Myasthenia gravis and invasive thymoma: a 20-year experience.

In 20 years, 19 patients with myasthenia gravis and invasive thymoma have been seen by the Neurology Service at the UCLA Center for Health Sciences. This represents 4 percent of 493 myasthenia gravis patients seen during the same time and 37 percent of myasthenic patients with thymomas. Eight are still alive and 11 have died. Fifteen patients had the onset of myasthenic symptoms before discovery of the thymoma, while only four patients had chest symptoms and/or radiographic evidence of an anterior mediastinal mass prior to the onset of weakness. Radical excision of the tumor, if possible, and the remaining thymus, high dosage alternate day prednisone, and radiation therapy, if indicated, seem the treatments of choice. Recurrences of tumor nodules may necessitate further local radiation or the use of cytotoxic agents.     

BDNF and its receptors in human myasthenic thymus: implications for cell fate in thymic pathology

Here we show that in myasthenic thymus several cell types, including thymic epithelial cells (TEC) and immune cells, were the source and the target of the neurotrophic factor brain-derived growth factor (BDNF). Interestingly, many actively proliferating medullary thymocytes expressed the receptor TrkB in vivo in involuted thymus, while this population was lost in hyperplastic or neoplastic thymuses. Furthermore, in hyperplastic thymuses the robust coordinated expression of BDNF in the germinal centers together with the receptor p75NTR on all proliferating B cells strongly suggests that this factor regulates germinal center reaction. Finally, all TEC dying of apoptosis expressed BDNF receptors, indicating that this neurotrophin is involved in TEC turnover. In thymomas both BDNF production and receptor expression in TEC were strongly hindered. This may represent an attempt of tumour escape from cell death.     

Thymectomy in the treatment of myasthenia gravis: report of 247 patients

Summary We made a retrospective assessment of the long-term outcome in 247 consecutive patients with myasthenia gravis (MG) who underwent thymectomy in the period January 1971–December 1985. In 84 cases a thymoma was found at surgery, while 163 patients had a non-neoplastic thymus. The duration of symptoms before surgery, the age at onset of the disease and the presence of germinal centres in the thymus did not appear to influence the prognosis. Patients with a non-neoplastic thymus showed a better response to thymectomy. Thymoma was associated with more severe disease and with a higher mortality; moreover, more thymoma patients required corticosteroid treatment in order to achieve good therapeutic results. In our opinion, thymectomy is indicated in the treatment of generalized MG, while ocular myasthenia seems not to be improved by the removal of the thymus.     

The thymus gland in elderly patients with myasthenia gravis.

This study was undertaken to determine the amount and histologic appearance of the persistent thymic tissue removed post mortem from 20 patients over 60 years of age with myasthenia gravis. One patient died several days after thymectomy. No recognizable thymic tissue on gross examination was seen in any patient. On microscopic examination, 11 patients had no thymic tissue. The other nine patients, including the one with thymectomy, all showed marked involution of the thymus. No germinal centers were seen. The thymus glands of two additional patients, still alive after thymectomy at ages 62 and 70, showed similar findings. Marked involution of the thymus also was found in each of six elderly controls. Thymectomy is not likely to be effective treatment of the elderly myasthenic patient.     

A reappraisal of the significance of thymic germinal centers in myasthenia gravis.

The morphology of thymuses removed from 16 cases of myasthenia gravis was studied in an attempt to correlate clinical response following thymectomy with the frequency of thymic germinal centers. In these patients, the presence of germinal centers in the thymus did not appear to influence response to thymectomy.     

Myasthenia gravis developing after discovery of thymoma

We report 4 cases of myasthenia gravis in which myasthenic symptoms developed after a thymoma was known to be present. They include 3 invasive thymomas and one thymoma. In 3 of them, myasthenic symptoms developed 2–7 months after removal of the thymoma; in 1 case, myasthenic symptoms developed 11 years after the thymoma was known to be present. We also discuss here the possible pathogenetic mechanism of post-thymomectomic myasthenia gravis, and propose that it is due to the natural course of the disease.     

Thymus cells in myasthenia gravis: a two-colour flow cytometric analysis of lymphocytes in the thymus and thymoma

Summary The thymus in patients with myasthenia gravis has germinal centres and the thymic lymphocytes spontaneously produce anti-acetylcholine receptor antibody in vitro. This suggests indirectly that the myasthenic thymus contains mature T and B cells that are autoreactive. We report a two colour flow cytometric analysis of the surface antigen phenotype of lymphocytes in the thymus and in thymoma in 24 patients and in 14 normal thymuses. The results show a decline in the proportion of double positive immature thymocytes with age. This process seems to be partially disrupted in patients with myasthenia gravis. In addition titres of anti-acetylcholine receptor antibody were positively correlated with the proportion of mature single positive T cells and non-T DR positive cells.     

Thymectomy in myasthenia with pure ocular symptoms.

Eighteen patients with exclusively ocular symptoms of myasthenia were thymectomised. Suspected thymoma, resistance to pyridostigmine therapy or relapse following immunosuppressive therapy were taken as indications for surgery. The mean preoperative observation period before operation was 40 months, and after operation was 26 months. There was no operative or postoperative morbidity or mortality. Histological thymic abnormalities were found in all patients (in one case, thymoma; in four, persistent thymus; in 13, thymic hyperplasia). The histological abnormalities were identical to those found in generalised myasthenia. This included the distribution of T-cell subtypes as identified by use of monoclonal antibodies. The severity of ocular symptoms was rated using a score developed for this purpose. The score progressively declined after surgery to an average of 70% of its initial amount in 80% of patients. Full remission occurred in three cases. No patient developed generalized myasthenia. Antibody titres against acetylcholine receptors if elevated preoperatively also dropped following surgery, with one exception. Clear criteria for the expected therapeutic success of thymectomy could not be identified. Based on our results, and on the assumed significance of the thymus gland for pathogenesis, thymectomy should be considered in patients with pure ocular symptoms.     

Two cases of myasthenic syndrome with thymoma, polymyositis, myocarditis, and thyroiditis

A clinical and pathological study of 2 cases of a myasthenic syndrome in patients with an unusual combination of multiple visceral lesions (thymoma, polymyositis, myocarditis and thyroïditis) is reported. Histological study of these 2 cases emphazises that a myasthenic syndrome should be considered as the result of an auto-immune disease, but also that the thymus can be a target organ in the pathological process.     

Body computerized tomography and the thymus.

Preoperative body computerized tomography (CT) should be of value in depicting the size, extent, and location(s) of the thymus in myasthenic patients undergoing thymectomy. To date, we have been unable to visualize the thymus in three patients with myasthenia gravis using body CT. However, in two nonmyasthenic patients, large thymomas were clearly delineated. Although application of this technique currently appears limited by the size, location, and density of the thymus and the resolution of the scanners, we feel that CT of the mediastinum is an indicated procedure in the evaluation of the patient before thymectomy, especially in those myasthenic patients with a high risk of thymoma.     

Dropped head syndrome as prominent clinical feature in MuSK-positive Myasthenia Gravis with thymus hyperplasia

MuSK-positive Myasthenia Gravis is in most cases clinically characterized by a progressive course with severe oculobulbar involvement or prominent neck, shoulder and respiratory muscle weakness. It is also distinguished from other forms of myastehnia through its lack of germinal centers or lymphocytic infiltrates in the thymic tissue. We present the case of a MuSK-positive female myasthenic patient with over four years slowly progressive weakness of the neck extensor muscles in the presence of thymus hyperplasia and discuss its uncommon and markedly focal clinical and electrophysiological features, as well as the excellent course under medication with pyridostigmine and prednisone, especially after thymectomy.     

Genetic associations between myasthenia gravis and the HL-A system.

HL-A antigens were determined in 159 myasthenic patients, 112 of whom were females and 47 males. Fifty-seven patients were thymectomized. The relationship between 23 different HL-A antigens and myasthenia gravis (MG) with reference to sex, age at onset, clinical course of MG, thymus histology, and auxiliary diseases of the patients, as well as the significance of these antigens to 245 relatives of myasthenics, were analysed. The frequencies of HL-A1 and HL-A8 were highly significantly higher in myasthenic patients than in normal Finnish controls. The increase of HL-A1 is secondary and due to a strong linkage disequilibrium between HL-A8 and HL-A1. HL-A8 appeared most often in females with onset of MG before the age of 35 years, and inpatients with thymus hyperplasia. No significant HL-A deviations were found in males or in females with later onset of disease. In seven thymoma patients the occurrence of W10 antigen was almost significantly increased.     

Effect of corticosteroids on the thymus in myasthenia gravis

The weight and histological appearance of the thymus from patients with myasthenia gravis were studied. Nine patients treated with corticosteroids were compared with 10 patients not treated with corticosteroids before thymectomy. The thymuses of corticosteroid-treated patients were found to have significantly increased fat and connective tissue, decreased germinal centers, and poorer corticomedullary differentiation than those of untreated patients. The glandular weight and degree of myoepithelial stroma were the same in both groups. The changes following corticosteroid treatment mimic those following aging or acute stress, with retention of the myoepithelial stroma but depletion of thymic lymphoid elements. In myasthenic patients not undergoing thymectomy, the possibility remains that persistent myoepithelial tissue can adversely affect the prognosis.     

Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG

In generalized myasthenia gravis (MG) patients without detectable acetylcholine receptor (AChR) antibodies (SNMG), the thymus is often reported as "normally involuted." We analyzed thymic compartments in 67 patients with generalized MG, with AChR antibodies (AChR+, n = 23), with muscle-specific kinase (MuSK) antibodies (MuSK+, n = 14) or with neither (MuSK-, n = 30), and in 11 non-MG controls. Four of 14 MuSK+ thymi had rare small germinal centers, but overall they were not different from age-matched controls. However, approximately 75% MuSK- samples showed lymph node-type infiltrates similar to those in AChR+ patients, but with fewer germinal centers. These variations may explain some apparent differences in responses to thymectomy in SNMG.     

Thymic lymphocytes in myasthenia gravis.

Lymphocytes from the thymus glands of myasthenic patients and controls were characterized in terms of their percentages of B- and T-cells and their ability to stimulate the proliferation of autologous peripheral blood lymphocytes. Percentages of B- and T-cells were the same in the thymuses of myasthenic and control subjects. Autologous peripheral lymphocyte stimulation by thymocytes was observed in only 1 of 3 myasthenic patients, and this was with a thymus gland containing a thymoma. These results thus differ from those of other investigators.     

Myasthenia gravis and thymoma coexisting with myotonic dystrophy type 1

We describe a 34-year old man presenting with subacute generalized myasthenic symptoms. His clinical features and laboratory investigations demonstrated both myasthenia gravis and myotonic dystrophy type 1. The computerized tomography of chest revealed anterior mediastinal mass. The lymphocyte-rich thymoma was removed surgically and he received radiotherapy. Recent observations suggested that the patients with myotonic dystrophy may have an increased risk of benign and malignant tumours but its coexistence with thymoma is very rare. The risk of thymoma associated with myotonic dystrophy is unknown.     

CLINICAl AND IMMUNOPATHOLOGICAL.OGICAI. STUDY ON THE THYMUS IN MYASTHENIA GRAVIS

Objective Directing towards the thymus and emphasizing mainly on the clinical and immunopathofogical study to probe its actior of the diagnosis,treatmeant and pathogcnesis cfmyasthema gravis(MG). Results tnd Dicusslons I .Diagnosis of MG with thymus pathologic lesions: I.MG with thymus hyetplasta It was shown by midstemum. CT scanning Germinal center arises from B ceil was determined by immunohistologic stain(Tol 5 marked); 2MG with thymoma It usualy occures at midaged man and apt to relapses on myasthenic crises. Positive rate of serum CAE-Ab(anti-citric acid extract antibody of human skeletal musie) was used tc find small thymoma early Rabbit Anti-serum against human CAE was labeled to determine thymoma AgNOR(argyrophilic stain of nuclear organizer region)was used to differentiate bemgn and maligant thymoma .As Muller-Hermlink' s classfication.thymoma of cortical type occurred more common and reliable to infiltration Ⅱ Treatment of MG with thymus pathoiogic lestons Except for symptomatic treatment with anti-acytlecholine drugs.MPSS or CTX intravenous perfusion had effect to relieve the myasthenic cnsis Using thymus radiation therapy to 134 cases, the complete remission and remarkable improvement rates were 66.5%.Rhe long-term effect followed up was rather stable. Using percutanous paracentesis into thymus gland for intervention treatment to 13 cases, all of them showed effect within one week.10 cases followed up more than 3 years,9 cases were complete remission or remarkable improvement Thymectmy is still a basic therapy for MG.In 102 cases with thymectomy,the complete remission and remarkable improvement rates were 59.8%,mortanty was 176%.Continual observation of CAE-Ab could contribute to determine the pateint' s prognosis,9 patients in severe condition followed up within 3 years,their serum CAE-Ab antibody titers persisted at high lever,3 Of them died,but 7 patients followed up within I year,those of their serum antibodies decreased quickly,5 cases of them got complle remission. Asides the question whether being thymectomied or not operate.it seems that treatment should direct towards the thymus,had better to take corresponding treatment early,indivually and from time to time and use each trcatment correctly under strict monitor to make effort for heigh effcct;It also needs futher following up and creating new therapy for to raise long-term effect Ⅲ .Thymus for the pathogenises of MG: 1.Thymus and skeletal muscie both exist nAchR common antigen; 2.T-cells play the crucial role in MG autoimmune response,they form the complex of TCR-nAchR MHC ,and become the basis of immune resconsibillity in MG; 3.Thymus epithelium cells and thymocytes make interaction abnormally to response again, st foreign antigen(as virus infection);and result in autoimmune response for self-antigen owing to lose immunotolerance. 4 Thymoma epithelium cells exist different inheritance susceptibilities,the alamine at position 57(Ala 57) of HLA - DO β gene expressing is more signiticant association with Chinese MG patients with thymoma.     

CA-antibody: an immunological marker of thymic neoplasia in myasthenia gravis?

We have examined sera from 141 patients with myasthenia gravis and 11 non-myasthenia gravis patients with thymoma for antibodies to a citric acid extract of skeletal muscle (CA-antibodies). Sera were obtained from 5 different centers. The thymus histology was defined in each case. Sera from 56/66 patients (85%) with thymoma contained CA-antibodies, while such antibodies were only detected in 6/75 (8%) of the non-thymoma patients. None of the patients with thymus hyperplasia had CA-antibodies. One MG patient who developed MG after a bone-marrow transplantation, also developed CA-antibodies. The remaining 5 CA positive non-thymoma MG patients were all greater than 65 years and had thymic atrophy. Two of them had myasthenia gravis and polymyalgia rheumatica. In 2 thymoma patients with non-detectable levels of CA-antibodies before thymectomy, such antibodies were demonstrated in high titres after the operation. In 2 other sera from thymoma patients, the titres of CA-antibodies fell to less than 32 after thymectomy. There were 3 sera with CA-antibodies among 11 sera from non-MG patients with thymic tumours.     

A case of myasthenia gravis appearing after thymomectomy: with histopathological investigation]

We report a 64-years old man who had myasthenia gravis (MG) appearing after surgical removal of thymoma. His thymoma was not removed completely due to adhesion with other organs. Histopathologicaly, the thymoma was an invasive and predominantly epithelial type. CD45RO positive cells increased in the thymus. After five months of thymectomy, he received radiation therapy because the remaining tumor grew up slightly. The radiation was effective, and the recurrence of tumor has never been detected after that. However, nine months after the surgery, he noticed ptosis and double vision, and he was diagnosed as MG because of positive serum anti-AchR antibody and positive Tensilon test. He received oral prednisolone, and he has kept a good condition. Previous reports have shown that an extensive thymectomy tends to reduce the incidence of post-operative MG. In our case, the remaining thymoma might increase the risk of MG. And the removed thymus might contain an unknown regulatory factor that could inhibit a development of MG. The risk factor for development of post-operative MG should be investigated in future.     

Occurrence of invasive thymoma after thymectomy for myasthenia gravis: report of a case

We report the occurrence of an invasive thymoma following a median sternotomy with removal of a normal involuted thymus in a patient with myasthenia gravis and stress the prompt reevaluation of post-thymectomy patients who have an initial good response and then deteriorate.