Multiple Sclerosis

MS is one of the most frequent neurological diseases of early adulthood, affecting as many as 400,000 patients in the United States, 85% of whom are between the ages of 20 and 50 years old (Mayr et al., 2003). Clinically, this disease is most often marked by a relapsing and remitting pattern of neurological dysfunction, frequently leading over time to a secondary progressive disease pattern marked by accumulative loss of neurological function (Noseworthy et al., 2000). The relapsing-remitting phase is characterized by clinical symptoms such as loss of visual acuity, weakness, ataxia, fatigue, and clumsiness that develop over a period of several days, stabilize, and then resolve over the course of several weeks (Noseworthy et al., 2000). At least early in the disease, corticosteroid treatment accelerates recovery from clinical deficit. Frequently, some dysfunction may persist after relapse, and an accumulation of such persistant clinical deficit ultimately results in a progressive impairment termed secondary progressive MS (Noseworthy et al., 2000).

Although clinically characterized by pathological and functional hallmarks such as focally demyelinated lesions and gadolinium enhancement, as detected by magnetic resonance imaging (MRI), the cellular and molecular locus of MS is distinctly heterogeneous (Lucchinetti et al., 2000). Although all lesions contain an inflammatory infiltration of T-cells and macrophages, further analysis suggests that four distinct patterns of pathology are present in active lesions. The first two patterns are marked by well-delineated perivascular demyeli-nation and simultaneous loss of immunoreactivity for all myelin proteins within the lesion, but relative sparing of oligo-dendrocytes and active repopulation of demyelinated lesions with oligodendrocytes during remyelination (Lucchinetti et al., 2000) (Fig. 1). This is consistent with previous reports show

Figure 1 Examples of immune cell infiltration in a mouse model of MS. (A) Evidence of perivascular immune cells near a demyelinated lesion. (B) Macrophage with lipid inclusions associated with a demyeli-nated lesion. (C) Two immune effector cells in direct contact with the myelin sheath of an axon. Immune cell infiltration is strongly associated with Pattern I and Pattern II MS pathology.

Figure 1 Examples of immune cell infiltration in a mouse model of MS. (A) Evidence of perivascular immune cells near a demyelinated lesion. (B) Macrophage with lipid inclusions associated with a demyeli-nated lesion. (C) Two immune effector cells in direct contact with the myelin sheath of an axon. Immune cell infiltration is strongly associated with Pattern I and Pattern II MS pathology.

ing abortive attempts at remyelination in MS lesions (Prineas and Connell, 1979; Prineas et al., 1989) (Fig. 2). The second pattern is unique in that actively degenerating myelin is associated with pronounced immunoglobulin and complement reactivity (Lucchinetti et al., 2000). The third and fourth patterns do not exhibit perivascular localization, and the borders of active lesions are only poorly defined. Oligodendrocytes are not spared and repopulation of lesions is not observed. Finally, the third pattern is uniquely associated with greater loss of myelin-associated glycoprotein immunoreactivity than other myelin proteins (Lucchinetti et al., 2000). This pattern is consistent with the concept of "dying-back oligodendrogliopathy," in which the primary injury is to the oligodendrocyte. The earliest morphological manifestation of this pattern is degeneration of the inner myelin sheath and oligodendroglial loops, the most distal extensions of the oligodendrocyte (Rodriguez, 2003) (Fig. 3). Of importance, heterogeneity is found among patients but not within individuals. All lesions of any given patient are of the same phenotype, suggesting a single pathogenic mechanism within a patient but multiple mechanisms across the population.

The heterogeneity observed in patients with MS is also reflected in animal models of MS. The two best studied models of human MS are immune-mediated encephalo-

myelitis induced by immunization with CNS antigens and viral-induced demyelination. Lesions commonly found in patients with the first and second pattern of MS pathology are similar to those observed in T-cell-mediated and antibody-mediated autoimmune demyelination. Likewise, lesions observed in the third and fourth patterns of human MS are typical of the oligodendrogliopathy and demyelina-tion induced by viral infection (Lucchinetti et al., 2000; Paz Soldan and Rodriguez, 2002; Rodriguez, 1985).

The functional correlate of any of the patterns described previously is generally considered to be loss of axon conduction resulting from demyelination. During the relapsing-remit-ting phase of MS, the regression of symptoms is likely due to resolution of inflammation and remyelination, resulting in a return of axon function. However, as the disease progresses and as each round of repair accumulates demyelination that is not resolved, axonal function deteriorates (Noseworthy et al., 2000) (Fig. 4). This is marked by redistribution of sodium channels along demyelinated axon segments, and eventually by loss of the axon altogether (Rivera-Quinones et al., 1998) (see Chapters 7 and 8). Because axons are the absolute locus of neuronal function and transmission, it is likely that understanding and reversing axon failure and loss will be required for any rational therapeutic program.

Figure 2 (A) Demyelination in the brain of a patient with MS. (B) Evidence of spontaneous remyelination in the brain of a patient with MS. Spontaneous remyelination occurs in Patterns I and II lesions, but fails to occur in Pattern III MS lesions.

Figure 3 Evidence of "dying-back" oligodendrogliopathy. Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage. This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte. The most distal extension of the oligodendrocyte is the inner myelin lamellae. Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell.

Figure 3 Evidence of "dying-back" oligodendrogliopathy. Note the degeneration of the inner myelin sheath, presenting an "inside-out" type of myelin damage. This type of pathology is present in Pattern III MS lesions in which the attack is primarily directed against the oligodendrocyte. The most distal extension of the oligodendrocyte is the inner myelin lamellae. Therefore, injury to the inner sheath with relative preservation of the other myelin lamellae is indicative of primary injury to the myelin-producing cell.

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