This study showed that there was statistically significant cord expansion at the T10 vertebral level in RRMS/CIS versus controls and statistically significant cord atrophy at the C1-C2 and C3 vertebral levels in PPMS/SPMS versus RRMS/CIS, after correction for multiple comparisons. There were non-statistically significant trends toward cord expansion at all other vertebral levels in RRMS/CIS versus controls and trends toward cord atrophy at all other vertebral levels in PPMS/SPMS versus RRMS/CIS. Together, these results suggest that spinal cord atrophy is more prominent in patients with PPMS than relapsing forms of MS. These findings are, in general, in agreement with prior studies showing that patients with progressive subtypes are more prone to developing spinal cord atrophy.2,8,10
There was another interesting and somewhat unexpected finding in our study. Patients with RRMS/CIS showed a trend toward increased spinal cord volume at all vertebral levels in comparison with healthy controls (). Several prior studies have failed to find spinal cord atrophy in patients with RRMS versus healthy controls.12,13,16,26
A longitudinal study of early RRMS was able to detect the development of upper cervical spinal cord atrophy when individual patients were serially scanned; however, the rate of atrophy did not correlate with clinical disability.15
Mann et al16
found no significant difference in cervical spinal cord cross-sectional area in patients with RRMS compared with controls, and a trend toward increased cervical spinal cord cross-sectional areas in this study was interpreted as possibly related to inflammation and edema in the RRMS spinal cords.
The increase in cord volume in patients with RRMS/CIS versus healthy controls may represent cord inflammation and edema that would mask (offset) any destructive changes such as axonal loss, which would otherwise result in atrophy.16
Similar findings have been noted in cerebral white matter. In a longitudinal study of early RRMS, Dalton et al27
used MR imaging to segment cerebral gray and white matter and found a significant decrease in gray but not white matter volume in patients in the first 3 years after their first attack of demyelination. Significantly increased white matter volume in early RRMS was thought to be the result of inflammation/edema. Supporting this mechanism from the opposite perspective is the finding of cerebral “pseudoatrophy” in the first few months immediately following initiation of immune-modifying or immunosuppressive therapies such as interferon β and natalizumab in patients with RRMS.28
This most likely reflects a net loss of inflammatory cells and edema due to therapeutic effects rather than tissue destruction.1,29
While none of our patients were experiencing acute relapses in the 4 weeks before MR imaging, we did not perform postgadolinium imaging or an assessment of the relationship between T2 hyperintense lesions and cord volume at the same vertebral levels. Thus, the precise mechanisms leading to cord expansion in our patients with RRMS/CIS is unclear. Because opposing pathologic factors are likely influencing the degree of spinal cord expansion or contraction, the specificity of these measurements for neuroprotective therapeutic effect may be limited in the early stages of MS. However, we urge caution in generalizing our findings to larger RRMS cohorts because our patients with RRMS were mildly disabled and may not be fully representative.
The general and overall clinical consequences of MS are typically measured by comprehensive scales of disability, such as the EDSS score.20
In the present study, our interest was in level-specific spinal cord damage. Thus, we did not explore relationships between EDSS and local cord atrophy, with the thought that the EDSS receives contributions from a diverse anatomic distribution of damage. The integrity of spinal cord axons can be measured via somatosensory-evoked potentials and other similar neurophysiologic investigations. Due to the high attenuation of fiber tracts within the spinal cord, cord volume loss can produce greater disability compared with equivalent volume loss within the cerebral hemispheres.30,31
Future studies on spinal cord atrophy in MS should test correlations between the degree of atrophy at specific levels and measures of neurophysiologic function and clinical disability that are thought to be related to cord dysfunction at those specific levels.
Statistical analysis in this study showed that many of the observed group differences failed to remain statistically significant after correcting for multiple comparisons. However, many of these differences showed trends toward significance, which may have reached significance with a larger sample size. Thus the study may have been underpowered to detect the full biologic effects at all vertebral levels. In addition, the trends observed in the differences between the groups showed that various spinal regions had consistent trends. The trends observed in our study should serve as a basis for larger studies in the future to confirm and extend our findings.
In this study, image quality did not allow reliable parsing of gray and white matter within the spinal cord, so the relative contribution of volume changes of gray matter versus white matter remains in question. As the spatial resolution and contrast capabilities of MR imaging continue to advance, future studies may allow segmentation and quantification of gray and white matter atrophy within the spinal cord. Advanced MR imaging techniques such as spectroscopy, diffusion tensor imaging, or magnetization transfer imaging could be combined with structural MR imaging to determine the relative contributions of axonal damage, demyelination, and gliosis to atrophy.32
Together these investigations will allow a better understanding of similarities and differences in the pathophysiology of progressive and relapsing forms of MS.