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Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis

Nature Reviews Neurology volume 19, pages 461–476 (2023)Cite this article

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Abstract

Growing evidence from cerebrospinal fluid samples and post-mortem brain tissue from individuals with multiple sclerosis (MS) and rodent models indicates that the meninges have a key role in the inflammatory and neurodegenerative mechanisms underlying progressive MS pathology. The subarachnoid space and associated perivascular spaces between the membranes of the meninges are the access points for entry of lymphocytes, monocytes and macrophages into the brain parenchyma, and the main route for diffusion of inflammatory and cytotoxic molecules from the cerebrospinal fluid into the brain tissue. In addition, the meningeal spaces act as an exit route for CNS-derived antigens, immune cells and metabolites. A number of studies have demonstrated an association between chronic meningeal inflammation and a more severe clinical course of MS, suggesting that the build-up of immune cell aggregates in the meninges represents a rational target for therapeutic intervention. Therefore, understanding the precise cell and molecular mechanisms, timing and anatomical features involved in the compartmentalization of inflammation within the meningeal spaces in MS is vital. Here, we present a detailed review and discussion of the cellular, molecular and radiological evidence for a role of meningeal inflammation in MS, alongside the clinical and therapeutic implications.

Key points

  • The meninges are an immunologically active tissue barrier, and they represent an intrathecal immunological niche that compartmentalizes chronic inflammation in multiple sclerosis (MS).

  • Lymphoid neogenesis is an aberrant process observed in the meninges in post-mortem tissue from a substantial proportion (about 40%) of individuals with progressive MS, with diffuse meningeal inflammation being observed in most of these individuals.

  • Increased diffuse or compartmentalized meningeal inflammation is associated with a ‘surface-in’ gradient of cortical cell pathology, including subpial demyelination and significant neuronal loss.

  • Combined high levels of meningeal inflammation and subpial cortical damage correlate with severe and rapid disease progression.

  • Meningeal inflammation represents a potential new therapeutic target to halt disease progression.

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Fig. 1: Cortical demyelination and leptomeningeal inflammation in multiple sclerosis.
Fig. 2: Meningeal lymphoid-like structures in multiple sclerosis and animal models.
Fig. 3: The physiological and pathological events associated with leptomeningeal infiltration in multiple sclerosis.
Fig. 4: Leptomeningeal inflammation and pathological and clinical burden of multiple sclerosis.

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Acknowledgements

The authors thank the UK Multiple Sclerosis Society Tissue Bank at Imperial College London, London, UK.

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Authors and Affiliations

  1. Neurology Section of Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy

    Roberta Magliozzi, Owain W. Howell & Massimiliano Calabrese

  2. Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK

    Roberta Magliozzi & Richard Reynolds

  3. Institute of Life Sciences, Swansea University, Swansea, UK

    Owain W. Howell

  4. Centre for Molecular Neuropathology, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Richard Reynolds

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All the authors wrote the article. R.M., O.W.H. and R.R. researched data and images for the article. R.M., O.W.H., M.C. and R.R. made substantial contributions to discussion of the content and reviewed and edited the manuscript before submission.

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Magliozzi, R., Howell, O.W., Calabrese, M. et al. Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis. Nat Rev Neurol 19, 461–476 (2023). https://doi.org/10.1038/s41582-023-00838-7

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