Abstract & Commentary

Source: Wegner B, Ahmed I. Intravenous immunoglobulin monotherapy in long-term treatment of myasthenia gravis. Clin Neurol Neurosurg. 2002;105:3-8.

Intravenous immunoglobulin (IVIG) is safe and effective therapy for acute exacerbations of myasthenia gravis (MG), myasthenic crisis, and for optimizing patients’ conditions in preparation for thymectomy. Its role in the long-term management of MG remains to be defined. Six patients with seropositive MG of 6 months to 10 years duration had been treated with a combination of Mestinon (n = 6), steroids (n = 4), plasmapheresis (n = 2), or thymectomy (n = 3). Intolerable side effects mandated a change in therapeutic regimen. All received IVIG infusion of 400 mg/kg/d for 5 days followed by IVIG 400 mg/kg/d for 1 or 2 days every 2 or 3 months. Follow-up extended for 24-36 months. All patients were successfully weaned off all MG medication, including Mestinon and prednisone, without worsening of their Osserman classification scores. No complications were experienced. Bi- or tri-monthly IVIG infusion, for merely a day or 2, can be a useful therapeutic alternative in the management of seropositive myasthenic patients.


What about myasthenics who are acetylcholine receptor (AchR) antibody-negative? Upward of 20% of myasthenics are so-called seronegative. Nevertheless, they respond to plasmapheresis and immunosuppression, and their serum IgG causes neuromuscular transmission failure in mice. What is their target antigen? Muscle specific tyrosine kinase (MuSK) antibodies were found in 17 of 24 seronegative myasthenic patients,1 suggesting that the target may be MuSK, an integral part of the agrin receptor at the neuromuscular junction (NMJ).

How does this fit in, so to speak, with NMJ physiology? Development of the NMJ is complex, involving both anterograde (nerve to muscle) and retrograde (muscle to nerve) signals. Agrin, a nerve-derived signal, induces clustering of AchR on myotube surfaces at a density equivalent to that at the mature NMJ (12,000/mm2) suggesting that it is involved in the development of the post-synaptic complex.2 It is a member of the heparan sulfate proteoglycan family and is a multidomain protein, containing regions of homology with laminin (cell adhesion protein) and epidermal growth factor. It exists in several isoforms and is present in brain and spinal cord, as well as muscle, liver, kidney, and lung. MuSK is a single transmembrane polypeptide, and evidence suggests that it forms at least part of the agrin receptor at the NMJ.

IgG from seronegative patients inhibits agrin-induced AchR clustering, offering a mechanism for NMJ failure in these patients. Indeed, patients negative for both AchR and MuSK antibodies also appear to have activity in their non-IgG serum fraction, which inhibits AchR function, as reported in 8 of 12 such patients.3 AchR phosphorylation with consequent AchR dysfunction may be the pathophysiologic mechanism in these myasthenics.3 Elucidation of the precise target in such patients will improve understanding of NMJ physiology, as well as improve diagnosis in seronegative patients.

Similar antibody phenomenology is seen in Lambert Eaton myasthenic syndrome (LEMS) in which 85% of patients demonstrate antibodies to P/Q type voltage gated calcium channels, while 15% are seronegative. When purified IgG obtained from "seronegative" LEMS serum was injected into mice, quantal contents of the end plate potentials decreased, as they did following seropositive serum injection. Controls showed no change.4 Seronegative LEMS, like seronegative MG, appears to be antibody mediated. Identification of the antibody and antigen in these patients is the next step in understanding their etiopathogenesis. — Michael Rubin

Dr. Rubin is Assistant Editor of Neurology Alert and Professor of Clinical Neurology at New York Presbyterian Hospital—Cornell Campus.


1. Hoch W, et al. Nat Med. 2001;7:365-368.

2. Liyanage Y, et al. Muscle Nerve. 2002;25:4-16.

3. Plested CP, et al. Neurology. 2002;59:1682-1688.

4. Nakao YK, et al. Neurology. 2002;59:1773-1775.