Making progress on the natural history of multiple sclerosis

Typically, the clinical course of multiple sclerosis is characterized by episodes, from which recovery may occur, and by progression. These phases usually evolve in sequence as part of the natural history. The number and frequency of episodes and the interval between first presentation and the often somewhat blurred transition to disease progression are generally held to be rather unpredictable. By definition, progression is not preceded by episodes in individuals with primary progressive multiple sclerosis. At one time, the essential pathological process in multiple sclerosis was thought to be loss of the myelin sheath that normally surrounds axons in the CNS, as a result of local inflammation, from which followed a cascade of secondary events culminating in development of the multifocal sclerotic lesions from which the disease gets its name. Thus, episodes were considered to be the critical component of the disease, and their reduction presented a natural and sufficient target for treatment.That perspective changed with the rediscovery of axonal pathology as a significant additional component of the disease process and its correlation with the accumulation of disability, especially during the progressive phase. The concept of multiple sclerosis as a focal inflammatory demyelinating disorder took a further step backwards with the recognition that, in this disorder, normal appearing white matter is far from normal. The evidence is both histological and radiological, but the available observations do not resolve the ambiguous relationship between inflammation and neurodegeneration that remains central to understanding mechanisms of tissue injury in multiple sclerosis, and the relative contribution of each to clinical deficits occurring during different phases of the disease. Thus, magnetic resonance spectroscopic studies of whole brain white matter in multiple sclerosis show abnormalities indicating widespread axonal changes in the absence of apparent tissue inflammation (Filippi et al ., 2003). But, while MRI and spectroscopy allow …