History of therapy in multiple sclerosis

Montreal Neurological Institute, Montreal, Quebec, Canada

Although Charcot, in his Lectures on the Diseases of the Nervous System (1877), was able to define the classic clinical-pathologic features of multiple sclerosis (MS), he further stated with regard to therapy that "the time has not yet come when such a subject can be seriously considered." More than 100 years would pass before the era of clinical trials leading to approved therapies for the disease would begin. In the intervening years multiple therapeutic claims were made often in response to a current postulate regarding disease pathogenesis e.g. infection, toxin, ischemic, nutritional (Therapeutic Claims in Multiple Sclerosis – IFMSS, 1982).

The initial “modern” therapeutic trial era of MS has to date been directed at the presumed immune mediated basis of MS. Because of the requirement to have well established disease to be certain of the diagnosis in the pre-MRI era and the toxicity of the agents such as cyclophosphamide, the early trials were largely conducted on patients who were evolving from the initial relapsing-remitting (RR) phase of MS into a secondary progressive (SP) phase of disease, characterized by persistent neurologic deficits. The development of recombinant forms of beta interferon (βIFN), coupled with use of MRI as a surrogate marker, allowed large scale studies of all phases of MS, and confirmed the pioneering observations of Larry Jacobs and colleagues, conducted using natural βIFN. Current insights suggest that βIFN acts via immune-modulation rather than by its initially suspected anti-viral effect. The agent is effective against the initial inflammatory phase (RR phase) of MS with little if any effect on the later irreversible tissue destructive phase (SP phase) of disease.

Glatiramer acetate is a random polymer comprised of 4 amino acids created initially by Michael Sela and colleagues to mimic the effects of myelin basic protein immunization as an inducer of experimental auto-immune encephalomyelitis (EAE), an animal disorder used as a model of immune mediated CNS demyelination. The agent was subsequently shown to have a protective effect in this model. Clinical trials indicate its effect on the early or RR phase of MS, likely as a result of deviation of the immune response from a pro-inflammatory (Th1) toward an anti-inflammatory (Th2) direction. Multiple other antigen specific and cytokine directed therapies have shown efficacy in the EAE model and have entered clinical trial. Some have had unexpected non-neurologic toxicity or actually enhanced disease activity e.g. tumor necrosis factor (TNF) antibody and soluble receptor indicating the dilemma of moving from the bench to the bedside.

Currently there are no approved therapies for the progressive phase of MS. Axonal loss is considered to account for a significant component of the evolving neurologic disability. Only recently have initial therapies aimed at blocking the axonal degeneration that occurs secondary to demyelination and redistribution of sodium channels (eg blocking calcium influx by blocking the Na+/Ca++ exchanger). One hopes that the era of neural-directed therapy will now begin.

Session VIII -- Multiple Sclerosis Seminar
Monday, 28 June 2004, 11:00 am - 1:00 pm

Ninth Annual Meeting of the International Society for the History of the Neurosciences (ISHN)

Montreal, Quebec, Canada