Chronic active neuroinflammation represents a primary driver of sustained disability accumulation across the spectrum of multiple sclerosis. Neuroimaging research increasingly focuses on chronic active lesions, which reflect compartmentalized smoldering inflammation behind a closed blood-brain barrier. In particular, slowly expanding lesions serve as critical magnetic resonance imaging markers identified by progressive, radial expansion on serial conventional scans. A comprehensive systematic review and meta-analysis led by Andreas Liampas and colleagues synthesized existing clinical data to quantify the exact burden of these lesions. Consequently, their findings clarify the prevalence of slowly expanding lesions and illustrate their pathological overlap with susceptibility-based imaging biomarkers.

Understanding Slowly Expanding Lesions in Multiple Sclerosis

Historically, clinicians monitored multiple sclerosis primarily through acute gadolinium-enhancing lesions and new T2 hyperintensities. However, standard surveillance frequently overlooks low-grade, persistent demyelination occurring within existing lesion boundaries. Slowly expanding lesions capture this insidious destructive process through deformation field mapping and longitudinal volumetric assessments. In contrast to transient acute flares, these lesions exhibit continuous radial expansion over months or years. Neuropathological studies demonstrate that expanding lesion edges contain activated microglia and macrophages driving sustained axonal loss. Therefore, tracking slowly expanding lesions provides clinicians with a sensitive window into chronic tissue injury that standard imaging often misses. As a result, recognizing this chronic activity remains vital for understanding progressive neurodegeneration across all disease stages.

Key Findings on the Prevalence of Slowly Expanding Lesions

The systematic review evaluated 20 studies incorporating 4,786 patients with multiple sclerosis to determine overall lesion distribution. The pooled analysis revealed that slowly expanding lesions accounted for 14% of all cerebral T2 lesions across the evaluated cohorts. Furthermore, approximately 78% of all individuals with multiple sclerosis harbored at least one slowly expanding lesion. Following sensitivity analyses, the mean per-patient volume of slowly expanding lesions reached 1.42 mL, compared to 10.6 mL for total T2 lesion volume. Subgroup evaluations demonstrated that while individual lesion proportions remained consistent at 15% in both relapsing-remitting and progressive forms, the proportion of affected patients was significantly higher in progressive disease. Thus, chronic active inflammation represents an exceptionally widespread phenomenon across clinical phenotypes.

Overlap Between Slowly Expanding Lesions and Paramagnetic Rim Lesions

Magnetic resonance imaging identifies chronic active lesions through two principal modalities: longitudinal expansion or susceptibility-weighted rim detection. Specifically, paramagnetic rim lesions reveal peripheral rings of iron-laden microglia on susceptibility-sensitive sequences. Interestingly, the meta-analysis found that only 11% of slowly expanding lesions directly overlapped with paramagnetic rim lesions. This modest convergence suggests that while both entities reflect smoldering neuroinflammation, they likely represent distinct pathological phases or complementary biological mechanisms. For instance, some chronic active lesions may sustain active rim inflammation without rapid volumetric enlargement, whereas others expand through diffuse tissue destruction without prominent iron accumulation. Consequently, utilizing both imaging markers in combination offers a far more comprehensive assessment of compartmentalized central nervous system inflammation.

Clinical Implications for Disease Progression and Treatment

The high prevalence of chronic active lesions carries profound clinical implications for routine practice and therapeutic decision-making. Smoldering lesions correlate strongly with accelerated brain atrophy, physical disability accumulation, and cognitive decline independent of clinical relapses. Standard disease-modifying therapies effectively suppress peripheral lymphocyte infiltration and acute focal relapses; however, they demonstrate limited efficacy against compartmentalized inflammation. Therefore, identifying persistent lesion expansion highlights an urgent clinical unmet need for therapies capable of penetrating the central nervous system. Novel therapeutic classes, such as Bruton tyrosine kinase inhibitors, are currently undergoing investigation specifically to modulate microglial activation and halt chronic expansion. In addition, tracking these lesions during clinical trials could establish sensitive surrogate endpoints for disease progression.

Technical Challenges and Methodological Heterogeneity in SEL Detection

Despite their substantial prognostic value, implementing slowly expanding lesion detection in routine clinical radiology poses notable technical hurdles. The meta-analysis identified considerable between-study heterogeneity, largely driven by varying image acquisition protocols and divergent computational algorithms. Specifically, software tools utilize differing deformation field thresholds, co-registration parameters, and scan interval timings to classify expansion. Furthermore, standard identification requires high-quality, isotropic three-dimensional MRI scans acquired across multiple consistent follow-up time points. Minor patient repositioning or scanner hardware upgrades can inadvertently introduce registration noise that mimics true biological expansion. Consequently, international neuroimaging consortia must establish standardized acquisition protocols and automated, robust post-processing pipelines before clinicians can routinely integrate volumetric expansion tracking into daily practice.

Frequently Asked Questions

What are slowly expanding lesions in multiple sclerosis?

Slowly expanding lesions are chronic active white matter lesions that demonstrate steady, concentric enlargement over serial MRI scans. Unlike acute inflammatory plaques characterized by transient blood-brain barrier breakdown, these lesions reflect ongoing, low-grade microglial activity and continuous myelin destruction. Consequently, they serve as objective radiological biomarkers for smoldering neuroinflammation and gradual neuroaxonal degeneration independent of clinical relapses.

How do slowly expanding lesions differ from paramagnetic rim lesions?

Slowly expanding lesions require longitudinal conventional MRI to detect progressive volumetric growth over time. In contrast, paramagnetic rim lesions are detected on single-time-point susceptibility-weighted MRI through an iron rim generated by chronically activated macrophages. Research shows only an 11% overlap between them, indicating that each marker captures distinct facets or temporal phases of chronic active pathology.

Why is tracking chronic active lesions important for MS management?

Tracking chronic active lesions provides crucial prognostic insight because their presence correlates with accelerated disability accumulation, brain volume loss, and progression independent of relapse activity. Furthermore, identifying these lesions helps clinicians evaluate therapeutic failure under standard immunomodulators. This tracking guides the potential selection of next-generation central nervous system-penetrant therapies designed to suppress compartmentalized microglial activation.

Disclaimer: This content is for informational and educational purposes only, and does not substitute professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Liampas A et al. Prevalence of Slowly Expanding Lesions in Patients With Multiple Sclerosis: A Systematic Review and Meta-Analysis. Neurology. 2026 Oct 13. doi: 10.1212/WNL.0000000000218474. PMID: 42679340.
Calvi A et al. Relationship between paramagnetic rim lesions and slowly expanding lesions in multiple sclerosis. Mult Scler. 2023;29(2):206-216.
Maggi P et al. Chronic active lesions in multiple sclerosis: classification, terminology, and clinical significance. Ther Adv Neurol Disord. 2024;17:17562864241306684.