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Mechanism of Action of Intravenous Immunoglobulin and Therapeutic Considerations in the Treatment of Autoimmune Neurologic Diseases

From the Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Address correspondence and reprint requests to Dr. Marinos C. Dalakas, Chief, Neuromuscular Diseases Section, NINDS, National Institutes of Health, Building 10, Room 4N248, 10 Center Drive MSC 1382, Bethesda, MD 20892-1382.

Abstract.

On the basis of controlled clinical trials, high-dose intravenous immunoglobulin (IVIg) has emerged as a critical therapy in the management of patients with various autoimmune neurologic diseases. Different interpretations of the clinical trial results, the expected benefit of IVIg compared to that of alternate therapies, off-label use, results from anecdotal or empirical clinical trials, issues about safety and cost and, most importantly, the uncertainty about mechanisms of action of IVIg have generated concerns among practicing neurologists. Understanding the mechanisms of action of IVIg and its potential risks or side effects is expected to help us make more judicious use of this powerful immunomodulating agent. This article provides evidence that IVIg has multiple actions which may operate in concert with each other but that for each disease a predominant mechanism may prevail according to the underlying immunopathogenetic cause of the respective disorder. The most relevant actions of IVIg in the therapy of neurological diseases include (a) inhibition of complement binding and prevention of MAC formation, (b) neutralization of certain pathogenic cytokines, (c) downregulation of antibody production, and (d) modulation of Fc-receptor mediated phagocytosis. Additional actions include the effect of IVIg on superantigens, modulation of T-cell function and antigen recognition, and enhancement of remyelination. On the basis of our experience with more than 130 closely monitored patients, I provide guidelines on how to use the drug, kinetics of IVIg, adverse reactions, and risk factors. In addition, the incidence, morbidity prevention and treatment of the common or rare side effects, including thromboembolic events, increased serum viscosity, aseptic meningitis, headaches, skin reactions, renal failure, and hemolysis are described. Spurious results of serologic tests, such as false hyponatremia and elevated sedimentation rate, as well as a transient rise in various viral titers, are described in an effort to avoid misinterpretations by treating neurologists. Finally, details on the latest findings of viral safety of IVIg are provided.