Neurodegeneration in multiple sclerosis: defining the problem.

It is increasingly apparent that neurodegeneration in multiple sclerosis (MS) begins earlier in the course of the disease than was previously believed. The loss of axons, which results in permanent deficits, is distributed beyond regions of abnormal-appearing CNS white matter, and a constant background of neuron loss continues to take place while clinical symptoms wax and wane. It is therefore important to precisely define the scope of neurodegeneration so that experimental and clinical approaches to providing neuroprotective therapies can be devised that will halt and reverse neuron damage. Some of the complexities involved in cellular interactions in the normal-appearing and obviously affected CNS are reviewed here as a starting point for the consideration of approaches to neuroprotective strategies.