Thymomatous Myasthenia Gravis Research Articles

Anti-cardiac ryanodine receptor antibodies in thymoma-associated myasthenia gravis.

Sera from myasthenia gravis (MG) patients with thymoma were examined in Western blot for the presence of antibodies to proteins in the sarcoplasmic reticulum (SR) of cardiac muscle. Fourteen of 30 MG thymoma sera had IgG antibodies to a protein with the same electrophoretic mobility as cardiac muscle ryanodine receptor (RyR). Anti-cardiac RyR antibodies were not detected in any of the 45 sera from MG patients without thymoma. The same 14 MG thymoma sera, but none of the others, bound to RyR from skeletal muscle as well. Neutralization experiments showed that the anti-RyR antibodies in MG patient cross-reacted with cardiac and skeletal muscle RyR. Since skeletal and cardiac muscle RyRs are antigenically different, our findings may indicate that autoantibodies to RyR in MG originate by sensitization to a peptide shared by cardiac and skeletal muscle RyR, rather than to the complete native RyR.

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 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.

Extrathymic malignancy in patients with myasthenia gravis

The presence of extrathymic malignancies was investigated in 296 thymectomised myasthenia gravis (MG) cases. In 5 of the 296 cases, extrathymic malignant tumours were observed. 4 of the 5 cases had thymomatous MG. 3 cases had malignant fibrous histiocytoma. Extrathymic malignancies were observed more frequently in thymomatous MG than in non-thymomatous MG. 59 cases (60 tumours), including our 5 cases, who had MG and extrathymic malignant tumours were compiled from the literature. In the 60 extrathymic malignancies, leukaemia and reticulo-endothelial sarcoma were the most frequent types.

Heart Muscle Antibodies in Myasthenia Gravis

Myasthenia gravis (MG) may in some patients, especially in those with a thymoma, involve the heart. Using an ELISA, we measured heart muscle antibodies in sera from 75 MG patients and in 173 control sera. Heart muscle antibodies were detected in 29/30 thymoma MG patients, in none of 30 young onset MG patients with thymic hyperplasia and in 7/15 late onset MG patients with thymic atrophy. Among the controls, four sera had a very low concentration of heart muscle antibodies. Absorption studies showed that the heart muscle antibodies cross-react with skeletal muscle, but are unrelated to acetylcholine receptor antibodies.

Myasthenic thymus and thymoma are selectively enriched in acetylcholine receptor–reactive T cells

We compared T-cell proliferative responses to acetylcholine receptor (AChR) and to purified protein derivative (PPD) (of tuberculin) of hyperplastic thymus, thymoma, and blood cells from patients with myasthenia gravis (MG). Hyperplastic MG thymus cells gave significantly higher and more consistent responses to AChR than parallel cultures of autologous blood cells, whereas responses to PPD showed an opposite trend. Thus there was a preferential localization of AChR-reactive T cells in the hyperplastic MG thymus. Furthermore, there was a strong correlation between blood and thymus cell responses to PPD (but not to AChR), arguing that the hyperplastic MG thymus contains a sample of sensitized peripheral T cells. By contrast, both AChR- and PPD-responsive T cells were almost undetectable in thymus from nonmyasthenic patients, which is evidently much less receptive to circulating T cells. Cells from MG thymomas showed the highest stimulations by AChR but did not consistently react to PPD. However, the uninvolved thymus adjacent to these thymomas behaved almost identically to the hyperplastic samples described above. Our interpretation is that AChR-specific T cells are initially sensitized in the MG thymoma but are selectively trapped in the hyperplastic thymus after being primed elsewhere.

Radiological diagnosis of thymoma in myasthenia gravis (MG): Review of a series of 523 surgically controlled patients

Radiological diagnosis of thymoma in myasthenia gravis (MG): Review of a series of 523 surgically controlled patients

Thymectomy in myasthenia gravis. Results of 662 cases operated upon in 15 years.

The results of thymectomy in the treatment of myasthenia gravis (MG) are reviewed in the light of a personal series of 662 MG patients, operated upon during the last 15 years. In 500 MG patients without thymoma, the following results have been achieved: remission 37.9%, improvement 49.4%, unchanged or worse 7.4%, dead 5.2%. There is no sex prevalence and the remission rate is higher in patients under 40 years of age (P less than 0.01), with mild disease (P less than 0.05), with a MG duration of less than 1 year (P less than 0.05) and with a follow-up length of between 5 and 10 years (P less than 0.01). No correlations are found between outcome and thymic histology. The results of 162 MG patients with thymoma are: remission rate 15.7%, improvement 60.3%, unchanged or worse 3.7% and dead 20.1%. The remission rate is higher with mild symptoms (P less than 0.05) and when the tumour is encapsulated (P less than 0.02). The postoperative mortality is 0.8% (none in the last 5 years) for non-thymomatous MG and 4.9% for thymomatous MG (2 of 8 patients died of pancytopaenia and 1 of pulmonary embolism).

Thymomatous myasthenia gravis.

The clinical course of 195 cases of myasthenia gravis was studied. Among them, 90 myasthenia patients received thymectomies, and of these, thirty cases of thymoma were pathologically proven. The incidence of thymomatous myasthenia gravis in these thymectomized patients was 33.3%. The average age of these 30 cases was 44.4±14.2 years and the sex ratio was almost equal. Their onset age was at 42.2±14.6 years. Before thymectomy, the clinical severity of 89.7% of thymoma patients were of a generalized type, especially typeⅡb, Ⅲ or Ⅳ. Compared with the two groups of thymic hyperplasia and hypoplasia, thymoma patients had a later onset with an equal sex distribution, and manifested a more severe myasthenia. The thymoma may be detected on radiological examination of the chest, especially by mediastinal CT scan. But in 16% of cases, the tumors were so small that they were found only after thymectomy. All patients underwent maximal thymectomy. The pathology of the thymus in these patients was predominantly of the lymph-epithelial type. Four cases (13.3%) were malignant thymoma and received radiation therapy after thymectomy. The histology of the tumor seemed to have no relationship to the severity of the myasthenia gravis. On follow-up of the showed improvement; 13.8% were in the state of remission; 65.5% showed improvement; 13.3% were unchanged and the mortality rate was 6.8%. Postoperative improvement was either immediate or gradual.

Surface phenotypes of lymphoid cells altered in the human myasthenic thymus.

We investigated surface phenotypes of peripheral blood lymphocytes and thymic lymphoid cells from patients with myasthenia gravis (MG) by fluorocytometry, using monoclonal antibodies to human lymphoid cells. There were no significant differences in peripheral blood lymphocyte subsets in myasthenic patients, with or without a thymus. In the MG hyperplastic thymuses, the percentage of OKIa1+ cells or CCB1+ cells was significantly increased compared with controls. Although there were no significant differences in the percentage of T-cell lineage (CD3+, CD4+, CD8+, or CD1+ cells) between MG hyperplastic thymuses and the controls, the surface densities of T-cell lineage antigens (CD3, CD4, and CD8) were significantly increased on lymphoid cells in MG hyperplastic thymuses, compared with those in control thymuses. There were no significant differences in the percentage or fluorocytograph of lymphoid cells between the MG thymomas and the controls.

Clinical Characteristics and Prognosis of Myasthenia Gravis with Other Autoimmune Diseases

Of 277 patients with myasthenia gravis (MG) who underwent thymectomy, including 78 with thymomatous MG, 33 patients had other autoimmune diseases. The clinical characteristics of MG with other autoimmune disease were investigated. Graves's disease and rheumatoid arthritis were the most common autoimmune diseases seen. The association rate of autoimmune disease in patients with thymomatous MG (3.8%) was significantly lower than that in patients with nonthymomatous MG (15.1%). The positive rate for a germinal center in the thymus was significantly higher in patients with other autoimmune disease than in those without such disease. Thymectomy was effective for MG in patients with an associated disease as well as in those without such a complication. The clinical course of the associated autoimmune disease did not seem to be adversely affected by thymectomy. Therefore, thymectomy should be performed in MG patients with other autoimmune disease.

Continuous remission of myasthenia gravis with the recurrence of thymoma

The etiologic role of the thymus and thymoma in myasthenia gravis (MG) is still obscure. In this report, we presented a MG patient affected with thymoma whose myasthenic symptoms had disappeared after the surgical removal of thymoma together with non-thymomatous thymus. The patient had been continuously in remission when the thymoma recurred 6 years after.We have speculated that there is a possibility that either the thymomatous or non-thymomatous thymus can have an effect positively or negatively on the development of myasthenic symptoms.

Extractable Nuclear Antigen autoantibodies and their association with other autoantibodies and thymoma in myasthenia gravis

The presence of autoantibodies to Extractable Nuclear Antigens (ENA) in myasthenia gravis (MG) was evaluated. These antibodies represent a subset of antinuclear antibodies (ANA), with ENA consisting of RNA and nucleoprotein. ENA autoantibodies had a prevalence of 44% in MG when tested by an

Invasive thymoma with myasthenia gravis.

In 261 surgically treated patients with myasthenia gravis (MG), 26 had an invasive thymoma and 49 had a noninvasive thymoma. Invasive thymoma was seen in 41% of thymomatous MG patients older than 40 years of age, and 28% in patients younger than 40 years of age. Of 19 patients who underwent total or subtotal thymothymomectomy accompanied by irradiation (4000 rad), 17 were still alive on an average 6.5 years after surgery. The deterioration of MG by the irradiation was observed in 7 of 20 irradiated cases. Thus, postoperative irradiation is effective but should be done with attention to the deterioration of MG. The prognosis of MG in patients with an invasive thymoma was poorer than that in patients with a noninvasive thymoma.

Myasthenia Gravis with Thymoma: Analysis of and Postoperative Prognosis for 65 Patients with Thymomatous Myasthenia Gravis

Sixty-five patients with thymomatous myasthenia gravis were investigated. Thymomas were present in 44% of the male patients and 19% of the female patients with myasthenia gravis. The incidence of thymomatous disease in male patients was higher than in female patients in all age groups. Eighty percent of men more than 50 years old and women more than 60 years old had myasthenia gravis with thymoma. Germinal center formation in the thymus of patients with thymomatous myasthenia gravis was positive in 91% and was high grade. The prognosis for patients undergoing extended thymectomy of thymomatous myasthenia gravis was significantly better than in those having transsternal simple thymectomy, but it was worse than the prognosis for patients with nonthymomatous myasthenia gravis. No increase in the rate of remission or palliation was seen one year after thymectomy. It is concluded that early thymectomy is effective in control of myasthenia gravis in thymomatous myasthenia gravis.

The diagnosis of thymoma in myasthenia gravis.

Between 10 and 15 per cent of patients with myasthenia gravis (MG) have a thymoma. We have evaluated the possibility of detecting such tumours on the basis of clinical features, radiological findings and immunological tests in a group of 70 MG patients. The mean age at onset of myasthenic symptoms was 67.6 years in the thymoma group and 33.8 years in the non-thymoma group. Otherwise, the clinical picture was similar. Radiological examination revealed a mediastinal mass in 2 patients. Six of the 70 MG sera contained antibodies to a citric acid (CA) extract of striated muscle. At thymectomy, a thymoma was found in these 6 patients. None of the remaining 64 patients had evidence of a thymoma. Antibodies to AChR were detected in 52 of the 70 MG sera. There was no relation between titres of AChR and CA antibodies. Three out of 5 sera from non-MG patients with a thymoma contained CA antibodies. Apparently, this assay is a valuable technique for the identification of a thymoma at an early stage.

Computed Tomography of the Thorax and Standard Radiographic Evaluation of the Chest

Comparison of standard radiographic evaluation of the chest with computed tomography (CT) was carried out in 109 patients who were examined on a prototype EMI CT5000 scanner. Forty-eight patients had lung problems, and 61 were evaluated because of a mediastinal mass or widening, or for the detection of an occult thymoma in myasthenia gravis. Computed tomography was of value in the staging of bronchogenic carcinoma, particularly in the detection of direct mediastinal and pleural extension, and in evaluating patients with solitary or multiple nodules by detecting additional lesions and calcification. Thymomas not detected on conventional imaging modalities were visualized in 4 of 33 patients with myasthenia gravis or red cell aplasia. One of these was a false positive. In 28 patients with a mediastinal mass or widening on the chest roentgenogram, incremental information was noted on CT in 22. These included a definitive diagnosis of lesions composed of fat, evaluation of the isolated esophagus after colon by bypass surgery,and identification of the cause of paraspinal widening.

Thymic and peripheral blood T‐and B‐cell levels in myasthenia gravis

We have compared the percentage of T and B lymphocytes in the thymus and peripheral blood populations of patients with myasthenia gravis. There were significantly fewer thymic T cells in myasthenic hyperplastic thymus (MG-H), but not in myasthenia gravis-thymoma (MG-T), compared with normal thymus biopsies obtained at cardiac surgery. Conversely, B cells were increased in MG-H versus MG-T and normals. Peripheral blood T and B cells were not different in any group of myasthenic patients compared to normal populations. In vitro autologous mixed lymphocyte reactions between thymus and peripheral blood lymphocytes occurred in MG-H, but did not correlate with the degree of thymic B-cell increases in these patients.

Anesthesia for Transcervical Thymectomy in Myasthenia Gravis

This review of anesthetic experience in 100 cases of transcervical thymectomy for myasthenia gravis (MG) at The Mount Sinai Hospital (1970-1974) underlines current trends in the surgical management at Mount Sinai, where transcervical thymectomy is the procedure of choice for all patients with nonthymomatous MG and for selected patients with thymomatous MG. The transthoracic approach is now limited to malignant thymomas and tumors not accessible through the transcervical approach. Formerly, patients coming for thymectomy either already had a preexisting tracheostomy, or an elective tracheostomy was performed at the time of thymectomy. Since 1972, none of these patients has had elective tracheostomy at the time of operation, and only four were performed in the postoperative period, patients being intubated orotracheally at the time of operation. The tube is usually removed within 1 hour after completion of thymectomy. All patients are followed in the intensive care unit for 24 hours or longer, under close supervision of experienced personnel aware of the inherent problems and able to assist ventilation at any stage. This approach has greatly changed the postoperative course of this disease.

Studies in myasthenia gravis: Effects of thymectomy: Results on 185 patients with nonthymomatous and thymomatous myasthenia gravis, 1941–1969

One hundred and eleven patients with myasthenia gravis and seventy-four patients with thymomatous myasthenia gravis underwent thymectomy between 1941 and 1969. Fifty per cent of the patients who achieved remission did so after a delay of two or more years. The time of onset of remission was directly related to the activity of the thymic germinal centers. In the nonthymoma patients remissions were stable and, with few exceptions, permanent. The percentage of patients in remission increased with each consecutive postoperative year, and 90 per cent of patients with a five year follow-up were in remission or had shown improvement. Sex, age and duration of symptoms had no marked influence on this trend. No death due to myasthenia occurred after the fourth postoperative year (excluding malignant thymomas); germinal centers were present in all the fatalities. These observations are consistent with the hypothesis that autoimmune diseases are due to abnormal clones of immunocompetent lymphocytes proliferating in the thymic germinal centers. In addition, the results suggest that thymectomy produces stable remission by eliminating these thymic centers; but its effect is delayed because of the long life span of the existing pool of small immunocompetent lymphocytes.