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Intravenous Immune Globulin Therapy for Neurologic Diseases

Marinos C. Dalakas, MD
[+] Article and Author Information

From the National Institutes of Health, Bethesda, Maryland. For the current author address, see end of text. For definitions of terms used in this article, see glossary at end of text. Acknowledgment: The author thanks B.J. Hessie for skillful editing. Requests for Reprints: Marinos C. Dalakas, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 4N248, 10 Center Drive, MSC 1382, Bethesda, MD 20892-1382.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1997;126(9):721-730. doi:10.7326/0003-4819-126-9-199705010-00008
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High-dose intravenous immune globulin (IVIg) has emerged as an important therapy for various neurologic diseases. Different interpretations of clinical trial results; the expected benefit of IVIg compared with that of alternate therapies; and issues about IVIg's safety, cost, and mechanisms of action have raised concern and uncertainty among practitioners. To clarify these areas, this paper examines the clinical, serologic, and immunologic data on more than 110 patients with various autoimmune neurologic diseases who received IVIg during the past 6 years at the National Institute of Neurological Disorders and Stroke. It also reviews work by other investigators on the efficacy, risks, benefits, and mechanisms of the action of IVIg in these diseases.

In controlled clinical trials, IVIg has been effective in treating the Guillain-Barre syndrome, multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, and dermatomyositis. In other controlled or open-label trials and case reports, IVIg produced improvement in several patients with the Lambert-Eaton myasthenic syndrome and myasthenia gravis but had a variable, mild, or unsubstantiated benefit in some patients with inclusion-body myositis, paraproteinemic IgM demyelinating polyneuropathy, certain intractable childhood epilepsies, polymyositis, multiple sclerosis, optic neuritis, and the stiff-man syndrome. The primary adverse reaction was headache; aseptic meningitis, skin reactions, thromboembolic events, and renal tubular necrosis occurred rarely. The most relevant immunomodulatory actions of IVIg, operating alone or in combination, are inhibition of complement deposition, neutralization of cytokines, modulation of Fc-receptor-mediated phagocytosis, and down-regulation of autoantibody production. Therapy with IVIg is effective for certain autoimmune neurologic diseases, but its spectrum of efficacy has not been fully established. Additional controlled clinical trials are needed.

Figures

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Figure 1.
Immunoglobulin molecule and formation of dimers in intravenous immune globulin (IVIg).Left.Right.

Structure of the immunoglobulin molecule. Immune globulin in a purified preparation derived from multiple donors contains 40% dimers, as the result of double-arm and single-arm binding, and 60% monomers.

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Figure 2.
Effect of immune globulin on complement deposition.MACwavy arrows[25, 65, 75]IVIgred ovalsØ

Activation of the complement pathway on the cell surface begins by the binding of the C1q on the antigen-antibody complex, triggering the cascade of C3 activation. This leads to the activation of C3b fragments and the formation of membranolytic attack complex ( ), which causes cell lysis. Immune globulin inhibits complement deposition ( ) by acting on the C3b fragments and preventing the incorporation of C3 molecules into the C5 convertase assembly . The effect is the inhibition of membranolytic attack complex formation and prevention of cell lysis. In addition, intravenous immune globulin ( ) may saturate the CR1 and CR3 receptors ( ) on activated macrophages ( ) and inhibit opsonization of immune complexes by preventing the binding of C3b and C3bi complement fragments.

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Figure 3.
Petechiae on the dorsum of a patient's foot 3 to 5 days after an intravenous infusion of immune globulin.
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