Lesion-level correspondence and longitudinal properties of paramagnetic rim and slowly expanding lesions in multiple sclerosis

Abstract

Background: Paramagnetic rim lesions (PRLs) and slowly expanding lesions (SELs) have been posited as markers of chronic active lesions (CALs).

Objective: To assess the lesion-level concordance of PRLs and SELs in MS and to characterize changes in brain tissue integrity in CALs over time.

Methods: MRIs were analyzed from a substudy of AFFINITY [NCT03222973], a phase 2 trial of opicinumab in relapsing MS. Assessments included (1) identification of SELs based on longitudinal MRIs over 72 weeks, and identification of PRLs on susceptibility-weighted imaging (SWI) filtered phase images at week 72; (2) evaluation of subject-level correlation of SEL and PRL counts, volumes, and degree of lesion-level overlap between SELs and PRLs; and (3) characterization of tissue integrity over time in overlapping and non-overlapping SELs and PRLs.

Results: In 41 subjects, 119 chronic PRLs and 267 SELs were detected. Of 119 (39.5%) chronic PRLs, 47 co-localized with a SEL; 46/267 (17.2%) SELs co-localized with a PRL. PRLs co-localized with SELs showed expansion and worsening microstructural damage over time. SELs with and without co-localization with PRLs showed ongoing tissue damage.

Conclusions: Chronic MS lesions identified as both PRL and SEL were associated with the most severe accumulation of tissue damage.

Trial registration: AFFINITY [NCT03222973].

Keywords: Chronic active lesions; MRI; multiple sclerosis; opicinumab; paramagnetic lesions; slow expanding lesions.

Figure 1.

Assessment of co-localization between PRLs and SELs and identification of PRL+/SEL− and SEL+/PRL− phenotypes. (a) T1-weighted image. (b) T2-weighted image. (c) Filtered SWI-phase image. (d) T2-lesion mask at baseline. (e) Manual PRL annotation at week 72. (f) T2-associated PRL at week 72. (g) SELs detected based on interval from baseline to week 72. (h) Voxelwise overlap of T2-associated PRLs and SELs (red = PRL only, blue = SEL only, yellow = both). (i) Co-localized PRL+/SEL+ mask (dark red). (j) Co-localized SEL+/PRL+ mask (dark blue). (k) PRL+/SEL− lesions (light red). (l) SEL+/PRL− lesions (light blue). Note that lesion boundaries are slightly different in (i) and (j) due to differences in PRL and SEL detection methods. PRL: paramagnetic rim lesion; SEL: slowly expanding lesion; SWI: susceptibility-weighted imaging; T2-assoc PRL: T2-lesion associated with a given paramagnetic rim.

Figure 2.

Evolution of tissue damage in PRLs and SELs based on lesion-level correspondence. PRLs are subcategorized into those that overlap with SELs (PRL+/SEL+, solid red line) and those that do not (PRL+/SEL−, dashed red line). SELs are subcategorized into those that overlap with PRLs (SEL+/PRL+, solid blue line) and those that do not (SEL+/PRL−, dashed blue line). Overall T2 lesions are included as a reference (solid green line). Least-squares estimates and [95%] confidence intervals of change over time are derived from MMRM with weeks since baseline modeled as linear continuous. (A) nMTR, (B) nT1, (C) RD, and (D) FA. FA: fractional anisotropy; MMRM: mixed-effect model of repeated measurement; nMTR: normalized magnetization transfer ratio; nT1: normalized T1 intensity; PRL: paramagnetic rim lesion; RD: radial diffusivity; SEL: slowly expanding lesion.

Figure 3.

Summary representation of CALs as described by histopathology versus imaging phenotypes of PRLs and SELs in MS.^, Figure is for representative purposes only, and the degree of overlap is not meant to convey a quantitative description of overlap between lesion types. CAL: chronic active lesion; PRL: paramagnetic rim lesion; SEL: slowly expanding lesion.