Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Active demyelination and ongoing neurodegeneration are invariably associated with inflammation, irrespective of the clinical course of the disease. The inflammatory reaction in the CNS in all disease stages is dominated by CD8⁺ T-lymphocytes, B-cells and plasma cells. In active phases of the disease high numbers of CD20⁺ B-cells are seen, while plasma blasts and plasma cells increase with chronicity of the disease. The CD8⁺ T-cells display a phenotype of tissue resident memory cells, which show focally and temporally restricted activation. While new contrast enhancing lesions dominate the pathology of early stages of MS, the chronic active and / or slowly expanding lesions are a characteristic feature of the pathology in the white matter in patients with progressive disease. Serial MRI scans at 7T show that such lesions gradually expand over a time period of more than 5 years. Another characteristic feature of progressive MS is the accumulation of widespread subpial demyelinated lesions in the cerebral and cerebellar cortex and on the surface of the brain stem and spinal cord. Such lesions are similar to slowly expanding lesions in the white matter and, when active, are associated with meningeal inflammation. Thus, pathology suggests that the substrate of disease progression in MS is the slow expansion of pre-existing lesions in the grey and white matter, which is likely to be driven by a compartmentalized inflammatory reaction, mainly located in the meninges and the large perivascular Virchow Robin spaces. This progressive injury gives rise to secondary Wallerian degeneration throughout the brain and spinal cord, followed by atrophy and, when it has passed the threshold of functional compensation, is reflected by slow and uninterrupted clinical disease progression.