Correspondence

Corticosteroids, Optic Neuritis, and Multiple Sclerosis

N Engl J Med 1994; 330:1238-1239April 28, 1994

Article

To the Editor:

The report by Beck et al. (Dec. 9 issue)1 on the effect of corticosteroids on the subsequent development of multiple sclerosis in patients with optic neuritis comes to some stupendous and puzzling conclusions about the natural course of multiple sclerosis.

First, the Optic Neuritis Treatment Trial,2 the source of the authors' data, was designed primarily to test the efficacy of corticosteroids in the treatment of acute optic neuritis. In their more recent trial1 the authors excluded all patients who had multiple sclerosis at entry, since the primary end point of this retrospective study was the development of the disorder. The authors never studied the natural history of multiple sclerosis, a disease clearly different from optic neuritis. It is well known that 30 to 70 percent of patients who have had optic neuritis do not subsequently have multiple sclerosis. Therefore, it is wrong to assume that intravenous methylprednisolone alters the natural history of multiple sclerosis, simply on the basis of the observation that the disease developed in fewer patients given this drug than in those given oral placebo or those given oral prednisone1.

Ironically, the authors did have an opportunity to study the natural history of multiple sclerosis since 65 patients in the original cohort had this disorder, but these patients were excluded. The authors offered no analysis of the patients who had already been given this diagnosis. Because of the variability of disease presentation, this is essential information. Yet, the authors claim that intravenous methylprednisolone convincingly altered the natural history of multiple sclerosis. A recent randomized, double-blind, placebo-controlled trial comparing oral with intravenous methylprednisolone in the treatment of acute relapses of multiple sclerosis showed efficacy of both treatments with no significant differences3.

We also believe that the authors' comparison of their study1 with the recently concluded interferon beta-1b study4 is improper. The latter was a randomized, double-blind, placebo-controlled prospective trial conducted to assess the efficacy of interferon beta-1b in patients with multiple sclerosis that had a relapsing-remitting course, whereas Beck et al. describe a retrospective study of patients with acute optic neuritis in whom multiple sclerosis subsequently developed.

At this time, there is insufficient evidence to suggest that corticosteroids can alter the natural history of multiple sclerosis.

Michael J. Olek, D.O.
Omar A. Khan, M.D.
Medical College of Virginia, Richmond, VA 23298-1510

4 References

1. 1

   Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. N Engl J Med 1993;329:1764-1769
   Full Text | Web of Science | Medline

2. 2

   Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992;326:581-588
   Full Text | Web of Science | Medline

3. 3

   Alam SM, Kyriakides T, Lawden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry 1993;56:1219-1220
   CrossRef | Web of Science | Medline

4. 4

   The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-661
   Web of Science | Medline

To the Editor:

It is unclear from the Methods section of the important report by Beck et al. whether the selection of a two-year follow-up interval for the comparison of therapies was made a priori, before the data were looked at, or not. The point estimate of the rate ratio for the development of multiple sclerosis with regard to therapy was maximal at two years and not nearly as impressive at one or three years (Figure 1 of the article). It is important to know how and when it was decided to focus on the two-year follow-up in this analysis, in order to assess the play of chance more accurately.

Robert G. Hart, M.D.
University of Texas Health Science Center, San Antonio, TX 78284-7883

Author/Editor Response

Dr. Beck replies:

To the Editor: Most of the comments by Olek and Khan are based on their misconception that multiple sclerosis is “a disease clearly different from optic neuritis.” There is ample evidence that in many patients, optic neuritis represents a forme fruste of multiple sclerosis1. Morrissey et al.2 found that 82 percent of 28 patients with optic neuritis and signal abnormalities on magnetic resonance imaging of the brain had clinically definite multiple sclerosis within five years. Thus, a study of patients with optic neuritis, in particular those with signal abnormalities like those present in the group in which we found a beneficial treatment effect, is in essence a study of patients who have had their first clinical manifestation of multiple sclerosis.

Olek and Khan misconstrue our study as retrospective. The assessment of the effect of corticosteroid treatment on the development of multiple sclerosis was a preplanned, secondary objective of the study; all data were collected prospectively. Although it might also have been interesting to assess the course of patients who had multiple sclerosis at study entry, there were too few for a valid comparative analysis of the effect of treatment.

Olek and Khan imply that the study of Alam et al.3 is at variance with ours. However, that study evaluated only neurologic recovery over a 28-day period after an acute exacerbation of multiple sclerosis and did not assess the subsequent neurologic course.

Our conclusions may have appeared “stupendous and puzzling” to Olek and Khan, but they did not appear so to an independent panel convened by the National Eye Institute consisting of five renowned authorities on multiple sclerosis and three eminent biostatisticians. The panel scrutinized our results and approved our manuscript before its submission. Moreover, members of that panel coauthored a recent editorial in Neurology that concluded that the results of our study are probably valid and that contrary to Olek and Khan's view, a comparative trial of intravenous methylprednisolone and interferon beta should be considered4.

In response to Dr. Hart's germane question: it was decided before the study began that the data would be analyzed on completion of two years of follow-up in all patients. We did not expect the benefit of treatment to be permanent; therefore, it is not surprising that the survival curves began converging by the third year of follow-up.

Roy W. Beck, M.D., Ph.D.
Jaeb Center for Health Research, Tampa, FL 33613

for the Optic Neuritis Study Group

4 References

1. 1

   Ebers GC. Optic neuritis and multiple sclerosis. Arch Neurol 1985;42:702-704
   Web of Science | Medline

2. 2

   Morrissey SP, Miller DH, Kendall BE, et al. The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis: a five-year follow-up study. Brain 1993;116:135-146
   CrossRef | Web of Science | Medline

3. 3

   Alam SM, Kyriakides T, Lawden M, Newman PK. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry 1993;56:1219-1220
   CrossRef | Web of Science | Medline

4. 4

   Kupersmith MJ, Kaufman D, Paty DW, et al. Megadose corticosteroids in multiple sclerosis. Neurology 1994;44:1-4
   Web of Science | Medline