IVIG for Myasthenia Gravis and Miller Fisher Syndrome

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, NewYork-Presbyterian Hospital, Weill Cornell Medical Center. Dr. Rubin is on the speaker's bureau for Athena Diagnostics, and does research for Pfizer and Merck.
This article originally appeared in the May 2007 issue of Neurology Alert. It was edited by Matthew E. Fink, MD, and peer reviewed by M. Flint Beal, MD. Dr. Fink is Vice Chairman, Professor of Critical Care Neurology, NewYork-Presbyterian Hospital, and Dr. Beal is Professor and Chairman, Department of Neurology, Cornell University Medical College. Drs. Fink and Beal report no financial relationships relevant to this field of study.

Synopsis: IVIG is safe and effective for worsening MG, but has no effect on the natural course of Miller Fisher syndrome

Sources: Zinman L, et al. IV immunoglobulin in patients with myasthenia gravis. A randomized clinical trial. Neurology. 2007;68;837-841; Mori M, et al. Intravenous immunoglobulin therapy for Miller Fisher syndrome. Neurology. 2007;68:1144-1146.

Despite reports touting the apparent benefits of intravenous immunoglobulin (IVIG) in myasthenia gravis (MG), level 1 evidence has been lacking until now. Between March 2004 and May 2005, the University Health Network Neuromuscular Clinic of the University of Toronto, Ontario, enrolled 51 MG patients with progressive weakness, 18 years of age or over, into a randomized, placebo-controlled, double-blind study, comparing IVIG to placebo (IV dextrose 5% in water, D5W). MG diagnosis was based on clinical evaluation, positive findings on single-fiber electromyography (SFEMG), previous response to treatment, and positive acetylcholine receptor antibodies and muscle-specific tyrosine kinase antibodies. Progressing weakness was defined as increasing ptosis, diplopia, dysarthria, chewing or swallowing difficulties, or limb weakness important enough to warrant change in medication. Exclusionary criteria included weakness due to intercurrent infection or medication, respiratory failure requiring intensive care admission, dysphagia with aspiration risk, recent (2 week) change in steroid dosage, renal, hepatic, or cardiac disease, hypercoagulable or hyperviscosity states, pregnancy, and lactation. Patients received either 2 G/kg of IVIG or D5W over 2 days, were premedicated in all instances with acetaminophen and diphenhydramine, and were evaluated by clinical examination at baseline, day 14, and day 28 by the same blinded examiner. Clinical assessments included the Quantitative Myasthenia Gravis (QMG) Score for Disease Severity and the Post-Intervention Status classification, with all anti-cholinesterase medication held for 12 hours prior to evaluation. Change in QMG Score for Disease Severity from baseline to day 14 was the primary outcome measure, whereas changes from day one to 28, and from day 14 to 28, served as secondary outcome measures, as did day 14 and 28 Post-Intervention Status, and changes in SFEMG and repetitive nerve stimulation studies from baseline to day 14. Student T test, x2, or Fisher exact test, and analysis of covariance (ANCOVA) were used for statistical analysis.

IVIG provided a small but significant improvement of QMG Score, compared to placebo, at day 14, which persisted, though it failed to reach significance at day 28. All the benefit was accrued by those with more severe disease, whose QMG score was > 10.5 at baseline. No IVIG patient worsened, compared to 4% on placebo, while 23% vs 42% experienced no change, respectively. Post-Intervention Status was also significantly improved by IVIG compared to placebo, 23% vs 8%, again appreciated only in the more severe cases, with none vs 6% worsening, respectively. No serious adverse events were experienced in either group, with headache, easily treated with over-the-counter medication, being the most common side effect.

Commentary

In contrast to its proven efficacy in myasthenia gravis and Guillain-Barré syndrome, intravenous immuno-globulin (IVIG) appears to be less useful for Miller Fisher syndrome (MFS). Among 92 MFS patients seen between 1979-2005 at the Chiba University Hospital and its affiliates in Japan, and treated with IVIG (n = 28), plasmapheresis (n = 23), or supportive care alone (n = 41). Mori et al reported no significant difference between the treatment groups. Only 4 (4%) remained symptomatic one year after disease onset; one each from the IVIG and control groups, and 2 from the plasmapheresis group. They all had persistent diplopia, and one patient also experienced persistent ophthalmoplegia. MFS is a terrifying, but relatively benign condition, and does not appear to benefit from IVIG. Almost all patients recover with or without treatment.