Abstract

Several experimental and clinical observations have suggested the presence of elevated inflammation, diffuse or organized in lymphoid structures that resemble secondary lymphoid organs, tertiary lymphoid structures (TLS), in the leptomeninges of either experimental animal model or post-mortem multiple sclerosis (MS) central nervous system (CNS), both in the brain and in the spinal cord. This feature, named lymphoid neogenesis, has been suggested to have a relevant role in maintaining intrathecal immune response in MS, as well as previosly shown in other chronic inflammatory diseases.

MS meningeal inflammation, particularly enriched in B cells and compartmentalized within cerebral sulci, is specifically linked to elevated demyelination and damage of the adjacent subpial cortical grey matter. In particular, elevated meningeal inflammationis associated with substantial “surface-in” gradient of cortical neuronal loss and microglia activation highest in the outer cortical layers, close to the cerebrospinal fluid (CSF)/pia boundary, compared to the inner ones.

The strict correlation between meningeal molecular profiling and paired CSF protein one in post-mortem MS cases with elevated cortical lesion load and aggressive disease course has suggested that meningeal infiltrates may represent one of the main intrathecal sources of inflammatory and cytotoxic factors that released in the CSF might orchestrate and/or exacerbate chronic local inflammation and following cortical pathology.

Similar intrathecal inflammatory pattern detected in naïve MS patients was able to predict 89% of the variance in cortical lesion volume and number at time of diagnosis and to distinguish patients at high risk of disease activity after 4 years follow-up.

Abstract

Background/Purpose: Inflammation in the meninges is increasingly recognized as a critical component of the underlying pathophysiology of multiple sclerosis (MS). Histopathologic data suggests direct links between meningeal inflammation and both local and distant cortical demyelination and axonal loss. Neuroimaging studies of leptomeningeal enhancement (LME), a possible surrogate of meningeal inflammation, show a relationship between LME and cortical atrophy, although findings relating LME to cortical lesions (CLs) have been more inconsistent. In this study, we aimed to evaluate the interrelationship between LME, CLs, and more distant neuronal atrophy through evaluation of retinal thickness by optical coherence tomography (OCT).

Methods: Forty participants with MS underwent whole brain 7T imaging on a Philips Achieva scanner with a volume transmit/32 channel receive head coil and optical coherence tomography on a Heidelberg Engineering Spectralis spectral domain OCT scanner at baseline, along with annual follow up OCT images. 7T scans involved pre- and post-contrast acquisition of magnetization prepared 2 rapid acquisition gradient echo (MP2RAGE) sequences acquired at 0.7 mm x 0.688 mm x 0.68 mm resolution and a magnetization prepared fluid attenuated inversion recovery (MPFLAIR) image at 0.7mm³ isotropic resolution. MRI images were reviewed for LME and CLs and processed for segmented volumes. OCT images underwent segmentation for individual retinal layers. MRI and OCT data were evaluated using correlation testing and mixed models regression, adjusted for age, sex, treatment status, and optic neuritis history.

Results: The cohort consisted of 26 (65%) females and were mostly of the relapsing-remitting phenotype (30/40 (75%). Thirty-two (80%) subjects had at least one focus of LME and all had CLs on 7T MRI. Baseline ganglion cell/inner plexiform (GCIP) layer and average macular thickness (AMT) correlated with normalized CL volume (r = -0.45, p = 0.006 and r = -0.34, p = 0.049 respectively). Macular RNFL (mRNFL) and GCIP thickness and AMT were -4.60 (-7.85, -1.35) μm, -8.12 (-14.16, -2.08) μm, and 15.073 (-28.61, -1.54) μm thinner, respectively, if LME was present (p = 0.006, 0.009, and 0.030, respectively). In subjects in whom spread/fill-sulcal pattern LME was present at baseline, mRNFL thickness declined -0.84 (-1.61, -0.07) μm/year faster (p = 0.033) and OPL thickness declined -1.23 (-2.33, -0.13) μm/year faster (p = 0.029).

Conclusion: This study provides support for a relationship between MRI findings of cortical pathology and LME and thinning of retinal layers as measured by OCT. These associations suggest meningeal inflammation may be a common link resulting in widespread demyelination, neuronal loss, and axonal degeneration throughout the CNS and the retina.

Background

We recently showed that 7T MRI leptomeningeal enhancement (LME) is common in relapsing-remitting multiple sclerosis (RRMS) and is related to gray matter (cortical/thalamic) and white matter (WMLs) lesions.

Objectives

To investigate the dynamics of LME longitudinal change and relationship to subsequent lesion accumulation using 7T MRI.

Methods

25 RRMS subjects [age 44.5±11.2 years (mean±SD), 68% women, Expanded Disability Status Scale (EDSS) 2.0±1.5, 92% on disease-modifying therapy-DMT] and 12 healthy controls (HC) underwent brain 3D MP2RAGE and FLAIR 7T MRI with 0.7 mm³ voxels at baseline and ~1 year. Gadolinium-enhanced 3D-FLAIR was evaluated for LME. WMLs, cortical lesions (CLs) and thalamic lesions (TLs) were expert-quantified. Wilcoxon rank-sum, two-sample t-tests and Spearman’s correlations were investigated.

Results

LME was found in 17/25 (68%) RRMS subjects at baseline and 18/25 (72%) at follow-up vs. a single stable focus in 1/12 HC (8.3%). In the RRMS group, 42 LME foci [mean 2.5±1.1 (range 1-5) per LME+ subject] were identified at baseline versus 48 foci [2.7±1.2 (1-5)] at follow-up. LME foci number at follow-up was unchanged in 18 (72%) RRMS subjects, increased in 6 (24%), decreased in 1 (4%). All 6 subjects with increased LME foci were on treatment [glatiramer acetate, interferon-β (2), rituximab, ocrelizumab, fingolimod]. The subject with LME resolution was treated with ocrelizumab. LME+ subjects had an on-study increase in volume of WMLs (baseline 11.0±14.4 vs. follow-up 12.6±16.3 ml, p<0.001), CLs (0.85±1.2 vs. 1.0±1.4 ml, p=0.002) and TLs (0.103±0.093 vs. 0.117±0.099 ml, p=0.005), whereas LME- subjects had an increase only in WML volume (2.7±2.3 vs. 3.3±2.6 ml, p=0.023). Baseline LME foci number correlated with 1-year change in CL (r=0.36, p=0.078) and WML (r=0.50, p=0.010) volumes. Minimal EDSS change over 1 year was noted. We used these data as the basis for a sample size calculation for a hypothetical trial of a putative therapy that would reduce the rate of MRI lesion accrual by 80% over 1 year. For a single-arm study with 1-year run-in on standard therapy and 1 year on new treatment to achieve 80% power, sample sizes of n=46, n=56 and n=79 were calculated for CL volume, TL volume and LME foci number, respectively.

Conclusions

The evolution of cerebral LME may be a dynamic process in the short term in RRMS, providing a monitoring tool, with about one quarter of patients showing new foci at one year. LME may pose a risk for the subsequent development of new lesions in widespread brain regions, implicating meningeal involvement as a marker or mediator of increased disease severity.