BACKGROUND. In some active multiple sclerosis (MS) lesions, a strong immune reaction at the lesion edge may contain growth and thereby isolate the lesion from the surrounding parenchyma. Our previous studies suggest that this process involves opening of the blood-brain barrier in capillaries at the lesion edge, seen on MRI as centripetal contrast enhancement and a colocalized phase rim. We hypothesized that using these features to characterize early lesion evolution will allow in vivo tracking of tissue degeneration and/or repair, thus improving the evaluation of potential therapies for chronic active lesions.
METHODS. Centripetally and centrifugally enhancing lesions were studied in 17 patients with MS using 7-tesla MRI. High-resolution, susceptibility-weighted, T1-weighted (before/after gadolinium), and dynamic contrast–enhanced scans were acquired at baseline and months 1, 3, 6, and 12. For each lesion, time evolution of the phase rim, lesion volume, and T1 hypointensity were assessed. In autopsies of 3 progressive MS cases, the histopathology of the phase rim was determined.
RESULTS. In centripetal lesions, a phase rim colocalized with initial contrast enhancement. In 12 of 22, this phase rim persisted after enhancement resolved. Compared with centripetal lesions with transient rim, those with persistent rim had less volume shrinkage and became more T1 hypointense between months 3 and 12. No centrifugal lesions developed phase rims at any time point. Pathologically, persistent rims corresponded to an iron-laden inflammatory myeloid cell population at the edge of chronic demyelinated lesions.
CONCLUSION. In early lesion evolution, a persistent phase rim in lesions that shrink least and become more T1 hypointense over time suggests that the rim might mark failure of early lesion repair and/or irreversible tissue damage. In later stages of MS, phase rim lesions continue to smolder, exerting detrimental effects on affected brain tissue.
TRIAL REGISTRATION. NCT00001248.
FUNDING. The Intramural Research Program of NINDS supported this study.
Martina Absinta, Pascal Sati, Matthew Schindler, Emily C. Leibovitch, Joan Ohayon, Tianxia Wu, Alessandro Meani, Massimo Filippi, Steven Jacobson, Irene C.M. Cortese, Daniel S. Reich
Chronic demyelination colocalizes with the phase rim at the lesion edge. There are no signs of ongoing remyelination and only rare oligodendrocyte precursor cells (OLIG2+/ASPA– cells, red arrows). In a cortical lesion, on the other hand, there is evidence of oligodendrocyte precursor cells as well as remyelination. Macrophages/activated microglia also colocalize with the phase rim at the lesion edge. Luxol fast blue (cyan) and lipofuscin (purple) inclusions within these cells suggest ongoing early and late myelin degradation process (×100 magnification). A rim of iron-laden CD68-positive cells are clearly present at the lesion edge (DAB-Turnbull staining alone and double staining with anti-CD68/DAB-Turnbull). Mature tissue macrophages expressing the scavenger receptor CD163 were also represented in the CD68 population, suggesting that the population was not homogeneous (double staining with CD68/CD163). Reactive astrocytes and axonal damage: Non–iron-laden reactive astrocytes were seen in the demyelinated lesion center and demyelinating lesion edge (double staining with GFAP/DAB-Turnbull). Residual axons within the lesion center showed evidence of impaired axonal transport (positive staining for nonphosphorylated neurofilaments expressing SMI32). Red arrows indicate the presence, at the lesion edge, of sparse SMI32-positive ovoids suggesting ongoing axonal degeneration. Scale bars: 50 μm (top row); 10 μm (left panel, middle row); 50 μm (right 3 panels, middle row); 50 μm (left 2 panels, bottom row); 20 μm (right 2 panels, bottom row).