Slowly eroding lesions in multiple sclerosis

Abstract

Background: At autopsy, 20%-40% of chronic multiple sclerosis (MS) lesions are labeled "slowly expanding" and feature myelin phagocytosis at the lesion edge. As pathological lesion classification relies on a single, terminal time point, the rate of lesion expansion cannot be directly measured.

Objective: To study long-term volume changes in individual MS lesions.

Methods: Volumes of individual lesions on proton density magnetic resonance imaging (MRI) acquired between 1992 and 2015 were measured in 22 individuals (one lesion per person). After correction for acquisition protocol, a mixed model evaluated lesion volume changes.

Results: The mean (standard deviation) lesion volume at baseline was 142 (82) mL, falling to 74 (51) mL after 16 (3) years. All lesions shrank over time. Change in lesion volume did not correlate with change in supratentorial brain volume ( p = 0.33). In simulations, the results could be explained by a process of slow radial expansion superimposed on substantially more rapid resorption of damaged tissue.

Conclusion: We noted sustained radiological contraction of MS lesions, a surprising result given that fresh myelin breakdown products within chronic active lesions are observed relatively frequently at autopsy. Therefore, the primary pathological process in chronic lesions, even those described as "slowly expanding," is likely to be tissue loss.

Keywords: Slowly expanding lesion; magnetic resonance imaging; multiple sclerosis; proton density.

Figure 1

Proton density weighted images acquired over 14 years in a representative individual with relapse onset MS, showing a reduction in the size of two discrete white matter lesions (red arrows).

Figure 2

Scan resolution affects lesion volume. Each line represents a discrete lesion in a separate individual, all measured within a single scanning session.

Figure 3

(a) The logarithm of the adjusted lesion volume (see Eq. 7) tracked over time (dashed line) for all 22 lesions. The mixed-effects model fit for each lesion is also shown (solid lines). 3(b): Supratentorial brain volume tracked over time, derived from the subset of data that was suitable for volumetric analysis. The mixed-effects model fit for each lesion is also shown (solid lines). 3(c) The rate of change in lesion volume was uncorrelated with the rate of change in supratentorial brain volume.

Figure 4

Simulations predict a stable erosion rate of ~4% per year (solid green line) when assuming that lesion tissue is resorbed as a fixed percentage of the volume, even while the lesion undergoes expansion at the edge at a rate proportional to its radius. This finding is consistent with our longitudinal in vivo data. On the other hand (dashed red line), in the simulation assuming that tissue is preferentially resorbed at the lesion center, even with ongoing expansion at the edge, the rate of lesion erosion accelerates over time, a situation not recapitulated in vivo.