Pathologic Heterogeneity Is Stage Dependent vs Patient Dependent

Barnett and Prineas, on the basis of finding extensive oligodendrocyte apoptosis in the absence of inflammation in a MS patient who died nine months after disease onset, and 17 hours after presentation with acute pulmonary edema, suggested that primary oligodendrogliopathy represents the initial lesion in relapsing-remitting disease, preceeding inflammation and active myelin breakdown (71). A combination of lesions, some showing remyelination and others complement activation, was interpreted as evidence of an overlap of pathological features that have been associated with patterns II and III, respectively. The authors proposed that immunopathological heterogeneity resulted from an initial lesion formed from a primary oligodendrocyte insult (resembling pattern III) followed by remyelination, and then an additional attack of active demyelination associated with complement activation (similar to pattern II) (71,72). This sequence of events could explain the coexistence of complement activation, remyelination, and oligodendrocyte apoptosis in this unique case, and challenges the hypothesis of pathogenic heterogeneity within MS patients.

It is important to note that since lymphocyte subsets were not examined, a role for inflammation in these lesions cannot be completely excluded. Other confounding features of this case include treatment with high dose corticosteroids prior to death, which may have dampened the inflammatory response, and the presence of probable hypoxia related to the patient's known perimortem pulmonary edema, which is known to result in an identical pattern of myelin and oligodendrocyte pathology (66).

An alternative view of patient-dependent immunopathological patterns has been advocated by Lucchinetti et al. (53). On the basis of detailed analyses of over 286 immunoclassified cases, no remnants of "pre-existing" pattern II lesions exhibiting fresh activity or overlapping of immunopathological patterns among actively demyelinating areas from a single lesion of a given patient have been noted (70). Although lesion patterns differed between patients, the pattern classification was identical among all active lesions examined from a given patient (70). In addition, all pattern III cases (n = 76) were associated with inflammation, in the setting of active myelin breakdown with no evidence for complement activation.

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