Thymectomy in the management of myasthenia gravis

There continues to be a debate regarding the effectiveness of thymectomy in the treatment of nonthymomatous myasthenia gravis (MG) and, when undertaken, which thymectomy technique is the procedure of choice. The debate persists primarily because of the lack of controlled prospective studies. Analysis has been complicated by the absence, until very recently, of accepted objective definitions of severity of the illness and response to therapy as well as variable patient selection, timing of surgery, type of surgery, and methods of analysis of results. Without resolution of these issues by properly controlled prospective studies, there can be no unequivocal determination of the effectiveness of thymectomy or valid comparison of the various thymectomy techniques. In this review, based on previous analyses, attempts will be made to clarify some of the controversial issues concerning thymectomy for nonthymomatous MG and make limited recommendations based on the best available evidence.     

CD4CD25 regulatory T cell in childhood ocular myasthenia gravis

Dysfunction of CD4⁺CD25⁺ regulatory T cell (Treg) has been demonstrated to play an important role in the development of autoimmune myasthenia gravis. This T cell subset, which has potent regulatory properties against immune response, has been reported to have a numerical or functional defect in patients with myasthenia gravis. We examined various T cell subsets, including CD4⁺CD25⁺Treg in peripheral blood mononuclear cells using flow cytometry in a pediatric patient suffering from ocular myasthenia gravis. Contrary to previous reports, the percentage of CD4⁺CD25⁺Treg in peripheral blood decreased significantly after successful treatment with prednisolone. This discrepancy could result from diversity within the immunopathogenesis of myasthenia gravis and may underpin a particular subgroup of myasthenia gravis seen in the East-Asian pediatric population.     

Thymectomy and anti-muscle autoantibodies in late-onset myasthenia gravis

Thymectomy is still widely carried out in myasthenia gravis (MG) patients, but its role, especially in late-onset MG patients, is not established. These patients are immunologically heterogeneous, some with thymoma-like and others with early onset-like features. We evaluated whether any therapeutic effects of thymectomy correlate with the presence of non-acetylcholine receptor (AChR) muscle antibodies. The severity of MG, and titin and ryanodine receptor (RyR) antibodies, were assessed yearly starting from MG onset in 21 thymectomized and 22 non-thymectomized AChR antibody positive late-onset MG patients, who were followed for 2, 3 and 5 years. Clinical or pharmacological remission were seen in six of 11 titin antibody negative but none of the 10 titin antibody positive thymectomized patients, however, the non-thymectomized cases showed an opposite trend. The three MG-related deaths were all in patients with titin antibodies. There was no significant difference in MG severity between thymectomized and non-thymectomized patients; 2 years after MG onset, both groups were significantly improved. This study showed no dramatic benefit from thymectomy in late-onset MG in general. Any limited improvement appeared less likely in cases with titin and/or RyR antibodies.     

Thymectomy: role in the treatment of myasthenia gravis

Thymectomy is a frequently used treatment for myasthenia gravis (MG) and is virtually always indicated in MG patients who have a thymoma. However, the evidence for thymectomy in non-thymomatous MG remains less certain—no randomised controlled trials have been published to date, although one is currently underway. We reviewed the management and clinical outcome of patients with MG who underwent thymectomy over a 12 year period. Eighty-nine patients who underwent transsternal thymectomy were identified. A thymoma was identified on histology in 24 %, whereas 48, 9 and 19 % had hyperplastic, atrophic and normal thymic histology, respectively. One patient developed post operative myasthenic crisis but generally the procedure was well tolerated. Outcome was favourable for the majority of patients, with 34 % achieving complete stable remission (CSR) and an additional 33 % achieving pharmacological remission. Moreover, steroid requirements fell progressively during follow-up. Patients with a hyperplastic gland had a significantly greater chance of achieving CSR compared to other histological subtypes and the incidence of CSR increased with a longer duration of follow-up. Thymectomy for MG is generally safe and well tolerated and is associated with a sustained improvement of symptoms in the majority of patients.     

Thymectomy in myasthenia gravis. Evaluation of the results in 73 patients

An evaluation of results obtained after 73 thymectomies is reported. A transthoracic approach was used on all of the patients. Thymomas were found in 9 out of the 73 patients with myasthenia. All of the 64 patients without thymomas suffered from generalized myasthenia gravis with predominance of severe forms. The results of the early, intermediate and late post-operative course were analysed. A comparative study of results as related to age, sex, duration of disease and presence or absence of thymomas was made. Statistical analysis failed to show any significant difference in the results of thymectomy between selected and randomly chosen patients without thymomas.     

Elevated cerebrospinal fluid CD4/CD8 T cell ratio in myasthenia gravis

The proportions of CD2+, CD4+ and CD8+ lymphocytes were determined with the 3-layer indirect immunoperoxidase technique in the cerebrospinal fluid (CSF) of 31 patients with myasthenia gravis (MG) and 21 control subjects without autoimmune or central nervous system (CNS) diseases. None of the MG patients were using immunosuppressive drugs and all were thymectomized shortly after CSF sampling. Analysis of the reference population showed that the percentage of CD4+ lymphocytes and accordingly the CD4+/CD8+ T cell ratio is normally higher in CSF than in peripheral blood (PB). Compared to the controls, the mean percentage of CD4+ lymphocytes and the mean CD4+/CD8+ ratio in CSF were significantly higher in MG patients. In addition, the CD4+/CD8+ ratio was elevated in the CSF of 15 MG patients (48%) as a result of an elevation in the proportion of CD4+ and/or a decrease in CD8+ T cells. Among MG subjects the mean proportion of CD4+ lymphocytes was higher in the CSF of patients with also an elevated number of enlarged stimulated lymphoid cells in their CSF, which implies that these lymphocytes are often of the CD4+ phenotype. The percentage of CD4+ T cells in CSF was significantly higher in MG patients with a hyperplastic thymus or a thymoma than in those with an involuted thymus. Neither in MG patients nor in the reference population could an association be observed between CSF and PB lymphocyte subsets. In the controls this suggests that immunologic events of the CNS are normally not directly reflected in PB.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical efficacy of tacrolimus for treating myasthenia gravis and its influence on lymphocyte subsets

Background

This study aimed to determine the clinical efficacy and effects of tacrolimus in treating myasthenia gravis (MG).

Thymectomy: its role in the management of myasthenia gravis

The management and clinical course of patients with myasthenia gravis admitted to a neurological intensive therapy unit (ITU) for thymectomy over a 66 month period were reviewed. There were 53 patients, 20 male and 33 female, mean age 35.2 years (18–74) and median ITU stay of 5 days (2–30). Indications for thymectomy were thymic enlargement on computed tomography (34%), persistence of generalized symptoms (38%), a combination of both (20%), steroid side effects or dependency (4%) and progressive bulbar symptoms (4%). Following thymectomy, thymic histology revealed thymic follicular hyperplasia (26/53; 49%), atrophy (11/53; 21%), thymoma (12/53; 23%) and normal thymus (4/53; 8%). Post-operatively 23% required prolonged intubation (> 48 hrs); two patients required a tracheostomy 10 and 13 days post-operatively. Plasma exchange was required for two patients (3.8%) due to persistent severe myasthenic weakness. Three patients (6%) developed a post-operative chest infection and one pseudomembranous colitis. There were no post-operative mortalities during the study period. After 2 years, 35% of patients were in remission and 46% had ocular or mild generalized symptoms only. Thymectomy for myasthenia gravis is followed by sustained clinical improvement in the majority of patients. The appropriate post-operative management of these patients is best undertaken in a specialized neuro-intensive care setting.     

Evidence against chronic antigen-specific T lymphocyte activation in myasthenia gravis

Myasthenia gravis (MG) is an antigen-specific autoimmune disease caused by antibodies against acetylcholine receptors (AChR) at the post-synaptic membrane of the neuromuscular junction. Clinical and immunological data imply the involvement of AChR-specific T lymphocytes as helper cells for autoantibody production. Direct data to support this hypothesis, however, remain sparse. In the present study, a large population of MG patients was studied for evidence of peripheral blood T cell activation by several assays. Assays based on non-specific measurements of T cell activation as well as assays of antigen-specific clonal expansion were utilized. Levels of soluble IL-2 receptor in serum were modestly elevated in some patients, suggesting T cell activation. However, peripheral blood cells did not show evidence of IL-2 receptor expression or enhanced reactivity to IL-2 in culture. Clonable T cells selected for hypoxanthine phosphoribosyl transferase (hprt) mutation, another non-antigen-specific marker for T cell activation, were not seen with increased frequency except in patients treated with purine analogs. Antigen-specific T cell activation was measured by proliferation assays using heterologous and autologous sources of AChR. Antigen-restimulated peripheral blood cell cultures were cloned by limiting dilution. The vast majority of patients failed to show convincing evidence of AChR specific T cell activation or clonal expansion; only 2 of 44 patients demonstrated clonable autologous AChR-specific T cells. An alternative hypothesis of T cell involvement in MG is proposed in which T cell activation is discontinuous and predominately directed at antigens other than AChR. © 1996 Wiley-Liss, Inc.     

Myasthenia gravis: steroid-induced effects on lymphocyte subpopulations in myasthenia gravis.

Lymphocyte subpopulations from patients with myasthenia gravis were evaluated during chronic steroid therapy. A marked lymphocytopenia (10-70%) was initially (day 3-21) noticed as well as a preferential depletion of thymus-derived cells which paralleled the clinical deterioration. Thus there was a relative increase in B cells, although their absolute number remained rather constant. These changes were reverted within 2-4 weeks in spite of continuous treatment. These findings are compatible with a release of myasthenic factors (anti-acetylcholine receptor antibodies?) during the initial steroid-induced cell damage, the long-term beneficial effects being due to loss or suppression of autoreactive helper t cells.     

Thymectomy and immunosuppression in myasthenia gravis: a prospective study

Between 1982 and 1988 24 women and 6 men with myasthenia gravis were included in a prospective and standardized diagnostic and therapeutic protocol. Age varied between 10 and 74 years (34 +/- 16, mean +/- standard deviation). Three patients with the ocular form were treated with pyridostigmine. Four patients with the generalized form and advanced age received steroids and/or azathioprine. Twenty-three patients with the generalized form underwent thymectomy followed by prednisone and/or azathioprine. One patient died after complex thymectomy for invasive thymoma. Another died soon after admission in myasthenic/cholinergic crisis. Two other patients had minor complications of thymectomy. Of 19 patients followed for 1-60 (mean 24) months, 11 (58%) are in remission, one of them without any medication.     

High serum adenosine deaminase activity and its correlation with lymphocyte subsets in myasthenia gravis

Serum adenosine deaminase (ADA) activity and peripheral lymphocyte subsets of patients with myasthenia gravis (MG) were simultaneously measured. The ADA activity in MG (n = 30) was significantly higher as compared with normal control (n = 150) and multiple sclerosis (n = 12) (P < 0.05). The ADA activity of generalized MG was higher than that of ocular MG, while a significant elevation of ADA activity was observed in grade IIB as compared with grade I of Osserman's classification (P < 0.05). A trend of high ADA activity was demonstrated in those whose disease had advanced to a severe degree associated with unstable clinical features (P < 0.05). In addition, there was a significant elevation of ADA activity in patients who disclosed positive anti-Ach-receptor-antibody as compared with negative one (P < 0.05). There was no specific trend among the proportions of the subsets of peripheral lymphocytes which could reflect the severity of MG, however, the proportion of OKIa1 +tended to be higher with advancing the grade of MG. Interestingly enough, a close correlation was found between the ADA activity and the proportion of OKIa1 +cells (P < 0.05). From the above results, it was concluded that high ADA may be responsible for the pathophysiology of MG through the alteration of peripheral lymphocyte function.     

The effect of ACTH treatment on lymphocyte subpopulations in patients with myasthenia gravis.

Blood lymphocytes were collected before, at various times during treatment and after treatment with ACTH in patients with myasthenia gravis. The relative proportions of thymus-derived (T cells) and bursa-derived (B cells) lymphocytes were determined. Eight of nine patients had a relative increase in B cells, whereas T cells showed a relative decrease. Myasthenic symptoms in these eight patients also were relieved. One patient who was not thymectomized showed virtually no relief in symptoms nor any changes in the relative T and B cell proportions or numbers, indicating a close association between the disease and the thymus-derived immune system.     

重症肌无力患者外周血T淋巴细胞亚群凋亡的研究

目的探讨外周血T淋巴细胞亚群凋亡在重症肌无力(MG)免疫发病机制中的作用及临床意义。方法采用流式细胞术结合免疫荧光抗体法测定了45例MG患者和40例正常对照组外周血CD4~ T淋巴细胞、CD8~ T淋巴细胞百分数及其凋亡状况,并对24例MG患者在应用糖皮质激素治疗后外周血T淋巴细胞亚群凋亡状况进行了观察。结果MG患者组外周血CD8~ T淋巴细胞百分率较正常对照组明显降低,CD4~ /CD8~ 比值较正常对照组明显升高：MG患者组外周血CD4~ T淋巴细胞凋亡程度较正常对照组明显降低；MG患者外周血CD4~ T淋巴细胞凋亡程度与MG类型、预后密切相关：应用糖皮质激素治疗后MG患者外周血CD4~ T淋巴细胞凋亡程度明显增强。结论MG患者存在T淋巴细胞亚群的分布异常及CD4~ T淋巴细胞凋亡功能障碍,其凋亡程度可能与MG类型、预后密切相关,糖皮质激素对MG患者外周血CD4~ T淋巴细胞凋亡缺陷具有纠正作用。     

重症肌无力患者外周血CD+4 CDhigh25 T细胞及其动态观察

目的 研究重症肌无力(myasthenia gravis, MG)患者外周血CD+4 CDhigh25 T细胞的水平,以及各种治疗方法对其的影响.方法 应用四色流式细胞仪检测55例MG患者(治疗前)与33名健康对照外周血CD+4 CDhigh25 T细胞百分率,对其中26例MG患者进行了治疗前后的动态检测.结果 MG患者与健康对照外周血CD+4 CDhigh25 T细胞百分率分别为6.22%±3.37%与5.16%±1.87%,两者差异无统计学意义(P=0.061),而21例非手术治疗患者其外周血CD+4 CDhigh25 T细胞百分率的变化与病情评分的变化呈负相关(r=-0.563, P=0.008).结论 这种非手术治疗前后短期内的CD+4 CDhigh25 T细胞的变化情况可能与病情相关,但胸腺切除前阶段观察的情况有所不同.     

Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis.

Antibodies to muscle acetylcholine receptors, to other muscle antigens, and to some cytokines are found in the majority of patients with thymic tumors (thymomas) and myasthenia gravis (MG). The role of the tumor in initiating autoimmunity, however, is unclear; in particular, it is not known whether the thymoma exports mature and long-lived T cells, which could provide help for antibody production in the periphery. Here, we quantified recently exported thymic T cells using the approach of measuring episomal DNA fragments [T-cell receptor excision circles (TRECs)], generated by T-cell receptor gene rearrangement. Compared to values in healthy individuals (n = 10) or in patients with late-onset MG (n = 8), TREC levels were significantly raised in both the CD4+ and CD8+ peripheral blood compartments of patients with thymoma and MG (n = 14, p = 0.002 and p = 0.0004 compared to healthy controls) but only in the CD8+ compartment of the three patients with thymoma without MG (p = 0.4 and p = 0.01 for CD4+ and CD8+). TREC levels decreased following thymectomy to values similar to controls but were substantially raised in patients who had developed tumor recurrence (n = 6, p = 0.04 and p = 0.02 for CD4+ and CD8+); this was associated with increased antibodies to interferon-alpha and interleukin-12 in the one case studied serially. Collectively, these results support the hypothesis that the neoplastic thymoma tissue itself can generate and export mature, long-lived T cells and that these T cells reflect the thymic pathology and are likely to be related to the associated autoimmune diseases. The results also provide a new approach for early diagnosis of thymoma recurrence.     

硫唑嘌呤合用皮质类固醇治疗重症肌无力危象的疗效观察

目的:硫唑嘌呤合用皮质类固醇治疗重症肌无力危象的疗效观察。材料和方法:男女各3例。年龄26～48岁。其中5例重症肌无力眼肌型,1例重症肌无力延髓型。病程1.5～8年。都经胸腺瘤切除,术后2～5月出现重症肌无力危象。当皮质类固醇激素治疗效果不佳时,加用硫唑嘌呤100～150mg/天治疗。结果:在3～4周内完全脱离人工呼吸机,除轻度眼睑下垂,2例肢体肌力Ⅴ度、4例肢体肌力Ⅳ度。结论:硫唑嘌呤合用皮质类固醇治疗重症肌无力危象是有效的。     

Anti-AChR antibodies, thymic histology, and T cell subsets in myasthenia gravis

The relationship between the titers of antibody against acetylcholine receptor (AChR) and T helper/suppressor balance (assessed by the OKT4/OKT8 ratio) were investigated in 74 patients with myasthenia gravis (MG). All patients with elevated AChR antibody titers (greater than 100 nM) had hyperplastic thymuses, while most patients with low or negative antibody titers (less than 1 nM) had involuted thymuses. All patients with thymoma had positive, though not very high, antibody titers. No correlation was found between anti-AChR antibody levels and OKT4/OKT8 ratios except for patients with thymoma. Thus, it appears that AChR antibody titers are more closely related to thymic pathology than to peripheral T cell imbalance. These results are consistent with the hypothesis giving a central role to thymic lymphocytes in the AChR antibody production, either as antibody producer B cells or helper T cells.     

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.