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La myasthénie associée aux thymomes : particularités cliniques et résultats chirurgicaux
Abstract
Objective
The aim of this study was to compare the characteristics of myasthenic patients with and without thymoma, and the results of thymectomy in both types of patients.
Material and methods
A retrospective study was conducted among 66 patients who underwent thymectomy for myasthenia gravis in our department over a 10-year period (2000–2010). The surgical approach was sternotomy or anterolateral thoracotomy. Patients were divided into two groups according to the presence of thymoma: with (T-MG) and without (NT-MG) thymoma. Complete stable remission (CSR) was the primary endpoint.
Results
Median age was 35.09 ± 9.89 years. The NT-MG group had 38 patients (57.57%) and the T-MG group 28 patients (42.43%). There was no difference between the two groups regarding the surgical approach (P = 0.52). T-MG patients were older (40.54 ± 15.16 vs. 31.37 ± 9.46) (P = 0.008) and predominantly male. There were more generalized forms (P = 0.01) and more bulbar involvement (P = 0.02) in the T-MG group. The rate of CSR at 5 years was 7% and 17% in the T-MG and NT-MG patients respectively (P = 0.70). At 10 years, it was 36% and 94.73% respectively (P = 0.03).
Conclusion
Thymomatous myasthenia gravis is characterized by the severity of its clinical features. Remission rate at 10 years was significantly lower in the myasthenia with thymoma group.
... In 20-70% of patients, OMG generalizes to involve the peripheral, bulbar and/or respiratory musculature (2)(3)(4). Furthermore, myasthenia gravis can be associated with thymoma and other autoimmune conditions (5). Hence, early diagnosis and adequate treatment is of utmost importance. ...
Timely and accurate diagnosis of myasthenia gravis, particularly in patients with fluctuating, isolated ocular involvement, remains challenging. Serological antibody testing and repetitive nerve stimulation of peripheral muscles usually have low sensitivity in these patients. Edrophonium testing may cause adverse events, single-fiber electromyography (SFEMG) is time-consuming and both tests are often unavailable outside specialized institutions. Repetitive ocular vestibular evoked myogenic potential (roVEMP) stimulation has recently been introduced to facilitate the diagnosis of myasthenia gravis. Similar to repetitive nerve stimulation, roVEMPs detect muscle decrements with the benefit of being non–invasive and allowing for direct measurement of the extraocular muscles. This review summarizes the clinical evidence of the diagnostic value of roVEMP for myasthenia. Prospective clinical trials have demonstrated high sensitivity and specificity. RoVEMPs are of particular interest in challenging myasthenia subgroups with isolated ocular involvement, negative serology, and/or negative conventional electrophysiological results. Optimal roVEMP repetition rates of 20–30 Hz have been identified. This promising novel diagnostic tool merits further attention and investigation to establish its value as a clinical test for myasthenia.
... Myasthenia gravis is an autoimmune disease of the neuromuscular junction characterized by fatigability and muscle weakness interesting oculomotor muscles, bulbar or skeletal muscles [1]. It is due to specifi autoantibodies responsible for dysfunction of neuromuscular transmission inducing muscle fatigability [2]. ...
Myasthenia gravis is a rare disease with very few confirmed cases described in the African setting. We report the case of a 41-year-old woman with a history of type 2 diabetes, high blood pressure (well monitored), and migraine with aura. She was received at the outpatient neurology consultation for a left ptosis, diplopia, chewing and walking difficulties. She reported abnormal and fluctuating muscle fatigability at effort, responsible for several falls. These symptoms were marked at evening, and were evolving since four years before her consultation in our center. She also reported a history of palpitations, exertional dyspnea, dysphonia, dysphagia and 20 kg weight loss. Neurological examination found a horizontal diplopia, a left ptosis and abnormal weakness at dynamic eyes and limb muscles testing. Otherwise the remaining neurological examination was unremarkable. Repetitive nerve stimulation found a significant compound muscle action potentials decrement. The immunological tests showed a very high level of antibodies to acetylcholine receptors (anti-AChR) at 1220.00 nmol/l (normal value <0.40 nmol/l). Thyroid tests and the remaining biological tests were normal. Thorax CT-scan was normal, with no thymoma. Considering these results, the diagnosis of anti-AchR myasthenia gravis was established. She was started on pyridostigmine 60 mg four times daily associated to her previous hypertension and diabetes therapy. Outcome after five months of treatment was marked by a complete recovery of muscle weakness and weight. Myasthenia gravis is a rare disease, frequently leading to a misdiagnosis. His association with diabetes is well established. It is worth to think about it when dealing with patients presenting fatigue with a history of diabetes.
... Myasthenia gravis is an autoimmune disease of the neuromuscular junction characterized by fatigability and muscle weakness interesting oculomotor muscles, bulbar or skeletal muscles [1]. It is due to specific autoantibodies responsible for dysfunction of neuromuscular transmission inducing muscle fatigability [2]. ...
Myasthenia gravis is a rare disease with very few confirmed cases described in the African setting. We report the case of a 41-year-old woman with a history of type 2 diabetes, high blood pressure (well monitored), and migraine with aura. She was received at the outpatient neurology consultation for a left ptosis, diplopia, chewing and walking difficulties. She reported abnormal and fluctuating muscle fatigability at effort, responsible for several falls. These symptoms were marked at evening, and were evolving since four years before her consultation in our center. She also reported a history of palpitations, exertional dyspnea, dysphonia, dysphagia and 20 kg weight loss. Neurological examination found a horizontal diplopia, a left ptosis and abnormal weakness at dynamic eyes and limb muscles testing. Otherwise the remaining neurological examination was unremarkable. Repetitive nerve stimulation found a significant compound muscle action potentials decrement. The immunological tests showed a very high level of antibodies to acetylcholine receptors (anti-AChR) at 1220.00 nmol/l (normal value <0.40 nmol/l). Thyroid tests and the remaining biological tests were normal. Thorax CT-scan was normal, with no thymoma. Considering these results, the diagnosis of anti-AchR myasthenia gravis was established. She was started on pyridostigmine 60 mg four times daily associated to her previous hypertension and diabetes therapy. Outcome after five months of treatment was marked by a complete recovery of muscle weakness and weight. Myasthenia gravis is a rare disease, frequently leading to a misdiagnosis. His association with diabetes is well established. It is worth to think about it when dealing with patients presenting fatigue with a history of diabetes.
We investigated the role of miR-522-3p in thymoma-associated myasthenia gravis (TAMG), and the mechanism of action in T cells. The miR-522-3p expression in normal serum, non-thymoma MG patient serum and TAMG patient serum and tissues was detected by quantitative real-time PCR (qRT-PCR), respectively. We assessed miR-522-3p expression in Jurkat cells and human CD4⁺ T cells after activation by anti-CD3 and anti-CD28 using qRT-PCR. The viability, proliferation, cycle distribution and the levels of CD25, CD69, interleukin-2 (IL-2) and IL-10 in transfected Jurkat cells were detected by Cell counting kit-8, 5-ethynyl-2′-deoxyuridine (EdU), flow cytometry, qRT-PCR, respectively. Targeting relationships of miR-522-3p and SLC31A1 were predicted and validated by bioinformatics analysis and dual-luciferase reporter. The viability, proliferation, cycle distribution and the levels of SLC31A1, CD25, CD69, IL-2 and IL-10 in transfected Jurkat cells were detected by above methods and western blot. The miR-522-3p expression was declined in TAMG and activated T cells. MiR-522-3p inhibitor promoted cell viability, EdU positive cells, cycle progression, and the level of CD25, CD69, IL-2 and IL-10 in Jurkat cells, while the effect of miR-522-3p mimic was the opposite. SLC31A1 was targeted by miR-522-3p, and miR-522-3p inhibited SLC31A1 expression. Overexpressed SLC31A1 reversed the inhibitory effects of miR-522-3p mimic on cell viability, EdU positive cell, cycle progression, and the levels of IL-2 and IL-10 in transfected Jurkat cells. MiR-522-3p expression was down-regulated in TAMG, and miR-522-3p inhibited proliferation and activation by regulating SLC31A1 expression in T cells.
Objectives
To summarize the clinical features of thymomatous myasthenia gravis (T‐MG), examine the association between MG and thymoma, and identify the related factors or predictors for long‐term prognosis of T‐MG.
Methods
A retrospective, observational study was conducted on 100 patients with T‐MG and 96 patients with non‐T‐MG (NT‐MG) between January 1, 2009 and December 31, 2019. The baseline characteristics were recorded for each patient. Logistic regression was used to measure the association between all clinical variables and T‐MG prognosis.
Results
Between the T‐MG and NT‐MG groups, age at onset (45.66±11.53 years vs. 39.06±14.39 years); age >40 years (72.0% vs. 40.6%); AChR‐Ab positive rate (100.0% vs. 83.3%); Myasthenia Gravis Foundation of America (MGFA) classification at the worst condition (≥grade III, 61.0% vs. 33.0%); thyroid dysfunction (7.0% vs. 20.8%); and outcome (complete stable remission+pharmacologic remission+improvement, 74.0% vs. 93.7%) were statistically significant (P<0.05). Presence of thymoma (OR=0.196, 95%CI=0.076–0.511, P=0.001) was a risk factor for MG. Male sex, postoperative complications, higher grade of MGFA classification, and thymoma Masaoka–Koga pathological stage were risk predictors for long‐term prognosis of T‐MG (P<0.1). Use of preoperative anticholinesterase drugs (OR=5.504, 95%CI=1.424–21.284, P=0.013) was identified as an independent predictor for T‐MG.
Conclusion
T‐MG is clinically different from NT‐MG, and thymoma is considered a risk factor for MG. Preoperative anticholinesterase drug use is a protective factor for long‐term prognosis of T‐MG. A comprehensive understanding of the characteristics of T‐MG will likely help improve its prognosis.
Objectives:
The receptor for advanced glycation end-products (RAGE) is a membranous immunoglobulin involved in the pathogenesis of numerous autoimmune diseases and tumors. The aim of this study was to investigate the possible involvement of RAGE in the pathogenesis of myasthenia gravis.
Material and methods:
This prospective study included 41 cases of myasthenia gravis treated at our institution between 2010 and 2015. There were 18 men and 23 women, with an average age of 36.44±14.47 years. The majority of patients (24.4%) were classified as IIb, according to MGFA scoring, and 21 of them required corticosteroid and/or immunosuppressive treatment. Assessment of RAGE in thymus specimens was done by immunohistochemistry using RAGE antibody (C-term). RAGE expression was assessed according to various clinical, paraclinical and pathological parameters.
Results:
Histopathological studies found 18 thymomas, 17 hyperplasias and six other types of pathology. Expression of RAGE was negative/weak in 19 cases and moderate/strong in 22 cases. It was more important in thymoma type B2 (P<0.001) and when the duration of myasthenia was short (P=0.04), and was not significantly related to either myasthenia clinical severity or preoperative treatment.
Conclusion:
Our results suggest that the RAGE pathway is involved in myasthenia gravis pathophysiology, especially at disease onset, and in forms with thymomas. Further studies would be indispensable to explore other aspects of this signaling pathway, especially the potential role of different ligands and soluble forms of RAGE.
A novel class of transcripts, long non-coding RNAs (lncRNAs), has recently emerged as a key player in several biological processes, and important roles for these molecules have been reported in a number of complex human diseases, such as autoimmune diseases, neurological disorders, and various cancers. However, the aberrant lncRNAs implicated in myasthenia gravis (MG) remain unknown. The aim of the present study was to explore the abnormal expression of lncRNAs in peripheral blood mononuclear cells (PBMCs) and examine mRNA regulatory relationship networks among MG patients with or without thymoma.
Microarray assays were performed, and the outstanding differences between lncRNAs or mRNA expression were verified through RT-PCR. The lncRNAs functions were annotated for the target genes using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway. The potential regulatory relationships between the lncRNAs and target genes were analyzed using the 'cis' and 'trans' model. Outstanding lncRNAs were organized to generate a TF-lncRNA-gene network using Cytoscape software.
The lncRNA and mRNA expression profile analysis revealed subsets of differentially expressed genes in MG patients with or without thymoma. A total of 12 outstanding dysregulated expression lncRNAs, such as lncRNA oebiotech_11933, were verified through real-time PCR. Several GO terms including the cellular response to interferon-γ, platelet degranulation, chemokine receptor binding and cytokine interactions were very important in MG pathogenesis. The chromosome locations of some lncRNAs and associated co-expression genes were demonstrated using 'cis' analysis. The results of the 'trans' analysis revealed that some TFs (i.e., CTCF, TAF1and MYC) regulate lncRNA and gene expression. The outstanding lncRNAs in each group were implicated in the regulation of the TF-lncRNA-target gene network.
The results of the present study provide a perspective on lncRNA expression in MG. We identify a subset of aberrant lncRNAs and mRNAs as potential biomarkers for the diagnosis of MG. The GO and KEGG pathway analysis provides an annotation to determine the functions of these lncRNAs. The results of the 'cis' and 'trans' analyses provide information concerning the modular regulation of lncRNAs.
The recommendations for clinical research standards published in 2000 by a task force of the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and acceptance of more effective and less noxious therapies for MG.
One half of cortical thymoma patients develop myasthenia gravis (MG), while 15% of MG patients have thymomas. MG is a neuromuscular junction disease caused in 85% of the cases by acetylcholine receptor (AChR) antibodies. Titin and ryanodine receptor (RyR) antibodies are found in 95% of thymoma MG and 50% of late-onset MG (MG onset ≥50 years), are associated with severe disease, and may predict thymoma MG outcome. Nonlimb symptom profile at MG onset with bulbar, ocular, neck, and respiratory symptoms should raise the suspicion about the presence of thymoma in MG. The presence of titin and RyR antibodies in an MG patient younger than 60 years strongly suggests a thymoma, while their absence at any age strongly excludes thymoma. Thymoma should be removed surgically. Prethymectomy plasmapheresis/iv-IgG should be considered before thymectomy. The pharmacological treatment does not differ from nonthymoma MG, except for tacrolimus which is an option in difficult thymoma and nonthymoma MG cases with RyR antibodies.
A histological classification of thymic epithelial tumors was presented by the World Health Organization (WHO) in 1999 and again in 2004 following slight modifications, in which thymic epithelial tumors were categorized as thymomas and thymic carcinomas. Whereas thymoma is defined as an organotypic (thymus-like) tumor, thymic carcinoma is a malignant epithelial neoplasm with a morphology similar to that of malignant neoplasms arising from other organs. Herein, the recent progress in research of thymic epithelial tumors is reviewed with reference to the WHO histological classification system, with the focus on thymomas. Thymomas are classified into five types--A, AB, B1, B2, B3--according to the shape and atypia of their epithelial cells as well as the abundance of lymphocytes. The invasiveness, prognosis, and genetic imbalance of thymomas have been shown to be related to this classification system. Myasthenia gravis is frequently associated with types B1 and B2. The WHO histological classification of thymomas is not only useful for treatment but reflects their biological characteristics, including genetic alterations. Advances are expected in future studies of thymomas from the standpoint of their clinical, pathological, and biological aspects.
The aim of this study was to elucidate the relationship between the impairment of excitation-contraction (E-C) coupling and anti-ryanodine receptor (RyR) antibody in patients with myasthenia gravis (MG).
Masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The E-C coupling time (ECCT) was calculated as the latency difference between CMAP and MRP. For each patient, we selected a representative data set when there was no abnormal decrement in response to repetitive nerve stimulation. The 26 data sets were divided into an anti-RyR-positive group (n=12) and an anti-RyR-negative group (n=14).
Masseteric ECCT was significantly longer (p=0.017) in anti-RyR-positive group (median, mean, range; 3.6, 3.8, 3.0-5.9 ms) than in anti-RyR-negative group (3.1, 3.1, 2.7-4.0) although there were no significant differences in masseteric CMAP amplitude and % decrement between the two groups. The bite force was significantly lower in anti-RyR-positive group than in normal controls.
Presence of anti-RyR antibodies is associated with significantly prolonged masseteric ECCT compared to absence of the antibodies in MG.
Anti-RyR antibody contributes to E-C coupling impairment in the masseter muscle in patients with MG.
The treatment of patients with myasthenia gravis (MG) may include thymectomy. The objective of this study was to analyze the outcome of video-assisted thoracoscopic surgical (VATS) extended thymectomy and to compare characteristics of patients with MG with and without thymoma.
Between 2002 and 2009, 247 patients with MG underwent VATS thymectomy in our department and were subdivided into 2 groups: MG without thymoma (n=176) and MG with thymoma (n=71). Complete stable remission (CSR) was the primary endpoint for efficacy.
There were no intraoperative deaths and 4 cases required conversion to median sternotomy. There was a significant difference between the 2 groups regarding preoperative and postoperative myasthenic crisis. Two hundred nineteen patients were followed for 4 months to 9 years: 152 had thymoma and 67 did not have thymoma. The cumulative probabilities of reaching CSR were 37.5% in patients with MG without thymoma and 28.3% in patients with thymoma, respectively. Forty months after surgery there was no significant difference in CSR between the 2 groups. Two years after surgery, 30 patients without thymoma achieved CSR and disease was exacerbated in 2 patients after CSR had been achieved. Ten patients with thymoma achieved CSR, and exacerbation occurred in 5 patients with thymoma. Two patients without thymoma died of myasthenic crisis, whereas 3 of 4 patients with thymoma died of myasthenic crisis, and 1 death was attributable to recurrent disease.
Video-assisted thoracoscopic surgery thymectomy can produce a satisfactory long-term result. MG with thymoma seems more severe and its prognosis after thymectomy is not as optimistic as that of MG without thymoma. Special perioperative attention should be paid to patients with MG and thymoma to decrease the possibility of postoperative myasthenic crisis and reduce postoperative death.
Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P=0.008, OR: 2.5, 95%CI: 1.24-3.07) and B1*0301(P=0.000, OR: 2.29, 95%CI: 1.48-3.54) were the most frequent allele; the frequencies of DQA1*0103(P=0.000, OR:0.24, 95%CI 0.13-0.49) and DQB1*0601(P=0.001, OR:0.40, 95%CI 0.22-0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P=0.011, OR:4.57, 95% CI 1.40-14.90) and DQB1 *0604 (P=0.001, OR:4.01, 95% CI 1.65-9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.
The aim of this study was to elucidate the relationship between the impairment of excitation-contraction (E-C) coupling of masseter and the bite force in patients with myasthenia gravis (MG).
In 20 patients with MG, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRP) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The E-C coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT, and bite force were performed before and after corticosteroid therapy alone or in various combinations with FK506, cyclosporin A, intravenous immunoglobulin and immunoabsorption.
Percent amplitude decrement in RNS and ECCT decreased significantly accompanying an increase in bite force after treatment. Simple regression analysis demonstrated a linear correlation among % decrement, ECCT and bite force. However, ECCT shortening accompanying bite force recovery without reduction in % decrement was observed in 4 patients.
Masseteric E-C coupling is impaired in some MG patients, and functional recovery of E-C coupling contributes at least in part to the increase in bite force after treatment.
Impaired E-C coupling contributes to muscle weakness in patients with MG.
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.
Thymectomy has been shown to be effective in the treatment of myasthenia gravis. The logical goal of operation has been complete removal of the thymus, but there has been controversy about the surgical technique and its relation to results. Surgical-anatomic studies have shown gross and microscopic thymus widely distributed in the neck and mediastinum. We believe that an en bloc transcervical-transsternal "maximal" thymectomy is required to remove all thymic tissue predictably. Ninety-five patients with generalized myasthenia gravis underwent "maximal" thymectomy consecutively between 1977 and 1985 and were evaluated 6 months to 89 months after operation. In Group A (N = 72), myasthenia gravis without thymoma, the uncorrected data revealed that 96% (69) had benefited from operation: 79% (57) had no symptoms; 46% (33) were in remission; 33% (24) were symptom free when receiving minimal doses of pyridostigmine; and none were worse. Life table analysis yielded a remission rate of 81% at 89 months. In group B (N = 8), myasthenia gravis without thymoma for which patients underwent reexploration for incapacitating weakness after earlier transcervical or transsternal operations, residual thymus was found in all. One patient was in remission, two were symptom free when receiving medication, one was unchanged, and none were worse. In group C (N 15), myasthenia gravis and thymoma, two patients were in remission and nine were symptom free when receiving medication. Two patients in this group died 2 and 4 years postoperatively in crisis. Response to thymectomy in group A was greater in patients with mild myasthenia gravis and may have been better in patients who had symptoms for less than 60 months preoperatively, but the response did not depend on age, sex, presence or absence of thymic hyperplasia or involution, or titers of acetylcholine receptor antibodies. The response to thymectomy in group B was striking but slower than in group A, perhaps because symptoms were more severe and of longer duration. The response in group C was also less good than in group A and proportionately fewer benefited. These results support the recommendation for thymectomy in the treatment of patients with generalized myasthenia gravis and indicate the desirability of a maximal procedure. For persistent or recurrent severe symptoms after previous transcervical or submaximal transsternal resections, reoperation by this technique is also recommended.
The prevalence of myasthenia gravis (MG) among middle-aged and older patients has increased. Patients with early-onset MG live longer than before, but there is also an increase in late-onset MG (onset of the disease after the age of 50 years in patients with no clinical or paraclinical evidence of a thymoma). Epidemiological data support using the age of 50 years to separate early- and late-onset MG. The main immunological difference between early- and late-onset MG is the presence of antibodies to muscle titin, which are detected in approximately 50% of patients with late-onset MG. Treatment of late-onset MG has to be tailored both to the age of the patient and to the immunological findings of that particular form of MG.
Factors determining predictability of response to thymectomy for myasthenia gravis (MG) vary in the literature.
A 25-year retrospective review (1974 to 1999) of all thymectomies performed at a single institution was undertaken.
In 113 consecutive thymectomies for MG, women comprised 79% (89 of 113 patients), and mean age was 40+/-15 years. Complications occurred in 14% of patients (16 of 113). In-hospital mortality was 0, but 90-day hospital mortality was 0.88% (1 of 113 patients). Follow-up was obtained in 81% (92 of 113 patients) at a mean of 51+/-59 months postoperatively. Complete remission was achieved in 21% of patients (19 of 92), and marked improvement of MG in 54% (50 of 92), for a total benefit rate of 75%. Fourteen percent (13 of 92) were unchanged, and 11% (10 of 92) were worse. Using univariate analysis, sex, age, and pathology correlated significantly with outcome (p < 0.05): 80% of women (57 of 70) benefited from the procedure, versus 57% of men (12 of 21). Eighty percent (57 of 70) of patients less than 51 years of age were improved or in remission, versus 57% (12 of 22) older than 50. Twenty-three percent (5 of 22) of patients with thymoma deteriorated, versus 7.1% (5 of 70) without thymoma. Sex did not significantly correlate in the multivariate model.
Sex, age, and thymic pathology are potential predictors of outcome in thymectomy for MG, and may shape treatment decisions and target higher-risk patients.
Thymectomy for the treatment of myasthenia gravis (MG) is well established. The extent of resection, however, remains a source for debate. Outcomes for newer surgical techniques need to be compared to more extensive procedures.
A retrospective review was done of 64 consecutive patients who underwent transsternal thymectomy with extended anterior mediastinal dissection for MG between 1979 and 2000 and who were operated on by a single surgeon.
Fifty-six patient charts were available, providing 58 operative procedures. Three patients had died of unrelated causes. The mean age of symptom onset was 36.0 +/- 2.5 years, with a mean duration of 3.3 +/- 0.5 years until surgery was undertaken. The mean length of follow-up was 6.8 +/- 0.8 years. Operative procedures were associated with a 10.3% major morbidity rate and no mortality. Drug-free remission was achieved in 50.0% of the patients, and symptoms were absent or improved in 76.8% of the patients. Patients followed up long-term (>10 years) achieved the greatest remission rate (71.4%) and symptomatic improvement (85.7%). After thymectomy, the mean dosages of prednisone and Mestinon decreased by 69.3% and 58.8%, respectively.
Extended thymectomy provides excellent overall symptom improvement, which is enhanced over time. This review provides a basis for long-term comparison with other less invasive and perhaps less extensive procedures.
Cortical-type thymomas are associated with myasthenia gravis (MG) in 50% of the cases. MG is caused by antibodies against the acetylcholine receptors (AChR), but additional non-AChR muscle autoantibodies such as those against titin and ryanodine receptor (RyR) are found in up to 95% of MG patients with thymoma. To elucidate the induction of non-AChR autoantibodies in thymoma-associated MG, we studied cortical-type thymomas from seven thymoma MG patients, and sera from six of them. All six had titin antibodies, and four had RyR antibodies. Titin and RyR epitopes were co-expressed along with LFA3 and B7 (BB1) costimulatory molecules on thymoma antigen-presenting cells (APC) in all thymomas. In normal thymus, the staining by anti-titin, anti-RyR, anti-LFA3, and anti-BB1 antibodies was weak and occurred exclusively in the medulla and perivascularly. Our results indicate a primary autosensitization against titin and RyR antigens inside the thymoma. In MG-associated thymoma, the mechanisms involved in the initial autosensitization against titin and RyR are probably similar to those implicated in the autosensitization against AChR. In all cases, there is an overexpression of muscle-like epitopes and costimulatory molecules indicating that the T-cell autoimmunization is actively promoted by the pathogenic microenvironment inside the thymoma.
The presence of thymoma may be a negative prognostic factor with respect to the outcome of myasthenia gravis (MG).
Of 122 consecutive patients with MG undergoing thymectomy between August 1994 and September 2000, 37 had a thymoma. Postoperative radiation was administered to all patients with stage II thymoma and higher. To determine differences in presentation and outcome, thymoma patients were compared with patients with atrophic (n = 49) or hyperplastic (n = 36) thymus gland on final pathology.
Thymoma patients were significantly older (52 +/- 14 vs 36 +/- 15 years, p < 0.0001) and included a significantly higher proportion of males (54% vs 28%, p = 0.006) than patients without thymoma. However, the preoperative Osserman grade and the duration of symptoms before surgery were not significantly different between groups. Mean follow-up after thymectomy was not significantly different between patients with or without thymoma (32 +/- 23 vs 37 +/- 19 months, respectively, p = 0.3). At last follow-up, the proportion of asymptomatic patients (63% vs 70%, respectively, p = 0.5) and the mean Osserman grade (0.6 +/- 0.9 vs 0.5 +/- 0.9, respectively, p = 0.6) were similar in both groups. In addition, the rate of complete remission reached 36% at 5 years in patients with or without thymoma (p = 0.8).
Although myasthenic patients with thymoma are significantly older and include a greater proportion of males, the overall outcome, including the rate of complete remission, was similar between patients with or without thymoma. Therefore, the presence of a thymoma should not necessarily be viewed as a negative prognostic factor regarding recovery from myasthenia gravis.
Data from 756 myasthenic patients were analyzed for diagnostic criteria, clinical aspects, and therapeutic approaches. The patients were followed up at our institution from 1981 to 2001. Clinical evaluation was performed according to the myasthenia gravis score adopted at our clinic. Clinical features of each patient (comprising demographic, clinical, neurophysiological, immunological, radiological, and surgical data, as well as serial myasthenia gravis scores) were filed in a relational database containing more than 7000 records. Clinical efficacy and variables influencing outcome were assessed by life-table methods and Cox proportional hazards regression analysis. Complete stable remission, as defined by the Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, was the end point for good prognosis. Four hundred and ninety-nine patients (66%) were female and 257 (34%) were male. Mean follow-up was 55.1 +/- 48.1 months. Onset of symptoms peaked in the third decade in females, whereas the male distribution was bimodal with peaks in the third and sixth decades. Modality of myasthenia gravis presentation was as follows: ocular, 39.3%; generalized, 28.5%; bulbar, 31.3%; and respiratory, 0.8%. Thymectomy was carried out on 63.7% of our patients by different approaches: (1) transcervical; (2) transsternal; (3) video-thoracoscopic mini-invasive surgery. The last approach has been preferentially used in more recent years and accounted for 62.4% of the thymectomized myasthenia gravis population. Univariate analysis and Kaplan-Meier analysis showed that variables such as sex (female), age at onset (below 40 years), thymectomy, and histological diagnosis of thymic hyperplasia were significantly associated with complete stable remission, whereas on multivariate analysis only age at onset below 40 years and thymectomy were confirmed.
Myasthenia gravis is by far the most common paraneoplastic syndrome of thymomas. There is little information regarding the influence of clinical variables and thymoma-associated factors on biologic development of myasthenia gravis. The aim of the study was to determine independent predictors of clinical outcome in thymoma with myasthenia gravis.
We studied 108 patients with thymoma-associated myasthenia gravis undergoing removal of the mediastinal mass between 1967 and 2000. Clinical and pathologic variables associated with clinical outcome of myasthenia were assessed by multivariate Cox regression analysis.
Patients were followed for a mean period of 10 years (9 months to 33 years). A total of 38 patients died (35.2%), in 14 cases (37%) because of myasthenia gravis and in 6 (16%) because of recurrence of thymoma. With respect to clinical outcome of myasthenia gravis, at the end of the follow-up period, the rate of remission was 16% (n = 17). Of the 91 patients in whom remission was not achieved, 55 had no symptoms with immunosuppressive medication and 36 had symptoms with medication.
In patients with thymoma-associated myasthenia gravis, well-differentiated thymic carcinoma (Müller-Hermelink system), age more than 55 years, and interval from the onset of symptoms to thymectomy of less than 1 year were found to be independent predictors of nonremission of myasthenia gravis after thymectomy.
This study sought to determine the efficacy and prognostic factors of extended transsternal thymectomy as a treatment for myasthenia gravis (MG).
Medical records of 147 patients who underwent extended transsternal thymectomy for MG from January 1991 to December 2002 were reviewed retrospectively. The complete stable remission (CSR) rate and prognostic factors for CSR were assessed in 106 female and 41 male patients.
The median age was 35 years (range 11-75 years). Ninety-eight patients had non-thymomatous MG and 49 patients had thymomatous MG. The median follow-up time was 89.7 months (range 12-167 months). Both non-thymomatous MG and thymomatous MG exhibited significant differences in population characteristics and CSR rates (29.6% vs 13.3% at 5 years, 45.2% vs 27.7% at 10 years, p = 0.022). Steroid therapy (hazard ratio: 0.234, p = 0.003) was a poor prognostic factor, while early onset (hazard ratio: 3.519, p = 0.048) was a good prognostic factor for CSR in non-thymomatous MG. In contrast, steroid therapy (hazard ratio: 0.061, p = 0.034) was poor prognostic factor for thymomatous MG.
Extended transsternal thymectomy is a good treatment tool to achieve CSR in MG. Thymomatous MG and non-thymomatous MG were significantly different in patient characteristics and prognosis. Prognostic factors were steroid therapy and age of onset in non-thymomatous MG, and steroid therapy in thymomatous MG.
The ideal operative technique for thymectomy in myasthenia gravis (MG) remains controversial. We present the largest series of extended transcervical thymectomy to provide outcomes data to compare with transsternal procedures.
A retrospective chart review/interview was made of 164 patients operated upon from 1992 to 2004. Complete remission (CR) was defined as asymptomatic off medication for 6 months or asymptomatic on low-dose single-drug therapy (< or = 10 mg/d prednisone or < or = 150 mg/d azathioprine). A modified Osserman classification based upon the Myasthenia Gravis Foundation of America quantitative disease severity score was employed.
The overall complication rate was 7.3%, and nearly all procedures were outpatient. Mean age at surgery was 43 years, and mean preoperative Osserman class was 2.3 (21% class 1; 39% class 2; 28% class 3; 12% class 4). Mean length of follow-up was 53 months. Mean postoperative Osserman class was 1.0. Nineteen percent of patients failed to improve. The crude cumulative CR rate was 37% (n = 58). Kaplan-Meier estimates of CR were 43% and 45% at 3 and 6 years, respectively. On multivariate analysis, only preoperative disease severity was significantly (inversely) associated with Kaplan-Meier CR rates. Longer-term follow-up (83 months) of only the earlier patients shows preserved CR rates (46%).
This largest series of extended transcervical thymectomy for MG confirms that the 5-year Kaplan-Meier CR rate is comparable with that obtained after transsternal procedures. Patients with less severe disease have higher CR rates. Complete responses are durable, as the CR rate remains stable with extended follow-up.
Myasthenia gravis (MG) is an autoimmune disease caused in 85% of the patients by acetylcholine receptor (AChR) antibodies. Non-AChR muscle antibodies, against titin and ryanodine receptor (RyR) are mainly found in sera of patients with thymoma or late-onset MG. The occurrence of RyR antibodies increases the risk for severe MG and should lead to active immunomodulating treatment already at MG onset. The aim in this study was to describe the association between symptoms at MG onset and antibody profile in 152 patients. Patients with RyR antibodies had the highest rate of bulbar, respiratory and neck involvement at MG onset. They also had the highest frequency of non-limb MG symptoms. Neck weakness occurred in 40%. Respiratory difficulties at MG onset occurred in patients with titin antibodies, with and without RyR antibodies. Patients with RyR antibodies have a distinctive non-limb MG symptom profile, with bulbar, ocular, neck, and respiratory symptoms. These features, identified as early as at the first examination by a neurologist, characterize the RyR antibody positive subgroup at MG onset.
The objectives of this study were to compare the clinical features and the outcomes after thymectomy between patients with and without thymoma and to evaluate the influence of thymectomy on the subsequent clinical course of myasthenia gravis.
Between 1995 and 2003, 64 consecutive patients underwent thymectomy, and of these, 60 patients were followed up for at least 12 months postoperatively. The study population was divided into 2 groups based on the presence of thymoma. We performed a retrospective analysis to compare the neurologic outcomes of thymectomy between patients with thymomatous myasthenia gravis and those with nonthymomatous myasthenia gravis.
Twenty-four patients had a thymoma. No significant differences were observed between the 2 groups regarding the preoperative severity of myasthenia gravis. There was no significant difference in the follow-up duration between the 2 groups. There was no significant difference in the overall remission rate between the 2 groups (P = .064). The mean time required to reach a remission was 10.6 months and 23.5 months in the thymoma and nonthymoma groups, respectively. The mean duration of remission was 43.1 months and 30.8 months in the thymoma and nonthymoma groups, respectively. In the early phase of follow-up, more patients reached remission in the thymoma group than those in the nonthymoma group (P = .040).
Neurologic outcomes of the thymoma group were no worse than those of the nonthymoma group. It is expected that earlier thymectomy is likely to result in a better prognosis by shortening the disease period, even for patients with nonthymomatous myasthenia gravis.
Myasthenia gravis patients with
- Romi F Ja Aarli
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