More MS news articles for January 2001

Interferon Beta-1a during a First Demyelinating Event


The New England Journal of Medicine
January 18, 2001
Vol. 344, No. 3

To the Editor:

Jacobs et al. (Sept. 28 issue) (1) suggest that interferon beta-1a therapy for some patients with a first clinically isolated syndrome of multiple sclerosis may delay the onset of clinically definite multiple sclerosis. The diagnosis of multiple sclerosis has long been based on dissemination in both space and time. If this approach still holds, can a valid assessment of a potential disorder be made before the appearance of the symptoms that define it? I find this study troubling for several reasons.

Optic neuritis is easy to identify, but no criteria are given for "incomplete transverse myelitis." Is it paraparesis, numbness of one arm, or gait ataxia? The term "brain-stem syndrome" is also vague: is this diplopia, facial weakness, or dysphagia? The criteria for findings on magnetic resonance imaging (MRI) are not helpful, since many conditions mimic multiple sclerosis on MRI. (2,3) Unfortunately, a radiologist's interpretation of the MRI scan is often the exclusive basis for the diagnosis of multiple sclerosis. In a previous study, this resulted in a 35 percent incidence of erroneous diagnoses, leading to interferon therapy for patients with disseminated encephalomyelitis and chronic fatigue syndrome. (4)

The study by Jacobs et al. did not address the clinical import of a second bout of multiple sclerosis. In my more than 40 years of experience, the majority of patients with multiple sclerosis had benign disease, even after many years. In only a handful of patients was the second episode devastating or did it fail to respond to corticosteroid therapy. O'Riordan et al. (5) noted that after 10 years, three fourths of patients with fewer than 10 lesions on magnetic resonance imaging at study entry had benign disease (score on the Expanded Disability Status Scale, less than or equal to 3). They waited six months after the clinically isolated syndrome in order to rule out disseminated encephalomyelitis, whereas Jacobs et al. chose to wait only one month. The lack of data on functional status and the length of time to clinically definite multiple sclerosis in the study by Jacobs et al. make its clinical applicability doubtful.

The lack of correlation between the number, size, and location of areas of increased signal intensity on T2-weighted MRI and the patients' clinical status militates against the validity of the popular concept of burden of disease. Its clinical significance may be similar to that of the optic atrophy and delayed visual evoked responses of some patients with multiple sclerosis who have perfectly normal vision.

Follow-up studies of clinically isolated syndromes of multiple sclerosis suggest that about half the patients have progression to clinically definite multiple sclerosis. (4) It would seem more prudent to delay treatment with disease-modifying drugs until the familiar criteria of dissemination in time and space are fulfilled.

Charles M. Poser, M.D.
Harvard Medical School
Boston, MA 02115


1. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898-904.

2. Triulzi F, Scotti G. Differential diagnosis of multiple sclerosis: contribution of magnetic resonance techniques. J Neurol Neurosurg Psychiatry 1998;64:Suppl 1:S6-S14.

3. Poser CM. An atlas of multiple sclerosis. Carnsworth, United Kingdom: Parthenon Publishing, 1998:104-22.

4. Misdiagnosis of multiple sclerosis and beta-interferon. Lancet 1997;349:1916.

5. O'Riordan JI, Thompson AJ, Kingsley DP, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS: a 10-year follow-up. Brain 1998;121:495-503.

To the Editor:

The article by Jacobs et al. suggests that the early treatment of a first demyelinating episode with intramuscular interferon beta-1a, when the episode is accompanied by at least two clinically silent lesions on MRI scanning, may be beneficial. This may have important implications, given the expense of the treatment and the current lack of data on the optimal duration of treatment. Before such a policy is applied as part of routine neurologic practice, all available evidence relating to the natural history of isolated demyelinating episodes needs careful review.

The placebo group in the study by Jacobs et al. may not be entirely representative of the natural history of multiple sclerosis. Jacobs et al. quote the findings of the Optic Neuritis Treatment Trial, (1) but in that study the risk of development of clinically definite multiple sclerosis after three years among patients with isolated optic neuritis and three or more clinically silent lesions on MRI was only 38 percent. This figure is very close to the 35 percent probability of progression to clinically definite multiple sclerosis in the group treated with interferon beta-1a in the present study but below that in the placebo group, suggesting that the placebo group had more aggressive disease than is usually seen in clinical practice. Furthermore, the dropout rate in both groups was about 15 percent, and this may have influenced the interpretation of the results. I believe that this study was prematurely terminated. There is no evidence that the treatment effect was becoming more pronounced with the passage of time.

Thomas F.G. Esmonde, M.D.
Royal Victoria Hospital
Belfast BT12 6BA, Northern Ireland


1. The Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis: experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:1404-13.

The authors reply:
To the Editor:

To be included in our study, patients had to have symptoms, objective clinical signs, and clinically silent lesions characteristic of multiple sclerosis of the brain on MRI. This combination of clinical and MRI findings is highly specific for multiple sclerosis. During follow-up, a causal diagnosis other than multiple sclerosis was made in only 1 of our 383 patients (a cerebellar infarct diagnosed after one month). We believe that these patients already have pathological multiple sclerosis and are at high risk for a second clinical event, which will fulfill the criteria for clinically definite multiple sclerosis. Clinically definite multiple sclerosis is diagnosed in more than 50 percent of such patients within 3 to 5 years and in more than 80 percent within 10 years. (1) In many patients the course is not benign. In one study, after 10 years, 44 percent of patients had moderate disability (score on the Expanded Disability Status Scale, greater than or equal to 3), and approximately 25 percent already had secondary chronic progressive multiple sclerosis. (1) The number and volume of lesions on T2-weighted MRI of the brain at the time of and after the initial demyelinating event have been shown to be predictive of long-term disability. (1,2)

In patients who meet the eligibility criteria used in our study, we believe it is appropriate to make a definitive diagnosis of multiple sclerosis and to consider early treatment with interferon beta-1a, an agent with proven efficacy for preventing or delaying subclinical, "smoldering" multiple sclerosis, which can cause inflammation, scarring, axonopathy, atrophy, wallerian degeneration, and cognitive decline, even early in the course of the disease. (3,4)

The three-year rate of clinically definite multiple sclerosis in our study cannot be directly compared with that of the Optic Neuritis Treatment Trial, (5) because the criteria for and the ascertainment of clinically definite multiple sclerosis differed in the two studies. In designing our trial, we extrapolated from the results of the Optic Neuritis Treatment Trial and other published data to project a three-year rate of clinically definite multiple sclerosis in the placebo group of 50 percent, which is what we found. The number of patients who withdrew early from the study was approximately what we had projected, and there was no indication that the withdrawals affected the observed treatment effect.

The trial was stopped early on the recommendation of an independent data and safety monitoring committee. Valuable information could have been gained from continued accrual of data, but the interim analysis so clearly supported the benefit of treatment with respect to both clinical and MRI measures of outcome that continued use of a placebo group was no longer ethically justified.

We agree that for patients in whom the diagnosis of multiple sclerosis is equivocal, interferon beta-1a therapy should not be started. However, when the diagnosis appears unequivocal, as in our patients, initiation of interferon beta-1a treatment at the time of the first clinical demyelinating event is justified and appears to be cost effective. (6)

Lawrence D. Jacobs, M.D.
Buffalo General Hospital
Buffalo, NY 14203

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

R. Phillip Kinkel, M.D.
Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland, OH 44195


1. O'Riordan JI, Thompson AJ, Kingsley DPE, et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS: a 10-year follow-up. Brain 1998;121:495-503.

2. Sailer M, O'Riordan JI, Thompson AJ, et al. Quantitative MRI in patients with clinically isolated syndromes suggestive of demyelination. Neurology 1999;52:599-606.

3. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278-85.

4. Simon JH, Kinkel RP, Jacobs L, Bub L, Simonian N. A Wallerian degeneration pattern in patients at risk for MS. Neurology 2000;54:1155-60.

5. The Optic Neuritis Study Group. The 5-year risk of MS after optic neuritis: experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:1404-13.

6. Kendrick M, Johnson KI. Long-term treatment of multiple sclerosis with interferon-beta may be cost effective. Pharmacoeconomics 2000;18:45-53.

Copyright © 2001 by the Massachusetts Medical Society. All rights reserved.