Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features.

Myasthenia gravis (MG) is an autoimmune disease caused in 85% of the patients by acetylcholine receptor (AChR) antibodies. Non-AChR muscle antibodies, against titin and ryanodine receptor (RyR) are mainly found in sera of patients with thymoma or late-onset MG. The occurrence of RyR antibodies increases the risk for severe MG and should lead to active immunomodulating treatment already at MG onset. The aim in this study was to describe the association between symptoms at MG onset and antibody profile in 152 patients. Patients with RyR antibodies had the highest rate of bulbar, respiratory and neck involvement at MG onset. They also had the highest frequency of non-limb MG symptoms. Neck weakness occurred in 40%. Respiratory difficulties at MG onset occurred in patients with titin antibodies, with and without RyR antibodies. Patients with RyR antibodies have a distinctive non-limb MG symptom profile, with bulbar, ocular, neck, and respiratory symptoms. These features, identified as early as at the first examination by a neurologist, characterize the RyR antibody positive subgroup at MG onset.

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-alpha (TNF-alpha) 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-alpha was increased in the CSF from PPS patients. The results are promising, but not conclusive because of the low number of patients studied.

Titin and ryanodine receptor antibodies in myasthenia gravis.

Some myasthenia gravis (MG) patients have antibodies against skeletal muscle antigens in addition to the acetylcholine receptor (AChR). Two major antigens for non-AchR antibodies in MG are the Ca(2+) release channel of the sarcoplasmic reticulum, the ryanodine receptor (RyR) and titin, a gigantic filamentous muscle protein essential for muscle structure, function and development. RyR and titin antibodies are found mainly in thymoma MG patients and in a few late-onset MG patients and correlate with a severe MG disease. The presence of titin antibodies, which bind to key regions near the A/I junction and in the central I-band, correlates with myopathy. The immunosuppressant (FK506), which enhances Ca(2+) release from the RyR, seems to have a symptomatic effect on MG patients with RyR antibodies. The RyR antibodies recognize a region near the N-terminus important for channel regulation and inhibit Ca(2+) release in vitro. However, evidence that antibodies against the intracellular antigens RyR and titin are pathogenic in vivo is still missing.

Myasthenia gravis: disease severity and prognosis.

OBJECTIVES: To examine myasthenia gravis (MG) severity and long-term prognosis in seronegative, seropositive, and thymoma MG. MATERIALS AND METHODS: Four series of patients were studied retrospectively. Severity and treatment were assessed each year, and muscle antibodies were assayed. RESULTS: Seropositive MG patients had a more severe course than seronegative MG patients. MG severity was higher in non-thymectomized compared to thymectomized early-onset MG patients. MG severity did not differ between thymectomized and non-thymectomized late-onset patients. There was no significant difference in MG severity between thymoma and non-thymoma MG patients. CONCLUSIONS: MG is more severe in seropositive MG patients. With proper treatment, especially early thymectomy, the long-term prognosis is good in seropositive MG patients. The present studies indicate a benefit of thymectomy in early-onset MG, but no dramatic benefit in late-onset MG. Similar MG severity and outcome was seen in thymoma and non-thymoma MG.

Epilepsy and the immune system.

OBJECTIVE: To discuss evidence that immune mechanisms are involved in the pathogenesis of some forms of epilepsy. DATA SOURCES: Computerized data sources and published indexes and articles. STUDY SELECTION: Published reports showing disorders of the immune system in patients with epilepsy and in animals with experimental epilepsy. DATA SYNTHESIS: Rasmussen encephalitis is an example of an autoimmune disorder of the central nervous system. Serum samples of patients with this disease contain antibodies to the glutamate receptor GluR3, and immunization of animals with GluR3 induces a disorder resembling the human disease. There are still few data to prove that immune mechanisms are involved in the pathogenesis of intractable childhood epilepsies other than Rasmussen encephalitis. Epilepsy is more common in patients with systemic lupus erythematosus who have antiphospholipid antibodies, and it is possible that these antibodies can lead to immune-mediated cortical damage. Immune defects in patients with epilepsy may occur as a consequence of long-term antiepileptic treatment or may represent a genetic coupling to the convulsive disorder. CONCLUSION: The finding of an immunological basis may offer new modalities for the treatment of selected cases of intractable partial epilepsies.

Late-onset myasthenia gravis: a changing scene.

The prevalence of myasthenia gravis (MG) among middle-aged and older patients has increased. Patients with early-onset MG live longer than before, but there is also an increase in late-onset MG (onset of the disease after the age of 50 years in patients with no clinical or paraclinical evidence of a thymoma). Epidemiological data support using the age of 50 years to separate early- and late-onset MG. The main immunological difference between early- and late-onset MG is the presence of antibodies to muscle titin, which are detected in approximately 50% of patients with late-onset MG. Treatment of late-onset MG has to be tailored both to the age of the patient and to the immunological findings of that particular form of MG.

Drug-induced IgA deficiency in epileptic patients.

Serum concentrations of IgA, IgG, and IgM were determined by immunodiffusion technique in 184 epileptic patients and 95 healthy individuals. Twenty-one percent of adult and 42% of children patients receiving anticonvulsants had serum IgA levels below 0.6 mg/ml (the lowest value detected in normal sera). Serum concentrations in non-drug-taking epileptic patients were normal. Deviations in IgG/IgM concentrations were smaller and less consistent. Serum IgA level was determined at intervals before and during phenytoin treatments. A fall in the IgA level occurred in several patients. In two patients, IgA deficiency developed within two to three months of treatment. Low IgA-responders were more frequent among men and children. The IgA anomaly was not specific for any type of epilepsy.

The severity of myasthenia gravis correlates with the serum concentration of titin and ryanodine receptor antibodies.

BACKGROUND: Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR). Non-AChR muscle autoantibodies are present in many MG serum samples, mainly from patients with thymoma or late-onset MG. The exact relationship between MG severity and several non-AChR muscle antibodies is unknown. OBJECTIVE: To study the correlation between the severity of MG and the concentration of antibodies against striated muscle tissue sections, titin, citric acid antigen, ryanodine receptor, and AChR. SETTING: The severity of MG was graded in 146 consecutive patients with MG, and their serum samples were tested for the presence of autoantibodies. Ten patients who were titin antibody positive were observed in longitudinal follow-up. RESULTS: No significant difference was found in MG severity between late-onset and thymoma MG. Titin, citric acid antigen, and ryanodine receptor antibodies occurred significantly more often among patients with severe MG than among patients with less severe disease. Changes in MG severity correlated with changes in titin antibody titer in the individual patient. Titin antibodies showed a better longitudinal correlation with disease severity than the AChR antibodies. CONCLUSIONS: Non-AChR muscle autoantibodies occurred more frequently in severe MG regardless of MG subgroup. Thymoma per se does not generate a more severe MG. It may well be the presence of a humoral immune response to non-AChR muscle antigens such as titin, citric acid antigen, and ryanodine receptor that leads to a severe disease, not the presence of thymoma or a late age of onset. These antibodies can serve as important prognostic markers in MG regardless of the presence of thymoma.

TNFA and TNFB polymorphisms in myasthenia gravis.

BACKGROUND: Tumor necrosis factor (TNF) alpha and TNF-beta are proinflammatory cytokines thought to be involved in the pathogenesis of myasthenia gravis (MG). OBJECTIVE: To examine whether TNF polymorphisms are associated with MG, MG subgroups, and the presence of titin and ryanodine-receptor antibodies. PATIENTS AND METHODS: We did genotyping on 30 patients with MG and 92 healthy blood donors for 2 biallelic TNFA polymorphisms (G to A at positions -238 and -308) and 1 TNFB polymorphism (NcoI digestive site) using methods based on the polymerase chain reaction. RESULTS: Patients with thymoma were typically homozygous for both the TNFA*T1 and the TNFB*2 alleles, but patients having an early onset of MG without thymoma were carriers of the TNFA*T2 and TNFB*1 alleles. Patients without thymoma who had the titin antibody had the same high frequency of TNFA*T1 and TNFB*2 as patients with thymoma, whereas patients without the titin antibody carried the same allele, TNFA*T2 and TNFB*1, regardless of age and thymic disease. No association was found with acetylcholine-receptor levels or disease severity for any of the TNFA or TNFB polymorphisms. CONCLUSION: Patients having MG, including those with thymoma, who have the titin antibody are most often homozygous for the TNFA*T1 and TNFB*2 alleles, whereas the presence of the TNFA*T2 and TNFB*1 alleles correlates with early-onset MG and the absence of titin antibodies.

Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia.

BACKGROUND: About 50% of patients with thymoma have paraneoplastic myasthenia gravis (MG). Myositis and myocarditis or neuromyotonia (NMT) will also develop in some. Patients with thymoma-associated MG produce autoantibodies to a variety of neuromuscular antigens, particularly acetylcholine receptor (AChR), titin, skeletal muscle calcium release channel (ryanodine receptor [RyR]), and voltage-gated potassium channels (VGKC). OBJECTIVE: To examine whether neuromuscular autoantibodies in patients with thymoma correlate with specific clinical syndromes. METHODS: Serum and plasma samples from 19 patients with thymoma-associated MG, of whom 5 had myositis and 6 had NMT, underwent testing for antibodies to AChR, titin, RyR, and VGKC. RESULTS: Antibodies to AChR and titin were found in 19 and 17 patients, respectively. Antibodies to RyR correlated with the presence of myositis (P = .03); they were found in all 5 patients with myositis and in only 1 patient with NMT, but also in 4 of 8 patients with neither disease. Antibodies to VGKC were found in 4 patients with NMT, 1 of 3 patients undergoing testing for myositis, and 2 of 7 patients undergoing testing with neither comorbidity. Presence of RyR antibodies correlated with high levels of titin antibodies. CONCLUSIONS: The results appear to distinguish partially between 3 groups of patients with thymoma-associated MG: the first with RyR antibodies and myositis or myocarditis, the second with NMT without RyR antibodies, and the third without RyR antibodies, myositis, or NMT. Differences in the thymoma may underlie these pathologic associations.

Sinemet CR in the treatment of patients with Parkinson's disease already on long-term treatment with levodopa.

The efficacy of controlled-release Sinemet was evaluated in a 52-week open trial involving 20 patients (14 men, 6 women; mean age 66 years, range 56 to 82) with idiopathic Parkinson's disease of 8 years' mean duration. The mean daily dosage of levodopa was 662.5 mg (200 to 1600 mg) on entering the study and 800 mg (200 to 2400 mg) after 52 weeks. The mean number of daily doses was reduced from 5.0 (2 to 16) at entry to 3.3 (1 to 6) after 52 weeks. Rigidity, tremor, and bradykinesia were scored at 3 intervals during baseline and 8 intervals during the study on controlled-release levodopa. All parameters improved, with maximum improvement seen at week 12. Side effects were less frequent on the controlled-release preparation. After 5 months, 1 patient developed protracted dyskinesia with freezing episodes and end-of-dose deterioration on dose frequency reduction.

Myasthenia gravis: difference between thymoma-associated antibodies and cross-striational skeletal muscle antibodies.

Serum from 20 of 137 patients (15%) with myasthenia gravis (MG) contained antibodies to a citric acid extract (CAE) of skeletal muscle. A thymoma was found in all 19 of these patients who were thymectomized. There was no evidence of thymoma in patients who did not have CAE antibodies. Serum from 40 of the same 137 patients (30%) contained antibodies that gave a cross-striational immunofluorescent pattern in skeletal muscle. This pattern was seen with serum from 16 of the 20 thymoma patients, but also with serum from 24 patients without thymoma. The cross-striation antibodies were not absorbed by CAE coated on to tanned sheep erythrocytes. Accordingly, antibodies detected in the two tests have different specificities.

IgG subclass distribution of myasthenia gravis thymoma-associated antiskeletal muscle antibodies.

Myasthenia gravis patients with thymoma often have serum antibodies directed against human skeletal muscle. We have developed an enzyme-linked immunosorbent assay to investigate the subclass distribution of these antibodies. Five thymoma patients all had IgG4 antibodies, whereas a patient who developed myasthenia gravis after bone-marrow transplantation had only IgG1 antibodies. The data suggest that IgG1 is the first subclass to appear in the autoantibody response against skeletal muscle.

Western Norway, a high-risk area for multiple sclerosis: a prevalence/incidence study in the county of Hordaland.

Prevalence studies and investigations based on death certificates and disability assistance have shown that western Norway has been a medium-frequency area for MS. The prevalence of definite/probable MS on January 1, 1963 was 20.1/100,000. Based on the same diagnostic criteria, the prevalence of definite/probable MS had increased to 59.8/100,000 on January 1, 1983 in the county of Hordaland. We consider this increase of MS cases in the population to be due to real biologic changes, although factors affecting the figures were found. Most important was a reduction in the interval from onset to diagnosis. The rise in prevalence was also supported by an increase in the annual incidence of the disease. The incidence rate averaging 2 per 100,000 in the period 1953 to 1962 rose to 3.5 for 1968 to 1977. This marked rise in prevalence/incidence supports the concept that an exogenous factor is important in the pathogenesis of MS.

Titin antibodies in myasthenia gravis: identification of a major immunogenic region of titin.

Approximately 15% of patients with myasthenia gravis (MG) have thymus neoplasia. These MG with thymoma (MGT) patients show autoantibodies to striated muscle as well as autoantibodies to acetylcholine receptor. To characterize these thymoma-associated muscle antigens, we cloned a number of immunopositive cDNAs by immunoscreening muscle cDNA libraries with sera from MGT patients. Analysis of the isolated cDNAs show that all share a common sequence encoding a distinct region of the titin gene. We expressed this main immunogenic region (MIR) of titin in Escherichia coli, and determined autoantibody serum titers directed against the obtained recombinant antigen in a variety of patients. We could detect titin MIR autoantibodies in 97% of sera from MGT patients but not in control sera from healthy blood donors. Therefore, expressed titin from the MIR of the molecule is a sensitive marker antigen for evaluating the presence of thymoma in MG.

Myasthenia gravis. Antibodies to skeletal muscle cell surface antigens.

Sera from 28 of 137 patients with myasthenia gravis (MG) (i.e. 20%) contained antibodies which stained the surface of skeletal muscle cells in an indirect immunofluorescence test. Forty of the 137 sera (i.e. 30%) contained cross-striational antibodies. Absorption experiments showed that the antibodies staining the muscle cell surface were different from those staining the cross-striational bands. Twenty of the sera (i.e. 15%) contained antibodies which agglutinated sheep erythrocytes (SE) coated with a citric acid extract of skeletal muscle (CAE). These antibodies were closely associated with the presence of a thymoma. There was a positive correlation between the antibodies agglutinating CAE-coated SE and those staining the muscle cell surface. Absorption experiments indicated that the antibodies to CAE were directed against muscular antigens located in or near the sarcolemma.

Thymoma-specific antibodies in sera from patients with myasthenia gravis demonstrated by indirect haemagglutination.

An indirect haemagglutination technique for the demonstration of antibodies to skeletal muscle is described. Eight out of 9 sera from unoperated myasthenia gravis (MG) patients with thymoma and 6 out of 22 sera taken from MG patients who had been operated upon for a thymoma, contained antibodies to this antigen. Twenty-five sera from MG patients with histologically verified thymus hyperplasia did not contain such antibodies. There was no relationship between these antibodies and antibodies to acetylcholine receptor.

Rabbit antiserum to a citric acid extract of human skeletal muscle staining thymomas from myasthenia gravis patients.

Rabbit antiserum to a citric acid extract of human skeletal muscle (CA) stained both the cell membrane and the cross-striational bands of skeletal muscle cells. The rabbit antiserum also stained the cell membrane of epithelial thymoma cells from myasthenia gravis (MG) patients. Normal and hyperplastic thymus tissue were not stained, apart from scattered myoid thymic cells. Absorption of the antiserum with CA abolished staining of the thymoma, indicating that human skeletal muscle and epithelial thymoma cells possess common antigens.

Thymomas express epitopes shared by the ryanodine receptor.

Myasthenia gravis (MG) patients with thymoma have antibodies against ryanodine receptor (RyR) of skeletal and heart muscle. In this study, thymomas were examined for reactivity with a panel of polyclonal rabbit antibodies against various short peptides of RyR. An antibody against peptide C2 in the transmembrane region of RyR stained thymoma epithelial cells in cryosections of 17/23 thymomas, and detected a 40-kDa peptide in Western blotting of a thymoma membrane fraction. The other RyR antibodies did not react with thymoma tissue. The anti-C2 RyR antibody did not react with normal thymus, tonsil or carcinoma of colon. The results strongly indicate that epithelial thymoma cells express an epitope shared by the transmembrane region of skeletal and cardiac muscle RyR.

Myasthenia gravis patients with a thymoma have antibodies against a high molecular weight protein in sarcoplasmic reticulum.

Our purpose was to investigate whether components of the sarcoplasmic reticulum (SR) are relevant antigens in myasthenia gravis (MG). Using enzyme-linked immunosorbent assay (ELISA), 75 MG sera and 120 control sera were examined for IgG antibodies against SR prepared from rabbit skeletal muscle. 16/30 thymoma MG patients had IgG antibodies that reacted with SR. 1/30 MG patients with thymic hyperplasia and 3/15 MG patients with thymic atrophy had SR antibodies in low concentrations. Control sera were negative. Using immunoblot, SR antibodies were detected in the thymoma group only. 14/30 sera from thymoma patients reacted with a protein of 320 kDa relative molecular weight. The only reported SR protein with similar electrophoretic mobility is the subunit of the spanning protein which links junctional SR to sarcolemma and functions as a calcium-release channel.