Modelling axonal loss caused by chronic demyelination and slow-burning inflammation at the rim of chronic lesions in MS patients

ObjectivesSlow-burning inflammation at the edge of chronic multiple sclerosis lesions and loss of myelin in the depths of the lesions have emerged as a key components of disease progression. However, their relative contribution to progressive axonal damage has not been investigated. Therefore, the aim of the study was to examine relative weight of those factors in axonal attrition inside the chronic MS lesions by measuring tissue rarefication of the lesion core. MethodsPre- and post-gadolinium 3D-T1, 3D FLAIR, diffusion tensor images, Optical Coherence tomography and multifocal visual evoked potentials were acquired from 52 patients. Analysis was performed between baseline and 48 months. Lesion expansion was measured using in-house software. The degree of lesional tissue damage was determined by measuring increase of Mean Diffusivity (MD) in lesion core normalised over MD dynamic range. ResultsThere were 104 expanding and 257 stable lesions. Rate of normalised MD (nMD) increase was several folds higher in expanding vs stable lesions (0.21% vs 1.12% per year, p=0.01). The magnitude of nMD change was significantly associated with the rate of lesion expansion (r=0.4, p<0.001). Analysis of visual system revealed the rate of axonal loss similar to the degree of tissue rarefication in stable lesions. InterpretationThe current study demonstrated a significant increase in water content in chronic MS lesions, which was, however, markedly higher in slowly expanding compared to stable lesions. This suggests that slow-burning inflammation at the lesion rim, when present, is likely to play a more significant role in axonal attrition than chronic demyelination.