http://www.nejm.org/content/2001/0344/0003/0229.asp
Correspondence
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.
References
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.
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.
References
The authors reply:
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.
Roy W. Beck, M.D.,
Ph.D.
R. Phillip Kinkel,
M.D.
References
Copyright ©
2001 by the Massachusetts Medical Society. All rights reserved.
Harvard Medical
School
Boston, MA 02115
Royal Victoria Hospital
Belfast BT12 6BA,
Northern Ireland
To the Editor:
Buffalo General
Hospital
Buffalo, NY 14203
Jaeb Center for
Health Research
Tampa, FL 33613
Mellen Center for
Multiple Sclerosis Treatment and Research
Cleveland, OH 44195