Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo

Abstract

Importance: In 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 ≥18 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.

Results: Of 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 results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Absinta reported grants from Conrad N. Hilton Foundation (17313) and the National Multiple Sclerosis Society (FG 2093-A-1) and support from the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. Dr Reich reported a collaborative research and development agreement with Vertex Pharmaceuticals and patents issued for "Method of analyzing multi-sequence MRI data for analyzing brain abnormalities in a subject" and "System and method of automatically detecting tissue abnormalities." No other disclosures were reported.

Figures

Figure 1.. Consolidated Standards of Reporting Trials Chart

MRI indicates magnetic resonance imaging; MS, multiple sclerosis.

Figure 2.. Cumulative Distribution and Histogram

A and B, Cumulative distribution and histogram of the frequency of chronic nonenhancing lesions with paramagnetic rims. The representative susceptibility-based 7-T magnetic resonance imaging scans of individuals were classified into 3 groups based on the number of rim lesions. C, Group 1 (no detectable rims) is a woman in her mid-20s with relapsing multiple sclerosis (MS). D, Group 2 (detection of 1–3 rims) is a man in his late 50s with relapsing MS and 2 rim lesions. E, Group 3 (detection of ≥4 rims) is a man in his early 30s with relapsing MS and 16 rim lesions. Rim lesions are indicated with arrowheads, and the insets show representative magnified views.

Figure 3.. Man in His Late 50s With Progressive Multiple Sclerosis and Expanding Rim Lesions

A, In vivo 7-T axial phase magnetic resonance imaging (MRI) acquired at age 59 years showing representative supratentorial rim lesions (magnified views are in the insets). B, Histogram of the 10-rim lesions analyzed by MRI and histopathology. The lesion area was measured on in vivo coregistered T1-weighted scans at ages 52 and 59 years. All 10-rim lesions expanded over 7 years. C and D, MRI-histopathology comparison of individual rim lesion evolution and pathology. Serial in vivo coronal T1-weighted MRI scans and relative patient age are shown in the first row of each section. Clearly expanding confluent areas are indicated by arrowheads. All expanding rim lesions were chronic-active by pathology results. An accumulation of iron-laden phagocytes (cluster of differentiation [CD] 68 and iron staining) was seen at the lesion edge (asterisks on myelin proteolipid protein [PLP] and Luxol fast blue–periodic acid–Schiff [LFB-PAS] staining). The MRI-pathology comparison for lesions 2 and 3 was previously published (Figure 6 and eFigure 3 in the Supplement, respectively, in Absinta et al). E, The paramagnetic rim localizes inflammatory demyelination. Smoldering demyelination can be inferred by the copresence of early (LFB+) and late (PAS+) myelin degradation products within phagocytes at the lesion edge. Most CD68+ cells contain iron and showed a downregulation of the homeostatic microglia marker transmembrane protein (TMEM) 119. A few perivascular CD8+ T lymphocytes (not shown here) and early activated peripheral macrophages (myeloid-related protein [MRP] 14+) can be seen at the edge. Reactive astrocytes were negative for iron. Some vessels at the lesion edge, but not within the lesion center, show fibrinogen deposition within the perivascular space, suggesting a subtle opening of the blood-brain barrier. Some degenerating axons are marked by staining for nonphosphorylated neurofilaments (SMI32+). Magnified views are shown in the insets. Scale bar, 50 μm. GFAP indicates glial fibrillary acid protein. Black font indicates the DAB staining method; blue font indicates the AP method.

Figure 4.. Chronic Multiple Sclerosis Lesions With and Without Paramagnetic Rim Evolve Dichotomously

A and B, Adjusted log-transformed lesion volume was tracked over time for all lesions (617 yearly points). The nonlinear spline regression model fit is shown for each lesion (solid curves). Raw data are represented as circles.