gadolinium enhancement images during inflammation [ 5 ]. Acute lesions are synonymous with transient blood–brain barrier disruption and are widely used as surrogate indicators of disease activity in clinical practice in MS [ 6 , 7 ].
Following the acute relapse, MS lesions may undergo some pathological processes, as they become quiescent, remyelinate (shadow plaques), or remain chronically active and form chronic active lesions (CALs) [ 8 , 9 ]. CALs are a key pathological feature in PwMS, particularly in progressive MS (PMS). These lesions contain a demyelinated core with axonal loss and an inflammatory rim composed of activated microglia and macrophages. The rims can be iron-laden, and perivascular B cells and T cells may also be present [ 10 ].
Two MRI-visible subtypes of CALs are important markers of this smoldering inflammation, including paramagnetic rim lesions (PRLs) and slowly expanding lesions (SELs) [ 11 ]. PRLs, visible on susceptibility-based MRI, are used as imaging markers of chronic active inflammation in MS. They have been associated with progressive disease course and worse long-term outcomes, and have been considered in the 2024 revised McDonald diagnostic criteria [ 3 , 12 ]. SELs manifest longitudinally on MRI as non-enhancing lesions that progressively enlarge over time, representing chronic demyelination and axonal loss [ 13 ].
SELs are considered key markers for diagnosing and monitoring disease progression in MS [ 14 ]. Notably, the presence of more SELs is associated with brain atrophy, increased disability, and a poorer response to treatment in MS [ 14 , 15 ]. As SELs provide valuable insights into developing therapeutic approaches to address the neurodegenerative processes underlying MS, evaluating their characteristics is critical. SELs may present a promising approach to preventing chronic disability and enhancing patient outcomes through early detection and treatment strategies [ 16 , 17 , 18 ].
Research on SELs in MS has increased recently. However, variations in study design, patient cohorts, and imaging methodologies led to inconclusive evidence [ 19 ]. These variations prevent forming direct inferences about the role of SELs as markers of chronic demyelination and disease progression in MS. Therefore, this review aimed to estimate the pooled prevalence and clinical relevance of SELs among PwMS.
2. Methods
This systematic review and meta-analysis was performed based on the PRISMA guidelines [ 20 ]. The protocol of this review was prospectively registered in PROSPERO (CRD420251163408).
2.1. Search Strategy
PubMed, Embase, Scopus, and Web of Science were comprehensively searched up to 25 May 2025. The search strategy included keywords related to “multiple sclerosis” and “slowly expanding lesions,” and their corresponding MeSH terms. Google Scholar and the reference lists of the included studies were manually searched to find more relevant studies. A detailed search strategy is presented in the Supplementary Material, Table S1 .
2.2. Study Selection
All search results were imported into EndNote X21, and duplicates were removed. Two independent reviewers (ZZ and HB) screened the titles and abstracts to eliminate studies that did not meet the inclusion criteria. Then, the full texts of potentially relevant articles were thoroughly reviewed. When any disagreement appeared, consensus was achieved through consultation with the third reviewer (OM).
2.3. Eligibility Criteria
Studies with the following criteria were considered eligible: (1) published in peer-reviewed journals; (2) written in English; (3) used observational designs, including cross-sectional, cohort, and case–control studies and clinical trials with relevant baseline data; (4) included adult participants (age more than 18 years); (5) involved individuals with a confirmed diagnosis of MS based on established diagnostic criteria; and (6) assessed or identified SELs in PwMS using MRI-based approaches, including longitudinal imaging analysis supported by dedicated lesion-analysis software or validated in-house computational methods. Studies were excluded with any of the following conditions: (1) publications in languages other than English; (2) reviews, preprints, institutional repositories, case reports, letters, or conference abstracts; (3) preclinical studies, including in vitro experiments and in vivo animal studies; (4) inclusion of participants with other neurological disorders that might interfere with the evaluation of SELs; or (5) insufficient data availability, even after contacting the corresponding authors for clarification or additional information.
2.4. Data Extraction
Data were independently extracted from the included studies by two reviewers (ZZ and HB). Any disagreements during this process were resolved by consulting the third reviewer (OM). Information, including study characteristics (first author, publication year, country, and design), participant demographics (sample size, gender ratio, and age), clinical features (MS subtype, EDSS score, and disease duration), MRI parameters (scanner type, analysis software, SEL definition, magnetic field strength, and image analysis software), and major findings of the study were extracted. Also, in longitudinal studies and RCTs where data were reported at multiple follow-up time points, we extracted baseline data for all relevant outcomes.
Moreover, the following information on the SEL assessment methodology was sought: the software used for MRI analysis (e.g., Jim 7 and 9, FreeSurfer 7.1.1, ANTs, Jazz, or in-house software) and the quantitative criteria used for lesion assessment.
In general, SEL assessment in all studies was based on longitudinal MRI of lesion growth. It entailed one or more of the following parameters: (i) the number of SELs per subject, (ii) the spatial growth or volumetric enlargement of individual lesions, and (iii) total SEL burden as the cumulative volume or surface area of all detected SELs. When available, automated or semi-automated software was used to monitor lesion radial growth and measure lesion enlargement between paired scans.
2.5. Risk of Bias Assessment
The methodological quality and risk of bias (ROB) of the included observational studies were assessed using the Newcastle–Ottawa Scale (NOS) [ 21 ], with a maximum score of 10 for cross-sectional studies. Cross-sectional studies scoring 7 to 10 were considered good quality (low risk), scoring 5 to 6 were satisfactory quality (moderate risk), and scoring 0 to 4 were unsatisfactory quality (high risk). ROB of the included studies was independently assessed by two reviewers (MF and SV). Any uncertainty or disagreement was resolved by involving the third reviewer (OM).
2.6. Data Analysis
Data analysis was performed using R software version 4.4.0 [ 22 ]. Data were summarized using descriptive statistics and expressed as frequencies and percentages. A meta-analysis was conducted to estimate the pooled prevalence of SELs among PwMS, and the findings were illustrated through forest plots. Regarding duplicate cohorts, those with the most comprehensive data were included in the meta-analysis. Considering the methodological heterogeneity among the included studies, we used a random-effects model to analyze the proportions on the logit scale and report results with 95% confidence intervals (CIs). Statistical heterogeneity among studies was evaluated using the χ 2 test and quantified with the I 2 statistic [ 23 ]. Publication bias or small-study effect was detected using Begg’s and Egger’s tests [ 24 , 25 ]. The statistical significance threshold for all analyses was p < 0.05.
3. Results
3.1. Literature Search and Study Selection
The database search initially yielded 2132 records. Duplicate removal was performed using EndNote X21, after which 1683 articles remained for screening. Title and abstract evaluation were conducted manually according to predefined inclusion and exclusion criteria, excluding irrelevant studies and leaving 84 articles for full-text assessment. Full-text review was also performed manually, resulting in the inclusion of 20 studies in the systematic review, of which five were incorporated into the meta-analysis ( Figure 1 ).
3.2. Characteristics of the Included Studies
The systematic review incorporated a total of 20 studies published between 2016 and 2025, covering a wide range of study designs, including cohorts, cross-sectional, and randomized controlled trials. The included studies enrolled diverse populations across multiple countries, such as Canada ( n = 5) [ 19 , 26 , 27 , 28 , 29 ], the United Kingdom ( n = 5) [ 18 , 30 , 31 , 32 , 33 ], the United States ( n = 5) [ 17 , 34 , 35 , 36 , 37 ], Italy ( n = 2) [ 38 , 39 ], Japan ( n = 1) [ 40 ], Switzerland ( n = 1) [ 41 ], and Australia ( n = 1) [ 42 ]. Participants in the included studies were 4970 PwMS (61.4% female) with a mean (SD) age of 42.9 (10.6) years, an EDSS of 3.6 (1.9), and a disease duration of 7.8 (6.7) years. All studies employed high-field MRI, with scanner strengths ranging from 1.5 to 7 Tesla (most commonly 3 Tesla), and they utilized various image analysis software. Jim software was commonly used for lesion analysis, whereas others applied FreeSurfer, Advanced Normalization Tools, or relied on in-house/automated methods. The operational definition of “slowly expanding lesion” varied between studies; many defined SELs qualitatively as chronic T2 lesions that expand radially over time [ 26 , 30 , 32 ], while some applied quantitative criteria (e.g., lesions enlarging by a certain volume or ≥12.5% per year on serial scans) [ 29 , 39 ], or required evidence of chronic active inflammation at the lesion edge (such as a paramagnetic rim) [ 37 ]. This heterogeneity reveals the lack of consensus on the standardized definition of SELs in the available literature [ 28 ]. More details on the principal characteristics of the included studies are presented in Table 1 .
3.3. Data Synthesis
A meta-analysis of five studies comprising 2449 PwMS estimated that the pooled prevalence of SEL in PwMS was 57.1% (95% CI: 44.9% to 69.3%, I 2 = 93%, p-heterogeneity < 0.01) ( Figure 2 ). Furthermore, Begg’s and Egger’s tests revealed no publication bias in this meta-analysis ( p -value = 0.14 and p -value = 0.11, respectively).
3.4. Narrative Synthesis of Findings
According to the literature review, SELs appeared as an imaging biomarker that indicates chronic neuroinflammation, ongoing demyelination, and progressive tissue degeneration in MS [ 19 , 26 , 27 , 28 , 37 , 42 ]. Some cohort studies demonstrated that SEL was associated with an increased risk of disability progression, particularly in progressive MS phenotypes [ 19 , 29 , 32 , 33 , 38 , 40 ]. SELs also have relationships with microstructural damage and axonal degeneration that are characterized by reduced magnetization transfer ratios (MTR), increased radial diffusivity, and increased tissue destruction at lesion rims [ 28 , 30 , 39 , 42 ]. Several studies identified that paramagnetic iron rims and sustained microglial activity surround SELs [ 31 , 37 , 42 ]. These findings are aligned with the hypothesis that SELs reflect a smoldering, chronically active inflammatory process characteristic of progressive MS pathology.
Interventional and therapeutic studies have identified SELs as potential biomarkers that may reflect treatment response in MS. In clinical trials, patients treated with Bruton’s tyrosine kinase inhibitors (BTK) like Evobrutinib or the phosphodiesterase inhibitors like Ibudilast exhibited significantly less SEL volume compared with those receiving a placebo [ 17 , 27 ]. Retrospective studies demonstrated that using fingolimod [ 18 ] or natalizumab [ 36 ] led to fewer or smaller SELs, whereas ocrelizumab did not lead to a significant change in the frequency of SEL prevalence compared with placebo in primary progressive MS (PPMS) [ 29 ].
3.5. Risk of Bias Assessment
Table 1 summarizes the ROB scores for each study. Of the 20 studies, 12 achieved scores of 8 or higher (good quality), while the remaining scored between 6 and 7. The mean (SD) NOS score was 7.6 (0.8), indicating an overall moderate to high methodological quality (satisfactory) for the included studies.
4. Discussion
This systematic review and meta-analysis indicated that SELs are a common finding in PwMS, with an overall pooled prevalence of 57.1%. Evidence suggests that SELs can serve as important MRI indicators of chronic neuroinflammation, persistent demyelination, and gradual axonal loss. In addition, a higher SEL burden is linked to greater disability progression, particularly in PMS.
4.1. Pathobiology and Cellular Mechanisms of SELs in MS
SELs are chronic active, or smoldering lesions, that develop from earlier acute inflammatory sites [ 43 , 44 ]. Autopsy studies in PwMS revealed that 20% to 40% of WMLs are SELs, which are typically made up of CD8 + T and CD20 + B lymphocytes in the center, some plasma cells, a peripheral lattice of iron-laden activated microglia and macrophages, and proliferating oligodendrocytes at the border of the lesion [ 45 , 46 ]. Activated microglia and invading macrophages secrete pro-inflammatory cytokines and reactive oxygen species, causing chronic demyelination and axonal degeneration, while cytotoxic T cells cause direct neuronal injury [ 44 ]. On the other hand, B cells worsen the process through antibody secretion, cytokine release, and remyelination inhibition [ 8 ].
Over time, these lesions contribute to the clinical picture of progressive disease, marked by incomplete or failed remyelination, irreversible myelin loss, and, ultimately, poorer long-term outcomes such as increasing disability [ 19 ]. SELs are mostly identified through longitudinal MRI studies, particularly using repeated T1- and T2-weighted sequences that allow clinicians to observe their subtle and gradual expansion over time [ 38 , 45 , 47 ]. They occur independently of gadolinium enhancement, have less intense baseline T1, and progressively decrease in T1 signal, representing progressive axonal loss and chronic tissue injury [ 19 ]. Susceptibility-based MRI sequences reveal hypointense rims, similar to iron deposition in macrophages and microglia, near the lesion border, validating their classification as CALs [ 9 ]. This MRI finding is present in all MS phenotypes, but is more pronounced in PPMS [ 44 ].
4.2. Clinical Consequences of SELs in MS
A recent study found that rim lesions were present in about 9.8% of individual lesions and in 41% of patients. CALs were seen in 12% of lesions and in 64.5% of patients [ 39 , 48 ]. Studies using 7T MRI reported a higher proportion of patients with lesions compared with studies using 3T MRI. In contrast, older age and longer disease duration were linked to fewer lesions at the individual lesion level. This might likely reflect the transition of active lesions into chronic inactive scars over time. MRI sequence, gender, and EDSS did not significantly affect SEL prevalence [ 48 ]. In line with these findings, our meta-analysis demonstrated that SELs occur in 57.1% of PwMS, supporting their potential as an MRI marker of chronic lesion activity.
Recently, PRLs have been at the forefront of interest in MS research and have been included in the 2024 McDonald criteria as a supportive imaging biomarker to increase diagnostic specificity [ 3 , 12 ]. Their presence points to worse outcomes from disease aggressiveness and persistent lesion activity. Due to the high specificity of PRLs, they help to diagnose uncertain cases [ 12 ]. SELs are not currently included within the diagnostic criteria [ 14 , 15 ]. Considering the possibility of their explaining ongoing lesion activity and disease progression [ 38 ], SELs are being further investigated as an emerging biomarker in MS.
It currently appears that the dominant driver of disability accumulation in PwMS is progression independent of relapse activity (PIRA) [ 49 ], and SELs appear to be an important biological substrate of this silent progression. Longitudinal MRI studies demonstrate that SELs exhibit ongoing microstructural degeneration, including declining fractional anisotropy and progressive demyelination [ 26 , 30 ], and their presence is associated with higher risk of PIRA and faster disability worsening [ 32 ]. Linking SEL-related smoldering pathology with the insidious, relapse-independent disability accumulation characteristic of PIRA [ 26 , 30 ] supports SELs as a key imaging marker for identifying patients at risk of early and sustained progression.
4.3. SELs and Disease-Modifying Therapies in MS
Growing evidence showed that several disease-modifying therapies (DMTs) can influence SELs in PwMS. A clearer understanding of the inflammatory and cellular mechanisms underlying SEL development helps explain why many DMTs are capable of slowing or reducing their expansion [ 50 ]. BTKs, such as evobrutinib and tolebrutinib, are one of these DMTs. Evobrutinib reduces SEL volume by suppressing BTK activity in B cells and myeloid cells, which leads to limiting microglial activation [ 27 ]. Similarly, tolebrutinib has shown favorable long-term outcomes in reducing SEL volume in a 2-year extension study [ 51 ]. Ibudilast is a phosphodiesterase inhibitor and neuroprotective agent that reduced SEL volume by 23% and attenuated microglial and astrocytic activation [ 17 ]. Among established MS treatments, fingolimod is a sphingosine-1-phosphate receptor modulator that decreases peripheral lymphocyte trafficking and limits T-cell entry into the CNS. Treatment with fingolimod resulted in a reduction in the count and volume of SELs in PwMS [ 18 ]. Natalizumab, as an α4-integrin inhibitor, blocks immune-cell migration across the blood–brain barrier and mitigates chronic inflammation. It decreased the prevalence of SELs among PwMS in a longitudinal study [ 36 ]. Taken together, these findings highlight SELs as potential treatment-responsive biomarkers of active immune-mediated tissue damage in PwMS.
4.4. Prognostic Biomarkers in Multiple Sclerosis
CALs have been identified as significant prognostic imaging biomarkers in MS [ 10 , 38 ]. The current consensus definition of CALs encompasses PRLs, MRI-defined SELs, and TSPO-positive lesions on PET imaging, all of which represent ongoing inflammatory activity [ 9 ]. PRLs are characterized by more severe disease [ 52 ], brain and spinal cord atrophy [ 53 ], and a higher number of leptomeningeal enhancement foci [ 54 ]. Similarly, a higher SELs burden is predictive of the long-term progression of disability [ 38 ], greater EDSS and functional worsening [ 38 ], higher risk of secondary progressive MS conversion [ 38 ], and a higher proportion of persisting black holes [ 55 ]. Imaging data are also supported by molecular biomarkers [ 56 ]. Neurofilament light chain (NfL) represents axonal injury and is predictive of relapse risk, gadolinium-enhancing lesions, and confirmed disability worsening independent of relapses [ 56 ]. Another biomarker, glial fibrillary acidic protein (GFAP) is associated with grey matter atrophy, progression independent of relapse activity, and is correlated with SEL number [ 34 , 57 ].
CSF biomarkers further refine prognostic assessment, as the presence of oligoclonal bands (OCBs) predicts an increased risk of disability progression, approximately disability doubling the risk of disability progression [ 58 ], and are associated with relapses [ 59 ], cortical lesion burden [ 60 ], and secondary progression [ 60 ], which all reflect chronic B-cell-driven inflammation. Other biomarkers, such as parvalbumin [ 61 ], the kappa free light chain (KFLC) index [ 62 ], composite indices such as the CHI3L1*GFAP/NfL, known as “Glia score” [ 63 , 64 ], inflammatory cytokine patterns (e.g., CXCL13, IL-6, TNF, IFNγ) [ 65 ], mitochondrial DNA [ 66 ], and CSF lactate [ 67 ], have been associated with grey matter damage, aggressive disease course, lesion burden, and neurological deficits [ 66 , 67 ]. Altogether, SELs and PRLs define the anatomical basis of chronic inflammation [ 53 ], fluid biomarkers measure axonal damage [ 62 ], astroglial activation [ 68 ], and immune system dysregulation [ 68 ], and their joint evaluation could offer a comprehensive approach to prognostic stratification in MS.
5. Limitations and Directions for Future Research
This study has several limitations that should be acknowledged. First, as the meta-analysis was conducted on a limited number of eligible studies and substantial heterogeneity was observed among them, this limits the strength of the pooled estimates. Moreover, we were unable to perform meta-analyses on correlations or other secondary outcomes. The included studies varied widely in design, sample size, MRI field strength, acquisition parameters, segmentation techniques, and image analysis software, which may have contributed to variability in reported SEL frequencies and associated outcomes [ 52 ]. Second, the absence of susceptibility-weighted or T2-weighted imaging limited the ability to identify iron-laden or paramagnetic rim lesions, while the lack of post-contrast sequences prevented confirmation that baseline T2 lesions were pre-existing rather than newly active [ 37 ]. The relatively short follow-up period of approximately two years may also have been insufficient to fully capture the slow evolution and chronic activity of SELs across the included studies. Third, some analyses were based on small sample sizes, particularly for advanced imaging measures such as MTR, which means that Begg’s and Egger’s tests should be interpreted with caution. Quantification of SELs remains unstandardized, and inconsistencies in defining key features, such as lesion enlargement and concentric expansion, make it difficult to compare results between studies and reproduce findings. Technical variables such as differences between MRI scanners and analyzing software can compromise the accuracy of volumetric measurements, and the longitudinal interval was different among studies. In addition to methodological variability, clinical heterogeneity should also be considered when interpreting our findings. The pooled population had a spectrum of mild to moderate disability and included different MS phenotypes. Given that lesion dynamics and progression patterns may differ across disease stages and phenotypes, this variability may have influenced the observed prevalence estimates and limited the generalizability of our results. Future studies with large and multicenter studies that employ standardized imaging protocols, longer follow-up periods, and advanced MRI sequences are needed to explore the reliability of findings and improve the pathological and clinical understanding of SELs in MS.
6. Conclusions
In summary, current evidence suggests that SELs are present in about half of PwMS, with an overall prevalence of 57.1%. These lesions may be a potential radiomarker of chronic neuroinflammation, persistent demyelination, and progressive tissue loss. Additionally, SEL burden is linked to disability and disease progression, particularly in PMS. Future studies using standardized imaging protocols are needed to clarify the underlying immune mechanisms responsible for the enlargement of SELs and the effects of DMTs on their evolution to further investigate the relationships between SELs and various features in PwMS, confirming SELs as predictive biomarkers in MS.
Acknowledgments
During the preparation of this work the authors used Chat-GPT in order to improve the readability and language of the manuscript. After using this service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.
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Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/neurosci7020034/s1 . Table S1: The searched syntax in each database.
Author Contributions
Conceptualization, O.M., M.F., V.S. and M.Y.P.; methodology, O.M. and M.Y.P.; validation, O.M., Z.Z., H.B., S.V., F.M., V.S. and M.Y.P.; formal analysis, M.Y.P.; investigation, Z.Z., H.B., F.M., V.S. and M.Y.P.; data curation, Z.Z., H.B. and S.V.; writing—original draft preparation, M.F. and M.Y.P.; writing—review and editing, O.M., F.M. and V.S.; visualization, M.F. and M.Y.P.; super-vision, O.M.; project administration, O.M. All authors have read and agreed to the published version of the manuscript.
Data Availability Statement
All relevant data are within the paper and its Supporting Information files .
Conflicts of Interest
The authors declare no conflicts of interest.
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