These observations suggest that there are three basic pathologic processes in MS. The hallmark of acute or relapsing MS is the focal inflammatory demyelinated white matter lesion, whereas the hallmark of chronic progressive MS additionally includes diffuse "NAWM" damage and cortical demyelination. These three pathological processes occur in parallel, as well as independent from one another, as supported by the lack of correlation between plaque load in the white matter and the extent and character of cortical demyelination or NAWM injury. These pathological observations appear consistent with MRI studies, which suggest a dissociation between white matter lesion load and diffuse global pathology in MS patients.
The substrate of disability in MS likely varies in relation to the phase of the disease. Regardless of the course or phase of the disease however, neurodegeneration in MS appears to occur on a background of inflammation. Early axonal loss within the MS lesion contributes to relapse-related disability. This injury correlates with the degree of inflammation in the lesion. Late axonal loss subsequently occurs distal to the lesion, as a consequence of Wallerian degeneration. This secondary tract degeneration may contribute to the gradual slow progression seen in most MS patients. The presence of global brain injury, involving the cortex and "NAWM", occurring diffusely and independent of focal white matter pathology may also contribute to the gradual progression of disability in MS.
Focal new white matter lesions are associated with blood-brain barrier damage, inflammation, and acute axonal injury both in the lesion, as well as distal to the lesion site due to Wallerian degeneration. This type of injury is likely to be limited by immunomodulatory and immunosuppressant drugs. However, diffuse global brain injury is associated with a compartmentalized inflammatory response that occurs typically behind an intact blood-brain barrier in the absence of ongoing focal white matter demyelination. Brain inflammation in slowly progressive MS is typically not associated with blood-brain barrier damage. There is no expression of blood-brain barrier disturbance markers on endothelial cells, and MRI studies typically demonstrate an absence of Gd-enhancing lesions in PPMS or non-relapsing SPMS (136). The limited benefit of anti-inflammatory or immunomodulatory therapy in the chronic, slowly progressive phase of MS may in part be explained by the compartmentalization of this inflammatory reaction in the CNS.
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