Johan A. Aarli

Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin

Patients with myasthenia gravis (MG) and thymoma have in their sera antibodies which react with non‐receptor antigens from striated muscle. The purpose of this investigation was to characterize the antigen(s). Polypeptides in homogenates from rat skeletal muscle were separated by SDS‐PAGE and trans‐blotted to nitrocellulose. Sera from six patients with MG and thymoma stained a large (molecular weight >500 kD) polypeptide. while no staining was observed with sera from 20 non‐thymoma MG patients. Titin is one of the large (> 500 kD) polypeptides of striated muscle and the antibody containing MG sera have antibodies that bind to titin in a preparation of myofibrillary proteins from rabbit skeletal muscle. The staining pattern is identical to that obtained with antiserum to titin, showing that the antigen has the same electrophoretic mobility as titin. Antibodies from the sera of the patients with MG and thymoma, affinity‐purified on the large polypeptide, reacted with skeletal muscle sections in a cross‐striational pattern, near the A/I band junction but within the I band, corresponding to the localization of one of the epitopes of titin. Our findings therefore indicate that the muscle antibodies found in the sera from some MG patients with thymoma are directed against titin.

Muscle autoantibodies in subgroups of myasthenia gravis patients

Abstract Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR), but several other muscle autoantibodies have also been identified in patient sera. We studied muscle autoantibodies against AChR, striated muscle tissue sections (SH), titin, citric acid antigen (CA), and ryanodine receptor (RyR) in sera from 146 consecutive MG patients to evaluate whether a single test or several tests together can predict a thymoma. The MG patients were divided into five subgroups; ocular MG, early-onset MG (< 50 years), late-onset MG (≥ 50 years), MG with thymoma, and AChR antibody negative MG. AChR, SH, titin, CA, and RyR antibodies were detected in 85%, 34%, 34%, 25%, and 14% of the MG patients, respectively. For thymoma MG, AChR, SH, titin, CA, and RyR antibodies were detected in 100%, 75%, 95%, 70%, and 70% respectively. SH, titin, CA, RyR antibodies, and computed tomography of the anterior mediastinum have similar sensitivity for thymoma MG. The specificity of RyR, titin, CA, and SH antibodies for thymoma was 70%, 39%, 38%, and 31%, respectively, which is significantly higher for RyR antibodies than for the others. No single muscle antibody assay can predict a thymoma, and a combination of several antibody assays is preferred, although RyR antibody testing alone showed 70% sensitivity and specificity for thymoma MG. SH and CA antibodies provided only little additional information.

Associated disorders in myasthenia gravis: autoimmune diseases and their relation to thymectomy.

ABSTRACT— The prevalence of myasthenia gravis (MG) in the counties of Hordaland and Sogn & Fjordane on January 1, 1984 was 9.6 per 100,000 inhabitants. Other autoimmune diseases were found in 11 out of 48 MG patients. The occurrence of autoimmune thyroiditis (5 patients, 10.4%) and systemic lupus erythematosus (4 patients, 8.3%) in the MG patients was clearly higher than that reported in the general population. Rheumatoid arthritis was found in 2 patients (4.2%). The autoimmune diseases were mainly recorded among the nonthymectomized MG patients. In addition to those with definite diseases of autoimmune nature, 3 other MG patients had thyroid antibodies and 1 had antinuclear factor without clinical evidence of autoimmune disease. Seven MG patients (14.6%) had unspecific arthralgia during active periods of MG. Two MG patients had ankylosing spondylitis.

Ryanodine receptor antibodies related to severity of thymoma associated myasthenia gravis.

Ryanodine receptor (RyR) antibodies are detected in about 50% of patients with myasthenia gravis who have a thymoma. The RyR is a calcium release channel involved in the mechanism of excitation-contraction coupling in striated muscle. In this study the severity of myasthenia gravis assessed by a five point disability score was compared between 12 patients with myasthenia gravis, a thymoma, and RyR antibodies and 10 patients with myasthenia gravis and a thymoma but without such antibodies. Symptoms of myasthenia gravis were significantly more severe in patients with RyR antibodies. The mean (SD) disability scores were 3.7(0.5) in patients with antibodies and 2.7 (0.9) in those without at peak of illness, (p = 0.01) and 3.4(1.4) v 1.6(0.7) at the end of an average observation period of five years (p = 0.002). The number of deaths due to myasthenia gravis was five of 12 RyR antibody positive patients, and none of 10 RyR antibody negative patients (p = 0.04). RyR antibody levels correlated positively with severity of myasthenia gravis. The presence of circulating RyR antibodies seems to be associated with a severe form of thymoma associated myasthenia gravis.

Myasthenia gravis: clinical, immunological, and therapeutic advances.

We give an update on clinical, immunological, and therapeutic advances in the field of myasthenia gravis, including a summary of suggested therapeutic recommendations.

EARLY PROGNOSTIC FACTORS FOR DISABILITY IN MULTIPLE-SCLEROSIS, A EUROPEAN MULTICENTER STUDY

The effects of initial clinical variables on short‐term prognosis are analyzed in a cross‐sectional study of 574 multiple sclerosis patients from 7 centers in 5 European countries. Patients with a primary progressive course had a 2.3 higher mean disability score (EDSS) than the primary remittent group after a mean duration of disease of 6.6 years. High age at onset was associated with a primary progressive course, and was also related to increased risk of a rapid shift to a secondary progressive course. Among the remittent patients without a secondary progressive course a high age at onset was significantly correlated to a higher disability score. In the whole remittent group the presence of pyramidal and cerebellar symptoms at onset predicted both a high disability score and a rapid shift to a secondary progression, while the effect was reverse for sensory and visual symptoms. No difference between the sexes was found.

Titin Antibodies in Patients with Late Onset Myasthenia Gravis: Clinical Correlations

We have tested sera from 21 thymectomized patients with onset of MG after 40 years of age and without thymoma for antibodies against titin, using ELISA with the titin peptide MGT-30. Titin is a myofibrillar protein unique to striated muscle and important for the elastic recoil of muscle cells. Titin antibodies were detected in 9 of the 21 sera. MG symptoms as assessed by a 6 point disability score (0-5) were significantly more severe in the titin antibody positive patients both at peak of illness; 3.7 vs. 3.1 (p < 0.02) and at latest follow up; 2.1 vs. 0.8 (p < 0.01). All titin antibody positive patients were on immunosuppressive drug treatment at least follow-up, whereas only 3 of 12 patients without titin antibodies used immunosuppressive drugs. The presence of circulating titin antibodies in late-onset non-thymoma MG patients indicates a more severe disease.

Seronegative myasthenia gravis: disease severity and prognosis

Around 10–20% of myasthenia gravis (MG) patients do not have acetylcholine receptor (AChR) antibodies (seronegative), of whom some have antibodies to a membrane‐linked muscle specific kinase (MuSK). To examine MG severity and long‐term prognosis in seronegative MG compared with seropositive MG, and to look specifically at anti‐AChR antibody negative and anti‐MuSK antibody negative patients. Seventeen consecutive seronegative non‐thymomatous MG patients and 34 age and sex matched contemporary seropositive non‐thymomatous MG controls were included in a retrospective follow‐up study for a total period of 40 years. Clinical criteria were assessed each year, and muscle antibodies were assayed. There was no difference in MG severity between seronegative and seropositive MG. However, when thymectomized patients were excluded from the study at the year of thymectomy, seropositive MG patients had more severe course than seronegative (P < 0.001). One seropositive patient died from MG related respiratory insufficiency. The need for thymectomy in seronegative MG was lower than in seropositive MG. None of the seronegative patients had MuSK antibodies. This study shows that the presence of AChR antibodies in MG patients correlates with a more severe MG. With proper treatment, especially early thymectomy for seropositive MG, the outcome and long‐term prognosis is good in patients with and without AChR antibodies.

Heart disease in myasthenia gravis

Abstract– Patients with myasthenia gravis (MG) may develop heart disease. Our data on 108 MG patients were examined to assess the type and frequency of this. 17 of 108 patients (16%) showed signs of heart disease which could be regarded as MG‐related. 11 of these, of whom 5 died suddenly, had clinical symptoms, mainly arrhythmias. Signs of heart disease were most frequent in thymoma patients (5 of 10), and all 3 microscopically examined hearts from these patients showed a focal myocarditis. 44 spinal muscular atrophy patients serving as controls showed a 16% frequency of signs of heart disease of unknown etiology. However, only 1 of 44 spinal muscular atrophy patients (2%) had clinical symptoms as compared to 11 of 108 MG patients (10%). Together with the characteristic focal nature of the myocarditis and the microscopic similarities between lesions of heart and skeletal muscle, this indicates that the heart disease is specifically related to MG.

Post‐polio syndrome patients treated with intravenous immunoglobulin: a double‐blinded randomized controlled pilot study

Post‐polio syndrome (PPS) is characterized by new muscle weakness, atrophy, fatigue and pain developing several years after the acute polio. Some studies suggest an ongoing inflammation in the spinal cord in these patients. From this perspective, intravenous immunoglobulin (IvIg) could be a therapeutic option. We performed a double‐blinded randomized controlled pilot study with 20 patients to investigate the possible clinical effects of IvIg in PPS. Twenty patients were randomized to either IvIg 2 g/kg body weight or placebo. Primary endpoints were changes in pain, fatigue and muscle strength 3 months after treatment. Surrogate endpoints were changes in cerebrospinal fluid (CSF) cytokine levels. Secondary endpoints were pain, fatigue and isometric muscle strength after 6 months. Patients receiving IvIg reported a significant improvement in pain during the first 3 months, but no change was noted for subjective fatigue and muscle strength. CSF levels of tumour necrosis factor‐α (TNF‐α) were increased compared with patients with non‐inflammatory neurological disorders. In conclusion, in this small pilot study no effect was seen with IvIg treatment on muscle strength and fatigue, however IvIg treated PPS patients reported significantly less pain 3 months after treatment. TNF‐α was increased in the CSF from PPS patients. The results are promising, but not conclusive because of the low number of patients studied.