As the prevalence and functional consequences of multiple sclerosis (MS)-related cognitive dysfunction became more widely recognized, several definitive trials of disease-modifying medications for relapsing remitting MS and progressive MS incorporated neuropsychological (NP) outcome measures. This chapter lists clinical trials designed to assess the efficacy of medications as symptomatic treatment for cognitive impairment. Several factors complicate the assessment of NP outcomes in MS trials, although none is insurmountable. With the recent development of functional magnetic resonance imaging (fMRI), it has been possible to image MS patients while they perform cognitive tests in the scanner. In general, these fMRI studies have demonstrated that, even when cognitive testing is comparable to healthy controls, MS patients exhibit a larger number of activated regions, an increase in MR signal change and spatial extent in regions also activated by controls, and a decrease in laterality indices.

This chapter summarizes interferon (IFN) biological effects, its possible mechanisms of action, and the key studies in clinically isolated syndromes (CIS), relapsing remitting multiple sclerosis (RRMS), and progressive MS. Measures of specific IFNβ-induced products, such as oligoadenylate synthetase (OAS), β-2 microglobulin, or neopterin, have been useful in pharmacodynamic studies to determine the magnitude and duration of the IFNβ-response, since serum levels of IFNβ are undetectable following injections. A consistent finding of follow-up studies from the three pivotal IFNβ RRMS trials and two CIS trials is that early treatment is beneficial compared with delayed treatment. IFNβ is partially effective in clinical trial groups. Since approval 18 years ago of the first IFNβ product for RRMS, treatment effects of β at all stages of MS have become fairly clear. The development of β for MS has illustrated many of the challenges in developing treatments for MS.

Relapsing remitting multiple sclerosis (RRMS) patients have periodic relapses occurring at variable rates, but generally less than one per year. The factor complicating MS clinical trials is disease heterogeneity, which is one of the hallmarks of MS. The annualized relapse rate or the number of relapses is the most common primary outcome measure for RRMS clinical trials. Relapses are subjective. As symptoms fluctuate, and are influenced by many factors- fever, high ambient temperature, anxiety, intercurrent illness, and sleep deprivation, among others - it is often not clear whether an individual MS patient has experienced a relapse or not. Also, the required duration beyond which symptoms must persist has not been standardized. There are no demonstrably effective therapies for primary neuroprotection, though it appears possible to slow the neurodegerative process in early-stage MS with immunomodulatory or immunosuppressive drugs. Presumably, this form of neuroprotection is secondary to the anti-inflammatory effect.