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Caveat regarding immunoglobulin therapy in multiple sclerosis.

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Caveat Regarding
Immunoglobulin Therapy
in Multiple Sclerosis
Anne H. Cross, MD, John L. Trotter, MD, and
William M. Hart, Jr, MD, PhD
We wish to sound a strong note of caution regarding the
letter by van Engelen and co-workers 111. We write this letter
out of concern after other clinicians (not specializing in multiple sclerosis), excited about the van Engelen letter, sought
our opinion as to whether to use intravenous immunoglobulin (IVIg) in multiple sclerosis (MS) patients. W e believe
the data presented in the van Engelen letter to be far too
preliminary and speculative to suggest the use of IVIg therapy in MS patients at this time. The authors report the results
of a variety of visual function tests in a series of 5 patients
and have made several mistakes in setting up the study.
First, the study was uncontrolled and unblinded. Controls
are of paramount importance in any therapeutic trial in MS
{Z, 31 because MS patients treated with placebo frequently
demonstrate improvement during the course of MS clinical
trials [4). Furthermore, the natural course of visual acuity in
optic neuritis is to improve {5, 61, so that without sufficient
patient numbers and the proper controls, data such as those
presented in the van Engelen letter are completely uninterpretable. Second, visual acuity testing is notoriously prone to
bias except when examiners are masked and follow a standardized protocol [7, 81. Simple bias (such as more careful
testing of patients after therapy) could have produced a spurious increase in visual acuity. The 1 patient who underwent
visual evoked potential (VEP) testing (a more objective test)
before and after IVIg treatment showed prolongation of the
VEP after treatment. Third, IVIg is extremely expensive. Its
widespread use is certain to elevate the cost of medical care
of MS patients in exchange for unsubstantiated benefit.
Finally, the authors freely draw parallels between remyelination in mice treated with hyperimmune anti-spinal cord homogenate IgG 191and humans treated with nonspecific IVIg.
At the very least, the authors should perform similar experiments using the same nonspecific Ig therapy in mice before
assuming such parallels exist. We look forward to reports of
such experiments.
Department of Neurology
Department of Ophthalmology and Visual Sciences
Washington University School of Medicine
St Louis,M O
1. van Engelen BGM, Hommes OR, Pinckers A, et al. Improved
vision after intravenous immunoglobulin in stable demyelinating
optic neuritis. Ann Neurol 1992;32:834-835
2. Brown JR, Beebe GW, Kurtzke JF, et al. The design of clinical
studies to assess therapeutic efficacy in multiple sclerosis. Neurology 1979;29:1-23
3. Weiner HL, Ellison GW. A working protocol to be used as a
guideline for trials in multiple sclerosis. Arch Neurol 1984;
4. Rose AS, Kuzma JW, Kurtzke JF, er al. Co-operative study in
the evaluation of therapy in multiple sclerosis: ACTH versus
placebo. Neurology 1970;5:1-59
Earl CJ, Martin B. Prognosis in optic neuritis related to age.
Lancer 1967;1:74-76
Bradley WG, Whitty CWM. Acute optic neuritis: its clinical features and their relation to prognosis for recovery of vision. J
Neurol Neurosurg Psychiatry 1967;30:531-538
Meinert CL, Tonascia S. Clinical trials: design, conduct and analysis. Oxford University Press, New York, 1986
Blackhurst DW, Maguire MG, the Macular Photocoagulation
Group. Reproducibility of refraction and visual acuity measurement under a standard protocol. Retina 1989;9:163-169
Rodriguez M, Lennon VA. Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 1990;27:12-17
Baziel G . M. van Engelen, MD,"
Otto R. Hommes, MD, PhD," Alfred Pinckers, MD, PhD,"
Johan R. M. Cruysberg, MD," Frederik Barkhof, MD,"
and Moses Rodriguez, MDt
We thank D r Cross and colleagues for their interest in our
observations suggesting the potential for intravenous immunoglobulins to promote CNS remyelination. We will respond
to the three comments they made.
First, our intention was to perform a pilot study to see if a
more extended controlled and blinded study in the future
would be worthwhile. To have performed a double-blind
controlled study based on the available literature reports of
immunoglobulin administration in MS would have been premature. We agree that the natural course of visual acuity in
acute optic neuritis is to improve. Complete recovery of visual
function occurred in 65% of patients according to a recent
prospective study [l]. When recovery begins, it is rapid
(within days to weeks), and in the great majority normal
vision is achieved within the first 2 months {2). Therefore
we selected patients who had a stable nonrecovering demyelinating optic neuritis for at least 6 months. After that time,
spontaneous improvement of visual acuity is not to be expected. All patients had failed to improve after 10 days of
high-dose intravenous methylprednisolone.
Second, we agree that visual acuity testing is notoriously
prone to bias. That is the reason why assessment of optic
nerve function including visual acuity was tested by ophthalmologists following a standardized protocol 13). Probably Dr
Cross and associates have misread the table. The table does
not show that in only 1 patient visual evoked potentids
(VEP) were measured before and after immunoglobulin. It
shows that all patients underwent VEP testing before and
after immunoglobulin administration: 4 eyes showed improvement, 2 eyes showed deterioration, and 2 eyes showed
no changes.
Third, immunoglobulin has been reported to be beneficial
for more than 35 diseases {4]. W e did not intend the expansion of such a therapy to another disease such as MS or optic
neuritis. Contrary to other recent publications on immunoglobulin treatment in MS [ S , 61, nowhere in the report did
we advise the treatment of MS patients with immunoglobulin. As we stated, the purpose of our pilot study was to test
the basic hypothesis that IgG in humans (rather than being
involved in the pathogenesis of MS o r optic neuritis) may
play a role in CNS remyelination, similar to the therapeutic
660 Copyright 0 1993 by the American Neurological Association
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