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Eur J Cardiothorac Surg 2006;30:525-528
© 2006 Elsevier Science NL

Complete stable remission after extended transsternal thymectomy in myasthenia gravis

In Kyu Parka, Sung Sil Choib, Jin Gu Leea, Dae Joon Kima, Kyung Young Chunga,*

a Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, CPO Box 8044, Seoul 120-752, South Korea
b Department of Thoracic and Cardiovascular Surgery, Jae Saeng Hospital, Bundang, South Korea

Received 3 April 2006; received in revised form 2 June 2006; accepted 6 June 2006.

* Corresponding author. Tel.: +82 2 2228 2140; fax: +82 2 393 6012. (Email: kychu{at}yumc.yonsei.ac.kr).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Objective: This study sought to determine the efficacy and prognostic factors of extended transsternal thymectomy as a treatment for myasthenia gravis (MG). Methods: 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. Results: 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. Conclusions: 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.

Key Words: Myasthenia gravis • Extended transsternal thymectomy • Complete stable remission


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
Myasthenia gravis (MG) is an autoimmune disease affecting neuromuscular transmission at muscle nicotinic acetylcholine receptors (AchR) [1]. By medical treatments, directed to the control of symptom (cholinesterase inhibitors) or suppression of autoimmune response (corticosteroids, azathioprine, etc.), expected spontaneous remission rate is relatively low [1,2]. Moreover, chronic medical treatment can induce serious side effects [1]. Thymectomy is a reliable and definite modality that can reverse the course of MG. There are several thymectomy methods, which are classified by the Myasthenia Gravis Foundation of America (MGFA) according to their approach and extent of resection. The extended transsternal thymectomy is classified as T3-b [3], and is a simple and straightforward approach that can achieve thymectomy with relatively high efficacy and low risk [4,5]. Complete stable remission (CSR), also defined by the MGFA, is a clear end point for evaluation of treatment results and can minimize inter-observer discrepancies [3]. However, CSR is a time dependent event, and prognostic factors that lead us to assume the result of treatment are still unclear. As such, we conducted this retrospective study to clarify the possibility of achieving CSR and to identify prognostic factors for CSR after extended transsternal thymectomy in the treatment of MG.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
The records of total 150 patients who underwent T3-b thymectomy for myasthenia gravis between January 1991 and December 2002 were reviewed retrospectively. In all patients, the procedure was conducted through the median sternotomy, and the thymus and mediastinal fat tissues were excised. The borders of resection were the diaphragm caudally, the thyroid gland orally, and the phrenic nerves laterally as described by Masaoka et al. [4]. Three patients who were lost during follow-up were excluded, so the clinical outcomes of 147 patients were evaluated and analyzed. Data were collected by review of medical records and the current status of patients was determined by clinical examination or telephonic interview.

Preoperative and postoperative evaluations and medical treatments of patients were conducted by Department of Neurology. Diagnosis of MG was established on the basis of clinical symptoms, anticholinesterase test values, and electromyographic findings. The anti-AchR antibody assay was not performed on all patients. Disease status was established according to the modified Osserman classification (Table 1 ). The presence of thymic pathology was evaluated before surgery by chest computerized tomography.


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  		Table 1. Modified Osserman classification
 
Thymic histology was classified as thymomatous MG or non-thymomatous MG. The Masaoka system [6] was used for staging of the thymomas. CSR was used as the end point for evaluation of the efficacy and prognostic factors. Patients were considered to be in complete stable remission status if he or she exhibited no symptoms of MG for at least 1 year and had received no therapy for MG during that time [3].

Age, sex, age at onset, duration of symptom to operation, preoperative modified Osserman classification, thymic pathology, steroid therapy, and history of MG crisis were considered for potential prognostic factors.

Categorical variables were compared by the {chi} 2 and Fisher's exact tests. Student's t-test was used for comparison of continuous variables. The cumulative probability of achieving CSR was assessed by the Kaplan–Meier method and differences in CSR were evaluated by log-rank test. The Cox proportional hazard model was used for multivariate analyses of prognostic factors for CSR. p values less than 0.05 were considered statistically significant. All statistical analyses were performed with Statistical Package for Social Science (SPSS 12.0, Chicago, IL, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
3.1 CSR in total patient population
The study population consisted of 41 males (27.9%) and 106 females (72.1%). The median age at onset was 35 years (range 11–75 years). The median follow-up time was 89.7 months (range 12–167 months). Preoperatively, 107 patients took anticholinesterase and 20 patients took steroids with or without anticholinesterase. The median time from diagnosis to surgery was 12 months (range 1–239 months).

There was no perioperative mortality. Four patients (2.7%) experienced postoperative surgical complications such as pericardial effusion, superficial wound infection, left recurrent laryngeal nerve palsy and re-exploration due to bleeding. There were no MG-related deaths. The cumulative probability of achieving CSR was 24.9% at 5 years and 37.3% at 10 years. The population characteristics of non-thymomatous MG and thymomatous MG differed significantly, as shown in Table 2 . The CSR rates of the two groups were also significantly different (Fig. 1 ).


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  		Table 2. Differences between non-thymomatous MG and thymomatous MG patients
 

Figure 1
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  		Fig. 1. Cumulative CSR rates of non-thymomatous MG and thymomatous MG.

 
3.2 Non-thymomatous MG
Of the 98 patients, there were 15 males and 83 females, with a median age of 32 years (range 11–61 years). The thymic histology was normal in 25 patients, and follicular hyperplasia was found in 66, involution in 2, thymolipoma in 3, and a thymic cyst in 2 patients. CSR was achieved in 37 patients, and their cumulative probability of achieving CSR was 29.6% at 5 years and 45.2% at 10 years. There were no late deaths. From univariate analysis, steroid therapy (Fig. 2 ) was found to be a poor prognostic factor, while early onset was a good prognostic factor for CSR, and multivariate analysis showed both to be significant prognostic factors (Table 3 ).


Figure 2
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  		Fig. 2. Difference in cumulative CSR rates by the use of steroid therapy in non-thymomatous MG.

 

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  		Table 3. Hazard ratio (with 95% confidence interval) of prognostic factors for CSR after thymectomy
 
3.3 Thymomatous MG
Thymoma was found in 23 males and 26 females with the median age of 44 years (range 20–75 years). The distribution of Masaoka stages in this group was as follows: stage I, 23 patients; stage II, 19; stage III, 6; stage IV, 1. None of the patients received preoperative radiotherapy or chemotherapy. Postoperative adjuvant therapy was provided to 33 patients, and CSR was achieved in six patients. The cumulative probability of achieving CSR was 13.3% at 5 years and 27.7% at 10 years. There were seven late deaths: three thymoma-related deaths and four non-thymoma-related deaths. In both univariate (Fig. 3 ) and multivariate analyses (Table 3), steroid therapy was a negative prognostic factor for CSR.


Figure 3
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  		Fig. 3. Difference in cumulative CSR rates by the use of steroid therapy in thymomatous MG.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
Thymectomy is an established therapeutic modality for the treatment of myasthenia gravis, which can yield improvement of symptoms and complete remission [2,7]. There are several types of thymectomy classified according to the extent of surgery and method of approach. The extended transsternal thymectomy, T3-b by MGFA, is the procedure of choice at our clinic as in many other institutions, as it can be done easily, has a low complication rate, removes most of the mediastinal fat tissue, and exhibits good reported long-term results [3–5,8]. The assessment method for the results of thymectomy is very important for evaluation of the efficacy of thymectomy. It is difficult to compare reported outcomes about thymectomy in MG, as the end point is vague and multifarious. The end point of our study is the ‘CSR’, which is defined by MGFA. The CSR has a straightforward definition, which can minimize inter-observer discrepancies. The general trend which emerged was the longer the follow-up after thymectomy, the better the results. As such, the simple calculated response rate at any given time point cannot completely explain the true efficacy of thymectomy. Thus, for the analysis of the cumulative probability of achieving CSR after thymectomy, we used Kaplan–Meier method that is the best available statistical technique [2].

Mantegazza et al. [9], who used life-table analysis, showed that the CSR rate is 51.0% at 5 years post-thymectomy in non-thymomatous MG. In that study, video-assisted thoracoscopic extended thymectomy (n = 159) and extended transsternal thymectomy (n = 47) were combined, but there was no difference in CSR rates between the two types of thymectomy. Our CSR rate was 29.6% at 5 years and 45.2% at 10 years in non-thymomatous MG. The lower rate of CSR in this study was may be due to the larger portion of patients with late onset (25.5%) than in the previous report (8.1%). Masaoka et al. [4] used an extended transsternal thymectomy and showed arithmetic remission rates to be 45.8% at 5 years and 55.7% at 10 years in non-thymomatous MG.

There were discrete differences between thymomatous MG and non-thymomatous MG patients. Three thymoma-related deaths were observed in thymomatous MG. In agreement with other reports [4,10–12], thymomatous MG had a significantly worse prognosis than non-thymomatous MG.

The age at onset was generally divided into two groups: early onset and late onset. Most investigators use 40–50-year-olds as a lower cut-off in epidemiologic data. In general, early onset has been shown to be an optimistic factor on clinical outcome [4,9,13]. Furthermore, Romi et al. [14] reported that in late onset MG, the clinical improvement after thymectomy is transitory and no longer detectable at 2 years after thymectomy. We found that early onset (age ≤40 years) was a potent prognostic factor for achieving CSR, especially in non-thymomatous MG.

Steroid therapy is immunosuppressive, and the use of immunosuppressive treatment was reported as a poor prognostic factor [9]. According to Téllez-Zenteno et al. [15], preoperative use of steroid therapy was a poor prognostic factor for remission after thymectomy. In our study, steroid therapy was a poor prognostic factor in both types of MG, both preoperatively and postoperatively. Steroid therapy was the primary immunosuppressive treatment of our neurologist and was started in response to a myasthenia crisis, or when the symptoms were aggravated and insufficiently controlled by anticholinesterase drugs. As such, initiation of steroid therapy in our study meant a decline in the clinical condition and a higher grade according to modified Osserman classification. However, our results showed that Osserman classification could not predict the prognosis after thymectomy, suggesting that we need to apply a more objective evaluation system of clinical status such as the quantitative MG scoring system by MGFA [3] or other tools such as immunochemical parameters (AchR antibody, ryanodine antibody, titin antibody, anti-MuSK antibody, etc.) to reflect the disease activity [16–18].

Some authors reported that thymectomy yielded better results in patients who had a shorter time period between onset of MG and thymectomy, and that this is one of the most important prognostic factors [4,11], likely due to a long disease duration provoking increasing damage to the neuromuscular plate. However, Budde et al. and Özdemir et al. [12,19] reported that there was no significant relationship between symptom duration and outcome; we also observed that the time between MG onset and thymectomy was not a prognostic factor. Gender as a factor shows disparate associations among studies [5,13,19]; gender was not a prognostic factor in CSR in our work.

The extended transsternal thymectomy proved to be a safe procedure. Perioperative mortality rates of thymectomy were less than 1%, and there was no perioperative mortality in this series of patients. The complication rate was also low (2.7%), and there was only 1 (0.7%) permanent morbidity by laryngeal nerve palsy among the 147 patients.

On the basis of our results, we conclude that the extended transsternal thymectomy is a safe and beneficial procedure for the treatment of MG. Thymomatous MG and non-thymomatous MG differ in baseline characteristics and prognosis. Prognostic factors are steroid therapy and age of onset in non-thymomatous MG and steroid therapy in thymomatous MG.


   Footnotes
 
{star} Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzig, Germany, September 12–15, 2004.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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