This is the first study to evaluate how lesions and volume in each subregion of the CNS differentially correlates with clinical disability in a small population primarily comprised of treated, mildly disabled RRMS patients. In our study, only upper cervical (C2–3) spinal cord volume significantly correlated with physical disability on the EDSS scale, indicating a relationship between cervical cord atrophy and clinical status. Other MRI measures of CNS lesions and volume did not show significant correlations with the EDSS score or T25FW, including whole brain lesions and volume, cerebral GM volume, cerebral WM volume, spinal cord lesion volume, or volume of the thoracic spinal cord.
As has been observed in prior studies, T2 lesion volume in the brain or spinal cord did not show significant correlations with EDSS score.13,24
. Previous studies found correlations between CNS regional or global atrophy and disability, but did not specifically evaluate the relative importance of the array of measures pertaining to brain vs. cord pathology in RR patients.8,10,14–17,19,28
A study of SP patients found that all MRI compartmental volumes (cerebral GM, cerebral WM, and cervical cord) correlated with the multiple sclerosis functional composite score, but only cervical spinal cord cross-sectional area correlated with EDSS score.15
Full cervical/thoracic or whole spinal cord volumes were not assessed in that study.
The relative clinical importance of cervical spinal cord atrophy may reflect three anatomical considerations. First, the cervical volume may be an accurate correlate of upper motor neuron mediated limb and trunk motor function as it contains all descending corticospinal fibers destined for motor targets in the trunk, arms and legs. Second, the cervical cord is a crossroads for all cerebrospinal descending and spinocerebral ascending pathways. Thus, as compared to other brain and cord locations, damage to the cervical cord disproportionately affects myriad CNS functions. Third, the cervical cord volume also reflects remote volume by its reciprocal connectivity with distant brain and thoracolumbar cord axons and neurons. Thus, Wallerian degeneration in widespread CNS regions both rostral and caudal to the cervical cord will be reflected in spinal cord atrophy.
Of note, we found a lack of correlation between all brain and cord lesion/volume measures and T25FW, a clinical measure of ambulatory function. Other MRI measures have been shown to correlate with measures of ambulatory dysfunction, including cervical spinal cord volume, GM volume, brainstem volume, damage in cerebral normal appearing WM, and GM dentate nucleus T2 hypointensity.18,32–35
One potential explanation for the lack of correlation in our study and differences with previous studies is a restricted range in our sample. Our patients had generally well preserved ambulatory function and overall were mildly disabled. In addition, the sample size was small and thus, may not have been adequately powered to show such correlations between MRI measures and T25FW in the particular study population.
Our study also evaluated the relationship between brain and cord pathology as defined by MRI, including both compartment-specific and region specific atrophy of the brain and cord. We found no significant relationships between brain and cord lesions or volume. This is in line with previous studies that found no correlation between cervical cord and brain MRI metrics (T2 lesion volume, CNS volumes, and DTI measures).36,37
Both our findings and those from previous studies suggest a non-uniform disease process in MS. Thus, the degenerative and inflammatory processes may affect each region independently. Furthermore, there may exist phenotypes or HLA-related genotypes within MS cohorts who have selective brain or cord involvement.38
Additionally, cord volume measures are relatively insensitive to atrophy early in the disease course of MS, which is secondary to the offsetting effects on (expansion of) cord volume caused by edema and inflammation.23
Furthermore, brain volume measures, particularly the contribution from WM, suffer from similar transitory effects that can mask ongoing atrophy.11
Thus, tissue destruction in the brain and cord may occur in parallel, but may not be adequately reflected in global volume measures. These results need to be confirmed in a larger study group across a broader range of clinical disability and MS subtypes.
The strengths of this study include the novel means of volumetric analysis – full cord and brain segmentation and volume analysis at high resolution (3T) MRI. This improves upon our work and that done by others, using validated methods of volumetric analysis.28,39–42
Limitations include small study size and the predominance of mildly disabled RR patients. The study only offers a limited view into those severely impaired by MS, as the study population was treated and relatively high functioning, which limits the generalizability of these study results. Our results should be considered preliminary because of these limitations. The two main findings of this study should be confirmed in larger populations of RRMS, SPMS, and PPMS patients: (1) cervical cord atrophy is the best predictor of clinical disability in MS; (2) a weak relationship exists between MRI-defined spinal cord and brain pathology assessed by overt lesions and atrophy. Furthermore, studying other aspects of structural damage such as cerebral T1 hypointensities, cortical lesions, and diffuse damage assessed by advanced MRI techniques may provide additional insights into the effects and role of brain vs. cord pathology in MS.