Does Early Immunotherapy Reduce the Conversion of Ocular Myasthenia Gravis to Generalized Myasthenia Gravis?

Myasthenia gravis (MG), an autoimmune disorder affecting those of all ages, has a prevalence of approximately 20/100,000. MG limited to the extraocular and levator palpebrae muscles (“ocular myasthenia gravis,” OMG) occurs about half as often, with a prevalence of 12/100,000 (1). Although advances in laboratory neurophysiology and molecular neurobiology have provided insights into the pathophysiology of MG, little progress has occurred in the treatment of OMG. Clinicians remain mired in the debate as to whether OMG merits the risk of immunomodulatory therapy (2,3). Diplopia and ptosis often are not considered debilitating, and despite the knowledge that 40–50% of patients with OMG will develop generalized myasthenia gravis (GMG), 90% of them within 2 years, many physicians believe that pyridostigmine therapy is sufficient until more serious disease develops. They suggest that delaying immunomodulatory therapy will provide the same benefit as earlier treatment. In this issue, the study of Mee et al. (4) joins the growing number of retrospective investigations suggesting that early immunomodulatory treatment (5–7), particularly with corticosteroids, can delay and possibly reduce the frequency of progression of OMG to GMG. The authors retrospectively analyzed the charts of 34 patients with OMG and abnormal serum acetylcholine receptor antibody to avoid inclusion of non-myasthenic causes of ophthalmoparesis (4). In doing so, they have chosen patients with the highest risk of developing GMG (7). The edrophonium test was positive in 86% of patients tested, which is slightly lower than the previously reported rate of 96%, (7) possibly due to methodological differences (8). Nineteen (86%) of 22 patients treated with pyridostigmine alone developed GMG, whereas only 2 (16.7%) of 12 patients receiving immunomodulatory therapy (corticosteroids, azathioprine, thymectomy, individually or in combination) developed GMG during a follow-up period of approximately 90 months. The selected cohort may not accurately reflect the entire population with OMG, given that the conversion rate to GMG in the pyridostigmine group was higher than has been reported in larger studies (7,9,10). One explanation for these differences is that patients with asymptomatic GMG, who might have been uncovered with a detailed clinical neuromuscular examination, were included. They were bound to eventually demonstrate GMG signs and symptoms. Additionally, the authors eliminated several patients who developed GMG within 6 months of immunomodulatory therapy, introducing potentially favorable bias toward immunomodulatory therapy. One approach to modulate the immune response in myasthenia gravis has been to perform thymectomy. In the current study, five patients without thymoma, including two who were not included in the data analysis, underwent thymectomy (4). Although thymectomy has been reported to restore vision and prevent GMG in small case series, typically the surgery has been performed late in the illness when the risk of developing GMG was low. In fact, thymectomy remains unproven by modern clinical trial criteria in the treatment of GMG, so a clinical trial is in the process of being established. There is a scientific basis for using corticosteroid treatment to prevent GMG, even at doses that do not cause immunosuppression. Corticosteroid treatment of in vitro human muscle cultures increases the number of acetylcholine receptors (11,12) and prevents receptor loss induced by the serum from GMG patients. Neuromuscular junctions increase in size, and the length, number, and depths of postsynaptic folds increase after weeks of corticosteroid exposure (13). The data on azathioprine delaying or preventing GMG is not as robust (6). Mycophenolate mofetil appears to be an adjunctive therapy in GMG and has not been investigated adequately to determine whether it can affect conversion of OMG to GMG. It is time for clinicians to come to a consensus on the treatment of OMG. The primary issue is whether a therapy can reduce the conversion to GMG without causing major adverse effects. A secondary issue is whether this treatment restores binocular vision and improves quality of life. These questions can be answered only by prospective data collection in a rigorously designed clinical trial. Because the diagnosis of OMG is made clinically (Table), and because acetylcholine receptor antibody-negative patients do develop GMG, a clinical trial that includes only antibody-positive subjects would bias the study toward patients prone to develop GMG and unreasonably limit recruitment. A large randomized trial would be an opportunity for neuro-ophthalmologists and neurologists interested in neuromuscular disease to collaborate.