Axonal pathology in multiple sclerosis: relationship to neurologic disability

In this review, data is summarized supporting the hypothesis that axonal lo ss is a major pathologic process responsible for irreversible neurologic di sability in patients with multiple sclerosis. Pathologic studies implicate inflammatory demyelination as a principal cause of axonal transection and s ubsequent axonal degeneration. Axonal degeneration caused by chronic demyel ination in the absence of active inflammation may also contribute to progre ssive disability in the later stages of the disease. Studies using magnetic resonance spectroscopy suggest that axonal loss begins at the onset of the disease, and studies using magnetic resonance imaging have documented brai n atrophy in the earliest stages of multiple sclerosis. Brain atrophy incre ases during the relapsing-remitting disease stage without concurrent disabi lity progression. This suggests that compensatory mechanisms maintain neuro logic function, despite progressive brain tissue loss during the early stag es of the disease. Beyond a threshold, however, further axonal loss leads t o continuously progressive neurologic disability. We hypothesize that the r ate and extent of axonal loss during relapsing-remitting multiple sclerosis determines when a patient enters the secondary progressive stage of the di sease. This view of disease pathogenesis has several important implications . First, surrogate markers of axonal loss are needed to monitor the disease process for patient care and for clinical trials. We propose brain parench ymal fraction, a precise measure of whole-brain atrophy, as an attractive c andidate for this purpose. Second, disease-modifying therapy should be used early in multiple sclerosis patients, before extensive axonal loss has occ urred. Third, neuroprotective drugs should be tested in combination with an ti-inflammatory drugs in multiple sclerosis patients. Finally, studies of t he time course of axonal loss, and its mechanisms are critical for effectiv e therapeutic intervention. (C) 1999 Lippincott Williams & Wilkins.