From inflammation to degeneration: the lessons of clinical trials.

About two-third of patients with multiple sclerosis (MS) accumulate severe disabilities before the age of 50. Disability depends mostly on axonal loss even if persistent conduction block also may be a contributing factor. Axonal loss is predominant in the early phase of the disease and is strictly related to the inflammatory activity. In this phase the axonal damage is mostly, if not exclusively, determined by axonal transection inside the lesions, so that reduction of the lesion rate results in a proportional effect of the irreversible tissue damage. With disease evolution, the redundancy of the central nervous system (CNS) starts to be insufficient to compensate the axonal loss resulting from reactivation (or persistence at a low degree) of inflammatory activity inside the lesions, secondary axonal degeneration of axons damaged by previous attacks and (possibly) by a primitive axonal degeneration. In this phase of the disease, most of the irreversible damage does not depend on new lesions; as a consequence, the reduction of disease activity produces only marginal efforts on nervous tissue degeneration. Clinical trials demonstrate that the positive effect of immunomodulatory and anti-inflammatory therapies is maximal in patients with clinically isolated syndromes and it starts to decrease in relapsing-remitting phases and is almost lost in secondary-progressive phases. From the practical point of view, early treatment is mandatory.