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
Images shown are from lesions 2 and 3 in Figure 8. (A) In vivo and postmortem 7T MRI shows 2 periventricular lesions with persistent phase rims that become partially confluent over time as the lesion expands (between 2006 and 2013). The rims were visible on an in vivo 7T MRI in 2013 (not shown), as well as postmortem (red arrows). On the in vivo 7T 3D T1-MPRAGE (2013), these lesions appear strongly hypointense (mean lesion T1 intensity values, respectively: –25.1 and –21.2 in units of SD of normal-appearing white matter signal; mean cerebrospinal fluid T1 intensity: –29.9). Scale bar: 5 mm. (B) In vivo and postmortem MRI-guided histopathology allowed precise localization of the target area. MRI-matched thumbnails of representative serial sections (10-μm-thick sections) show the Luxol fast blue/periodic acid–Schiff (LFB-PAS) stain for myelin, myelin proteolipid protein (PLP) immunohistochemistry, and Bielschowsky staining for axons. Insets i–v are indicated as red squares on the thumbnails to facilitate their localization and the interpretation of the pathological data. Both lesions were completely demyelinated. (i–iii) The lesion edge, where the phase rim was detected on MRI, is characterized by the presence of an extensive CD68-positive cellular infiltrate, corresponding to macrophages/activated microglia (inflammatory infiltrate thickness ~200–400 μm). Luxol fast blue–positive myelin debris (cyan, black arrows) and late myelin degradation products (lipofuscin, purple) can be seen within macrophages at the lesion edge, suggesting ongoing demyelination (ii). The majority of CD68-positive cells also stained positive by the DAB-Turnbull method, indicating the intracellular accumulation of iron (iii). (iv and v) Extensive axonal loss with transection and dystrophy of the remaining axons is seen throughout the lesion center (v). At the lesion edge, some axons were better preserved, and fiber bundles could be discerned (iv). Scale bars: 200 μm (i); 10 μm (ii); 50 μm (iii–v).