Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo

Abstract

IMPORTANCEIn multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target.OBJECTIVE To assess whether rim lesions are associated with patient disability and long-term lesion outcomes. DESIGN, SETTING, PARTICIPANTS We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age Ն18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992). MAIN OUTCOMES AND MEASURES(1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions. RESULTSOf 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (−3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation.CONCLUSIONS AND RELEVANCE Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These r...

The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody

“…As described already in the earliest reports of MS pathology [40], the demyelinated lesions arise around focal perivenous inflammatory aggregates as acute plaques, which further expand by a zone of lesional activity surrounding the inactive core (chronic active lesions; [36]). A subset of these chronic active MS lesions are smoldering plaques with a rim of activated microglia at the edge and very sparse macrophages with early myelin degradation products [20,36], which enlarge slowly over months or years [2,10]. Thus, chronic active focal white matter lesions are typical for multiple sclerosis pathology and present at all disease stages [20].…”

“…Although our cohort is skewed toward early disease, a secondary progressive course typical of MS rarely if ever occurs in MOGAD [30]. As a subset of smoldering lesions have an iron ring in MRI [2,10], it would be helpful to determine whether MOGAD patients ever develop iron ring lesions.…”

Identifying Progression in Multiple Sclerosis: New Perspectives

“…6,7 Automatic detection of SELs based on conventional T1-and T2-weighted sequences has been proposed for both RRMS and PPMS. 23 The identification of lesions with iron-laden rims using susceptibility-based sequences at 3 or 7T is another option for detecting SELs, 24 which are associated with a more disabling disease course. 24 However, it remains unclear whether these rims should be considered a distinct feature of PMS.…”

“…23 The identification of lesions with iron-laden rims using susceptibility-based sequences at 3 or 7T is another option for detecting SELs, 24 which are associated with a more disabling disease course. 24 However, it remains unclear whether these rims should be considered a distinct feature of PMS. The proportions of rim lesions are extremely heterogeneous among the different clinical phenotypes (CIS/RRMS from 6% to 53%, PMS from 7.2% to 62%), with some studies showing a higher prevalence in PMS compared to RRMS, 25 but this was not confirmed in others.…”

Fully Automated Detection of Paramagnetic Rims in Multiple Sclerosis Lesions on 3T Susceptibility-Based MR Imaging

“…Chronic active lesions, which are a subset of MS lesions that are more prevalent in patients with more severe disease (5)(6)(7), have imaging and histopathology findings suggestive of ongoing tissue damage (8)(9)(10) and have until recently only been detectable by histopathology. These lesions have been variously termed chronic active, slowly expanding, or smoldering lesions.…”