Predicting a window of therapeutic opportunity in multiple sclerosis

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Charcot (1877) described patients with multiple sclerosis, some of whose symptoms remitted whereas others progressed, suggesting a connection between clinical features and prognosis. It was soon established that in most cases of multiple sclerosis there are two stages: a relapsing–remitting (attack) phase, followed, in the majority of patients, by disease progression, although a minority are progressive from onset (Muller, 1949). The standard classification of the course is based on this description (Lublin and Reingold, 1996). A contemporary analysis is that relapses represent multifocal inflammatory lesions, whereas the later, progressive phase is mainly driven by neurodegeneration (Hauser and Oksenberg, 2006). Most targets of the autoimmune inflammation in multiple sclerosis are myelin proteins, glycoproteins and, as more recently reported, glycolipids (Kanter et al. , 2006). It is plausible that neurodegeneration may develop through the loss of supporting myelin (Garbern et al. , 2002). Alternatively, inflammation and axonal degeneration may occur in parallel and independently throughout the course. Thus, there is evidence that extensive axon loss occurs during attacks (Trapp et al. , 1999) and the immunopathology may persist, albeit in an altered form, throughout the progressive phase, with chronic blood–brain barrier lesions, widespread cellular infiltrates and probably extension of the spectrum of target antigens. Meningeal lymph node-like structures develop inside the blood–brain barrier during the progressive phase (Magliozzi et al. , 2007). A conspicuous difference between relapsing–remitting and progressive multiple sclerosis is that immunomodulatory therapy, shown increasingly to be effective in the attack phase, has no proven effect on disease progression (Coles et al. , 2006). Against this background, several observational studies have sought to define the relationship, if any, between the pattern of early symptoms and subsequent progression (Confavreux et al. , 2003; Eriksson et al. , 2003). But the issues are unresolved, both from the perspective of predicting prognosis …