Neurodegeneration in multiple sclerosis, relationship to neurological disability

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, Most MS patients follow a relapsing-remitting course (RR-MS) for 8 to 15 years that transforms into a secondary progressive disease course (SP-MS). In this review, we discuss current data that describe MS as a neurodegenerative disease in which axonal loss is the major cause of irreversible neurological disability in MS patients. Neurological deficits in MS patients have two pathogeneses: acute inflammatory demyelination and axonal degeneration. Disability caused by inflammatory demyelination clinically dominates the early stages of RR-MS and is reversible. Axonal transection occurs at sites of inflammation and begins at disease onset but is clinically silent in RR-MS because the CNS compensates for neuronal loss. Once a threshold of axon loss is exceeded, MS patients enter an irreversible secondary progressive stage. In SP-MS, axonal degeneration is caused by chronic demyelination and may be irreversibly progressive. This view of MS provides a conceptional framework that explains conversion of RR-MS to SP-MS and provides a rationale for early aggressive anti-inflammatory and neuroprotective therapies.