Clinical Paraclinical Correlates

If immunopathological patterns evolve over time, an association between the immuno-pattern and time from onset to biopsy/autopsy would be expected. Preliminary data on a large sample size (n = 75, biopsies with face-to-face clinical assessment), however, have shown no such correlation. Although it is difficult to determine lesion duration prior to symptom onset or biopsy, and if a lesion is clinically symptomatic, most cases underwent biopsy within days to weeks of symptom onset (median 1 month, range 0.1-15 months). Assuming that all active lesions begin with a single pattern, one would expect to find an over-representation of pattern III lesions in cases with the shortest interval between onset and biopsy, which was not found in our material to date. In patients biopsied up to four years after onset, and in autopsy cases dying after more than five years disease duration, a similar distribution of immunopathological patterns was noted. These findings challenge the assertions of Barnett and Prineas and suggest that heterogeneous patterns of myelin destruction can be identified at later MS phases. However, it is necessary to confirm these data, and additional immunopathologically classified biopsy and autopsy cases with sufficient clinical data to ascertain disease duration prior to tissue sampling need to be examined.

The hypothesis of pathogenic heterogeneity in MS may be important for future studies on the etiology and therapy of the disease. The potential to apply these findings to MS patients requires the development of strategies that allow the stratification of MS pathologic subtypes without being dependent on brain biopsies. Immunopattern specific clinical and paraclinical surrogate markers need to be identified. A detailed clinical follow-up of the biopsy cohort (n = 99 patients) has failed to reveal any correlation between time of symptom onset, date of biopsy, and pathological pattern (73). In addition, a striking correlation between therapeutic response to plasma exchange in MS patients with evidence for antibody and complement activation (pattern II pathology, n = 10) on biopsy, compared to no response in pattern I (n = 3) or pattern III (n = 6) cases, has been observed, suggesting this classification scheme may have important pathogenic and treatment implications (74). Neuroimaging studies suggest the sharp border at the active plaque edge with accumulating macrophages typical of active lesions in pattern I and II. MS lesions is highly associated with the presence of ring enhancement on gadolinium (Gd)-MRI and hypointense T2 rims, whereas these imaging features are not found in pattern III lesions (P < 0.001; 54 cases examined) (75). In addition, review of follow-up MR images from pattern III cases (n = 13) has not revealed ring enhancing lesions thus far, further supporting the hypothesis of pathogenic heterogeneity. If lesion heterogeneity reflected a stage-dependent phenomenon, one would expect a ring enhancing lesion in pattern III cases. Additional studies with longer follow-up are needed before concluding that there is pathogenic heterogeneity in immune effector mechanisms involved in MS lesion formation, rather than a single mechanism dominating the formation of all lesions. Since the immunopattern classification scheme developed by Lucchinetti et al. relies on identifying active MS lesions defined by the presence of macrophages containing early myelin degradation products, and as such is largely derived from early biopsy or acute autopsies, it is unknown whether immunopathologic heterogeneity persists in the slowly expanding smoldering rims typically seen in established MS patients with longstanding active disease.

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