Multiple Sclerosis

Clinical descriptions have often failed to point out that the predilection for myelin damage in MS is only relative or have left unmentioned the development of axonal damage and loss even though this has been a consistent theme in most careful pathological descriptions (Charcot, 1868; Dawson, 1916; Ganter et al., 1999; Bjartmar et al., 2000; Evangelou et al., 2000; Lovas et al., 2000; Lassmann, 2003). Despite the fact that axonal changes in MS have been documented for more than a century, the substantial extent of axonal damage and its contribution to functional disability have only been emphasised in recent years (Davie et al., 1995; Lossef et al., 1996; Wujek et al., 2002).

Pathological studies validate the existence of axonal damage and build on the significance of axonal pathology in MS by revealing not only that axonal damage is an early feature of the disease, but that axonal loss is substantial (Ganter et al., 1999; Lovas et al., 2000; DeLuca et al., 2004). Through the use of ß-APP immunohistochemistry, it has been demonstrated that the bulk of acute axonal injury occurs during early lesion formation and is most pronounced in actively demyeli-nating regions of both active and chronic active plaques (Ferguson et al., 1997; Kornek et al., 2000; Kuhlmann 2002). Although it is not known to what extent such axonal damage is reversible, there is evidence that some acutely injured axons become transected resulting in axonal degeneration distal to the site of injury (Trapp et al., 1998). Recent postmortem studies confirm such axonal degeneration by quantifying the amount of axonal loss in normal-appearing white matter (NAWM). In one study examining the distribution and extent of axonal loss of the functionally important long tracts (i.e., the corticospinal and sensory tracts), it was observed that axonal loss in MS was widespread, and its extent was tract-specific (Table 1) (DeLuca et al., 2004a). In the corticospinal tracts, axonal loss occurred throughout the length of the spinal cord, with maximal axonal loss in the NAWM of approximately 41%. The sensory tracts, in contrast, only showed a reduction in total axon number in the upper regions of the spinal cord, with a maximal axonal loss of approximately 24%. In both tracts, the nerve fiber loss appeared to be size selective, in that only fibers of small diameter (i.e., <3 mm2) were affected, with large fibers remaining relatively preserved (Fig. 2, top right). The axonal loss observed in these tracts did not correlate with duration of disease, validating the idea that axonal loss begins at an early stage of the disease, at least in some patients.

Although axonal damage and loss may be an early feature of MS pathology, most patients acquire irreversible functional disability only after they have entered the progressive

Figure 2 Palmgren-stained transverse sections of corticospinal tract axons in the spinal cord in a control case, a multiple sclerosis case, a case of hereditary spastic paraplegia, and amyotrophic lateral sclerosis (x 400). There is a reduction in the density of axonal fibres in the corticospinal tract in each condition.

Figure 2 Palmgren-stained transverse sections of corticospinal tract axons in the spinal cord in a control case, a multiple sclerosis case, a case of hereditary spastic paraplegia, and amyotrophic lateral sclerosis (x 400). There is a reduction in the density of axonal fibres in the corticospinal tract in each condition.

phase of the disease. Pathological studies examining the extent of axonal loss in secondary progressive MS (SP-MS) have reported reductions in axonal density of approximately 57% to 61% in spinal cord lesions. (Bjartmar et al., 2000; Lovas et al., 2000). In a prospective postmortem analysis, axonal loss in both lesions and NAWM was found to be significantly correlated with a decrease in ^-acetyl aspartate (NAA) as measured by high-performance liquid chromatog-raphy. Therefore, the observations that (1) axonal loss is significant in SP-MS, (2) axonal loss correlates with reductions in NAA in postmortem tissue, (3) magnetic resonance spectroscopy (MRS) measures of NAA in vivo decrease in MS brains over time, and (4) MRS NAA reduction correlates with permanent neurological disability all support the claim that axonal loss in excess of a certain threshold contributes to the acquisition of permanent neurological disability (Bjartmar et al., 2000). Experimental evidence relating the loss of axons to clinical disability in a chronic relapsing-remitting mouse model of MS (EAE) directly supports the hypothesis that cumulative axonal loss determines disability in patients with MS (Wujek et al., 2002).

There is no doubt that pathological studies have provided valuable insight into the distribution and extent of axonal loss in MS; however, they have not been overwhelmingly successful at directly relating changes in axonal populations to functional disability. Studies performed using autopsy material often lack detailed retrospective clinical information, making it difficult to relate pathological findings to various clinical parameters, such as the Expanded Disability Status Scale. In addition, autopsy material is necessarily biased toward including patients with increased disability and longer duration of disease than might be ideal in understanding the dynamics of axonal loss. Although there is evidence that patients with short duration of disease have extensive axonal loss, it must be acknowledged that patients with disease of short duration coming to autopsy will have been selected for more aggressive disease. These limitations of human autopsy material in studying the clinical effects of axonal loss underline the importance of using surrogates for this feature in living human patients and animal models of MS described elsewhere in this chapter.

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