Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis

Abstract

Objective: To determine the frequency and nature of leptomeningeal contrast enhancement in multiple sclerosis (MS) via in vivo 3-tesla postcontrast T2-weighted, fluid-attenuated inversion recovery (FLAIR) MRI and 7-tesla postmortem MRI-pathology correlation.

Methods: Brain MRI, using the postcontrast T2-weighted, FLAIR technique, was prospectively collected in 299 MS cases and 37 age-matched neurologically healthy controls. Expert raters evaluated focal gadolinium enhancement in the leptomeningeal compartment. Two progressive MS cases came to autopsy after in vivo MRI characterization. Pathologic and immunohistochemical examination assessed the association of enhancement with leptomeningeal inflammation and adjacent cortical demyelination.

Results: Focal contrast enhancement was detected in the leptomeningeal compartment in 74 of 299 MS cases (25%) vs 1 of 37 neurologically healthy controls (2.7%; p = 0.001). Enhancement was nearly twice as frequent (p = 0.009) in progressive MS (39/118 cases, 33%) as in relapsing-remitting MS (35/181, 19%). Enhancing foci generally remained stable throughout the evaluation period (up to 5.5 years). Pathology showed perivascular lymphocytic and mononuclear infiltration in the enhancing areas in association with flanking subpial cortical demyelination.

Conclusion: Leptomeningeal contrast enhancement occurs frequently in MS and is a noninvasive, in vivo marker of inflammation and associated subpial demyelination. It might therefore enable testing of new treatments aimed at eliminating this inflammation and potentially arresting progressive MS.

Figure 1. In vivo leptomeningeal enhancement: Radiology

(A) Examples of leptomeningeal contrast enhancement in 4 representative MS cases. Foci of high signal (boxes) on 3T postcontrast T2-FLAIR images indicate leptomeningeal enhancement. From left to right: a 54-year-old woman with relapsing-remitting MS (EDSS score = 1.5); a 51-year-old woman with primary progressive MS (EDSS score = 6.5); a 38-year-old woman with relapsing-remitting MS (EDSS score = 1); and a 62-year-old man with primary progressive MS (EDSS score = 6.5). The findings are magnified in the corresponding boxes (arrows). In no case was enhancement present on precontrast T2-FLAIR scans (not shown). Extracerebral tissues have been masked for clarity. (B) Longitudinal assessment of leptomeningeal enhancement. High signal indicating leptomeningeal enhancement within a parietal sulcus (arrows) was stable over 4 years in a 55-year-old man with relapsing-remitting MS (EDSS score = 2.5). (C) Signal intensity on different MRI sequences. Three foci of leptomeningeal enhancement are visible on postcontrast T2-FLAIR scans (left column), but not on the corresponding precontrast T2-FLAIR (middle column). In the right column, postcontrast T1-weighted images show minimal abnormal signal that would not routinely be classified as enhancement. The first row shows images from a 42-year-old woman with relapsing-remitting MS (EDSS score = 2); second row: 30-year-old woman with relapsing-remitting MS (EDSS score = 6); and third row: 61-year-old woman with primary progressive MS (EDSS score = 6). (D) Association with meningeal vessels: high-resolution 7-tesla MRI from a 51-year-old woman with primary progressive MS (EDSS score = 6.5) shows that leptomeningeal enhancement is perivascular. T2*-weighted gradient-echo scans showing (a) the vessel (red arrow) as it appears before contrast injection; (b) bright signal around the vessel 5 minutes after contrast injection; (c) an enlarging area of bright signal 20 minutes postcontrast; and (d) partially resolving signal 40 minutes postcontrast, reflecting mixing with the slightly less bright CSF. Other vessels did not show the same finding. EDSS = Expanded Disability Status Scale; MS = multiple sclerosis; T2-FLAIR = T2-weighted, fluid-attenuated inversion recovery.

Figure 2. Leptomeningeal enhancement: Multimodal MRI-histopathology examination

In vivo 3-tesla postcontrast T2-FLAIR MRI. The presence of stable focal leptomeningeal contrast enhancement in the right middle frontal sulcus is depicted in the 7 available postcontrast T2-FLAIR MRI scans (coronal reformations) acquired on different 3-tesla MRI scanners between 2010 and 2013. Leptomeningeal enhancement (white arrows) is located deep within the sulcus, adjacent to the cerebral cortex, and visible on 4 consecutive coronal 1-mm T2-FLAIR sections (inset, representative scans from October 2011). The expected location of in vivo leptomeningeal enhancement is indicated with red arrows in the postmortem MRI and histologic representative sections. Postmortem 7-tesla MRI: Extensive cortical and juxtacortical signal abnormality affects the brain parenchyma adjacent to the sulcus where leptomeningeal enhancement was detected in vivo (CISS sequence, 150-μm isotropic voxel resolution, representative slices). The cortical signal abnormality was not detected on in vivo MRI, although juxtacortical signal abnormality was noted. Myelin staining: In vivo and postmortem MRI-guided histopathology allowed precise localization of the target area. Serial LFB-PAS staining and myelin/proteolipid protein (PLP) immunohistochemistry were performed every 100 µm (10-μm-thick cryosections). Representative sections are well matched to both in vivo and postmortem MRI. CISS = constructive interference in steady state; LFB-PAS = Luxol fast blue/periodic acid–Schiff; PLP = proteolipid protein; T2-FLAIR = T2-weighted, fluid-attenuated inversion recovery.

Figure 3. Histopathologic analysis of in vivo leptomeningeal enhancement

A, C, and E show perivascular inflammatory infiltrates in the leptomeninges (arrows and boxes, with magnification of the boxes in B and D) in the area of in vivo leptomeningeal-compartment enhancement shown in figure 2 (representative 10-μm-thick hematoxylin & eosin sections; scale bars: 200 μm). B, D, and F show details of the predominantly lymphocytic infiltrate, with scattered hemosiderin-laden macrophages (brown cells, dashed arrows). Asterisks indicate meningeal blood vessels. Triple fluorescence for DAPI (nuclei, blue), CD45 (leukocyte common antigen, green), and CD68 (macrophages, purple) markers is shown in G and H (corresponding to the dashed box in E and prepared from the contiguous 10-µm sections; scale bar: 20 μm) and I and J (prepared from the adjacent 10-µm section to that in A; scale bar: 10 µm). The infiltrate consists of mostly clustered leukocytes (green; DAPI⁺ CD45⁺ CD68⁻) as well as scattered macrophages (purple; DAPI⁺ CD45⁺ CD68⁺). DAPI = 4′,6-diamidino-2-phenylindole.