Axonal loss in multiple sclerosis: causes and mechanisms

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the leading cause of non-traumatic neurologic disability in young adults in the United States and Europe. The disease course is variable and starts with reversible episodes of neurologic disability which transforms into continuous and irreversible neurologic decline. It is well established that loss of axons and neurons is the major cause of the progressive neurologic decline that most MS patients endure. Current hypotheses support primary inflammatory demyelination as the underlying cause of axonal loss during earlier stages in MS. The transition to progressive disease course is thought to occur when a threshold of neuronal and axonal loss is reached and the compensatory capacity of the central nervous system is surpassed. Available immunomodulatory therapies are of little benefit to MS after entering this irreversible phase of the disease. Elucidation of mechanisms that are responsible for axonal loss is therefore essential for the development of therapies directed to stop neurologic decline in MS patients. The current chapter reviews existing data on mechanisms of axonal pathology in MS.