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Eur J Cardiothorac Surg 2003;23:233-237
© 2003 Elsevier Science NL


Predictors of clinical outcome following extended thymectomy in myasthenia gravis

Nezih Özdemira*, Murat Karab, Erkan Dikmenb, Aydin Nadira, Murat Akala, Nezih Yücemenc, Sinasi Yavuzera

a Department of Thoracic Surgery, Ankara University Faculty of Medicine, bn-i Sina Hospital, 06100, Sihhiye, Ankara, Turkey
b Department of Thoracic Surgery, University of Kirikkale, School of Medicine, 71100, Kirikkale, Turkey
c Department of Neurology, Ankara University Faculty of Medicine, bn-i Sina Hospital, 06100, Sihhiye, Ankara, Turkey

Received 19 July 2002; received in revised form 23 October 2002; accepted 4 November 2002.

* Corresponding author. Kuleli Sokak 37/2, Gaziosmanpasa, TR-06700, Ankara, Turkey. Tel.: +90-312-310-3333; fax: +90-312-310-6371
e-mail: ozdemir{at}medicine.ankara.edu.tr


    Abstract
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objective: Thymectomy remains as the optimal treatment of choice in patients with myasthenia gravis (MG), however, the selection criteria for surgery remains controversial. Methods: We examined the data charts of patients with MG underwent extended thymectomy. We investigated the possible correlations between the clinicopathologic features and clinical outcomes, and analyzed the data to clarify the effect of prognostic factors on clinical outcome. Results: A total of 61 patients with a mean age of 35.8±12.2 years (range, 13–66 years) were analyzed. The overall improvement/remission and clinical worsening rates were 81.9 and 18.1%, respectively. Ossermann stage (P=0.011) and presence of mediastinal ectopic thymic tissue (P=0.007) showed a significant correlation with the clinical outcome. Multivariate analysis confirmed Ossermann stage (P=0.0158), and presence of mediastinal ectopic thymic tissue (P=0.0100) as independent predictors on clinical outcome. Conclusion: Ossermann stage and the presence of mediastinal ectopic thymic tissue are potential predictors on clinical outcome in patients with MG undergoing extended thymectomy.

Key Words: Myasthenia gravis • Thymectomy • Clinical outcome


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Myasthenia gravis (MG) is a chronic autoimmune disease characterized by an impaired neuromuscular transmission with symptoms of weakness and fatigue resulting from the binding of antibodies to acetylcholine receptors [1]. Although medical treatment modalities including the anticholinesterase drugs, corticosteroids, plasma exchange, immunoglobulin administration, immunosuppressive drugs have been shown beneficial, thymectomy still remains as the optimal treatment of choice in the management of MG. However, numerous studies investigating the clinical outcomes in patients with MG undergoing thymectomy have reported controversial results regarding clinicopathologic features such as age, gender, duration of symptoms, Ossermann stage of the disease, coexistence of thymoma and presence of mediastinal ectopic thymic tissue [18]. Thus, the optimal selection criteria for surgery remains controversial. We conducted a study to clarify the effect of prognostic factors in a series of 61 myasthenic patients underwent extended thymectomy.


    2. Patients and methods
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
2.1. Patient selection
We collected the data of 73 patients with MG, who underwent an extended thymectomy in bn-i Sina Hospital of Ankara University School of Medicine between January 1990 and December 2000. Patients with advanced stage, apart from one case with stage III who showed an acute onset of respiratory failure within 1 month, were excluded from the study. Likewise, three cases with thymic carcinoma and nine patients who were lost at follow-up were excluded from the analyzes. Conclusively, a total of 61 patients, 27 (44.2%) male and 34 (55.8%) female with a mean age of 35.8±12.2 years (range, 13–66 years) were enrolled into this study.

The mean duration of symptoms was 9.2±9.4 months (range, 1–60 months). Diagnosis of MG was established on the basis of clinical symptoms, a positive response to edrophonium-chloride, serum acethylcholine receptor antibody assay, and electroneuromyographic findings. Patients were examined with chest X-rays and computerized tomography. Preoperative and postoperative medication including anticholinesterase agents (Anti-Che), steroid therapy and immunotherapy (azathioprine) were administered by neurology consultants. Patients were preoperatively evaluated according to their clinical status regarding the Ossermann stage, medication requirements and duration of symptoms. Operations in patients receiving high doses of anticholinesterase agents or steroid therapy were postponed to a further date that they received minimum doses of drugs. All patients received plasma exchange in the preoperative period with a mean number of 2.8±0.9 (range, 1–5).

All patients underwent an extended thymectomy through a median sternotomy including the anterior mediastinal fat inferiorly, inferior aspect of thyroid gland superiorly, and each phrenic nerve laterally as described previously [5]. Hyperplasia was the most common histologic diagnosis in 25 (41%) specimens followed by thymoma in 15 (24.6%), atrophy (involution) in 12 (19.7%), normal tissue in 7 (11.5%), thymolipoma in 1 (1.6%), and thymic cyst in 1 (1.6%) specimen. Ectopic mediastinal thymic tissue was found in a total of 17 (27.8%) patients.

Morbidity developed in 11 (18%) patients. Two (3.2%) patients had severe respiratory failure requiring ventilatory support. Dyspnea occurred in two (3.2%) patients, postoperative atelectasia in three (4.8%) patients, apical pneumothorax in one (1.6%) patient, and bleeding in one (1.6%) patient who underwent resternotomy. One patient showed myasthenic crisis that was treated by intravenous pyridostigmin and high dose corticosteroids, and another patient had acute adrenal failure. Mortality was not observed.

2.2. Data collection and follow-up
We retrospectively reviewed the data charts and clinical outcomes of the patients. Follow-up data were obtained with the information of referring physicians and telephone calls, or direct clinical examination. Clinical outcome was evaluated at least 1 year after the operation. The median follow-up time was 46 months (range, 12–81 months).

2.3. Definitions and statistical analysis
Patients were staged according to modified Ossermann classification as follows; grade I, ocular involvement; grade IIa, mild generalized ocular myasthenia; grade IIb, moderate generalized myasthenia involving bulbar musculature; grade III, acute fulminant form; and grade IV, severe late myasthenia [9]. The criteria for the evaluation of the clinical outcome was classified as described previously [10]; remission, no symptoms without any medication; improvement, no or fewer symptoms with the same or less medication; worse, same symptom with more medication, or deterioration of disease. The clinical outcomes were dichotomized as improvement/remission and clinical worsening for statistical comparisons.

Age, gender, duration of symptoms, number of plasma exchange, Ossermann stage, thymic histology, the presence of ectopic thymic tissue in the anterior mediastinal fatty tissue, and postoperative complications were included in the assessment of statistical comparisons with the clinical outcomes. Age was grouped as; less than 50 years old (<50); and equal or greater than 50 years old (>=50). Duration of symptoms and number of plasma exchange were classified as a high- or low-group relative to the median value. Ossermann stage was stratified as I+IIA and IIB+III. Thymic histology was stratified as thymoma and non-thymoma, thymoma and hyperplasia.

Categorical variables were analyzed with the {chi}2 and Fisher's exact tests as appropriate in contingency tables, whereas Student's t-test and Mann–Whitney U-test were performed as appropriate for comparison of continuous variables. The logistic regression analysis along with a stepwise procedure was applied for univariate and multivariate analyzes to confirm the impact of the factors on clinical outcomes. Data were expressed as mean±the standard deviation. A P value less than 0.05 was considered statistically significant. All statistical analyzes were performed with the Statistical Package for Social Sciences (SPSS, version 11.0, Chicago, IL, USA).


    3. Results
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
3.1. Correlations
The mean age did not show any difference between the subgroups of clinical outcome (P=0.201) (Table 1). The age subgroups (P=0.670), and gender (P=0.740) did not correlate with the clinical outcome. The subgroups of symptom duration (P=0.325), and the overall means of symptom duration (P=0.197) did not show a significant association with the clinical outcomes. Similarly, no significant association existed between the groups neither in the number of plasma exchange (P=0.294), nor the overall means (P=0.578). However, Ossermann stage significantly correlated with the clinical outcomes (P=0.011). Improvement/remission rates were higher as 100 and 85.7% in patients with stages I and IIA, respectively. Thymomatous patients had a greater rate of clinical worsening (26.7%), than that of non-thymomatous patients (15.2%) and than that of patients with hyperplastic thymus (20%) however, either of these did not reach a significant difference (P=0.439 and P=0.705, respectively). Patients with ectopic thymic tissue had a comparatively worse clinical outcome (P=0.007).


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Table 1. Characteristics of patients with myasthenia gravis regarding clinical outcomes

 
3.2. Univariate and multivariate analysis
Significant univariate predictors of clinical worsening were Ossermann stage (IIB+III) (P=0.0104) and presence of mediastinal ectopic thymic tissue (P=0.0068) (Table 2). Thymic histology (thymoma) did not show a significant effect on clinical outcome (P=0.3225) (Fig. 1) . Multivariate analysis revealed Ossermann stage (P=0.0158) and presence of mediastinal ectopic thymic tissue (P=0.0100) as independent predictors of clinical outcome (Table 3).


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Table 2. Univariate prognostic factors analysis of the 61 patients by logistics regression analysis

 


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Fig. 1. Clinical outcomes within thymomatous and non-thymomatous myasthenic patients.

 

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Table 3. Multivariate prognostic factors analysis of the 61 patients by logistic regression analysis

 

    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Thymectomy has been considered as beneficial in the treatment of MG since the initial report by Blalock et al. [11]. It is considered as the standard care of patients with MG because the improvement and remission rates following surgery range from 54 to 94% and from 21 to 42%, respectively [2,6,12]. Similarly, our results revealed favorable improvement/remission and clinical worsening rates as 81.9 and 18.1%, respectively. However, the specific indications to surgery remain controversial. A number of factors influencing the success of thymectomy have been reported including the age, gender, duration of symptoms, Ossermann stage, coincidence of thymoma and pathologic features of the thymic tissue.

Age at the time of surgery has been shown to be a potential factor on clinical outcome. Some authors showed that patients under 50 years old had a better clinical outcome compared with elderly patients [2,5,7]. Perlo et al. [13] suggested that marked involution of thymic tissue in patients over 60 years of age indicated that thymectomy will be of no benefit in this age group. However, some reports outlined that age should not be a limitation for the operation, and it was not significantly associated with clinical outcome [1,3,4,6,10,14]. Likewise, our results were in line with the above reports, and we revealed that the improvement/remission (P=0.670), and postoperative complication rates (P=0.400) (data not shown) were not significantly different between the age groups. Thus, thymectomy appears clinically as safe and effective in myasthenic elderly patients as in younger patients.

It was stated that the male the patient, the more likely he is to achieve a favourable clinical outcome compared with female patients [3]. However, Nieto et al. [1] found no significant difference on clinical outcomes with respect to gender. Similarly, our results showed that gender had no significant adverse effect on clinical outcome (P=0.5621).

Although, it has been reported that the shorter the time from diagnosis to operation the better is the outcome after thymectomy [1,4,5,7], controversial reports appeared showing that the duration of symptoms had no effect on clinical outcome [2,3,6]. Similarly, our results were in accordance with these latter reports. We found that no significant difference existed between the clinical outcome of patients with respect to duration of symptoms. In addition, the follow-up time has been investigated for a possible effect on clinical outcomes; however, Roth et al. [15] showed that the difference between long and short-term results was not significant.

We stratified patients as I+IIA and IIB+III because we had no patients with stage IV. Upon the multivariate analysis, we found that modified Ossermann classification had a strong association with the clinical outcome. We found sevenfold increased risk of clinical worsening in patients with stage IIB+III. Similar reports appeared in the literature stating the significance of Ossermann stage at the time of surgery [1,6,7,16]. Nieto et al. [1] showed that patients with stages I and III had a better clinical outcome. Nussbaum et al. [6] and Venuta et al. [7] showed that patients with early I–II, and I–IIA Ossermann stages had more favourable clinical outcomes, respectively. On the other hand, some authors detected no relationship between the Ossermann stage and clinical outcome [2,5].

Thymic pathology has been shown a relatively consistent predictor of clinical outcome. Some authors reported that the presence of thymoma adversely affected the clinical outcome [2,5,7], however some others concluded that it was not relevant to the clinical outcome [1,3]. Although thymoma appeared as a relative risk factor, it was not a significant predictor on clinical outcome in univariate analysis (P=0.3225) in our study. On the other hand, thymic hyperplasia also has been claimed to correlate with increased improvement rates compared with thymoma in myasthenic patients [1,2]. Similarly, although we found a decreased risk of clinical worsening in patients having hyperplastic thymus compared with thymomatous patients, this was not a significant difference (P=0.6260) consistent with the previous reports [1,2].

The presence of mediastinal ectopic thymic tissue may be observed with a range from 20% up to 72% [8], and consequently may result in a failed procedure in cases undergoing simple thymectomy. In addition, anatomic variability of the thymic tissue has been reported as high as 98% of patients with MG [17]. An autopsy study in cases without MG revealed that 44% had ectopic thymic tissue in anterior mediastinal fat, and 7.4% had in the retrocarinal area [18]. The above findings indicate that a complete removal of the thymic tissue for a favorable clinical outcome is essential. Thus, we have been performing an extended thymectomy including the mediastinal fatty tissue so as to avoid any remnant of ectopic thymic tissue left behind. Furthermore, the presence of ectopic thymic tissue has been proposed as a prognostic factor because the patients with ectopic thymic tissue showed comparatively poorer clinical outcome [8]. We found the rate of ectopic mediastinal thymic tissue as 27.8% in our series. In addition, significant unfavorable effect of ectopic mediastinal thymic tissue justifying above findings appeared either in univariate (P=0.0068) or multivariate analysis (P=0.0100) in our study.

In conclusion, various clinicopathologic features have been suggested to have an influence on the clinical outcome after thymectomy in myasthenic patients. Among these, Ossermann stage of the patient and the presence of mediastinal ectopic tissue appear to be the most potential predictors on clinical outcome following thymectomy in myasthenic patients.


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

  1. Nieto I.P., Robledo J.P.P., Pajuelo M.C., Montes J.A.R., Giron J.G., Alonso J.G., Sancho L.G. Prognostic factors for myasthenia gravis treated by thymectomy: review of 61 cases. Ann Thorac Surg 1999;67:1568-1571.[Abstract/Free Full Text]
  2. Budde J.M., Morris C.D., Gal A.A., Mansour K.A., Miller J.I. Predictors of outcome in thymectomy for myasthenia gravis. Ann Thorac Surg 2001;72:197-202.[Abstract/Free Full Text]
  3. Bulkley G.B., Bass K.N., Stephenson G.R., Diener-West M., George S., Reilly P.A., Baker R.R., Drachman D.B. Extended cervicomediastinal thymectomy in the integrated management of myasthenia gravis. Ann Surg 1997;226:324-335.[CrossRef][Medline]
  4. Calhoun R.F., Ritter J.H., Guthrie T.J., Pestronk A., Meyers B.F., Patterson G.A., Pohl M.S., Cooper J.D. Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Ann Surg 1999;230:555-561.[CrossRef][Medline]
  5. Masaoka A., Yamakawa Y., Niwa H., Fukai I., Kondo S., Kobayashi M., Fujii Y., Monden Y. Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac Surg 1996;62:853-859.[Abstract/Free Full Text]
  6. Nussbaum M.S., Rosenthal G.J., Samaha F.J., Grinvalsky H.T., Quinlan J.G., Schmerler M., Fischer J.E. Management of myasthenia gravis by extended thymectomy with anterior mediastinal dissection. Surgery 1992;112:681-688.[Medline]
  7. Venuta F., Rendina E.A., De Giacomo T., Rocca G.D., Antonini G., Ciccone A.M., Ricci C., Coloni G.F. Thymectomy for myasthenia gravis: a 27-year experience. Eur J Cardiothorac Surg 1999;15:621-625.[Abstract/Free Full Text]
  8. Ashour M. Prevalence of ectopic thymic tissue in myasthenia gravis and its clinical significance. J Thorac Cardiovasc Surg 1995;109:632-635.[Abstract/Free Full Text]
  9. Ossermann K.E., Genkins G. Studies in myasthenia gravis: review of a 20-year experience in over 1200 patients. MT Sinai J Med (NY) 1971;38:497-537.[Medline]
  10. Tsuchida M., Yamato Y., Souma T., Yoshiya K., Watanabe T., Aoki T., Hayashi J. Efficacy and safety of extended thymectomy for elderly patients with myasthenia gravis. Ann Thorac Surg 1999;67:1563-1567.[Abstract/Free Full Text]
  11. Blalock A., Mason M.F., Morgan K.J., Riven S.S. Myasthenia gravis and tumors of the thymic region: report of a case in which the tumor was removed. Ann Surg 1939;110:544-651.[Medline]
  12. Maggi G., Casadio C., Cavallo A., Cianci R., Molinatti M., Ruffini E. Thymectomy in myasthenia gravis: results of 662 cases operated upon in 15 years. Eur J Cardiothoracic Surg 1989;3:504-511.[Abstract]
  13. Perlo V.P., Arnason B., Castleman B. The thymus gland in elderly patients with myasthenia gravis. Neurology 1975;25:294-295.[Abstract/Free Full Text]
  14. Monden Y., Nakahara K., Fujii Y., Hashimoto J., Ohno K., Masaoka A., Kawashima Y. Myasthenia gravis in elderly patients. Ann Thorac Surg 1985;39:433-436.[Abstract]
  15. Roth T., Ackermann R., Stein R., Inderbitzi R., Rösler K., Schmid R.A. Thirteen years follow-up after radical transsternal thymectomy for myasthenia gravis. Do short term results predict long-term outcome?. Eur J Cardiothorac Surg 2002;21:664-670.[Abstract/Free Full Text]
  16. Moore K.H., Mckenzie P.R., Kennedy C.W., McCaughan B.C. Thymoma: trends over time. Ann Thorac Surg 2001;72:203-207.[Abstract/Free Full Text]
  17. Jaretzki A.I.I.I., Wolff M. ‘Maximal‘ thymectomy for MG: surgical anatomy and operative technique. J Thorac Cardiovasc Surg 1988;96:711-716.[Abstract]
  18. Fukai I., Funato Y., Mizumo T., Hashimoto T., Masaoka A. Distribution of thymic tissue in the mediastinal adipose tissue. J Thorac Cardiovasc Surg 1991;101:1099-1102.[Abstract]



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