Neuroprotection in Ms: from Current Therapies to the Design of Future Clinical Studies*

Axonal degeneration and central nervous system (CNS) atrophy are common in patients with multiple sclerosis (MS). Clinical and experimental studies have described many pathophysiologic mechanisms that may be important in the development of MS, including the activity of immune cells, inflammatory mediators, neurotransmitters, and intracellular signaling pathways. Clinical trials have only recently begun to evaluate whether medications that target these pathophysiologic processes can slow the progression of CNS atrophy or improve clinical outcomes in patients with MS. Magnetic resonance imaging studies have found that some immunomodulatory therapies improve functional status and slow the rate of CNS atrophy in patients with MS. Other treatments do not appear to slow the progression of atrophy and may actually exacerbate atrophy when administered at high doses. Clinical trials being planned will soon begin to evaluate the neuroprotective effects of sodium-channel or calcium-channel blockade and of combining several different neuroprotective approaches. Future clinical trials may examine ways to restore CNS function after neurodegeneration, perhaps by manipulating gene expression of neurons or glia or providing growth factors that regulate neuronal survival. (Adv Stud Med. 2004;4(4B):S344-S348) D espite the importance of inflammatory processes in the pathogenesis of multiple sclerosis (MS), clinical trials of immunomodulating agents in MS have generally been disappointing as many of the available agents appear to have little effect on disease progression. Some medications have been shown to improve magnetic resonance imaging (MRI) outcomes on more sensitive clinical rating instruments, such as the Multiple Sclerosis Functional Composite (MSFC) scale, although even these agents have generally been more effective in the early course of the disease. One of the most disturbing features of MS is that the rate at which functional status decreases in patients with progressive disease after an Expanded Disability Status Scale (EDSS) of 4.0 is reached is generally consistent from patient to patient and is largely independent of the preceding course of illness. Although the time that patients spend with relapsingremitting MS (RRMS) varies considerably, most patients exhibit a decline in EDSS score from 4 to 6 over a period of approximately 5 to 6 years, regardless of whether the initial onset of disease was relapsing or progressive and regardless of the time that elapsed between initial diagnosis and the assignment of an EDSS score of 4. This suggests the possibility that the early relapsing and remitting course of the disorder is caused by the exacerbation and resolution of inflammation but that the emergence of progressive disease reflects a process of irreversible neurodegeneration. Neurodegeneration in patients with MS has been described in several recent clinical studies that used MRI techniques to evaluate the progression of CNS atrophy. Some studies have found that treatments that improve the functional status of patients with MS also reduce the progression of atrophy, although this has not been demonstrated with all medications. In a large PROCEEDINGS