NEUROLOGY 2007;68:803–804
IVIG in myasthenia gravis
Getting enough “bang for the buck”
Matthew N. Meriggioli, MD
IV immunoglobulin (IVIG) is a widely accepted treat-
ment for autoimmune myasthenia gravis (MG), usu-
ally utilized in rapidly progressive or exacerbating
disease.1 As with many MG treatments, evidence-
based support of its efficacy is scarce and not entirely
definitive. Two randomized controlled trials reported
no difference in treatment response compared to
plasma exchange,2,3 and one randomized trial
showed no superiority of 2 g/kg dosing compared to 1
g/kg in MG exacerbation.4 IVIG is sometimes used in
a chronic or serial manner, an approach for which no
support exists in the form of evidence-based data. In
this issue of Neurology, Zinman et al.5 report the
results of a randomized controlled trial of IVIG in a
distinct clinical scenario, namely the short-term
treatment of mild to moderate MG with worsening
weakness. This is a well-conducted clinical trial that
provides needed evidence supporting the use of IVIG
in less than severe exacerbations of MG. The authors
demonstrate a significant improvement in the quan-
titative myasthenia gravis (QMG) score in subjects
receiving IVIG (2 g/kg) compared to those receiving
placebo at 14 days after initiation of treatment.
As Zinman et al. point out, while significant, the
magnitude of improvement in the IVIG cohort was
surprisingly small. The QMG score was used as the
primary efficacy measure in this study, and has been
endorsed as a favored tool for the evaluation of clini-
cal change in prospective MG trials.6 Subjects receiv-
ing IVIG improved by a mean of 2.54 QMG units,
compared to an improvement of 0.89 units in sub-
jects receiving placebo. This magnitude of effect did
not reach the standard of 3.5 QMG units, cited by
the authors as clinically meaningful, and used to
determine the sample size for the study. Further-
more, individual QMG score changes of up to 2.6
units may occur due to the variability of repeated
observations.7 Why such modest improvement? Is
the demonstrated benefit in this study clinically
meaningful, and does it provide adequate justifica-
See also page 837
From the Department of Neurology and Rehabilitation, University of Illinois at Chicago.
Disclosure: The author has received grant support and honoraria from Aspreva Pharmaceuticals.
Address correspondence and reprint requests to Dr. Matthew N. Meriggioli, Department of Neurology and Rehabilitation, University of Illinois at Chicago,
912 S. Wood Street, 855N, M/C 796, Chicago, IL 60612; e-mail: mmerig@uic.edu
Editorial
tion for the substantial expense associated with IVIG
therapy?
The inclusion of a large number of patients with
purely ocular or mild disease (29% of IVIG group,
37% of placebo) and even modest worsening of symp-
toms may be the most obvious explanation for the
less than expected observed overall improvement.
While including these patients (and excluding pa-
tients with more severe oropharyngeal or respiratory
weakness) was likely a necessary strategy to ethi-
cally justify the use of a placebo arm and allow for
adequate subject recruitment, their inclusion clearly
impacted the results, as a subgroup analysis showed
that the magnitude of improvement was more robust
(4.1 QMG units), and likely more clinically meaning-
ful, in moderate to severe patients (as defined by a
baseline QMG score of ⬎10.5), while the therapeutic
effect was lost in the subgroup analysis of patients
with a baseline QMG score ⬍10.5.
The above observations come as no surprise to
most experienced clinicians, as patients with acute
exacerbations of moderate or severe MG are those
treated with IVIG in clinical practice. It is in this
clinical scenario where the clinician relies on a rapid
clinical response to avoid further, possibly danger-
ous, deterioration. Accordingly, the results of Zin-
man et al. provide evidence that IVIG is effective in
patients with more than mild, exacerbating MG,
demonstrating an onset of benefit within 14 days.
Importantly, the duration of beneficial effect was not
determined, as improvement compared to placebo
was not reported at 28 days in the subgroup analy-
sis, and significant improvement was lost at 28 days
in the entire treatment cohort. With regard to the
mild subgroup, one wonders whether these patients
would respond to relatively conservative additions/
modifications in corticosteroid or anticholinesterase
doses, considerably less costly interventions. Pa-
tients with predominantly ocular or mild MG are
also more likely to spontaneously improve—with or
Copyright © 2007 by AAN Enterprises, Inc. 803
without intervention—particularly in the setting of a
clinical trial. Further complicating matters is the
fact that a lesser magnitude of QMG change may be
clinically important in ocular or mild MG where
baseline QMG scores are lower. Differential weight-
ing of individual items in the QMG score may better
reflect clinical responses to therapy in cohorts of pa-
tients with varying patterns and severity of disease.
This discussion brings out one of many important
challenges of the design of clinical trials in MG. Not
only is it important to select a valid and reliable
outcome measure that is responsive to meaningful
clinical change, it is just as important that the pa-
tient population be homogeneous enough to allow for
the accurate application of the chosen outcome mea-
sure in all subjects.
Based on the work of Zinman et al., those of us
who treat MG now have evidence-based data indicat-
ing that IVIG induces rapid, short-term improve-
ment in patients with MG and worsening
myasthenic symptoms. The subgroup of patients
with more than mild myasthenic weakness demon-
strated a robust and likely clinically relevant benefit.
The results of this study may therefore be applied in
the clinic to patients with worsening weakness with
at least moderate disease severity, where the treat-
ing physician gets more “bang for the IVIG buck.”
However, important unanswered questions remain,
including the following:
1) Can IVIG be used to mitigate against the para-
804 NEUROLOGY 68 March 13, 2007
doxical worsening that may occur with the initiation
of steroid therapy?
2) Is IVIG effective as an adjunct to chronic immu-
nosuppressive medications in stable MG?
3) Is IVIG truly as effective and rapid in onset as
plasma exchange in myasthenic crisis?
The definitive answers to these questions will re-
quire separate, appropriately designed clinical trials
with careful attention to the homogeneity of the
study population and consideration of the most clini-
cally meaningful outcomes.
Acknowledgment
The author thanks Julie Rowin, MD, for comments on this article.
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