Myasthenia Gravis 2004

Abstracts & Commentary

Sources: Monsul NT, et al. The effect of prednisone on the progression from ocular to generalized myasthenia gravis. J Neurol Sci. 2004;217:131-133; Guillermo GR, et al. Response of thymectomy: Clinical and pathological characteristics among seronegative and seropositive myasthenia gravis patients. Acta Neurol Scand. 2004;109:217-221; Koopman WJ, et al. Prediction of aspiration in myasthenia gravis. Muscle Nerve. 2004;29:256-260.

Does prednisone, administered early in the course of ocular myasthenia (OMG), affect its progression to generalized disease? Fifty-six patients with OMG were followed for a minimum of 2 years were retrospectively evaluated to address this question. Diagnosis of OMG was clinical and confirmed with EMG, antiacetylcholine receptor antibody titers, edrophonium test, and ice or sleep test. Patients were excluded if they were younger than 16 years of age or had a thymoma or thymectomy. Pyridostigmine had been administered to all and prednisone was added, 40-60 mg/d initially followed by a 3-6 month taper, if symptoms persisted. Patients were included in the prednisone-treated group if they had received at least 3 months of prednisone within 2 years of diagnosis, whereas those who did not fulfill this criteria were included in the non-prednisone-treated group for purposes of analysis. Statistical analysis was provided by the 2-tailed t-test and chi square analysis.

Among the 56 patients, 27 were in the prednisone- treated group and 29 in the non-treated group. Age, gender, and receptor antibody positivity were comparable in both groups. Significantly, only 3 prednisone-treated patients (11%) developed generalized disease compared to 10 (34%) in the non-treatment group (P = 0.04). None of the prednisone-treated patients developed diabetes, hypertension, compression fracture, ulcer, or infection, although mild edema and weight gain were reported in some. These results are promising and warrant larger prospective trials to answer the question definitively.

Do seronegative myasthenia gravis patients benefit from thymectomy as much as do seropositive patients? Does their thymic pathology differ? Using parametric and nonparametric tests for statistical analysis, 57 seropositive patients were compared to 14 seronegative cases, all of whom had been thymectomized between 1987 and 1997. Similar response rates were seen in both groups. Remission was achieved in 21% in both, with improvement in 30% (n = 17) and 36 % (n = 5), respectively; no change in 44% (n = 25) and 36% (n = 5), respectively, and worsened in 5% (n = 3) and 7% (n = 1), respectively. Seropositive patients were older, mean age 42.9 years vs. 32 years for seronegative patients (P = 0.01), and demonstrated a higher frequency of thymoma, 9% (n = 5) vs none in the seronegative group. Prognosis is similar regardless of antibody status.

Which test might best predict aspiration risk in myasthenia gravis (MG) patients? Twenty MG patients with dysphagia, 10 men and 10 women, participated in a comparison study of 4 noninvasive bedside tests to assess such risk. Testing included a self-directed questionnaire (SDQ, 14 questions evaluating dysphagia), a bedside neurological exam performed by a neurologist who then predicted presence or absence of aspiration risk, the quantitative MG (QMG) score, and a bedside speech pathology assessment. All assessments were performed over a 4-hour period and assessors were blinded to the results of the other tests. Videofluoroscopic assessment of swallowing served as the gold standard for comparison and statistical analysis was performed by independent t-tests, linear regression analysis, and Fisher’s exact test.

Two SDQ questions correlated with aspiration: Do you have a hard time moving food or liquids around in your mouth? and: Does it hurt for you to swallow? Neurological examination prediction also correlated with aspiration as did the bulbar subset of the QMG score. However, total QMG score was less useful as was speech pathology evaluation. Simple bedside tests appear to be useful predictors of aspiration but these findings require confirmation in larger studies.

Commentary

Despite the commonality of anti-acetylcholine receptor antibodies (AChR Ab) in seropositive myasthenia gravis (SPMG), it appears to be a rather heterogeneous disease, both from the perspective of thymic pathology and based on presence of serum anti-titin antibodies. Thymic hyperplasia is more common in women, with early age of onset and high titer antibodies, whereas thymoma is equally common in both sexes and is associated with severe disease. Absence of any thymic pathology combined with positive anti-titin antibodies identifies a group with older age of onset (mean, 65 years) and intermediate levels of AChR Ab levels.

Family members are at significantly increased risk, 2-4%, of developing myasthenia compared to the general population, and twin studies, though limited, also support a genetically complex mode of inheritance. Involvement of the HLA complex, including class I alleles B8 and A1, class II alleles DR3 and Dw3, HLA-linked genes including complement C4 and TNF-alpha, and more recently the HLA-DR3 B8 A1 haplotype, associated with MG and thymic hyperplasia, provide further evidence for the direct effect of genetic factors in the development of myasthenia gravis. Interestingly, DR3 which is positively associated with MG and thymic hyperplasia, and DR7 which is negatively associated, show a reverse association in patients with myasthenia, no thymic abnormalities and positive anti-titin antibodies where DR7 is increased and DR3 decreased.

Which candidate gene might influence genetic susceptibility to myasthenia? CHRNA,1 a gene that codes for the alpha subunit of the muscle acetylcholine receptor, seems a good bet given that it contains the main immunogenic region against which most antibodies are directed. It is directly involved in acetylcholine binding, and it presents the only functional polymorphism known at the protein level in the alpha subunit. — Michael Rubin

Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.

Reference

1. J Autoimm. 2003;21:105-110.