Conclusion and Implications for Therapy

When the extensive MR imaging and spectroscopy literature is considered as a whole, it can be concluded that neuro-axonal damage and loss is present from the earliest clinical stages of MS, although frank axonal loss and atrophy is probably mild or minimal in patients with a first clinical episode (CIS). The process of neuroaxonal degeneration involves white matter lesions, NAWM, and gray matter and becomes increasingly prominent with increasing disability and the progressive phase of MS. The two most specific MR methods for detecting neuroaxonal loss are atrophy and decreased NAA. The former has been preferred in clinical trials because more reproducible and sensitive methods are available to detect it. To date, no therapy has been shown to have a robust and consistent effect in slowing the rate of tissue atrophy, although some studies have suggested that there may be a partial delayed effect of beta interferon in relapsing-remitting MS.

Fractional anisotropy measured from diffusion tensor images has potential to provide distinctive information on the structural integrity of white matter pathways. Although other MR markers of diffuse disease are not specific for axonal loss (e.g., MTR, T1, diffusion coefficient), they do provide—along with atrophy—a sensitive measure of a diffuse, progressive underlying process that appears relevant to clinical progression and MTR may reflect myelination.

The generally modest correlation of atrophy and intrinsic NAWM and gray matter abnormalities with lesion load, even in the earliest clinical stages of disease, suggests that these diffuse processes are at least partly independent of focal lesions. They may nevertheless also be partly related in providing a trigger for (Werring et al., 2000) or being a consequence of focal inflammation (the latter, by causing axonal transection [Trapp et al., 1998], will lead to secondary Wallerian degeneration in the NAWM). The potential importance of atrophy, NAWM, and gray matter measures for predicting future disability—although not yet confirmed—is readily apparent. It is therefore recommended that atrophy should be measured in trials aiming to prevent disability at all stages of disease (CIS, relapsing-remitting, primary, and secondary progressive) and where feasible, NAA should also be measured along with other techniques to monitor progressive NAWM and gray matter abnormality (e.g. MTR).

It is nevertheless important to remember that the MR surrogates for neuroaxonal loss and diffuse disease are not yet proven beyond doubt as predicting future disability and its prevention by treatment. Long-term follow-up studies of well characterized cohorts, including those participating in controlled clinical trials, will be needed to clarify the relationship. Meanwhile, definitive trials should continue to measure an appropriate clinical endpoint.

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