The Expanded Disability Status Scale (EDSS) represents the most widely accepted measure of disease progression in multiple sclerosis (MS), and is used in many natural history studies. This chapter discusses natural history of relapsing onset MS, primary progressive MS, changes in natural history and impact on clinical trial design, traditional prognostic factors, and other factors which may influence prognosis such as race, comorbid diseases, and health behaviors. Pharmacoepidemiological studies using real world data derived from clinical practice represent a cost-effective means of evaluating the long-term effectiveness of immunomodulatory drug treatments for MS. Along with evidence from the basic sciences, epidemiological studies can provide insights into potentially novel treatments, as well as the rationale and hypotheses for testing these treatments in clinical trials. For example, vitamin D and estrogen are being evaluated in clinical trials based partly on epidemiological observations. Heterogeneity remains the hallmark of MS.

The atypical characteristics of primary progressive multiple sclerosis (PPMS) have presented problems in the recruitment to and design of therapeutic trials. The problem areas in the implementation of therapeutic trials are: diagnostic criteria, sample size calculations, and choice of outcome measures. Although there is no definitively proven disease-modifying treatment available for PPMS, several randomized controlled trials have now been specifically designed for this group. The clinical trials in PPMS are based on glatiramer acetate and rituximab. The planned clinical trials in PPMS are based on fingolimod (FTY720) and cladribine. The smaller trials in PPMS are based on Interferon beta-1a, Interferon beta-1b, mitoxantrone and riluzole. A retrospective open-label study of intravenous cyclophosphamide and methylprednisolone in progressive MS included 128 patients with PPMS. PPMS may be the ideal model to investigate disease progression and neuronal protection, and is becoming an important focus for treatment trials in these areas.