It has been possible to begin to compose a picture of the natural history of axonal loss in MS by the application of putative MR neuroaxonal markers in vivo at all stages of the disease. The insights obtained will be summarized but first it should be emphasized that there are three general limitations that should be recognized when interpreting the existing data. First, none of the putative imaging surrogates provides a precise and direct measure of axonal loss—the potential limitations will be considered for each method, and inherent in the discussion are certain assumptions between the imaging measure and axonal loss that may not always prove to be reliable. Secondly, in order to obtain a complete picture of natural history, very long-term follow-up studies are needed in individual subjects, ideally followed from onset of disease—so far, almost all serial studies have been limited to at most only a few years. Thirdly, many different methodologies have been employed to evaluate the surrogate markers, and comparison between studies is therefore often difficult. It follows that the present understanding of the natural history of neuroaxonal loss is incomplete. Although it is based in part on consistently observed data, it also involves assumptions and extrapolations some of which may not be verified when more definitive data is available. Nevertheless, the considerable information already generated provides a useful basis for describing the natural history of neuroaxonal damage and loss in MS.
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