Based on observations from MR imaging studies, the natural history of the MS lesion appears to be progression from an acute enhancing lesion, corresponding to the early inflammatory stage, with evolution to a chronic T2 hyperintense lesion, which is the non-specific 'footprint' of the prior event. In addition to accumulation of these relatively non-specific lesions, we find in longitudinal evaluations that patients with only mild to modest disability are already developing significant cerebral atrophy. Atrophy, particularly that resulting from volume loss around the third ventricle, appears to be predicted by the presence of prior temporally and anatomically distant enhancing lesions. One can speculate that the initial enhancing-inflammatory lesion events in the brain, place into motion, at an early stage, the processes that ultimately lead to cerebral atrophy, and these processes may include early axonal injury.