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In young female rats, thymectomy causes RER alterations and a slight increase in SER. PCN augments SER in the hepatocytes of both intact and thymectomized rats. Thymectomy prolongs zoxazolamine paralysis and PCN treatment decreases the duration of zoxazolamine paralysis both in intact and operated rats.
Clinical remission in myasthenia gravis after thymectomy and immune suppressive treatment may be reflected by changes of immunoregulatory cytokines. Mononuclear cells from paired blood samples from fifteen patients with myasthenia gravis before and after thymectomy and immunosuppressive therapy were examined by in situ hybridization for acetylcholine receptor-induced mRNA expression of the T helper type 1 proinflammatory cytokines interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) and TNF-beta, the T helper type 2 cytokines interleukin 4 (IL-4) and IL-10 and the immune response downregulating cytokine tumor growth factor beta (TGF-beta). A significant change was observed for TGF-beta, with increased expression after treatment and induction of clinical remission. Augmentation of TGF-beta may play a role in the induction of remission in myasthenia gravis.
Twenty-two cases of purely ocular myasthenia gravis were reviewed to evaluate the long-term effects of thymectomy. Remission rate increased gradually with time (11.8% at 3 years, 23.1% at 5 years, and 33.3% at 10 years). Analysis of factors influencing remission with time showed that patients with short duration of illness attained remission significantly earlier (p = 0.035 at 5-year follow-up). One of 22 patients with purely ocular myasthenia gravis (4.5%) had disease progression. Because ocular myasthenia gravis often progresses to the generalized type and because duration of illness before operation is one of important factors influencing remission, we conclude that thymectomy in the earlier stages of the disease is the preferred treatment for ocular myasthenia gravis, just as for generalized myasthenia gravis.
Different age-related immune pathogenetic mechanisms in myasthenia gravis (MG) have been suggested because of restoration after thymectomy (Tx) of altered zinc, thymulin (TH) and T-cell subsets exclusively in early-onset patients (younger <50 years), not in late-onset patients (older >50 years). In this context interleukin-2 (IL-2), interleukin-6 (IL-6) and thymoma are crucial because both involved in MG pathogenesis and correlated with acetylcholine receptors (AchRs) Ab production. Moreover, IL-2 and IL-6 are zinc-dependent, are altered in aging and related with zinc and TH age-dependent declines. Moreover, zinc is relevant for immune efficiency. In order to confirm these different age-related pathogenetic mechanisms further, the role of thymoma, zinc, TH, IL-2 and IL-6 is studied in MG patients with generalized MG with and without thymoma before and 1 month and 1 year after Tx. The high IL-2, IL-6, zinc, and AChR Ab levels observed before Tx are significantly correlated each other in younger MG patients (<50 years) independently by thymoma and in older MG patients (>50 years) with thymoma. No correlations exist in older MG patients without thymoma. Thymulin is not correlated with other parameters considered to be both in younger and older MG patients independently by the thymoma. Thymectomy restores zinc; immune parameters and AChR Ab are exclusively in the younger group, not in the older one. These findings suggest that IL-2 and IL-6, via zinc, rather than TH, may be involved in different age-related pathogenetic mechanisms mainly in early-onset MG. By contrast, thymoma may be involved in MG etiology in late-onset representing, as such, a useful discriminant tool for MG etiology between early and late-onset MG patients. Because autoimmune phenomena may rise in aging, a parallelism with altered immune functions during aging is discussed.
A 35 year-old woman developed severe systemic lupus erythematosus 9 years after thymectomy for myasthenia gravis. "Seric Thymic Factor" (STF) was low; T helpers subset, T helpers/T suppressors ratio and to a lesser extent T suppressors subset were decreased. Suppressor cell function investigated by Concanavaline A lymphocyte reactivity was low. Under cyclophosphamide, plasmapheresis and steroids all clinical and biological symptoms improved but STF remained low; T helpers, T suppressors subsets and T helpers/T suppressors ratio increased but did not reach the normal range. Statistical and immunological arguments suggest that the association between systemic lupus erythematosus and myasthenia gravis did not occur only by chance. Moreover, thymectomy might have played a role by decreasing the number and function of some subpopulations of lymphocytes.
Pure red cell aplasia (PRCA) is well known to be concomitant with myasthenia gravis (MG), but it is difficult to predict the development of PRCA in patients with MG. Of 135 patients with MG, four (2.9%) had PRCA. All patients developed PRCA after thymectomy during a period when MG was in remission. The frequencies of thymoma, bulbar involvement and high anti-acetylcholine receptor (AChR) antibody levels were significantly higher in four patients with PRCA. Japanese MG patients with these characteristics at presentation were at significant risk for the development of PRCA after thymectomy.
Juvenile myasthenia gravis is rare, representing just 10% of all myasthenia gravis. Treatment of the juvenile form is similar to the adult form, although concerns of long-term side effects limit use of immunomodulators and thymectomy in children, especially the very young. We review the clinical course of three children with juvenile myasthenia gravis, as well as the current status of intravenous immunoglobulin and thymectomy as treatments for juvenile myasthenia gravis.
Macrophages produced proinflammatory cytokines and inflammatory responses can cause many symptoms of depression, including direct stimulation of the HPA axis and secretion of cortisol. In depressed patients, hypercortisolism has been well described as one of the major symptoms and also as the cause for hippocampal atrophy and memory impairment. In this paper, the relationships between thymectomy, increased IL-1 levels, and changes in corticosterone and neurotransmitter concentrations in rats are discussed, as well as their implications for memory impairments and depression. In thymectomized rats, deficits in both spatial and fear conditioned memory have been observed. Thymectomy decreases noradrenaline and dopamine levels, and increases serotonergic neurotransmission in limbic areas, without affecting corticosterone concentrations. In a depression model, thymopeptides or IL-2 treatment significantly attenuated changes in behavior, lymphocyte proliferation and neurotransmitters caused by bulbectomy. The reduction of thymic functions may increase IL-1 synthesis. Central IL-1beta administration impairs rat's spatial memory in the Morris water maze and 8 arms radial maze, but enhances conditioned memory in the passive avoidance. These changes can be reversed by either IL-1 receptor antagonist or a glucocorticoid receptor antagonist (RU 486). Furthermore, IL-1-induced changes in some neurotransmitter systems are similar to those observed in thymectomized rats. However, both acute and sub-chronic IL-1 administration increases plasma corticosterone concentrations. Together, these findings suggest that changes in the function of the thymus gland may play an important role in the unbalance between macrophages, cytokines, and lymphocytes, which induces neurotransmitter and neuroendocrine changes, and memory disturbances in depressive illness.
Thymectomy has been shown to be effective in the treatment of myasthenia gravis patients. Rarely, bilateral chylothorax, was noted as a complication of thymectomy via median sternotomy. Probably unseen division of mediastinal lymphatics, remote from thoracic duct, can explain this phenomenon. We report the case of a patient, female, who developed bilateral chylothorax after the former surgical approach, and our initial conservative policy to treat it (unilateral chest tube, total parenteral nutrition and subcutaneous administration of octreotide, a long-acting somatostatin analog), with good results.
A consistent, planned approach to thymectomy for patients with myasthenia gravis has been used at the University of North Carolina since 1977. This involves a sternotomy, with excision of the entire thymus and adjacent fatty tissues from the thyroid to the diaphragm and laterally to 1 cm from each phrenic nerve. Between 1977 and 1993, 100 consecutive patients were treated in this manner with no mortality. Eight-four percent of patients were extubated in the operating room or within 1 hour of surgery, and no patients experienced postoperative respiratory difficulty. After a mean follow-up of 65 months, 78% of all patients improved by at least one modified Osserman classification, and 69% of patients with preoperative class I, II, or III disease (maximal preoperative severity) are in pharmacological remission. We conclude that transsternal thymectomy is associated with minimal morbidity and no mortality, and results in long-term improvement in symptoms for patients with myasthenia gravis.
Myasthenia gravis is a challenging situation for anaesthesiologists due to its neuromuscular involvement. The main concerns are respiratory muscle weakness and side effects due to a heavy dose of anticholinesterases. This limits the use of sedatives, hypnotics and muscle relaxants. Inhalational anaesthetics are best suited. We describe our experience with sevoflurane as a sole anaesthetic in a child having juvenile-type myasthenia gravis with thymoma, who underwent thymectomy by midsternal incision. Very smooth and short duration of induction (35 s) and easy intubation within 60 s without use of muscle relaxant were the remarkable features. Sevoflurane in oxygen and nitrous oxide (MAC=0.5-0.7) was used for maintenance of anaesthesia. Recovery was smooth and fast with no residual respiratory insufficiency. Hence we found sevoflurane to be a highly suitable agent for thymectomy in mysthenia gravis.
Treatment-related chronic myeloid leukaemia (CML) is a less commonly recognised entity. It differs from treatment-related acute leukaemias in frequency, clinical course, and prognosis. Previously two cases of CML have been described following treatment of myasthenia gravis associated with thymoma treated by thymectomy. We report a 25-yr-old man with myasthenia gravis without thymoma who developed CML, 68 months after thymectomy. Cytogenetic study showed translocation (9,22)(q34;q11) with 10% showing double Ph chromosome. Reverse-transcriptase polymerase chain reaction (RT-PCR) of peripheral blood demonstrated the presence of p210(BCR/ABL) with b3a2 transcripts. He was treated with hydroxyurea, and still remained in the chronic phase during the last 6 months of follow up. His myasthenic symptoms remained stable.
Three hundred and eighty-two patients undergoing thymectomy for myasthenia gravis at 4 London hospitals during the years 1942-64 have been followed to the end of 1967. Five of these patients died from extrathymic tumours while 5·5 would have been expected to do so from the national experience. An additional 5 patients developed non-fatal extrathymic tumours during the period of follow-up. These data provide no evidence that adult thymectomy is followed by an increased risk of neoplastic disease, but more prolonged follow-up will be required before a final conclusion can be drawn.
The number of lymphocytes discharged from the mesenteric lymphatic duct was measured over several days of continuous lymph drainage in adult guinea pigs which had been thymectomised at birth or as young adults. The reduced output of lymphocytes during the first few days of lymph drainage from neonatally thymectomised guinea pigs indicated that removal of the thymus at birth produced a deficiency in the mobilizable lymphocyte pool. Adult thymectomy led to a decrease in the mobilizable lymphocyte pool which did not become apparent until 35 days after removal of the thymus. This indicated that the production of lymphocytes by the thymus is important in the guinea pig for maintaining adequate numbers of recirculating lymphocytes during adult life. The concentration of lymphocytes was reduced in the peripheral blood of guinea pigs which had been thymectomised at birth. In female guinea pigs this lymphopenia was accompanied by an increase in the number of lymphocytes bearing Kurloff bodies. The concentration of lymphocytes in bone marrow was not significantly altered following neonatal thymectomy.
In vivo depletion of lymphocyte subsets is a direct approach used for dissection of the mechanisms of protective immunity. Long-term in vivo depletion of bovine T lymphocyte subpopulations with monoclonal antibody (mAb) treatment alone has been difficult to achieve. The objective of this study was to determine whether both thymectomy and anti-CD4 mAb treatment would optimize long-term in vivo depletion of functional bovine CD4+ T lymphocytes. Calves were thymectomized and treated with high doses of anti-CD4 mAb (approximately 5 mg/kg) over 4 days followed by subsequent lower doses (approximately 0.3 mg/kg) administered twice weekly for an additional 7 weeks. Depletion of CD4+ T lymphocytes from blood, spleen and peripheral lymph nodes was significantly improved in thymectomized calves compared to thymus-intact anti-CD4 mAb-treated calves. Significant differences in percentages of CD4+ T lymphocytes between thymectomized and thymus-intact calves were sustained for the duration of the 8-week study. Depletion of CD4+ T lymphocytes from thymectomized calves resulted in complete abrogation of lymphoproliferative responses to ovalbumin. In addition, thymectomized calves treated with anti-CD4 mAb had significantly reduced immunoglobulin G1 and no detectable immunoglobulin G2 ovalbumin-specific antibody responses compared to thymus-intact anti-CD4 mAb-treated calves. The results of this study demonstrate that both thymectomy and treatment with anti-CD4 mAb are required for long-term in vivo depletion of functional bovine CD4+ T lymphocytes.
Between 1985 and 1998 42 transsternal thymectomies were performed. The median duration of symptoms in myasthenia gravis patients (n = 27, 25/27 patients in stadium I/II of the Ossermann classification) was 40.3 weeks and 70.8 days between first diagnosis and operation. In 12 patients a thymoma was found (11/12 patients with stadium I/II of Masaoka classification), which was associated with myasthenia gravis symptoms in 10 cases. In 3 patients thymic tumors of other origin were verified histologically. After surgery these patients have an increased risk of pulmonary complications. We changed 1996 the perioperative anesthesiological procedure using total intravenous anesthesia with propofol/remifentanil and systemic patient-controlled analgesia with piritramide in the first two days after transsternal thymectomy. This management allows a quick extubation after operation and improved lung function postoperatively.
The effects of thymectomy and thymus graft restoration upon the in vitro primary responses to alloantigens and PHA have been studied. It has been found that neonatal thymectomy substantially eliminates both PHA reactivity and responsiveness to alloantigens assayed in vitro in host spleen cell populations. Analysis of albumin density gradient-separated subpopulations of the spleen and thymus in such animals was also performed. It was found that the total and proportional representation of the individual density subpopulations was identical in neonatally thymectomized, in normal, and in thymectomized and thymus graft-restored animals. Therefore, thymectomized mice appear to retain a nonfunctioning, small, dense, lymphocyte population. Reconstitution of thymic-dependent in vitro reactivity was nearly complete when syngeneic, but not allogeneic or semisyngeneic thymus was employed. Occasional partial restoration did occur when F(1) thymus was employed, but never when allogeneic thymus was grafted. The grafted thymus contained PHA and alloantigen-reactive cells in a large, less dense B layer subpopulation, whereas the restored animals, as in the case of normals, showed these reactivities to be a property of a small, more dense cell population.
In this study the role of the thymus in the development of sessile T cell populations resident in spleen and lymph nodes (LN) was contrasted with the development of recirculating T cell populations trafficking between blood and lymph. Extensive analysis of the composition and the rate of growth of the secondary lymphoid tissues and recirculating lymphocyte pool coupled with neonatal thymectomy revealed that the sessile and recirculating T cell populations showed different degrees of thymic dependency and increased in size at different rates, suggesting these two populations might be under separate homeostatic control. Neonatal thymectomy also resulted in a much greater depletion of CD8+ and gammadelta TCR+ T cell subsets compared with CD4+ T cells in the sessile and recirculating T cell pools, and greatly reduced the number of T cells homing to peripheral lymph nodes compared with those homing to the gut.