Walsh & Hoyt: Pathogenesis

Demyelination associated with inflammation and limited remyelination are major pathologic features of MS, but axonal transection is also a prominent and irreversible component. Evidence of alteration of the bloodbrain barrier occurs concomitantly with these pathologic changes. Computed tomographic (CT) scanning shows changes consistent with leakage of intravenously injected iodinated compounds, MR imaging shows similar leakage of intravenously administered paramagnetic substances, and haptoglobin polymers appear in the CSF. In addition, immunocytochemical studies of frozen tissue removed at autopsy from recently active cases of MS show annular patterns of protein-rich leakage, damage to vascular walls within MS plaques associated with intramural deposition of complement on smooth-muscle components, an infiltration of HLA-DRpositive macrophages, and particulate matter consisting of both complement and immunoglobulins within macrophages and astrocytes inside MS plaques. These abnormalities are most apparent within hours to days of the acute attack and may actually precede clinical evidence of neurologic dysfunction; they disappear spontaneously over subsequent weeks to months. Interestingly, similar changes in the permeability of retinal venules also may occur at this time. This alteration of the bloodbrain barrier may be of importance in the pathogenesis of MS, because it may permit the entry of immunocompetent cells, antibody, or other effectors into the CNS, leading to the destruction of myelin. On the other hand, because breakdown of the bloodbrain barrier occurs as part of many different infections and inflammations, it also is possible that it is an epiphenomenon in patients with MS. Nevertheless, the occurrence of bloodbrain barrier breakdown may add to a cascade of events that might otherwise be more benign, self-limited, or both.