Thymoma-associated Myasthenia Gravis Research Articles

Clinical and immunological predictors of prognosis for Japanese patients with thymoma-associated myasthenia gravis

There are no immunological markers to predict the prognosis of thymoma-associated myasthenia gravis (MG). Clinical and immunological factors associated with thymoma recurrence or MG relapse were examined by logistic analyses in 56 Japanese patients with thymoma-associated MG. Patients with anti-Kv1.4 antibodies showed higher frequencies of thymoma recurrence and MG relapse compared to those without. Anti-Kv1.4 antibody, Masaoka stage 4, World Health Organization type B3, and adjuvant radiotherapy were associated with thymoma recurrence. Multivariate analyses showed that anti-Kv1.4 antibody was the only independent factor associated with MG relapse. Anti-Kv1.4 antibody is a useful predictor of the prognosis of thymoma-associated MG.

胸腺腫を合併した抗筋特異的受容体チロシンキナーゼ抗体陽性重症筋無力症の1例

We report a 60-year-old male with thymoma-associated myasthenia gravis with anti-MuSK antibodies. In October 2010, he had diplopia, ptosis, and dysphagia. He was diagnosed to have MG in February 2011. The neurological examination disclosed external ophthalmoplegia, bilateral ptosis, mild dysphagia, and fatigability. Repetitive nerve stimulation of the right facial nerve showed CMAP decrement greater than 10%. Patients showed an improvement in ptosis after administration of edrophonium.Anti-acetylcholine receptor antibody was negative, and anti-muscle specific receptor tyrosine kinase antibody was 66.8 nmol/l (cut-off value: 0.05 nmol/l). Prednisolone (50 mg every other day) were started. Contrast-enhanced chest MRI showed a mediastinal mass suggestive of thymoma. Extended thymectomy was performed in March 2011. Histological examination disclosed a type B1 thymoma. After resection of the tumor, the symptoms of MG improved with prednisolone (100 mg every other day). This is a rare case of MG with anti-MuSK antibodies and thymoma, which has been reported previously only in 2 cases.

Structure of the neuromuscular junction: function and cooperative mechanisms in the synapse

As an overview of the structure of the neuromuscular junction, three items are described focusing on cooperative mechanisms involving the synapse and leading to muscle contraction: (1) presynaptic acetylcholine release regulated by vesicle cycling (exocytosis and endocytosis); the fast-mode of endocytosis requires a large influx of external Ca(2+) and is promoted by the activation of G protein-coupled receptors and receptor tyrosine kinases; (2) postsynaptic acetylcholine receptor clustering mediated by the muscle-specific, Dok7-stimulated tyrosine kinase (MuSK) through two signaling mechanisms: one via agrin-Lrp4-MuSK (Ig1/2 domains) and the second via Wnt-MuSK (Frizzled-like cysteine-rich domain)-adaptor Dishevelled; Wnts/MuSK and Lrp4 direct a retrograde signal to presynaptic differentiation; (3) muscle contractile machinery regulated by Ca(2+) -release and Ca(2+) -influx channels, including the depolarization-activated ryanodine receptor-1 and the receptor- and/or store-operated transient receptor potential canonical. The first mechanism is dysfunctional in Lambert-Eaton myasthenic syndrome, the second in anti-acetylcholine receptor-negative myasthenia gravis (MG), and the third in thymoma-associated MG.

Surgical approaches for stage I and II thymoma-associated myasthenia gravis: feasibility of complete video-assisted thoracoscopic surgery (VATS) thymectomy in comparison with trans-sternal resection

Complete resection could be achieved in virtually all myasthenic patients with Masaoka stage I and II thymoma using the trans-sternal technique. Whether this is appropriate for minimally invasive approach is not yet clear. We evaluated the feasibility of complete video-assisted thoracoscopic surgery (VATS) thymectomy for the treatment of Masaoka stage I and II thymoma-associated myasthenia gravis, compared to conventional trans-sternal thymectomy. We summarized 33 patients with Masaoka stage I and II thymoma-associated myasthenia gravis between April 2006 and September 2011. Of these, 15 patients underwent right-sided complete VATS (the VATS group) by using adjuvant pneuomomediastinum, comparing with 18 patients using the trans-sternal approach (the T3b group). No intraoperative death was found and no VATS case required conversion to median sternotomy. Significant differences between the two groups regarding duration of surgery and volume of intraoperative blood loss (P = 0.001 and P < 0.001, respectively) were observed. Postoperative morbidities were 26.7% and 33.3% for the VATS and T3b groups, respectively. All 33 patients were followed up for 12 to 61 months in the study. The cumulative probabilities of reaching complete stable remission and effective rate were 26.7% (4/15) and 93.3% (14/15) in the VATS group, which had a significantly higher complete stable remission and effective rate than those in the T3b group (P = 0.026 and P = 0.000, respectively). We conclude that VATS thymectomy utilizing adjuvant pneuomomediastinum for the treatment of stage I and II thymoma-associated myasthenia gravis is technically feasible but deserves further investigation in a large series with long-term follow-up.

PTPN22 and CTLA-4 gene polymorphisms in resected thymomas and thymus for myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease of striated muscle tissue mediated by autoantibodies. MG is often treated with thymectomy. Protein tyrosine phosphatase non-receptor 22 (PTPN22) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have recently been found to be the genes that predispose to autoimmune diseases. The mechanisms of PTPN22 and CTLA-4 single nucleotide polymorphisms in resected thymomas and thymuses in MG remain unclear. In the present study, 90 patients with thymomas, including 44 patients with MG, 46 patients without MG, and 35 MG patients without thymoma were studied, with 50 healthy people as the controls. The +1858C>T polymorphism of the PTPN22 gene and the 49A>G polymorphism of the CTLA-4 gene were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The PTPN22 -1123G>C polymorphism at the promoter site was genotyped using single allele-specific primer polymerase chain reaction (SASP-PCR). The PTPN22 +1858C>T polymorphism was not significantly different between the patients and the controls. Statistically significant differences in the allelic and genotypic frequencies of PTPN 22 -1123G>C and CTLA-4 49A>G were observed between the MG(+)-thymoma group and the controls (P = 0.000, 0.003), but not between the MG(-)-thymoma and MG-thymoma(-) groups and the controls (P = 0.192/P = 0.214 and P = 0.067/P = 0.254). Statistically significant differences in allelic and genotypic frequencies of the 49A>G for CTLA-4 were observed between the MG(+)-thymoma group and the controls (P = 0.000, P = 0.003), but not between the MG(-)-thymoma and MG-thymoma(-) groups and the controls (P = 0.077/P = 0.261 and P = 0.058/P = 0.058). Individuals with the PTPN22 CC genotype and the CTLA-4 G alleles had an increased risk of developing paraneoplastic MG (odds ration [OR]= 4.722, 95% confidence interval [CI]: 1.460-15.277) compared with those with the PTPN22 G allele and the CTLA-4 AA genotype. The results show an association between the PTPN22 1123G>C genotype and thymoma-associated MG, with significant synergy with the CTLA-4 G alleles.

Childhood-Onset Myasthenia Gravis With Thymoma

Juvenile myasthenia gravis is an acquired, autoimmune disease occurring before age 16 years. Thymoma is exceedingly rare in children, especially in association with juvenile myasthenia gravis. We describe a 14-year-old boy with juvenile myasthenia gravis and thymoma. He presented with difficulties chewing and swallowing, nasal speech, and fluctuating weakness of the leg muscles. Neurologic examination revealed masticatory and bulbar muscle weakness with nasal speech, proximal muscle weakness, fatigability of the arms and legs, and distal muscle weakness of the legs. A diagnosis of juvenile myasthenia gravis was confirmed by a positive neostigmine test, a decremental response on repetitive nerve stimulation, and increased titers of serum anti-acetylcholine receptor antibodies. The patient received anticholinesterases, corticosteroids, azathioprine, and thymectomy. A pathohistologic analysis of the thymus gland indicated thymoma, Masaoka grade II. After 2 years of an unstable disease course, remission was achieved. Because only 10 cases of thymoma-associated myasthenia gravis are described in the pediatric population, this report offers an important contribution to a better understanding of this rare association.

Radioligand-Binding Assay Reveals Distinct Autoantibody Preferences for Type I Interferons in APS I and Myasthenia Gravis Subgroups

Patients with autoimmune polyendocrine syndrome type I (APS I) or acquired thymoma-associated myasthenia gravis (MG) surprisingly share several common features, including defective expression of the transcription factor AIRE and autoantibodies against type I interferons. Here, we have adapted and validated the radioligand-binding assay we recently developed against (35)S-Met-interferon-ω, for rapid and specific screening for autoantibodies against interferons-α2 and -α8. We then investigated their potential for diagnosis and for predicting clinical manifestations in patients with APS I and different subgroups of MG. Autoantibodies against interferons-ω, -α2, and -α8 occurred more often in patients with APS I (100%) and MG with thymoma (73%) than in late-onset MG (39%) and early-onset MG (5%). These autoantibodies showed preferences for interferon-ω in APS I and for the interferon-αs in MG, hinting at thymic aberrations in both groups. The exact profile of type I interferon antibodies may indicate MG subtype and may hint at thymoma recurrence.

Chemotherapy Definitions and Policies for Thymic Malignancies

Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat.1 Thymomas are usually localized to the anterior mediastinum and are frequently eligible for upfront surgical resection, which is the mainstay of the curative-intent treatment.1 However, approximately 30% of patients present with an advanced tumor at the time of diagnosis, with invasion of neighboring organs, dissemination to the pleura, the pericardium, or less frequently extrathoracic organs. In such cases, chemotherapy has been used both to reduce the tumor burden—possibly allowing subsequent surgery or radiotherapy—and to achieve prolonged disease control. Recurrence after resection may be similarly treated with chemotherapy. Thymic carcinomas, although rare, are usually already advanced at the time of presentation, and systemic therapy is important for almost all of these patients. Knowledge regarding chemotherapy for thymic tumors has mainly been based on retrospective series,2–9 although several prospective trials have also been conducted.10–21 These studies have clearly demonstrated the chemosensitivity of thymoma, and to a lesser extent thymic carcinoma, to various cytotoxic agents and combinations. However, details of patient selection are often lacking (either disease extent or general condition), and the intent of the treatment sequence is often vague. Adoption of a common language and definition of terms is crucial for the International Thymic Malignancies Interest Group (ITMIG) effort to develop a international prospective database of thymic tumors. The article by Huang et al.22 provides definitions for survival and endpoints for recurrences assessment and discusses how to measure response to treatment. Herein, we discuss additional points with regard to chemotherapy, including treatment sequence, general modalities, and impact of corticosteroids.

Thymoma-associated myasthenia gravis without acetylcholine receptor antibodies

Patients with myasthenia gravis and thymoma usually present antibodies to the acetylcholine receptor (AchR-Ab). Only two cases of thymoma-associated myasthenia gravis without AchR-Ab have been previously reported. We describe a case of seronegative thymoma-associated myasthenia gravis as a further evidence of the variability of myasthenia gravis in terms of antibody profile and thymic pathological findings.

Video-assisted thoracoscopic surgery or transsternal thymectomy in the treatment of myasthenia gravis?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was how video-assisted thoracoscopic surgery (VATS) compares to median sternotomy in the surgical management of patients with myasthenia gravis (MG)? Overall 74 papers were found using the reported search, of which 15 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that VATS produces equivalent postoperative mortality and complete stable remission (CSR) rates, with superior results in terms of hospital stay, operative blood loss and patient satisfaction at the expense of a doubling of operative time. Six studies comparing VATS and transsternal sternotomy in non-thymomatous myasthenia gravis (NTMG) patients found VATS to have lower operative blood loss (73.8±70.7 vs. 155.3±91.7 ml; P<0.05), reduced total hospital stay (5.6±2.2 vs. 8.1±3.0 days; P=0.008), whilst maintaining equivalent remission rates (33 vs. 44.7%; P=0.16) and mass of thymic tissue resection (37 vs. 34 g; P>0.05). One study comparing video-assisted thoracoscopic extended thymectomy to transsternal thymectomy in only thymoma-associated myasthenia gravis (T-MG) patients found equivalent CSR (11.3 vs. 8.7%, P=0.1090) at six-year follow-up. Thymoma recurrence rate (9.64%) was not significantly different (P=0.1523) between the two groups. Eight studies comparing VATS and transsternal approach in mixed T-MG and NTMG patients found a lower hospital stay (1.9±2.6 vs. 4.6±4.2 days, P<0.001), reduced need for postoperative medication (76.5 vs. 35.7%, P=0.022), lower intensive care unit stay (1.5 vs. 3.2 days, P=0.018), greater symptom improvement (100 vs. 77.9%, P=0.019) and better cosmetic satisfaction (100 vs. 83, P=0.042) with VATS. In concordance with NTMG and T-MG alone patient groups, VATS and transsternal methods had equivalent complication rates (23 vs. 19%, P=0.765) with no mortalities in either group. Even though VATS has a longer operative time (268±51 vs. 177±92 min, P<0.05), its improved cosmesis, reduced need for postoperative medication and equivalent disease resolution outcomes make it a preferable surgical option to the transsternal approach.

Caspr2 Antibodies in Patients with Thymomas

Myasthenia gravis is the best known autoimmune disease associated with thymomas, but other conditions can be found in patients with thymic tumors, including some that affect the central nervous system (CNS). We have become particularly interested in patients who have acquired neuromyotonia, the rare Morvan disease, or limbic encephalitis. Neuromyotonia mainly involves the peripheral nerves, Morvan disease affects both the peripheral nervous system and CNS, and limbic encephalitis is specific to the CNS. Many of these patients have voltage-gated potassium channel autoantibodies. All three conditions can be associated with thymomas and may respond to surgical removal of the underlying tumor together with immunotherapies and symptomatic treatments. Herein, we review the results of our recent studies that show that voltage-gated potassium channel autoantibodies are not principally directed against the potassium channels themselves but in some patients are directed against a protein that is complexed with potassium channels in both the peripheral nervous system and CNS, contactin-2 associated protein (Caspr2). These antibodies are common in the subgroup of patients with thymic malignancies.

Assessment of multimodality therapy for thymoma.

This study was designed to analyze the accuracy and reliability of several prognostic indicators for long-term survival of thymoma patients. Data from 142 patients treated for thymoma at the Tianjin Medical University Cancer Hospital from January 1954 to January 2001 were retrospectively analyzed. The Kaplan-Meier method and Cox's proportional hazards model test were used for single and multi-variable analyses respectively. The Log-rank test was used to compare survival between groups. The sizes and extent of the tumors were classified as I - IV according to the Masaoka clinical staging scale. Respective 5- and 10-year survival rates were: 93.8% and 79.2% in stage I, 79.3% and 55.2% in stage II, 53.1% and 34.4% in stage III, and no survivors in stage IV. Among 30 patients with associated myasthenia gravis, 19 had generalized myasthenia gravis and 11 had ocular myasthenia gravis; 5- and 10-year survival rates were 83.3% and 60.0%, respectively. The 5- and 10-year survival rates for 112 patients without myasthenia gravis were 53.6% and 42.0%, respectively. Eighty-four patients had radical resection and nine had palliative resection. Eighty-nine patients had radiotherapy and 55 patients had postoperative radiotherapy. Single or multi-variable analyses showed that the main prognostic indicators are Masaoka clinical staging, thymoma-associated myasthenia gravis, and the treatment method. The most important indicators of long-term survival in thymoma are Masaoka clinical staging and the completeness of resection. The primary treatment method for thymoma should be wide tumor resection. Pre- and/or postoperative radio- and/or chemotherapy should be given according to individual treatment requirements.

Factors associated with response to calcineurin inhibitors in myasthenia gravis

The objective was to assess which clinical factors of patients with myasthenia gravis (MG) are associated with responsiveness to calcineurin inhibitors (CNIs, cyclosporine and tacrolimus). We retrospectively analyzed the 6-month effects of CNIs in 62 MG patients. We excluded the influence of other immune treatments and determined factors associated with response to CNIs. The frequency of patients who achieved neither a > or =3-point reduction in quantitative MG score nor a > or =25% reduction in daily dose of prednisolone (poor responders) reached 35.5% (22/62) and 64.5% (40/62), respectively, compared with patients who achieved at least one of these improvements (responders). Neither dose nor blood concentration of CNIs differed between groups. Multivariate logistic regression analysis revealed time since onset of disease [odds ratio (OR) = 0.85, P = 0.005] and presence of thymoma (OR = 5.56, P = 0.05) as clinical factors that predict response to CNIs. As for MG-related autoantibody status, an autoantibody against a voltage-gated potassium channel, Kv1.4, was associated with response (OR = 9.01, P = 0.04) and showed a correlation with the presence of thymoma (P < 0.01). In MG, the early stages of disease and thymoma-associated MG are responsive to treatment with CNIs.

The PTPN22gain-of-function+1858T(+) genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis

Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) inhibits T-cell activation and interleukin-2 (IL-2) production. The PTPN22(gain-of-function)+1858T(+) genotypes predispose to multiple autoimmune diseases, including early-onset (non-thymomatous) myasthenia gravis (MG). The disease association and the requirement of IL-2/IL-2 receptor signaling for intrathymic, negative T-cell selection have suggested that these genotypes may weaken T-cell receptor (TCR) signaling and impair the deletion of autoreactive T cells. Evidence for this hypothesis is missing. Thymoma-associated MG, which depends on intratumorous generation and export of mature autoreactive CD4(+) T cells, is a model of autoimmunity because of central tolerance failure. Here, we analyzed the PTPN22 +1858C/T single nucleotide polymorphism in 426 German Caucasian individuals, including 125 thymoma patients (79 with MG), and investigated intratumorous IL-2 expression levels. Unlike two previous studies on French and Swedish patients, we found strong association of PTPN22 +1858T(+) genotypes not only with early-onset MG (P=0.00034) but also with thymoma-associated MG (P=0.0028). IL-2 expression in thymomas with PTPN22 +1858T(+) genotypes (P=0.028) was lower, implying weaker TCR signaling. We conclude that the PTPN22(gain-of-function) variant biases towards MG in a subgroup of thymoma patients possibly by impeding central tolerance induction.

Myasthenia gravis und myasthene Syndrome

Neuromuscular transmission is compromised in a variety of disorders due to immunological, toxic or congenital mechanisms. Myasthenia gravis (MG) is the most frequent among these disorders. In about 15% of cases, MG is associated with a second autoimmune disorder mainly seen in rheumatologists. Some of the drugs used in rheumatology can exacerbate MG or even trigger immunologically the occurrence of MG. In most MG patients, antibodies to the acetylcholine receptor (AChR) are present, but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-specific kinase antibodies which define a different subgroup of myasthenia. Among those MG patients with anti-AChR antibodies, a number of clinical subtypes can be identified including early-onset MG (onset <or= 40 years), late-onset MG (onset after 40 years) and thymoma-associated MG. Even though less common, it is important to recognize Lambert Eaton myasthenic syndrome (LEMS). The abnormality in LEMS is a presynaptic failure to acetylcholine release caused by antibodies to voltage-gated calcium channels. More than half of LEMS patients have small-cell lung cancer.

Modified Maximal Thymectomy for Thymic Epithelial Tumors: Predictors of Survival and Neurological Outcome in Patients with Thymomatous Myasthenia Gravis

Thymic epithelial tumors are characterized by slow growth and variable malignant behavior. We present our experience on the surgical management of these tumors. We conducted a retrospective analysis of patients with thymomas undergoing modified maximal thymectomy over a period of 16 years. Evaluated parameters included gender, age, Masaoka stage, WHO histology, R0 resection, myasthenia gravis, and adjuvant radiotherapy. In thymoma-associated myasthenia gravis, further analysis was made according the Osserman stage, the time from myasthenia diagnosis to thymectomy, and the steroid treatment. End points were survival for the total study group and achievement of complete stable remission (CSR) in patients with myasthenia gravis. The study group consisted of 15 male and 24 female patients. There was no perioperative mortality. Overall survival was 91.6% and 75.1% at 5 and 10 years. Univariate analysis identified the following predictors of survival: myasthenia (P < 0.001), Masaoka stage (P < 0.001), R0 resection (P < 0.001), and WHO histology (P = 0.007). Only the WHO histology was an independent predictor of survival in multivariate analysis (P = 0.003). Myasthenia patients had CSR prediction of 51.9% and 75.9% at 10 and 15 years. Preoperative steroid treatment (P = 0.007) and WHO histology (P = 0.021) were independent predictors of CSR on multivariate analysis. Modified maximal thymectomy is safe and efficient in the treatment of thymomas. WHO histology is the prime determinant of tumor aggressiveness and patient survival. Paraneoplastic myasthenia gravis and its outcome after thymectomy is significantly correlated with the WHO classification subtypes; however, lower CSR rates are not necessarily associated with more aggressive histological subgroups.

Rituximab for the Treatment of Thymoma-Associated and De Novo Myasthenia Gravis: 3 Cases and Review

Myasthenia gravis (MG) is an immune-mediated disorder associated with autoantibodies against postsynaptic nicotinic acetylcholine receptors at neuromuscular junctions. Rituximab, a monoclonal antibody specific for CD20, is used primarily to treat B-cell non-Hodgkin lymphoma. Although it has been used for treatment of a number of autoimmune diseases, there is limited experience in MG. Three patients with refractory MG (2 with concurrent thymoma) were given rituximab. Symptoms stabilized and reductions in immunosuppressive medications were tolerated for extended periods, without adverse effects or infectious complications. These observations support the concept that rituximab may be helpful for the treatment of MG. Remissions in patients with or without thymoma are achievable with rituximab given in combination with commonly used modalities. Furthermore, rituximab is not necessarily contraindicated for the treatment of MG in patients being treated for thymoma. Controlled studies are called for to define its role in the treatment of refractory MG.

Thymoma-associated myasthenia gravis: Outcome, clinical and pathological correlations in 197 patients on a 20-year experience

We studied 197 patients with thymoma-associated myasthenia gravis (T-MG) to identify variables that can influence the natural history of the disease and the therapeutical approaches. Multivariate analysis showed that neither clinical nor pathological variables were associated with a better chance to reach complete stable remission. The video-assisted thoracoscopic extended thymectomy (VATET) was not significantly correlated with a lower chance of achieving complete stable remission compared with the classical transsternal approach (T-3b) ( p = 0.1090). Thymoma recurrence was not correlated with surgery by VATET or T-3b. VATET was safe and reliable for removal of thymoma. The low chance of achieving remission (9.64%) in T-MG underlines the importance of an early diagnosis as well as the need for more aggressive therapeutic strategies.

Hypothetical review: thymic aberrations and type-I interferons; attempts to deduce autoimmunizing mechanisms from unexpected clues in monogenic and paraneoplastic syndromes

In sporadic autoimmune disorders, dendritic cells are increasingly being incriminated as agents provocateurs. However, the mechanisms and any 'danger signals' that induce them to autoimmunize remain enigmatic. Here, we focus on unexpected clues from two prototypic/ highly informative autoimmune syndromes, acquired thymoma-associated myasthenia gravis and the monogenic autoimmune polyendocrine syndrome type-1 (APS1), caused by mutations in the AutoImmune Regulator (AIRE). Both involve the thymus, and in both we find early, persistent, highly prevalent and high-titre neutralizing autoantibodies against type-I interferons, regardless of the exact AIRE genotype or the characteristically variable clinical phenotype in APS1. Thus these key innate<-->adaptive immune intermediaries are now implicated in APS1 and paraneoplastic myasthenia as well as in systemic lupus erythematosus and other sporadic autoimmune disorders. The currently accepted notion that autoimmunization proceeds automatically (by 'default') does not explain how, when or where autoimmune responses are initiated against which targets in APS1, or whether exogenous or internal danger signals are involved, or predict whether the primary auto-immunogenic targets are AIRE-dependent. As the parallels between these syndromes must hold novel clues to these puzzles, they demand explanations. To unify these and other findings, we propose that autoimmunization occurs centrally in aberrant thymic environments rendered 'dangerous' by AIRE-deficiency (possibly by excess undegraded nucleic acids/dead cell debris). The ensuing autoreactivity focuses early on the locally abundant type I interferons and then on other peripheral tissue autoantigens that are still expressed despite the absence of AIRE. These ideas raise numerous questions that others may already have the materials to address.

Two cases of thymoma-associated myasthenia gravis without antibodies to the acetylcholine receptor

Thymoma-associated myasthenia gravis is considered a more severe disease compared with non-thymomatous myasthenia gravis and is generally associated with antibodies to the acetylcholine receptor (AChR-Ab). Even though a single case of thymoma-associated myasthenia gravis with anti-muscle specific kinase (MuSK) antibodies has been reported, to our knowledge, seronegative thymoma-associated myasthenia gravis has not been described. We report on two cases of this disease without antibodies to AChR or MuSK as a further evidence of the variability of myasthenia gravis in terms of antibody profile and thymic pathological findings.