Chronic Lesion Expansion in RRMS Contributes to Disease Progression, Study Reveals

The expansion of chronic white matter lesions in people with relapsing-remitting multiple sclerosis (RRMS) determined the increase in total lesion volume and significantly contributed to disease progression, a study has revealed.

The study, “Expansion of chronic lesions is linked to disease progression in relapsing-remitting multiple sclerosis patients,” was published in the Multiple Sclerosis Journal. 

MS is characterized by inflammatory demyelination — loss of myelin, the protective coat of nerve fibers — that presents as new lesions in the white matter of the brain and is the primary cause of nerve fiber (axon) damage. 

While new lesion activity is typically measured as changes to the combined volume of new lesions plus the growth of pre-existing (chronic) lesions, recent evidence suggest that mechanisms underlying the formation of new lesions are different from the ones involved in the slow expansion of chronic lesions. 

Examination of chronic lesions found an inactive core surrounded by a rim of inflammation, ongoing demyelination, and axon damage. This slow-burning inflammation at the edge of chronic MS lesions may be associated with lesion expansion leading to the progressive loss of axons and worsening disability. 

To investigate further, a team led by researchers based at The University of Sydney in Australia examined the incidence and extent of the growth of chronic white matter lesions in 33 people with RRMS followed for five years.

The average age of participants (13 men and 20 women) was 42.6 years, with an average disease duration of 6.5 years. All patients were receiving disease-modifying therapies except one. MRI scans and clinical assessments were conducted in the pre-study period (0 months) to find new lesions, and at 12 months (baseline) and 60 months (follow-up). 

Of the 569 lesions identified as chronic at baseline, 261 (46%) were classified as expanding lesions, 236 (42%) were stable, and 72 (12%) were shrinking. Also, 139 new lesions were detected. 

Lesion expansion was the primary reason for volume change, with the average volume in expanding lesions being significantly larger than the average volume of shrinking lesions — 120 cubic millimeter (mm3) vs. 37 mm3 in shrinking lesions. 

Overall, there was a significant increase in the total brain lesion volume from baseline at 12 months (average volume of 6,680 mm3) to follow-up at 60 months (average 7,951 mm3), which was mostly due to an increase in chronic lesion volume (67.3%) over new lesion volume (32.7%). 

While the rate of chronic lesion change varied considerably, 15 out of 33 patients demonstrated a greater than 10% enlargement of chronic lesions.

Patient age was significantly associated with the percentage of chronic lesion volume change, with older individuals showing a larger number of expanding chronic lesions. In contrast, the volume of new lesions was independent of age. 

Although the researchers found no association between expanding chronic lesions and the patient’s sex, type of therapy used, disease duration, or baseline lesion volume, there was a significant correlation with brain shrinkage (atrophy) as well as a change in the expanded disability status scale (EDSS) score (a measure of disability). 

These findings indicated that the “expansion of chronic lesions is associated with both radiological and clinical markers of disease progression,” the researchers wrote. 

Statistical analysis found both new and chronic lesions contributed to brain atrophy, with the effect of chronic lesions playing a larger role. A similar analysis using EDSS progression demonstrated only chronic lesion expansion contributed to disability. 

The degree of tissue damage within chronic lesions was measured by mean diffusivity, in which an increase indicates progressive damage. 

The degree of chronic lesion volume change correlated significantly with the level of mean diffusivity within lesions at baseline, during the study period, and by the end of follow-up, suggesting that the “degree of progressive tissue loss inside chronic lesions is associated with ongoing inflammation at the lesion rim,” the researchers wrote. 

The rate of chronic lesion volume change and an increase of mean diffusivity inside lesions during the follow-up period was also strongly correlated. Growing chronic lesions primarily drove these changes in mean diffusivity within the lesion core.  

“In summary, the expansion of chronic white matter lesions in patients with RRMS is the primary determinant of the increased … total lesion load and significantly contributes to disease progression,” the team wrote. “Low-grade inflammation at the lesion rim is driving, at least partially, axonal loss inside the chronic lesions and brain damage outside of lesional tissue.”