23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS)
12th Annual Conference of Rehabilitation in MS (RIMS)

11.10.2007 - 14.10.2007
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Home - 14.10.2007 - Charcot Award Lecture and presentation of awards

Charcot Award Lecture and presentation of awards

Sunday, October 14, 2007, 10:30 - 11:15

A peculiar lesion in the cord with atrophy - is multiple sclerosis an inflammatory or neurodegenerative disease?

D.A.S. Compston (Cambridge, GB)

In 1838, Robert Carswell described 'two cases of a remarkable lesion of the spinal cord accompanied with atrophy': 169 years later, the nature of atrophy and its contribution to the clinical course of multiple sclerosis remain to be fully understood. The use of Campath-1H (alemtuzumab) first dissociated effective suppression of inflammation from on-going axon degeneration in the central nervous system. An extensive neuropathology and imaging-based literature detailing the extent and timing of axonal injury leaves unanswered questions on the mechanisms of axonal injury, their clinical phenotype, relationship to focal or diffuse brain inflammation and options for treatment or prevention. Lymphocyte infiltration occurs early in multiple sclerosis: inflammatory mediators per se interfere reversibly with conduction in structurally intact myelinated fibres; migrating T cells also promote focal brain inflammation through microglial activation leading to demyelination and acute axonal injury; axonal loss accumulates with diffuse microglial activation in normal appearing white matter; and failure of remyelination accentuates this attrition through loss of trophic support normally provided by cells of the oligodendrocyte lineage. Cumulative axonal injury is expressed as clinical progression and disability. The evidence gathered from genetic and epidemiological studies, neuropathology and both in vitro and in vivo experimental observations is for a complex inter-dependence of disease mechanisms. At any one time, the amount of tissue injury reflects the interplay of active inflammation and the evolving vulnerability of intact axons. And although the absolute amount of inflammation may reduce with time, its impact is not altogether reduced given the increasing susceptibility of injured axons to any residual inflammatory insult. It follows that there is a need to identify the pivotal point in the pathogenesis of multiple sclerosis at which intervention will most effectively inhibit the cascade of all the events expressed as progression and disability. For all the fertile ideas based on the many research disciplines applied to this problem, the only secure way rigorously to test the best emerging hypothesis is through a clinical trial. Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen present on all lymphocytes achieving profound and prolonged circulating lymphopaenia. As open-label studies and the final 3 year analyses of CAMMS223 will show, alemtuzumab (given once or as annual pulses) is highly effective at reducing relapse rate and stabilizing or even improving disability in multiple sclerosis over a time-course of several years. Nevertheless, therapy has its complications of which the most unexpected is reactive autoimmunity, affecting other organs, during the period of lymphocyte reconstitution due to perturbations of lymphocyte apoptosis. But the evidence that effective treatment of early active multiple sclerosis stabilizes all aspects of the clinical course whereas its use in the secondary progressive phase does not, provides both an explanation and a practical solution to the 'remarkable lesion(s) of the (brain and) spinal cord accompanied with atrophy'.