The immunologic role of thymectomy in the treatment of myasthenia gravis: implication of thymus-associated B-lymphocyte subset in reduction of the anti-acetylcholine receptor antibody titer

BACKGROUND AND PURPOSE: Thymectomy is generally accepted as the major option of treatment for myasthenia gravis. To elucidate the biological role of thymectomy in the treatment of myasthenia gravis, the immunologic characteristics of the thymus was studied in association with the postoperative kinetics of the anti-acetylcholine receptor antibody titer. MATERIALS AND METHODS: Thirty-four patients with nonthymomatous myasthenia gravis who had positive anti-acetylcholine receptor antibody titer and undergoing extended thymectomy were subjected to the study. Reduction of anti-acetylcholine receptor antibody titer was evaluated in terms of the proportion of anti-acetylcholine receptor antibody titer at 1 year after thymectomy to that before the operation. The numbers of B lymphocytes (CD19(+) cells) and the germinal center B lymphocytes (CD19(+)CD38(high) cells) present in 1 g of the thymic tissue were calculated by flow cytometry. RESULTS: The proportion of anti-acetylcholine receptor antibody titer at 1 year after thymectomy ranged from 27.5% to 150%. The numbers of B lymphocytes and the germinal center B lymphocytes in 1 g of the thymic tissue ranged from 0.19 x 10(6)/g to 162.8 x 10(6)/g and from 0.09 x 10(6)/g to 33.4 x 10(6)/g, respectively. The proportion of anti-acetylcholine receptor antibody titer at 1 year after thymectomy had a significant inverted correlation with the number of B lymphocytes (P =.002) as well as that of the germinal center B lymphocytes (P =.007). CONCLUSION: Effectiveness of thymectomy was dependent on predominance of B lymphocytes and the germinal center B lymphocytes in the thymus, suggesting that one of the biological roles of thymectomy in the treatment of myasthenia gravis is removing the thymus-associated germinal centers.     

Prognostic factors for myasthenic crisis after transsternal thymectomy in patients with myasthenia gravis

OBJECTIVE: The purpose of this study was to assess which clinical features of patients with myasthenia gravis predict postoperative respiratory problems due to myasthenic crisis after transsternal thymectomy. METHODS: One hundred twenty-two patients who underwent transsternal thymectomy in our institute were analyzed retrospectively. Fourteen of those experienced myasthenic crisis and required prolonged (48 hours or more) postoperative mechanical ventilation. The following factors were evaluated: sex, age, body mass index, grade of symptom, disease interval, existence of thymoma, history of preoperative crisis, doses of anticholinesterase drugs, steroid use, pulmonary function, serum anti-acetylcholine receptor antibody, history of pulmonary disease, presence of other disease, operation time, and blood loss. RESULTS: Univariate analysis revealed preoperative bulbar symptoms (odds ratio = 14.246, P =.001), history of preoperative myasthenic crisis (7.091,.018), and preoperative serum level of anti-acetylcholine receptor antibody > 100 nmol/L (4.098,.044) were prognostic factors for postoperative myasthenic crisis. On the other hand, multivariate logistic regression analysis revealed preoperative bulbar symptoms (33.333,.004), preoperative serum level of anti-acetylcholine receptor antibody > 100 nmol/L (7.874,.020), and intraoperative blood loss > 1000 mL (18.519,.048) were prognostic factors for postoperative myasthenic crisis. CONCLUSIONS: In this study, postoperative myasthenic crisis after transsternal thymectomy in 122 patients with myasthenia gravis was affected by the existence of preoperative bulbar symptoms, history of preoperative myasthenic crisis, preoperative serum level of anti-acetylcholine receptor antibody > 100 nmol/L, and intraoperative blood loss > 1000 mL. Meticulous preoperative and postoperative care should be carried out to prevent postoperative myasthenic crisis in patients with these prognostic factors.     

Anesthetic considerations for thymectomy in a patient having an anti-acetylcholine receptor antibody without myasthenia gravis

A patient having an anti-acetylcholine receptor (AChR) antibody without myasthenia gravis was scheduled for thymectomy. Neuromuscular blockade monitoring showed a normal response to vecuronium in the patient. This finding suggests that sensitivities to neuromuscular blocking agents in the patients depend not on the titers of the antibody but also on the presence or absence of the preoperative symptoms such as muscle weakness. It is, however, recommended that neuromuscular blocking agents should be administered carefully under monitoring the neuromuscular function, as is the case for myasthenia gravis, because little is understood about the effect of neuromuscular blocking agent on the neuromuscular function in the asymptomatic patients having anti-AChR antibody.     

外科治疗重症肌无力的疗效分析

目的评价外科治疗重症肌无力的效果,探讨影响术后肌无力危象发生的因素以及预防治疗要点。方法回顾性分析1985年6月至2005年6月78例接受外科治疗重症肌无力患者的临床资料,对影响术后肌无力危象发生及程度的因素进行分析,比较不同围手术期处理方案的疗效差异。结果肌无力症状完全缓解21例,明显改善38例,改善11例,无变化8例。病程长短、血清抗乙酰胆碱受体抗体水平、Osserman分期和胸腺病理类型均是术后肌无力危象发生的独立相关危险因素。在围手术期处理方面,新方案疗效明显优于旧方案。结论外科治疗重症肌无力具有良好的效果和可行性。     

A successful two-step integrated protocol of anti-HBV vaccination in chronic uremia.

A prospective study was performed in 40 chronic uremics which included: (1) the intramuscular administration to all patients of 40 micrograms of a DNA-recombinant vaccine (Engerix-B) at 0, 1, 2, 6 months; (2) an intramuscular booster dose of 40 micrograms at 18 months in patients having an anti-HBs titer greater than 100 mIU/ml at the 7th month (group A); (3) a further intramuscular supplementary dose of 40 micrograms at 12 months (besides that at 18 months) in patients developing an antibody titer less than 100 mIU/ml at the 7th months (group B); (4) an intradermal course of 5 micrograms of vaccine every 2 weeks until the protective titer (greater than or equal to 10 mIU/ml) was achieved, and then every month for a total of 6 months in patients who did not develop a protective titer even after 19 months (group C). At the end of the study, all patients had developed a protective titer: 77.5% after the 4th intramuscular dose, 12.5% after the 5th and 10% after 3.5 +/- 0.5 (mean +/- SEM) intradermal inoculations. The mean antibody titers were 1,461 +/- 98 mIU/ml in group A, 594 +/- 684 in group B and 131 +/- 133 in group C. In conclusion, our two-step integrated protocol gives an anti-HBs protective titer in all our patients.     

Thymectomy for myasthenia gravis: 14-year experience.

Forty-eight consecutive patients with myasthenia gravis (MG) attended by generalized weakness were treated by complete thymectomy, performed transsternally in 46 patients and through a left thoracotomy in two with thymomas. There were no operative deaths. A 12-year-old child with fulminating MG died of acute pneumonia shortly after hospital discharge. Of the remaining 47 evaluable patients, thymectomy resulted in complete remission in six, marked improvement with a reduced need for medication in 20, and mild improvement on the same dosage of medication in 18. Neither the age of the patient, nor the histopathology of the excised thymus, nor the postoperative change in acetylcholine receptor antibody titer were found to have a significant influence on the response to thymectomy. If the ten patients who were 20 years of age or younger were excluded, the patients with a shorter duration of MG achieved a better response to operation. The authors conclude that thymectomy is effective treatment for MG, regardless of the age of the patient or the type of thymic pathology.     

Hepatitis B vaccination and interleukin 2 receptor expression in chronic renal failure

Only 50 to 60% of dialysis patients develop anti-HBs antibodies following hepatitis B vaccination. The nonresponder state correlates with impaired monocyte function, decreased interleukin-2 (IL-2) production of T cells, and an upregulation of the IL-2 receptor system. In the present study we examined anti-HBs production after hepatitis B vaccination and the in vitro expression of IL-2 receptors in nondialyzed patients with various degrees of chronic renal failure. Forty-four patients with impaired renal function were immunized with 2 micrograms recombinant hepatitis B vaccine and boostered after one and six months. Prior to the first injection IL-2 receptor expression of activated T cells was studied by an in vitro proliferation assay. Sixty-four healthy subjects served as controls. After completion of the third vaccination 55.0% of the patients acquired antibody titers greater than 10 U/liter. The seroconversion rate did not differ between patients with lower (less than 3.5 mg/dl) and higher (greater than 3.5 mg/dl) creatinine levels. In nonresponders IL-2 receptor expression (stimulation index, SI = 10.09 +/- 1.80) was elevated compared to healthy controls (SI = 4.62 +/- 0.35, P less than 0.002) or patients who responded with a high antibody titer (greater than 50 U/liter, SI = 3.12 +/- 0.43, P less than 0.001). Patients who produced low antibody titers (less than 50 U/liter) also presented with enhanced IL-2 receptor expression. These data show that an impaired antibody production following hepatitis B vaccination and an enhanced IL-2 receptor expression of T cells may already be present in early stages of chronic renal failure.     

A case of thymoma with an increased sensitivity to pancuronium

It is well-known that anesthesia and surgery may precipitate muscle weakness in the patients with myasthenia gravis and some patient were not recognized as myasthenia until such episodes. A 74-year-old woman with increased sensitivity to pancuronium who, in spite of the very high titer of anti-acetylcholine receptor antibodies, showed no clinical manifestation of myasthenia gravis before operation. And computed tomographies revealed the presence of a thymoma in her anterior mediastinum. Although we have performed extended thymectomy, ptosis appeared 4 month after the operation. This patient might be called as "premyasthenic state" or "subclinical MG".     

Anesthetic management of a patient with postthymectomy myasthenia gravis]

A 56-year-old male who had received total thymectomy for treatment of myasthenia gravis was scheduled for sigmoidectomy under general anesthesia. Since his symptoms had become worse after the thymectomy along with increased anti-acetylcholine receptor antibody titer, preoperatively we could not estimate his sensitivity to non-depolarizing muscle relaxants. We initially tried tracheal intubation without using a non-depolarizing muscle relaxant immediately after intravenous injection of propofol 2 mg.kg-1 and fentanyl 4 micrograms.kg-1. Since the intubation was unsuccessful, however, vecuronium 0.01 mg.kg-1 was repeatedly administered until TOF ratio reached 0%. Successful intubation was performed with 3.5 mg of vecuronium. We conclude that the initial trial of tracheal intubation should be performed without a non-depolarizing muscle relaxant in patients with myasthenia gravis whose symptoms have become worse after thymectomy. If first attempt is unsuccessful, the tracheal intubation should be performed with a smaller dose of vecuronium using an electrical nerve stimulator.     

胸腺切除后血清乙酰胆碱受体抗体改变及与疗效关系

随访２３例因重症肌无力行胸腺切除术的病人。运用灵敏度高、特异性强的ＢＡＳ—ＥＬＩＳＡ法检测手术前、后血清乙酰胆碱受体抗体（ＡｃｈＲ抗体）水平，所得结果均进行统计学分析。２３例病人胸腺切除后，１８例临床症状改善，有效率７８％。术后１４例（６１％）病人血清ＡｃｈＲ抗体水平下降，统计结果表明，手术前后血清ＡｃｈＲ抗体水平差异有显著性（Ｐ＜０．０５），但与症状改善无关（Ｐ＞０．０５）。手术前后血清ＡｃｈＲ抗体水平不影响疗效（Ｐ＞０．０５）。     

Measurement of antiacetylcholine receptor antibody in patients with thymoma without myasthenia gravis complications

OBJECTIVE: Some patients with thymoma reported to show higher antiacetylcholine receptor antibody titers without the preoperative occurrence of myasthenia gravis and some have suffered postoperative complications of myasthenia gravis despite being negative for antiacetylcholine receptor antibody preoperatively. We evaluated changes in antiacetylcholine receptor antibody titers and the occurrence of myasthenia gravis in thymoma patients. METHODS: Subjects were 31 of 44 patients with thymoma undergoing thymothymectomy at Tokyo Women's Medical University Hospital between 1987 to 1999 in whom antiacetylcholine receptor antibody titers were measured preoperatively. We studied postoperative changes in antiacetylcholine receptor antibody titers and the presence or absence of myasthenia gravis. RESULTS: Eight patients were positive for antiacetylcholine receptor antibody preoperatively, suggesting the presence of subclinical myasthenia gravis. Neither postoperative changes in antiacetylcholine receptor antibody titers nor the occurrence of myasthenia gravis was observed in these 8 patients. Recurrent thymoma and rapid elevation of antiacetylcholine receptor antibody titers were observed postoperatively in 1 patient negative for antiacetylcholine receptor antibody preoperatively, resulting in manifestation of myasthenia gravis symptoms. CONCLUSION: We found no correlation between preoperative titers and myasthenia gravis symptoms. Rapid titer elevation indicates the occurrence of myasthenia gravis symptoms or the recurrence of thymoma.     

The result of extended thymectomy in patients with myasthenia gravis of pure ocular type

We studied postoperative status of 14 patients with myasthenia gravis of ocular type who underwent extended thymectomy. Nine patients were in remission, three improved, and two unchanged. No patient became worse and died. The remission rates at one, three, five, and ten years after operation were 50.0%, 58.3%, 60.0%, and 80.0%. The palliation rates at one, three, five, and ten years after operation were 64.3%, 75.0%, 80.0%, and 100%. The remission rate at one year after operation in patients of ocular type was significantly (p less than 0.05) higher than that in generalized type (191 patients). The mean preoperative duration of symptoms in patients who obtained remission after surgery was 7.2 +/- 6.5 months, while mean duration was 85.6 +/- 45.8 months in those patients who could not obtain remission, indicating a significant difference (p less than 0.05) of duration of symptoms between two groups. Among 89 patients with generalized as well as ocular symptoms before extended thymectomy, 62 patients (69.7%) still complained of ocular symptoms and 48 patients (53.9%) had generalized symptoms with or without ocular symptoms in 1 to 12 years after operation. This result shows that ocular symptoms do not disappear more easily than generalized ones. We conclude that extended thymectomy should be performed even in patients with myasthenia gravis of pure ocular type.     

Two cases of post-thymectomy myasthenia gravis]

The first patient was a 37-year-old man with an invasive and lymphoid cell dominant thymoma (stage III). He underwent extended total thymectomy and partial resection of the upper lobe of the left lung. Four years after the operation, he had ptosis and diplopia and was diagnosed as having myasthenia gravis (positive Tensilon test and raised antiacetylcholine receptor antibody titer). His symptoms improved with the steroid therapy. The second patient was a 37-year-old woman with an invasive and mixed type thymoma (stage III). Extended total thymectomy with combined resection of the mediastinal pleura and right phrenic nerve was performed, but the tumor recurred in the right thorax 2 years postoperatively. Subtotal resection of the parietal pleura and recurrent tumors was performed by right thoracotomy, and steroid therapy was given. She developed malaise, ptosis and diplopia three months later, and was diagnosed as having myasthenia gravis. Her symptoms disappeared after the steroid therapy was stopped. A review of the Japanese literature is presented and problems regarding the pathogenesis of this disease are discussed.     

Experience in the treatment of acute fulminating myasthenia gravis]

During past 15 years, 188 myasthenia gravis (MG) patients underwent thymomectomy or thymectomy with extended resection of the adipose tissue around the thymus in our institution. Four of 188 patients (2%) had to be given respiratory support within 2 months after the onset of MG. We defined this MG as the acute fulminating type. There were 2 male and 2 female patients, ranging in age from 22 to 44 years (average, 32.5 years). Three of these patients had thymoma. One of these patients was post-thymomectomy myasthenia gravis and another patient was d-penicillamine induced myasthenia gravis. Two patients admitted on respirator for respiratory crisis. All patients underwent operation within 2 weeks after admission. The duration of respiratory support ranged from 10 to 120 days (mean 44) after operation. The period of the hospital stay ranged from 8 months to 2 years 1 month (mean 1 year 5 months). During acute stage after operation, the patients needed ACTH, steroid, immunosuppressants (azathioprine, Bredinin) and plasma pheresis depending on their severity of myasthenic symptoms. In 2 patients dose of steroid could be reduced without deterioration of the symptoms. They are doing well with small dose of steroid. In one patient plasma pheresis was performed 6 years after thymectomy. Various symptoms due to myasthenia gravis and rheumatoid arthritis has recurred 10 years after thymectomy. The titer of acetylcholine receptor antibody of this patient has been continuing in high level.     

Thymectomy for myasthenia gravis

Between 1951 and 1971 thymectomy was performed on 41 patients with myasthenia gravis. They were selected from a total group of 95 myasthenic patients receiving anticholinesterase therapy. The criteria for selecting patients for thymectomy and the assessment of their progress after operation are described. All the patients have been examined by us at intervals and the results of this follow-up are presented. The survey has shown that substantial improvement after thymectomy occurred in 21 patients (group A), seven of whom had complete remissions without medication for periods of up to 12 years after operation. Considerable benefit from the operation was also observed in seven patients (group B); although their response was less spectacular, in that their daily requirement of anticholinesterase drugs was not changed, their functional activities were significantly enhanced. The most favourable results were seen in female patients aged 15 to 40 years, six of whom had one or more successful pregnancies. Thymectomy did not improve the general condition or progress of six patients (group C). There were three deaths within 16 days of operation, and two patients died within one year. Eight patients survived for periods of 3 to 16 years; six of these died from causes other than directly from myasthenia, and two died at home without established cause.     

Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma?

Background Although the presence of tumor cells in the blood of patients with metastatic melanoma suggests widely disseminated disease many of these patients enjoy prolonged survival or cure after surgical resection. Our previous study of adjuvant vaccine therapy after complete resection of metastatic melanoma revealed a strong correlation between postoperative survival and elevated antibody titers to a 90-kDa tumor-associated antigen (TA90) expressed by melanoma cells of the vaccine. We hypothesized a similar correlation between postoperative survival and endogenous anti-TA90 antibody titers induced by the patient’s melanoma in the absence of postoperative adjuvant immunotherapy. Methods From 1970 to 1996, 64 patients underwent complete resection of distant melanoma metastases and did not receive postoperative adjuvant immunotherapy. Serum collected within 4 months after surgery was tested in a coded and blinded fashion for anti-TA90 IgG and IgM by enzyme-linked immunosorbent assay, and for total IgG and IgM (controls) by radial immunodiffusion. Results Median follow-up for the study population was 19 months (range, 3–147 months). There was no significant correlation between anti-TA90 IgG titer and total IgG level (P=.4785), or between anti-TA90 IgM and total IgM (P=.0989). Univariate analysis showed that postoperative anti-TA90 IgM titer as a continuous variable was significantly associated with overall survival (OS); i.e, the higher the anti-TA90 IgM titer, the longer the OS. Using an established cutoff titer of 800, median OS was 42 months for patients with high anti-TA90 IgM titer (n=28) vs. 9 months for patients with low titers (n=36) (P=.0001). There was no significant correlation between total IgG/IgM and survival (P=.4107 and .4044, respectively). Multivariate, analysis identified anti-TA90 IgM as the most significant independent variable influencing OS after complete resection of distant melanoma metastases (P-.0001). Conclusions We conclude that the endogenous immune response to metastatic melanoma determines the outcome after surgical therapy. Enhancement of this specific immune response may prolong the survival of patients with distant melanoma metastases. Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

Postoperative myasthenic crisis successfully treated with immunoadsorption therapy

Myasthenia gravis (MG) is an autoimmune disorder characterized by loss of acetylcholine receptors (AChR) due primarily to the production of anti-AChR autoantibodies. We report a case of MG associated with elevated anti-acetylcholine receptor antibody (anti-AChR Ab) and refractory crisis after thymectomy, in which immunoadsorption therapy was used successfully to stabilize myasthenic symptoms and decrease the anti-AChR Ab titer. A 79-year-old woman underwent extended thymectomy under the diagnosis of MG. One day after surgery she suddenly underwent a myasthenic crisis and was successfully resuscitated. Immunoadsorption therapy with a tryptophan-linked polyvinyl alcohol adsorber was performed three times for the purpose of decreasing the anti-AChR antibodies. The anti-AChR Ab titer was reduced by immunoadsorption during each therapy session; however, the level of anti-AChR Ab before immunoadsorption was higher than that of the previous treatment. This case suggests that the absolute serum level of anti-AChR Ab does not always correlate with the severity of the disease. Removal of pathogenic factors, not only anti-AChR Ab but other antibodies with specificities to skeletal muscles or certain components of the complement system, may contribute to effective treatment of myasthenic crisis.     

Clinical outcomes following extended thymectomy for myasthenia gravis: report of 17 cases.

PURPOSE: This retrospective study was undertaken to assess the changes in the clinical status of patients with generalized myasthenia gravis (MG) treated with extended thymectomy and to identify prognostic variables that may be of significance in optimizing patient selection. PATIENTS AND METHODS: We reviewed the clinical outcomes of 17 patients who underwent extended thymectomy for MG. Main factors influencing the outcome are changes in clinical stage and medication requirement before and after thymectomy, age, sex, duration of disease, stage of disease, antibody status, histological characteristics of the thymus, and duration of follow-up. RESULTS: There was remission in 4 patients (23.5%), improvement in 9 patients (53%), and no change in 4 patients (23.5%). Patients in Osserman stage IIB and with a higher rate of decrease in acetylcholine receptor (AchR) antibody ratio showed a greater degree of postoperative improvement. Age of the patient, sex, presence or absence of thymoma, and time elapsed between diagnosis and operations were not found to be significant prognostic factors. CONCLUSION: The present study demonstrated that extended thymectomy for MG is an effective therapy with no great morbidity or mortality. Patients in preoperative stage IIB and with higher rate of change in the AchR antibody titer showed the greatest degree of postoperative improvement.     

Surgical treatment of myasthenia gravis and its evaluation]

30 cases of myasthenia gravis (MG) were treated with thymectomy. Before and after operation, peripheral blood lymphocyte subpopulation was determined in 10 cases and acetylcholine receptor antibody titer was determined in 6. The results confirmed the efficacy of thymectomy in treating MG. We suggest that application of hormone for regulating immune function of the body and/or plasma exchange for alleviating symptoms in patients with generalized MG before and after the operation. The results of treatment did not correlate with age, sex, length, and course of the disease. Radical operation, proper anaesthesia and appropriate antibiotics may ensure a smooth operation and high curative effect.     

Surgical aspects in the treatment of myasthenia gravis

We treated 81 patients suffering from myasthenia with thymectomy in a 10-year period (1991-2000). We think, that thymectomy must be carried out in the treatment of myasthenia gravis, unless contraindications are present. The operation is not urgent and in the preoperative period patients must reach optimal condition with the help of standard medical treatment. The result of the operation is influenced by the length of time between the beginning of the complaints and the operation. The best results can be expected when the operation is performed in less than 2 years time, however an operation performed later may also be successful. We operated on 63% (n = 51) of the patients between 4-12 months, on 18% (n = 15) between 13-24 months and on 18.6% (n = 15) more than 25 months after the beginning of the complaints. Complete thymectomy was performed in all patients through median sternotomy. We had no operative mortality. Our postoperative results were evaluated with Jaretzki classification: 75% of our patients are in remission and asymptomatic (n = 61).