Expansion of chronic lesions is linked to disease progression in relapsing–remitting multiple sclerosis patients

Abstract

Background: Slow-burning inflammation is putatively associated with lesion expansion and leads to progressive loss of axons and disability worsening. Objective: To investigate the incidence and extent of chronic white matter lesion expansion in relapsing–remitting multiple sclerosis (RRMS) patients and to evaluate its relationship with biomarkers of disease progression. Methods: Pre- and post-gadolinium T1, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 33 patients. Lesional activity were analysed between baseline and 48 months using custom-designed software. Results: A total of 569 lesions were identified as chronic at baseline, of which 261 were expanding, 236 were stable and 72 were shrinking. In addition, 139 new lesions (both confluent and free-standing) were observed. Chronic lesion expansion was associated with patient’s age and accounted for the bulk (67.3%) of total brain lesion volume increase, while only 32.7% was attributable to new lesion formation. Change in chronic lesion volume correlated with the rate of brain atrophy ( r = −0.57, p = 0.001), change of Expanded Disability Status Scale (EDSS; r = 0.38, p = 0.03) and an increase of isotropic diffusivity inside the lesions ( r = 0.75, p < 0.001). Conclusion: Expansion of chronic lesions in RRMS patients is the primary determinant of increased T2 total lesion load. It significantly contributes to disease progression and partially driving axonal loss inside the lesions and brain damage outside of lesional tissue.

The expansion and severity of chronic MS lesions follows a periventricular gradient

“…The latter finding is in agreement with earlier studies showing the more destructive nature of chronic active lesions 17,18 We recently demonstrated a close association between expansion of the lesion rim and progressive axonal damage inside the lesion and attributed this to Wallerian and retrograde degeneration of axons transected at the lesion rim. 3 Similarly, progressive tissue damage inside slowly expanding lesions has been reported by others groups. 2,19 The current study provides strong support for this notion by demonstrating that gradients of isotropic water diffusion and T1-intensity alteration inside lesions during the follow-up period are highly proportional to the periventricular gradient of lesion expansion, and, as a result, are likely to be secondary to slow-burning inflammation at the lesion rim.…”

“…The rate of lesion expansion within the ring was then calculated as a relative change in number of lesional voxels occurring during the follow-up. 3 To reduce the disproportionally large impact of small lesions on calculation of CSF-related gradient of lesion expansion, the weight corresponding to number of baseline lesional voxels in each ring was assigned to each lesion, as recently suggested. 12,10 For lesion-based analysis, the "center of mass" for each lesion was calculated using the weighted average of lesional voxels distributed across all the rings.…”

“…7,10 Similarly, the acute and chronic white matter lesions contribute independently to disease progression, implying that different mechanisms are likely to be responsible for acute and smouldering inflammation. 1,2,3,26,27 Finally, the gradient of tissue severity damage in NAWM and the presence of chronic active lesions are more prominent in patients with progressive forms of MS. 11,14 Therefore, it is plausible that some of the mechanisms proposed to explain the periventricular predominance of abnormalities in the NAWM, such as a neurotoxic effect of soluble CSF-derived factors, 12,28 hypoxia 29 , reduced remyelinating capacity 30 or increased compartmentalized inflammation 9 in periventricular region and microglial activation 12 are important mediators of the expansion of chronic lesions observed in our study.…”

“…While acute inflammatory demyelination, typically manifested as new white matter lesions, is thought to be a principal cause of axonal transection and subsequent axonal degeneration, slow-burning inflammatory demyelination at the edge of chronic lesions and its MRI equivalent (the expansion of chronic MS lesions) has been suggested as another major factor contributing to disease evolution, including progressive neurodegeneration, brain atrophy and disability worsening. 1,2,3,4 Although the mechanisms responsible for this phenomenon are still poorly understood, microglial activation and myelin breakdown play a central role. 5,6 A CSF-related gradient of tissue injury has recently been described in both normalappearing white matter (NAWM) and chronic lesions in patients with MS. 7,8,9,10,11 White matter magnetization transfer ratio (MTR) and Mean Diffusivity (MD) abnormalities were reported around the ventricles, with the most severe abnormalities bordering the ventricular surface.…”

“…Akin to pathomechanisms thought to be involved in slow lesion expansion, the periventricular injury gradient is linked to innate immune cell activation 12 and seems to be independent of formation of new lesions. 3,7 Therefore, the aim of the current study was to investigate whether slow-burning inflammation at the rim of chronic MS lesions (assessed by the degree of lesion expansion) is associated with proximity to the CSF; and to explore a potential relationship between lesion topography and the degree of progressive tissue injury within the lesional core (as measured by T1 hypointensity and MD).…”