Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI

Abstract

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6–62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation period were 1 (0–7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34–88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

Chronic active lesions: a new MRI biomarker to monitor treatment effect in multiple sclerosis?

“…In pathological studies, chronic active lesions represent up to 57% of all focal WM lesions, being more frequently described in patients with progressive (P) MS [1][2][3]. Chronic active lesions typically show a peripheral 'rim' of iron-laden activated microglia/macrophages associated with ongoing demyelination and axonal loss, around an inactive core without blood-brain barrier damage, thus reflecting a compartmentalized chronic inflammatory pathological process [1][2][3][4].…”

“…On these sequences, chronic active lesions show a paramagnetic hypointense rim (i.e. 'iron rim lesions') that corresponds pathologically to peripheral iron-laden microglia [3,4,6] (Figure 1(a)). Moreover, by combining susceptibility-based MRI scans and serial post-contrast T1weighted sequences rapidly acquired after gadolinium injection (i.e.…”

“…dynamic contrast enhancement [DCE]), chronic active lesions, ~9.4% of all chronic lesions, showed no contrastenhancement, thus they lack substantially abnormal bloodbrain barrier permeability that typically characterizes acute lesions [7]. Iron rim lesions are also characterized by a more limited lesional repair and have been described in all MS phenotypes although with heterogeneous reported rates: clinically isolated syndrome/relapsing-remitting (RR) MS from 6% to 53%, PMS from 7% to 62% [3,4,8,9]. By evaluating the longitudinal evolution of iron rim lesions over up to 7 years, a recent study with the longest follow-up currently available showed that such lesions are characterized by a slow rate of increase in size in the first years after their formation and then stabilize.…”

Quantitative susceptibility mapping captures chronic multiple sclerosis rim lesions with greater myelin damage: Comparison with high-pass filtered phase MRI

“…Following the transition into the chronic stage after BBB closure, some lesions have the ability to self-repair tissue injury, while others continue to undergo demyelination, which has been attributed to persistent low-grade microglial inflammation behind the sealed BBB (3). An important subset of chronic active lesions have a relatively inactive core surrounded by a slowly expanding rim of continuing demyelination and axonal loss infiltrated by iron-laden activated microglia and macrophages (3)(4)(5)(6)(7).…”

MS can be considered a primary progressive disease in all cases, but some patients have superimposed relapses – Yes

“…The adequate control of inflammatory parameters might provide a sense of false security, while a continuous smouldering process underpins the subtle clinical deterioration, which stands out as an important unmet treatment target. Changes in the whole brain and grey matter volume, 7 the accumulation of chronic slowing expanding lesions 8 and the microglia activation, both in the normal appearing white matter and in the perilesional areas, 9 are plausible drivers of PIRA events during the RR phase, when the focal inflammatory activity is the dominant clinical feature, albeit representing only the tip of the pathological iceberg.…”