An Introduction to Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by the destruction of the myelin sheath surrounding the axons of the central nervous system. The damaged oligodendrocytes which generate myelin cannot be restored. Scarring occurs, which results in an interruption of the salutatory conduction of an action potential down the axon. This slower conduction velocity results in weakness and lack of coordination in the individual suffering from MS (Beas, Connors, & Paradiso, 2001, p. 94). Previously, MS was thought to only involve white matter.

New research however has shed light on the disease, and changes in the central nervous system beyond demyelination may be involved. This paper is a review and discussion of three recent studies in which various MRI techniques were employed to examine changes beyond demyelination in MS patients.

Evanelou, et all. investigated the relationship between axonal losses in normal-appearing areas of the corpus callosum to the lesion volume in corresponding areas of cerebral white matter. The Researchers performed post-mortem brain imaging on eight patients with relapsing-remitting or secondary progressive MS and eight age- and sex-matched control subjects with no neurological conditions.

MR measured three regions of the corpus callosum for axonal density, the estimated number of axons crossing the corpus callosum, and the cross-sectional area. These results were compared to the calculated volume of lesions in the corresponding areas of the cerebral hemispheres. Comparisons of results between MS and control were performed with the Wilcoxon signed ranked test and the one-tailedPearson correlations. Relationships between the axonal and cerebral measures were applied by multiple regression analysis.

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sa significant difference was found between groups only in the total number of axons crossing the corpus callosum in each of the three regions. White matter lesion volumes in each region of the cerebrum correlated wth axonal density and the total number of axons crossing the corresponding region of the corpus callosum. The study concluded that loss of axons in normal-appearing areas of the corpus callosum is explained by Wallerian degeneration, which is caused by the occurrence of lesions in areas of white matter in which the axons traverse (2000).

Brain atrophy detected by MRI has recently been proven to be characteristic of MS. Many researchers believe that atrophy could be related to overall disability status. A study by Ge, et al. attempted to determine the amounts of gray matter vs. white matter to contribute t the total brain tissue volume loss in patients with MS. The results were then correlated with total lesion volume and measures of clinical disability. MRI results for fractional gray and white matter volume were compared between the subjects with relapsing-remitting MS and twenty-five age-matched, healthy control subjects. A clinical disability measure, the Kurtzke Expanded Disability State Scale (EDSS) was administered to the MS patients at the time of the MR, Measures between groups were analyzed with the least-squares regression. The Spearman rank correlation coefficient was applied to determine the relationships between the measurements of the MS patients. Highly significant differences were found between MS and control groups fr fractional white matter volume, but not for gray matter. WrthWithinup measures found a negative correlation between regional gray matter volume and total lesion volume. No correlation was found between fractional brain volume and the EDSS score. The authors concluded that brain atrophy is chiefly caused by the loss of white matter. This loss was attributed to myelinaxonal loss and ghosts. The authors explained that while no volumetric changes in a gray matter
were detected by the measures used, abnormalities may exist at a microscopic level not detected by MRI. The negative correlation between gray matter volume and lesion volumes suggested that “lesion load in white matter affects gray matter, a process of Wallerian degeneration by the upstream effect on neuronal cell bodies Bakshi, Dmochowski, Shaikh, and Jacobs explored a view of MS that implicates global changes including neuronal dysfunction, axonal transection, and brain atrophy. The purpose of the study was to determine whether hypointensity in various gray matter structures detected on T2-weighted MRI is associated with atrophy and the number of white matter lesions in the brains of MS patients, Hypointensity detected in gray matter reflects abnormalities in those structures. One hundred- fourteen patients with relapsing-remitting or secondary progressive MS were gender- and age-matched with 100 healthy control subjects, All subjects were scanned on the same MRI unit using the same protocol. Two observers rated the MRIs to ensure reliability. The degree of hypointensity in gray matter structures of the thalamus, caudate, putamen, and sensorimotor cortex was rated in comparison to a random age- and gender-matched control, The severity of lesions was computed as a percentage of total lesion volume to the entire size of the specific region of the brain where the lesions were found, Brain atrophy was calculated by comparing the enlargement of the ventricular cavities to that of the controls. Multiple linear regression was used to assess the association between gray matter hypointensity, plaques, and atrophy. The results of this study medicate that gray matter hypointensity is most strongly associated with white matter plaques in the frontal lobe and cerebellum aS well as brain atrophy which have been proven indicators of brain tissue damage in MS. Therefore, the authors concluded that hypointensity detected by T2 MRI is related to the severity of MS. The gray matter changes detected by T2 MRI were suggested to be a reflection of hypometabolism, tissue loss, or iron deposition in those structures (2001).

The results of the study by Evangelou et al. support the theory of Wallerian degeneration as discussed in the required text of Neuroscience OT 6000. Wallerian degeneration of axons occurs because axons cannot be sustained when separated from their parent cell bodies. This occurs because the normal flow of materials and nutrients from the soma is interrupted by an MS lesion. The conclusions of the study by Ge et al. expand on this theory. Lesions in white matter (axons) may also affect the gray matter (neuronal cell bodies). The authors hypothesized that Wallerian degeneration may also occur upstream to the soma of the affected axons. The results of the studies reviewed in this paper also suggest that the effects of MS go far beyond what was described by Bear, Connors, and Paradiso. The traditional perspective of MS Includes pathophysiology isolated to the destruction of the myelin sheath by T-cells and macrophages. The results from Bakshi, et al. support a view of MS that involves global changes in the brain, This study found that changes in gray matter structures including the thalamus, caudate, putamen, and sensorimotor cortex were highly correlated with the volume of lesions and overall atrophy detected in the brain (2001). The changes in those gray matter structures were postulated to be a result of iron deposition, which may cause membrane dysfunction and neuronal degeneration. The authors suggested that iron deposition in gray matter structures may play a part in the overall pathophysiology of MS.

The results ofthe studies reviewed have several important implications to clinical practice, The study bby Ge et a. suggested that clinical measurements such as the EDSS are not sensitive to loss of brain tissue. Brain atrophy measurements may be a better way to monitor the disease process in clinical wis (2001). Evangelou etal. suggest that there may be axonal oss in areas of the brain that appear normal. MS may affect more widespread areas and functions than indicated through traditional maging. The results also suggest that clinicians need to consider effects of lesions in immediate and distant areas of the brain, which are connected (2000). Finally, Bakshi et al. found that T2 hypointensity might be a good predictor of disease process and a useful measure in clinical tials. The ‘1eSults of this study also Support the view that MS may be a global degenerative disease with serious implications beyond demyelination (2001). Clinicians may need to consider this expanded view of MS when treating such patients.