Predictors of clinical outcome following extended thymectomy in myasthenia gravis

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1 European Journal of Cardio-thoracic Surgery 23 (2003) Predictors of clinical outcome following extended thymectomy in myasthenia gravis Nezih Özdemir a, *, Murat Kara b, Erkan Dikmen b, Aydın Nadir a, Murat Akal a, Nezih Yücemen c,s, inasi Yavuzer a a Department of Thoracic Surgery, Ankara University Faculty of Medicine, İbn-i Sina Hospital, 06100, Sıhhiye, Ankara, Turkey b Department of Thoracic Surgery, University of Kırıkkale, School of Medicine, 71100, Kırıkkale, Turkey c Department of Neurology, Ankara University Faculty of Medicine, İbn-i Sina Hospital, 06100, Sıhhiye, Ankara, Turkey Received 19 July 2002; received in revised form 23 October 2002; accepted 4 November 2002 Abstract 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, years) were analyzed. The overall improvement/remission and clinical worsening rates were 81.9 and 18.1%, respectively. (P ¼ 0:011) and presence of mediastinal ectopic thymic tissue (P ¼ 0:007) showed a significant correlation with the clinical outcome. Multivariate analysis confirmed (P ¼ 0:0158), and presence of mediastinal ectopic thymic tissue (P ¼ 0:0100) as independent predictors on clinical outcome. Conclusion: and the presence of mediastinal ectopic thymic tissue are potential predictors on clinical outcome in patients with MG undergoing extended thymectomy. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Myasthenia gravis; Thymectomy; Clinical outcome 1. Introduction 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, of the disease, coexistence of thymoma and presence of mediastinal ectopic thymic tissue [1 8]. Thus, the optimal selection criteria for surgery remains * Corresponding author. Kuleli Sokak 37/2, Gaziosmanpașa, TR-06700, Ankara, Turkey. Tel.: ; fax: address: ozdemir@medicine.ankara.edu.tr (N. Özdemir). 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 2.1. Patient selection We collected the data of 73 patients with MG, who underwent an extended thymectomy in İbn-i Sina Hospital of Ankara University School of Medicine between January 1990 and December 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, years) were enrolled into this study. The mean duration of symptoms was 9.2 ^ 9.4 months /02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. doi: /s (02)

2 234 N. Özdemir et al. / European Journal of Cardio-thoracic Surgery 23 (2003) (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 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 followup time was 46 months (range, months) 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,, 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. was stratified as I 1 IIA and IIB 1 III. Thymic histology was stratified as thymoma and non-thymoma, thymoma and hyperplasia. Categorical variables were analyzed with the x 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 3.1. Correlations The mean age did not show any difference between the subgroups of clinical outcome (P ¼ 0:201) (Table 1). The age subgroups (P ¼ 0:670), and gender (P ¼ 0:740) did not correlate with the clinical outcome. The subgroups of symptom duration (P ¼ 0:325), and the overall means of symptom duration (P ¼ 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 ¼ 0:294), nor the overall means (P ¼ 0:578). However, significantly correlated with the clinical outcomes (P ¼ 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 ¼ 0:439 and P ¼ 0:705, respectively). Patients with ectopic thymic tissue had a comparatively worse clinical outcome (P ¼ 0:007).

3 N. Özdemir et al. / European Journal of Cardio-thoracic Surgery 23 (2003) Table 1 Characteristics of patients with myasthenia gravis regarding clinical outcomes Variables (n ¼ 61) Improvement/ remission (n ¼ 50) (%) Clinical worsening (n ¼ 11) (%) P value Age (years) 35.8 ^ ^ ^ Age (years), (80.0) 10 (20.0) $ (90.9) 1 (9.1) Gender Male (85.2) 4 (14.8) Female (79.4) 7 (20.6) Duration of symptoms (months) 9.2 ^ ^ ^ Duration of symptoms (months) # (77.1) 8 (22.9) (88.5) 3 (11.5) Number of plasma exchange 2.8 ^ ^ ^ Number of plasma exchange # (83.6) 9 (16.4) (66.7) 2 (33.3) I (100) IIA (85.7) 5 (14.3) IIB 13 8 (61.5) 5 (38.5) III 1 1 (100) Thymic histology Thymoma (73.3) 4 (26.7) Non-thymoma (84.8) 7 (15.2) Thymic histology Thymoma (73.3) 4 (26.7) Hyperplasia (80) 5 (20) Mediastinal ectopic thymic tissue Present (58.8) 7 (41.2) Absent (90.9) 4 (9.1) Univariate and multivariate analysis Significant univariate predictors of clinical worsening were (IIB 1 III) (P ¼ 0:0104) and presence of mediastinal ectopic thymic tissue (P ¼ 0:0068) (Table 2). Thymic histology (thymoma) did not show a significant effect on clinical outcome (P ¼ 0:3225) (Fig. 1). Multivariate analysis revealed Ossermann stage (P ¼ 0:0158) and presence of mediastinal ectopic thymic tissue (P ¼ 0:0100) as independent predictors of clinical outcome (Table 3). 4. Discussion 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 ¼ 0:670), and postoperative complication rates (P ¼ 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.

4 236 N. Özdemir et al. / European Journal of Cardio-thoracic Surgery 23 (2003) Table 2 Univariate prognostic factors analysis of the 61 patients by logistics regression analysis Variable Relative risk 95% confidence interval P value Age (year), 50 versus $ Gender Female versus male Duration of symptoms (months) # 7 versus Number of plasma exchange. 3 versus # IIB 1 III versus I 1 IIA Histology Thymoma versus non-thymoma Thymoma versus hyperplasia Mediastinal ectopic thymic tissue Present versus absent 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 ¼ 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 1 IIA and IIB 1 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 1 III. Similar reports appeared in the literature stating the significance of 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 s had more favourable clinical outcomes, respectively. On the other hand, some authors detected no relationship between the 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 Table 3 Multivariate prognostic factors analysis of the 61 patients by logistic regression analysis Variable Variable risk 95% confidence interval P value Fig. 1. Clinical outcomes within thymomatous and non-thymomatous myasthenic patients. IIB 1 III versus I 1 IIA Mediastinal ectopic thymic tissue Presence versus absence

5 N. Özdemir et al. / European Journal of Cardio-thoracic Surgery 23 (2003) 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 ¼ 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 ¼ 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 ¼ 0:0068) or multivariate analysis (P ¼ 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, 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 [1] Nieto IP, Robledo JPP, Pajuelo MC, Montes JAR, Giron JG, Alonso JG, Sancho LG. Prognostic factors for myasthenia gravis treated by thymectomy: review of 61 cases. Ann Thorac Surg 1999;67: [2] Budde JM, Morris CD, Gal AA, Mansour KA, Miller JI. Predictors of outcome in thymectomy for myasthenia gravis. Ann Thorac Surg 2001;72: [3] Bulkley GB, Bass KN, Stephenson GR, Diener-West M, George S, Reilly PA, Baker RR, Drachman DB. Extended cervicomediastinal thymectomy in the integrated management of myasthenia gravis. Ann Surg 1997;226: [4] Calhoun RF, Ritter JH, Guthrie TJ, Pestronk A, Meyers BF, Patterson GA, Pohl MS, Cooper JD. Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Ann Surg 1999;230: [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: [6] Nussbaum MS, Rosenthal GJ, Samaha FJ, Grinvalsky HT, Quinlan JG, Schmerler M, Fischer JE. Management of myasthenia gravis by extended thymectomy with anterior mediastinal dissection. Surgery 1992;112: [7] Venuta F, Rendina EA, De Giacomo T, Rocca GD, Antonini G, Ciccone AM, Ricci C, Coloni GF. Thymectomy for myasthenia gravis: a 27-year experience. Eur J Cardiothorac Surg 1999;15: [8] Ashour M. Prevalence of ectopic thymic tissue in myasthenia gravis and its clinical significance. 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