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Finally, emerging clinical observations such as progression independent of relapse activity and silent progression, now thought to take hold very early in the course, together argue that an underlying cytodegenerative process, likely targeting the myelinating unit, may in fact represent the most proximal step in a complex pathophysiological cascade exacerbated by an autoimmune inflammatory overlay

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The presence of funnel plot asymmetry also suggests potential publication bias, which warrants further scrutiny