The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease

The pathophysiology of multiple sclerosis is reviewed, with emphasis on the axonal conduction properties underlying the production of symptoms, and th e course of the disease. The major cause of the negative symptoms during re lapses (e.g. paralysis, blindness and numbness) is conduction block, caused largely by demyelination and inflammation, and possibly by defects in syna ptic transmission and putative circulating blocking factors. Recovery from symptoms during remissions is due mainly to the restoration of axonal funct ion, either by remyelination, the resolution of inflammation, or the restor ation of conduction to axons which persist in the demyelinated state. Condu ction in the latter axons shows a number of deficits, particularly with reg ard to the conduction of trains of impulses and these contribute to weaknes s and sensory problems. The mechanisms underlying the sensitivity of sympto ms to changes in body temperature (Uhthoff's phenomenon) are discussed. The origin of 'positive' symptoms, such as tingling sensations, are described, including the generation of ectopic trains and bursts of impulses, ephapti c interactions between axons and/or neurons, the triggering of additional, spurious impulses by the transmission of normal impulses, the mechanosensit ivity of axons underlying movement-induced sensations (e.g. Lhermitte's phe nomenon) and pain. The clinical course of the disease is discussed, togethe r with its relationship to the evolution of lesions as revealed by magnetic resonance imaging and spectroscopy. The earliest detectable event in the d evelopment of most new lesions is a breakdown of the blood-brain barrier in association with inflammation. Inflammation resolves after approximately o ne month, at which time there is an improvement in the symptoms. Demyelinat ion occurs during the inflammatory phase of the lesion. An important mechan ism determining persistent neurological deficit is axonal degeneration, alt hough persistent conduction block arising from the failure of repair mechan isms probably also contributes.