Expanding the Myasthenic Phenotype

Abstract & Commentary

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: A rare form of myasthenia gravis with antibodies to clustered acetylcholine receptor has similar clinical features as the common form with nicotinic receptor antibodies.

Source: Devic P, et al. Antibodies to clustered acetylcholine receptor: Expanding the phenotype. Eur J Neurol 2013 Sep 21; doi: 10.1111/ene.12270. [Epub ahead of print].

Approximately 6-12% of myasthenia gravis (mg) patients are seronegative for antibodies to the nicotinic acetylcholine receptor (AchR), muscle specific kinase (MuSK), and lipoprotein receptor-related protein 4 (LRP4). Some of these seronegative patients have antibodies that bind high-density AchR clusters. How common are such patients in the MG population and how do these patients compare clinically to those with seropositive MG?

Through a nationwide, multicenter, collaboration of French neurologists, 37 seronegative MG patients were collected and included in this study. Inclusion criteria required a clinical picture of generalized MG, response to standard medication including cholinesterase inhibitors and immunosuppression, a > 10% decremental response on repetitive nerve stimulation, and absence of AchR and MuSK antibodies based on radio-immunoprecipitation assays. All 37 sera then underwent immunofluorescence analysis to detect antibodies to clustered AchR.

Among the 37 seronegative patients’ sera, those of four men and two women (16%), with a mean age of 45 years and mean disease duration of 11 years, contained antibodies to AchR only when clustered. Symptoms in these six patients resembled those of seropositive MG patients, including fluctuating ptosis, ophthalmoparesis, and limb weakness responsive to cholinesterase inhibitors, with three demonstrating bulbar involvement that was never predominant and all responding well to intravenous immunoglobulin. Early-onset disease, before 40 years of age, was seen in three, all of whom responded well to immunosuppression, with two undergoing thymectomy, one for thymoma, and the other showing thymic hyperplasia histologically. Only one older onset patient remained refractory to standard immunosuppression, including steroids, plasma exchange, and cyclophosphamide, ultimately responding well to rituximab. MG patients positive for antibodies to clustered AchR resemble those with the more common nicotinic AchR autoantibody.

Commentary

Among patients with generalized MG, approximately 80-85% have autoantibodies to muscle AchR and another 5% to MuSK. In 2011, three groups separately identified autoantibodies to low-density LRP4 in MG patients previously double seronegative. Enzyme-linked immunosorbent assay and the more sensitive radio-immunoprecipitation assay (RIPA) traditionally have been used to detect these autoantibodies but newer methods, not generally available, have shown that seronegative patients often have low levels of these same, as well as other low-affinity, antibodies. One such assay is the so-dubbed "two-step RIPA," which uses much larger volumes of serum than the traditional 5 ul, increasing the sensitivity of the assay. Cell-based assays (CBA), using cell lines expressing the autoantigen, can detect autoantibodies missed by RIPA, and have been used to document AchR antibodies in up to 50% of previously seronegative patients with ocular MG. CBA have also documented MuSK antibodies in patients with ocular MG in whom MuSK antibodies were previously described as rare. Other assays being tested include Luciferase immunoprecipitation systems (LIPS), which uses recombinant antigens fused to the enzyme reporter Renilla luciferase (Ruc) to detect patient antibodies, and fluorescence immunoprecipitation assays, which operate similar to LIPS but use AchR subunits fused to fluorescent proteins such as green fluorescence protein. Sensitive assays to further define the "seronegative" MG population are anxiously awaited.