# How Common Are Slowly Expanding Lesions in People With Multiple Sclerosis? A Comprehensive Review

This systematic review and meta-analysis pooled data from 20 studies and 4,786 patients with multiple sclerosis (MS) to estimate how common slowly expanding lesions (SELs) are. The researchers found that SELs made up about 14% of all T2 lesions, and 78% of patients had at least one SEL. About 11% of SELs overlapped with paramagnetic rim lesions (PRLs), suggesting these two imaging markers of chronic inflammation only partly correspond to each other.

# How Common Are Slowly Expanding Lesions in People With Multiple Sclerosis? A Comprehensive Review

## Table of Contents

- Key Points
- Background: Why This Research Matters
- What Are Slowly Expanding Lesions and Paramagnetic Rim Lesions?
- How the Research Was Conducted
- Who Was Included in the Studies
- How SELs and PRLs Were Detected
- Key Findings: All the Numbers
- Differences Between MS Types
- What This Means for Patients
- Limitations: What the Study Could Not Prove
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information

## Key Points

- In a review of 20 studies and 4,786 patients, about 14% of all T2 lesions were slowly expanding lesions (SELs).
- 11% of SELs overlapped with paramagnetic rim lesions, suggesting only partial correspondence between these markers.
- The proportion of patients with at least one SEL was higher in progressive MS than in relapsing-remitting MS.
- SELs are not yet ready for routine clinical use due to high variability and lack of standardized detection methods.

## Background: Why This Research Matters

Multiple sclerosis (MS) is a chronic disease in which the immune system attacks the central nervous system. This attack creates areas of damage called demyelinating lesions (patches where the protective coating of nerve fibers is stripped away). These lesions drive nerve degeneration and progressive disability over time.

Pathology studies (studies of tissue) have shown that chronic active lesions (CALs) make up a substantial portion of MS damage. CALs are lesions that remain actively inflamed rather than becoming inactive scars. According to the article, CALs account for up to 57% of all lesions. They are more common in secondary progressive MS (SPMS) than in relapsing-remitting MS (RRMS).

Two imaging markers can detect CALs on MRI scans: slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs). SELs are seen on conventional MRI scans as lesions that grow in a linear, concentric pattern over time. PRLs are seen on susceptibility-sensitive MRI scans and have a dark ring around their edge.

Despite growing interest in SELs as markers of chronic inflammation, the exact proportion of SELs among all MS lesions has been unclear. The overlap between SELs and PRLs across different studies has also been unknown. This study aimed to fill those gaps by combining data from many studies.

The researchers had two main goals. First, they wanted to estimate the proportion of SELs among all T2 lesions and the proportion of patients who have at least one SEL. Second, they wanted to assess how often SELs overlap with PRLs.

## What Are Slowly Expanding Lesions and Paramagnetic Rim Lesions?

SELs are identified on conventional MRI scans, specifically T1-weighted and/or T2-weighted images. They show concentric and linear expansion over time. Researchers detect this expansion using nonrigid, longitudinal deformation-based registration (a computer method that aligns scans taken at different times to measure change).

A recent immunologic and molecular profiling study found that SELs have a hypocellular core. A hypocellular core is an area with few cells. SELs also have a rim of macrophages and microglia (immune cells) at the lesion edge. Ongoing myelin degradation and axonal damage occur at this edge. Resident microglia with an M1 proinflammatory phenotype (a type of immune cell that promotes inflammation) were found at the lesion edge.

Gene expression profiling of SEL borders showed upregulation (increased activity) of immune-related and inflammation-related pathways. These included genes involved in microglial activation, lipid metabolism, and neurodegeneration. This supports a central role for microglia-driven chronic inflammation in lesion expansion.

PRLs are detected on susceptibility-sensitive MRI. They show a paramagnetic rim, which reflects iron-laden activated microglia and macrophages at the lesion edge. They also have a T2-hyperintense core (a bright center on T2 scans) that does not enhance with gadolinium contrast agent (a dye used in MRI).

One study showed that SELs are much more numerous than PRLs. Only a minority of SELs are known to have PRL features. The proportion of overlap between SELs and PRLs across studies was unknown before this review.

## How the Research Was Conducted

This was a systematic review and meta-analysis. A systematic review collects all relevant studies on a topic. A meta-analysis combines the numerical results from those studies into pooled estimates.

The researchers followed a published protocol registered with PROSPERO (an international database of systematic review protocols) under the number CRD42024603778. They reported their methods according to PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

The search covered four databases: PubMed, Scopus, Web of Science, and Embase. The researchers searched for studies published before February 2, 2026. In PubMed and Scopus, searches were limited to studies published in English and involving human subjects. The reference lists of all included studies were also manually screened for additional eligible publications.

Two reviewers independently screened titles and abstracts using a tool called Rayyan. They were blinded to each other's decisions. Disagreements were resolved by consensus with a third reviewer. Full-text screening was then performed independently by the same reviewers.

Studies were eligible for inclusion if they met four criteria:

1. Included adult patients (aged 18 years or older) with MS according to the McDonald criteria (any version)
1. Involved MRI acquisitions including T1-weighted and/or T2-weighted sequences and fluid-attenuated inversion recovery (FLAIR) sequences
1. Reported data on the number and/or volume of SELs
1. Were written in English

No restrictions were applied regarding geographic region or clinical setting. Manuscripts were excluded if they were review articles, letters, editorials, opinions, or conference abstracts. Studies based on postmortem findings or imaging techniques other than conventional MRI were also excluded, as were preclinical models.

When multiple publications reported data from the same cohort, the researchers considered all relevant prevalence estimates. However, only one study per cohort was included in each meta-analysis. For two overlapping cohorts, one study was included in lesion-level and mean volume analyses, while the other was included in patient-level meta-analysis, according to data availability.

Data were extracted using a structured coding scheme in Excel. This included study characteristics, patient characteristics, MRI scan characteristics, lesion numbers and volumes, and methodological information about SEL identification. Disagreements were resolved by discussion or adjudication by a third reviewer.

Methodological quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data. This checklist assesses sample representativeness, sampling methods, sample size adequacy, validity and reliability of outcome measurement, completeness of data, and appropriateness of statistical analysis. A total quality score from 0 to 9 was calculated for each study.

Although some cohorts came from randomized controlled trials (RCTs), SEL outcomes were derived from post hoc imaging analyses (analyses done after the trial was completed). Therefore, these cohorts were appraised as observational studies for prevalence estimation.

For the statistical analysis, the researchers used random-effects generalized linear mixed-effects models and inverse-variance methods. Before pooling, proportions were transformed using the Freeman-Tukey double arcsine method to stabilize variance. Between-study heterogeneity (how much studies differed from each other) was assessed using tau-squared (τ²) and the I² statistic. An I² below 40% indicated low heterogeneity, and an I² above 75% indicated significant heterogeneity.

Publication bias was assessed using funnel plots. Sensitivity analyses were performed to evaluate the robustness of pooled estimates. Subgroup analyses were based on MS phenotype, SEL identification methodology, and study design. Exploratory univariable meta-regression analyses examined potential sources of heterogeneity.

## Who Was Included in the Studies

The initial database search identified 5,980 records. After removing duplicates, 3,026 unique studies remained. After title and abstract screening, 173 full-text articles were assessed for eligibility. Of these, 153 were excluded. Ultimately, 20 studies published between 2016 and 2025 met all inclusion criteria and were included in the final analysis.

The 20 studies included a total of 4,786 patients with MS. The mean age was 43.6 ± 6.3 years, and 63.7% of patients were female. Sample sizes ranged from 15 to 1,889 patients.

Study designs varied:

- 5 were observational prospective cohort studies
- 8 were observational retrospective cohort studies
- 7 were secondary analyses of RCTs

Baseline MS phenotypes across the studies included:

- Relapsing-remitting MS (RRMS): 2,514 patients
- Secondary progressive MS (SPMS): 1,439 patients
- Primary progressive MS (PPMS): 673 patients
- Progressive-relapsing MS (PRMS): 1 patient
- Clinically isolated syndrome (CIS): 8 patients

One study did not specify the MS phenotype. The mean proportion of female participants was 63.7%, with a range from 52.9% to 80%. The mean age across studies ranged from 35.5 to 55.9 years. Disease duration ranged from 4.4 to 20 years. The mean follow-up period was 3.2 ± 2 years, although these variables were incompletely reported across studies.

The mean Expanded Disability Status Scale (EDSS) score varied across studies, ranging from 0 to 6.0. The EDSS is a scale that measures disability in MS, with higher scores indicating more disability. This range reflects variability in clinical severity among the study populations.

MRI field strengths included 1.5T, 3T, and 7T. SELs were most commonly located in deep white matter and periventricular regions (around the fluid-filled spaces in the brain). They were followed in frequency by juxtacortical areas (near the brain's surface) and, more rarely, cortical and deep gray matter involvement.

Across studies, SEL identification relied on longitudinal MRI assessments using at least two serial time points. However, the number and timing of imaging assessments varied. Some studies used two time points (baseline and a single follow-up scan), while others used multiple repeated assessments over extended follow-ups. Fixed imaging schedules were used in most studies, while others reported variable or incompletely specified imaging intervals.

## How SELs and PRLs Were Detected

All studies except one used automated tools to identify SELs. Most used Jacobian (deformation-based) methods. These methods used various software packages, such as advanced normalization tools (ANTs), Statistical Parametric Mapping 12 (SPM12), or NiftyReg. Five studies used in-house automated software based on lesional volumetric change.

In studies using the Jacobian analysis method, SELs were defined as lesions with concentric, gradual, linear expansion over time on serial T1-weighted and/or T2-weighted scans. These lesions measured at least 10 voxels in size and exhibited local expansion. In these studies, except one, the minimum local expansion used to define voxels within the SELs mask was 4% per year.

In two studies, lesion expansion was identified using a custom-designed algorithm, with a threshold of 50 or 100 voxels. For the identification of SELs, T1-weighted and/or T2-weighted images were used in all studies except three. In those three studies, SELs were identified on FLAIR images using an in-house tool.

PRLs were identified using susceptibility-weighted imaging (SWI) and phase-based techniques. These were acquired at varying field strengths, including 1.5T, 3T, and 7T. Across studies, PRL detection relied on expert visual assessment of the presence of a partial or complete hypointense rim (a dark ring) at the edge of nonenhancing T2 lesions. This was confirmed on consecutive slices and across orthogonal planes. Potential mimics, such as veins or susceptibility artefacts, were excluded. However, specific criteria varied across studies.

## Key Findings: All the Numbers

The meta-analysis produced several key estimates. Each estimate comes with a 95% confidence interval (CI), which indicates the range in which the true value likely falls.

**Proportion of SELs among all T2 lesions:** Sixteen reports from 15 original studies, including 4,240 people with MS, were included in the lesion-level analysis. The pooled proportion of SELs out of all T2 lesions was 14% (95% CI 10%–21%). Between-study heterogeneity was high (I² = 99.7%).

**Proportion of patients with at least one SEL:** Seventeen reports from 16 original studies, including 4,434 people with MS, were included in the patient-level analysis. The pooled proportion of patients with at least one SEL was 78% (95% CI 67%–85%). Between-study heterogeneity was high (I² = 95.1%).

**Mean per-patient volumes:** Mean per-patient volumes were pooled from 14 studies with a total of 4,189 people with MS. The mean volume of SELs was 2.32 mL (95% CI 0.12–4.51). The mean volume of total T2 lesions was 11.03 mL (95% CI 8.86–13.21). Between-study heterogeneity was high for both measures (I² = 99% for both).

**Overlap between SELs and PRLs:** To estimate the pooled proportion of SELs that were also identified as PRLs, the researchers pooled three studies including 125 people with MS. The pooled proportion was 27% (95% CI 5%–71%). Between-study heterogeneity was high (I² = 95.9%).

After sensitivity analysis, the per-patient mean volumes were 1.42 mL (95% CI 0.79–2.06) for SELs and 10.6 mL (95% CI 8.53–12.67) for total T2 lesions. In the main analysis, 11% (95% CI 6%–20%) of SELs overlapped with PRLs.

## Differences Between MS Types

In subgroup analyses, the proportions of SELs were similar in relapsing-remitting MS and progressive MS. Both types showed a proportion of 15%. However, the proportion of patients with at least one SEL was higher in progressive MS than in relapsing-remitting MS.

Between-study heterogeneity was high across all analyses. The researchers did not identify any significant sources of this heterogeneity through their meta-regression analyses. They examined several study-level factors as potential moderators. These factors included the time frame used for SEL identification, mean age, disease duration, and baseline EDSS score. They also included the proportion of patients receiving any disease-modifying therapy (DMT). They included the proportion receiving high-efficacy DMT. They included the proportion receiving non-high-efficacy DMT. They included the proportion receiving no DMT. They also included MRI scanner field strength. None of these factors significantly explained the variability between studies.

Detailed imaging variables were extracted but not included in subgroup or meta-regression analyses. This was because of heterogeneity in definitions and reporting, as well as the limited number of studies.

## What This Means for Patients

This study provides important information for patients and clinicians. Although SELs represent a minority of all T2 lesions (about 14%, or roughly 1 in 7), most patients with MS have at least one SEL (78%, or about 4 in 5). This means that SELs are a common finding in MS, even though they make up a small fraction of the total lesion burden.

The finding that 11% of SELs overlap with PRLs suggests a partial correspondence between these two imaging markers of chronic inflammatory activity. In other words, some SELs and PRLs are the same lesion seen in different ways, but many are not. This has implications for how researchers and clinicians use these markers to monitor MS.

The mean volume of SELs was 2.32 mL, compared with 11.03 mL for total T2 lesions. This means that SELs account for a relatively small proportion of the total lesion volume in the brain. However, because SELs are actively expanding and associated with ongoing inflammation, they may have effects that go beyond their size.

The higher proportion of patients with at least one SEL in progressive MS is consistent with one understanding. That understanding is that chronic active inflammation plays a larger role in progressive forms of MS than in relapsing-remitting MS. This finding may help explain why progressive MS tends to worsen steadily over time.

The high between-study heterogeneity means that different studies reported quite different results. This variability likely reflects differences in how SELs were identified, how many MRI scans were used, and how far apart those scans were taken. It also highlights the need for standardized methods for detecting and reporting SELs.

## Limitations: What the Study Could Not Prove

The researchers identified several limitations of their study. First, there was possible publication bias. This means that studies showing positive or significant results may be more likely to be published than studies showing negative or non-significant results.

Second, there was high unexplained heterogeneity across all analyses. The researchers could not identify the specific factors that caused studies to differ so much from each other. This makes the pooled estimates less precise.

Third, there were differences in SEL identification methods across studies. Some studies used Jacobian methods, others used in-house software, and the minimum expansion thresholds varied. Some studies used T1-weighted and/or T2-weighted images, while others used FLAIR images. These methodological differences could affect the reported prevalence of SELs.

Fourth, there were differences in the number and timing of MRI time points across studies. Some studies used only two time points, while others used multiple repeated assessments over extended follow-ups. The time frame used for SEL identification varied, which could affect how many SELs were detected.

Fifth, the study did not include detailed imaging variables in subgroup or meta-regression analyses because of heterogeneity in definitions and reporting, as well as the limited number of studies. This means that the researchers could not fully explore how imaging characteristics might affect SEL prevalence.

Finally, the analysis of overlap between SELs and PRLs was based on only three studies including 125 people with MS. This is a small number of patients, and the confidence interval was wide (5%–71%). This means the estimate of 27% overlap is uncertain and should be interpreted with caution.

## Recommendations and Next Steps

Based on this research, several recommendations emerge for patients, clinicians, and researchers.

For patients, it is important to understand that SELs are common in MS. Most patients have at least one SEL, and SELs are more common in progressive forms of MS. However, the presence of SELs does not necessarily mean that a patient will experience rapid worsening. The relationship between SELs and clinical outcomes requires further study.

For clinicians, this study highlights the potential value of using SELs as a marker of chronic active inflammation. However, because of the high variability between studies and the lack of standardized detection methods, SELs are not yet ready for routine clinical use. More research is needed to establish standardized protocols for SEL identification and reporting.

For researchers, this study identifies several important gaps in knowledge. First, there is a need for standardized methods for detecting and measuring SELs. Second, there is a need for larger studies with longer follow-up periods to understand how SELs change over time. Third, there is a need for studies that directly compare SELs with PRLs to better understand their relationship. Fourth, there is a need for studies that examine how SELs relate to clinical outcomes, such as disability progression and relapse rates.

The researchers also note that the overlap between SELs and PRLs was only partial. This suggests that these two imaging markers capture different aspects of chronic inflammatory activity. Future studies should investigate whether combining SELs and PRLs provides a more complete picture of chronic active inflammation than either marker alone.

Finally, the study protocol was registered with PROSPERO, and the researchers followed PRISMA guidelines. This transparency allows other researchers to replicate and extend the findings. The researchers used ChatGPT 5.0 to assist with language refinement and clarity, but all outputs were reviewed and verified by the authors, who take full responsibility for the content.

## Frequently Asked Questions

### What are slowly expanding lesions (SELs) in multiple sclerosis?

SELs are areas of damage seen on conventional MRI scans that grow in a linear, concentric pattern over time. They are detected by comparing scans taken at different times. SELs have a core with few cells and a rim of immune cells at the edge, where ongoing myelin breakdown and nerve fiber damage occur. They are considered a marker of chronic active inflammation.

### How common are SELs in people with MS?

A review of 20 studies including 4,786 patients found that about 14% of all T2 lesions were SELs. Also, 78% of patients had at least one SEL. This means SELs are a common finding, even though they make up a small fraction of the total lesion burden. The estimates varied widely between studies.

### Do SELs mean my MS will get worse faster?

The paper states, citing earlier studies, that SELs are more prominent in progressive MS and predict disability progression, and that they may represent an underlying mechanism of progression independent of relapse activity. In this review, the proportion of patients with at least one SEL was higher in progressive MS than in relapsing-remitting MS. Discuss any concerns with your neurologist.

### Are SELs more common in progressive MS than relapsing-remitting MS?

The proportion of SELs among all T2 lesions was similar in relapsing-remitting and progressive MS, both about 15%. However, the proportion of patients with at least one SEL was higher in progressive MS. This is consistent with the idea that chronic active inflammation plays a larger role in progressive forms of MS.

### Can SELs be used in routine clinical care now?

No, SELs are not yet ready for routine clinical use. The review found high variability between studies and a lack of standardized methods for detecting and measuring SELs. More research is needed to establish standardized protocols. For now, SELs remain a research tool, not a standard part of MS monitoring.

### What are the limitations of the research on SELs?

The review had several limitations. There was possible publication bias and high unexplained differences between studies. SEL identification methods varied, as did the number and timing of MRI scans. The overlap analysis between SELs and PRLs was based on only three studies with 125 patients, so that estimate is uncertain and should be interpreted with caution.

### When should a patient with multiple sclerosis seek a second opinion about slowly expanding lesions on MRI?

Slowly expanding lesions are common, appearing in about 78% of patients and making up roughly 14% of all T2 lesions, and they are more frequent in progressive forms of MS. Because detection methods vary widely between studies and no standardized protocol exists, SELs are not yet ready for routine clinical use. A second opinion can help clarify what your MRI findings mean and whether they should influence your care. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** Prevalence of Slowly Expanding Lesions in Patients With Multiple Sclerosis

**Authors:** Andreas Liampas, Artemios Artemiadis, Vasilis-Spyridon Tseriotis, Ferran Prados, Paolo Preziosa, Alberto Calvi, Georgios Hadjigeorgiou, Maria A. Rocca, Massimo Filippi, and Olga Ciccarelli

**Publication:** Neurology, 2026;107:e218474. doi:10.1212/WNL.0000000000218474

**Author affiliations:** Queen Square MS Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, United Kingdom; Department of Neurology, Medical School, University of Cyprus, Nicosia; Department of Neurology, Agios Pavlos General Hospital of Thessaloniki, Greece; Laboratory of Clinical Pharmacology, Aristotle University Campus, Aristotle University of Thessaloniki, Greece; Hawkes Institute, Department of Medical Physics and Biomedical Engineering, University College London, United Kingdom; Universitat Oberta de Catalunya, Barcelona, Spain; Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Neuroimmunology and Multiple Sclerosis Unit and Laboratory of Advanced Imaging in Multiple Sclerosis (ImaginEM), Hospital Clinic Barcelona, Spain; Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy; and National Institute for Health and Care Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre, United Kingdom.

**Funding:** The Article Processing Charge was funded by University College London.

**Open access:** This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Copyright:** Copyright © 2026 The Author(s). Published by Wolters Kluwer Health, LLC. on behalf of the American Academy of Neurology.

**Note:** This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace consultation with a qualified healthcare provider. Patients should discuss any questions about their MS diagnosis or treatment with their neurologist or MS specialist.


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