May 13, 2003
What management strategy would you suggest for a patient with secondary progressive multiple sclerosis (SPMS) with clinical relapses and gadolinium-enhanced brainstem and cerebellar lesions on MRI? The clinical deficits are mild -- with Kurtzke Expanded Disability Status Scale (EDSS) of 2 and cardiomyopathy with good left ventricular function. She is on interferon beta-1a, 44 micrograms 3 times a week.
Dr. Sharfuddin, United Kingdom
from Mark S. Freedman, MD, 05/13/2003
The diagnosis of SPMS in this patient might be a bit of a problem, as patients with this form of multiple sclerosis (MS) usually do not present with "mild" deficits. Most SPMS patients would, by definition, have progressed, usually in motor/cerebellar functions, to an EDSS of 3.5 or greater -- the minimum inclusion criterion for all SPMS studies.
More likely, this patient has relapsing remitting multiple sclerosis but is not experiencing complete recovery from relapses. Hence it appears that she is "progressing." It is not easy at times to discern "progression" from the accumulated deficits of relapses, especially early on.
Patients do not respond to interferons for many reasons. If the patient has been treated with an interferon for at least 6 months and continues to suffer relapses and multiple enhancing lesions, then it would appear that she is not responding well. She could be a poor responder or a poor healer. She also might have developed neutralizing antibodies to interferon (these can be measured). Finally, she might have a poor prognosis with accumulated disease that presents a larger burden than the routine disease-modifying drugs can handle.
So, in escalating beyond the disease-modifying drugs, one would consider mitoxantrone for this patient. Because of the patient's cardiac condition and the cardiac toxicities possible with this agent, however, its use would likely be contraindicated, but a cardiologist's opinion should be sought before therapy with mitoxantrone is ruled out.
The alternative would be to use another immunosuppressive regimen. Before the availability of mitoxantrone, we used the Harvard regimen with great success. The regimen consists of 1 g of intravenous methylprednisolone daily for 5 days; on day 4 the first dose of cyclophosphamide is added, at 800 mg/m2. For the first year, the regimen of 1 g methylprednisolone together with cyclophosphamide is given every 4 weeks, with the cyclophosphamide dose adjusted to produce a white blood cell count nadir of ~1.5 x 109/L. It is rare to increase the cyclophosphamide dose above 1400 mg/m2. In the second year this regimen is administered every 6 weeks, and then every 8 weeks the third year. By the end of the third year, maximal doses of cyclophosphamide will have been reached. This regimen is detailed in published reports.
Mark Freedman, MD, Professor of Neurology, University of Ottawa, Canada, and Director, Multiple Sclerosis Clinic, Ottawa Hospital, Canada.Medscape Neurology & Neurosurgery 5(1), 2003.
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