Managing MS— Oral vs. IV Steroids?

Source: Barnes D et al. Randomized trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 1997;349:902-906.

This double-blind, placebo-controlled study of oral vs. IV corticosteroids was performed at several London hospitals, treating an undefined relapse in 80 MS patients whose courses were monitored from first entry and at 1, 4, 12, and 24 weeks with the Kurtzke expanded disability status scale (EDSS), Hauser ambulatory index (AI), and an arm function index. The oral regimen was methylprednisolone 48 mg qd for seven days, 24 mg qd for seven days, and 12 mg qd for seven days (total dose, 588 mg). The IV course was 1000 mg qd over 30 minutes for three days. The primary outcome measure was a difference of one or more EDSS grades at four weeks.

No significant differences were found between the oral or IV groups at any stage in the study by any clinical measures. The mean difference in EDSS at four weeks was a minor 0.07 grades more in those on oral steroids (95% confidence interval -0.046 to 0.60). The most optimistic benefit for IV therapy was less than half a grade improvement on EDSS over oral treatment. The investigators concluded that the IV regimen used did not show any clear advantage over oral therapy.


MS is one of the most common causes of neurologic disability in young adults, and the management of acute relapses can consume significant medical resources. Many questions have been raised about the most optimal treatment intervention in acute MS, with some therapeutic nihilists suggesting from old literature that steroids may not alter the ultimate disability outcome in MS, or, as this study suggests, that IV steroids are no better than oral treatment. Clearly, these are important questions that require clear answers.

The inability to document a benefit of IV steroids over oral in this report, however, may largely be a function of inadequate study design. Indeed, as Barkhof and Polman note in their commentary (Barkhof F, Polman C. Lancet 1997;349:893-894), statistical errors resulting from too small a sample size and insufficient power of the study design by Barnes and colleagues may have led to the wrong conclusion.

We note several additional problems of study design that severely limit the interpretation of this study. For example, an extremely heterogeneous population of patients was included ranging from EDSS scores of 1.5-9.0 (i.e., fully ambulatory to quadraparetic). Patients had to have a relapse of "sufficient severity to justify steroid treatment," yet this critical inclusion criterion is a subjective decision of several investigators at several test sites. A better way to have defined a clinically definite relapse would require the investigators to document an objective increase in the EDSS (e.g., ³ 1). This standard definition of an attack that is used in most MS clinical studies would have required that a relapsing population of patients be followed every month to maintain a baseline "pre-attack" EDSS.

Another flaw in the study design is that patients were allowed to have had an attack any time within the previous four weeks, probably much too broad a treatment window when inflammation and injury in the central nervous system might be optimally managed in the first week to limit damage and speed recovery. Treating one month after an attack, when the cycle of inflammation has done its damage and is already resolving, might be closing the barn door after the horse has escaped.

Given that gadolinium-enhanced brain MRIs have been established as an objective and quantifiable measure of disease activity in MS, it is disappointing that serial brain MRIs were not included in this study as an index of clinical response. This would, of course, greatly increase the cost of what began as a rather limited, economical study, which, consequently, may not have reliably answered the questions it set out to address.

Perhaps the conclusions of a well-conducted study, the Optic Neuritis Treatment Trial ([ONTT]; Beck RW, et al. N Engl J Med 1992;326:581-588; Beck RW. Arch Ophthalmol 1995;113:136-137; Cleary PA, et al. J Neuro Ophthalmol 1997;17:18-28), should be heeded in this case. To this date in the ONTT, a better clinical outcome has been maintained in the IV steroid treated group compared to the oral steroid and placebo groups after many years of close follow-up. Barnes and colleagues’ findings need to be confirmed in a better designed study before oral steroids can be generally advocated for acute severe relapses in MS. —ba