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

Abstract

Background and Objectives: Expansion of chronic lesions in multiple sclerosis (MS) patients and recently described cerebrospinal fluid (CSF)-related gradient of tissue damage are linked to microglial activation. The aim of this study was to investigate whether lesion expansion is associated with proximity to ventricular CSF spaces. Methods: Pre- and post-gadolinium three-dimensional (3D)-T1, 3D FLAIR and diffusion tensor images were acquired from 36 relapsing-remitting MS (RRMS) patients. Lesional activity was analysed between baseline and 48 months at different distances from the CSF using successive 1 mm thick concentric bands radiating from the ventricles. Results: Voxel-based analysis of the rate of lesion expansion demonstrated a clear periventricular gradient decreasing away from the ventricles. This was particularly apparent when lesions of equal diameter were analysed. Periventricular lesional tissue showed higher degree of tissue destruction at baseline that significantly increased during follow-up in bands close to CSF. This longitudinal change was proportional to degree of lesion expansion. Lesion-wise analysis revealed a gradual, centrifugal decrease in the proportion of expanding lesions from the immediate periventricular zone. Discussion: Our data suggest that chronic white matter lesions in close proximity to the ventricles are more destructive, show a higher degree of expansion at the lesion border and accelerated tissue loss in the lesion core.

Short-term surrogate biomarkers of chronic lesion expansion

“…Several recent studies have reported that progressive increase of T1 hypointensity (whether by severity or by tissue volume) within pre-existing T2 lesions is linked to lesion expansion. progressive and significant decrease in T1 intensity within slowly expanding lesions compared to non-expanding lesions[38] [27] and more recent reports confirm that increased (non-gadolinium enhancing) T1 hypointense lesion volume is primarily restricted to chronic (pre-existing) T2 lesions [2][5] A shared pathomechanism underpinning increased MD and T1 hypointensity within ELs is corroborated by the recent observation that parallel worsening in these metrics follow a periventricular gradient [28].…”

“…While largely automated, this technique is limited to SEL count and does not allow accurate quantitative assessment of the brain tissue damage caused by the slow-burning inflammation. Manual lesion delineation, employed in other studies, while more quantifiable, requires long periods of follow-up (due to very slow lesion progression and inherent variability of manual masking), which is beyond the duration of a typical clinical trial and may delay the application of potentially beneficial treatments [3], [28].…”

“…This study also revealed that the contribution of white matter loss caused by axonal transection at the rim of expanding lesions accounts for more than 75% of CBA variability. The substantial contribution of lesion expansion to central brain atrophy may reflect the recent observation that expansion of chronic lesions is most apparent in proximity to the ventricles [28]. Therefore, it seems plausible that Wallerian and retrograde degeneration of axons transected at the site of lesion expansion would lead to predominant loss of periventricular white matter and consequently to expansion of the ventricles (i.e.…”

Cerebrospinal fluid–related tissue damage in multiple sclerosis patients with iron rim lesions

“…This result is in line with previous studies that demonstrated a periventricular-related tissue injury of T2-hyperintense MS lesions. 11 – 16 Of note, patients with ‘high’ IgG quotients showed a greater magnitude of negative correlation with ADC values compared to patients with ‘low’ IgG quotients.…”

“… 9 , 10 Indeed, previous studies have demonstrated a CSF-related gradient with a more severe tissue matrix damage in the normal-appearing white matter (NAWM) and chronic lesions in proximity to the inner and outer surfaces of the brain. 11 – 16 …”