Axonal and neuronal injury and loss are of critical importance for permanent clinical disability in multiple sclerosis patients. Axonal injury occurs already early during the disease and accumulates with disease progression. It is not restricted to focal demyelinated lesions in the white matter, but also affects the normal appearing white matter and the grey matter. Experimental studies show that many different immunological mechanisms may lead to axonal and neuronal injury, including antigen-specific destruction by specific T-cells and auto-antibodies as well as injury induced by products of activated macrophages and microglia. They all appear to be relevant for multiple sclerosis pathogensis in different patients and at different stages of the disease. However, in MS lesions a major mechanism of axonal and neuronal damage appears to be related to the action of reactive oxygen and nitrogen species, which may induce neuronal injury through impairment of mitochondrial function and subsequent energy failure. © 2009 Elsevier Inc.
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