Axonal Damage and its Significance for the Concept of Neurodegeneration in Multiple Sclerosis

In spite of tremendous scientific effort, the mechanisms underlying multiple sclerosis (MS) still remain to be elucidated. The prevalent pathogenetic concept adheres to the assumption of a strict hierarchical sequence of the triad inflammation, demyelination and axonal damage. However, recent studies have provided evidence that axonal pathology can occur independently of inflammation and demyelination. The present article critically re-evaluates the traditional paradigm of MS pathology. Potential cellular, humoral and metabolic mechanisms of axonal pathology are delineated and the development of isolated axonal damage is assessed. A better understanding of the pathological processes underlying MS is likely to result in an improvement of current therapeutic strategies. These should not only target the inflammatory, but also the neurodegenerative component of the disease.